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UBC Theses and Dissertations

Chemistry of the anions from isoxazolin-5-ones ; Lactone synthesis via β-keto ester dianion alkylaton Tischler, Samuel Arthur 1981

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I.  CHEMISTRY OF THE ANIONS FROM ISOXAZOLIN-5-ONES LACTONE SYNTHESIS VIA B-KETO ESTER DIANION ALKYLATION  II.  by SAMUEL ARTHUR B.Sc,  The U n i v e r s i t y  TISCHLER  of B r i t i s h  Columbia,  1976  A THESIS SUBMITTED IN PARTIAL FULFILLMENT OF  THE REQUIREMENTS  FOR THE DEGREE OF  DOCTOR OF PHILOSOPHY in THE  FACULTY OF GRADUATE STUDIES DEPARTMENT  We  accept to  THE  OF CHEMISTRY  this thesis  the r e q u i r e d  as  conforming  standard  UNIVERSITY OF BRITISH COLUMBIA January  Samuel A r t h u r  1981  Tischler,  1981  In  presenting  this  an a d v a n c e d d e g r e e the I  Library  further  for  agree  in  at  University  the  make  it  partial  freely  that permission  this  representatives. thesis  for  It  financial  for  gain  of  The U n i v e r s i t y  of  British  2075 Wesbrook P l a c e V a n c o u v e r , Canada V6T 1W5  of  of  Columbia,  British for  extensive by  the  Columbia  shall  not  the  requirements  reference copying of  Head o f  is understood that  written permission.  Department  fulfilment  available  s c h o l a r l y p u r p o s e s may be g r a n t e d  by h i s of  shall  thesis  I  agree  and this  be a l l o w e d  that  study. thesis  my D e p a r t m e n t  copying or  for  or  publication  w i t h o u t my  ABSTRACT  In of  part I of this  thesis  an e x a m i n a t i o n  o f the u t i l i t y  i s o x a z o l i n - 5 - o n e s , e . g . 114, as B - k e t o e s t e r  alents  i s presented.  one  114 and r e a c t i o n  140  in fair  Generation with  o f the anion o f i s o x a z o l i n - 5 -  various electrophiles  t o good y i e l d s .  E=TMS, B r , CgHt-S, and CgH^Se  In p a r t i c u l a r ,  illustrate  that  dianions.  gave  products  the c a s e s  where  the c h e m i s t r y o f  the a n i o n o f i s o x a z o l i n - 5 - o n e s i s c o m p l i m e n t a r y B-keto e s t e r  dianion equiv-  to that of  S e v e r a l r o u t e s or p o t e n t i a l  routes to  the p r e p a r a t i o n o f u n s a t u r a t e d  isoxazolin-5-ones are also  cussed.  i n v o l v e s the c o n d e n s a t i o n  reagent  One o f t h e s e pathways 141 w i t h  aldehydes.  The s u c c e s s o f t h i s  ii  p l a n was  disof W i t t i g  demonstrated  by t h e p r e p a r a t i o n  of unsaturated  142, R=CgH - and C H ( C H ) ~ , R'=H. 5  for  3  the c l e a v a g e  2  4  of isoxazolin-5-ones  Finally,  isoxazolin-5-ones  several  strategies  to B-keto e s t e r s  were  investigated. In p a r t ring is  lactones  described  I I o f t h i s d i s s e r t a t i o n , the s y n t h e s i s v i a an i n t e r n a l B - k e t o e s t e r (equation  i ) .  dianion  The B - k e t o e s t e r  of large  alkylation  halides  262 were  (i)  262 prepared  by t h e a l c o h o l y s i s o f a c e t y l Meldrum's a c i d  1,n-bromoalcohols.  The s t u d y  o f the c y c l i z a t i o n  iii  253  with  of B-keto  ester  halide  262g  alkylation  revealed  t h a t e l i m i n a t i o n as w e l l as i n t r a m o l e c u l a r  often occurred  (equation  ii).  The e f f e c t o f  t e m p e r a t u r e , l e a v i n g g r o u p , s o l v e n t , and c o u n t e r i o n cyclization  process  investigation halide amide  have  was t h e r e f o r e e x a m i n e d . shown t h a t c y c l i z a t i o n  262 was added  to three  in tetrahydrofuran  B-keto l a c t o n e s  when  equivalents  (0° -*• RT) .  the c h a i n  on t h e  The r e s u l t s o f t h i s  was o p t i m i z e d  when t h e  of lithium diisopropyl-  These c o n d i t i o n s  l e n g t h n >^ 9, w h i l e  provided  elimination  p r e d o m i n a t e d when n < 8. Finally, the  hydroxy  the p r e p a r a t i o n  acyl  fourteen-membered  and i n t r a m o l e c u l a r  alcoholysis of  Meldrum's a c i d 295 was c o n d u c t e d and gave t h e B-keto l a c t o n e  295  266e i n f a i r  yield.  26£e iv  TABLE OF  CONTENTS Page  ABSTRACT  i i  TABLE OF CONTENTS  V  L I S T OF SCHEMES  vi  L I S T OF TABLES  v i i  L I S T OF ABBREVIATIONS  viii  ACKNOWLEDGEMENTS INTRODUCTION SECTION I :  ix  - GENERAL BACKGROUND  1  CHEMISTRY OF THE ANIONS FROM ISOXAZOLIN-5-ONES  22  Introduction  22  R e s u l t s and D i s c u s s i o n  59  Conclusions  I l l  Experimental SECTION  . . 113  I I : LACTONE SYNTHESIS V I A 8~KETO ESTER DIANION ALKYLATION  142  Introduction A. B.  142  Synthesis o f M a c r o c y c l i c Lactones via to-Halocarboxylic Acids Synthesis of Macrocyclic v i a w-Hydroxycarboxylic  C. Results  The P r e s e n t  Approach  and D i s c u s s i o n  145  Lactones Acids  . . . . 147 175 180  Conclusions  221  Experimental  225  BIBLIOGRAPHY  260  SPECTRAL APPENDIX  272  v  L I S T OF SCHEMES  Scheme 1  Title  Page  Resonance H y b r i d s of  f o r Mono- and  Dianions  B-Diketones  7  o f y,y-Disubstituted  B-Keto E s t e r s  2  Preparation  3 4  S y n t h e s i s o f Jasmone (3_2) Selected Reactions of 1 , 3 - B i s ( t r i m e t h y l s i l y l ) 1 - m e t h o x y b u t a - l , 3 - d i e n e (8_7)  45  Mechanism f o r T h i a m i n e C a t a l y z e d t i o n o f P y r u v i c A c i d (9_8)  50  5 6 7  Isoxazolin-5-ones Equivalents  as B-Keto E s t e r  .  13 14  DecarboxylaDianion 59  P o s s i b l e Mechanism f o r t h e F o r m a t i o n o f P y r r o l e (115)  8  Classical  9  Lactone Formation v i a Double A c t i v a t i o n Using 2 - P y r i d i n e t h i o l E s t e r s  158  Mechanism P r o p o s e d Cyclizations  172  10 11 12  Preparation  61  Proposed Plan Formation Preparation  o f Nazarov Reagent  for Palladium  for Macrocyclic  146 . .  89  Catalyzed  8 Keto Lactone -  178  o f B-Keto E s t e r  Benzenesulfonate  277  204  13  Preparation  of Phenylthio  14  Preparation 295  o f Hydroxy  B-Keto E s t e r  Acyl  278 . . . 206  Meldrum's A c i d 216  vi  L I S T OF  Table 1 2  3  TABLES  Title  Page  A l k y l a t i o n o f L i t h i u m Sodium M e t h y l acetate in Tetrahydrofuran A l d o l R e a c t i o n s o f L i t h i u m Sodium Acetoacetate in Tetrahydrofuran Acylation  o f L i t h i u m Sodium  Aceto14  Methyl 18  Methyl  Acetoacetate  19  4  Baldwins'  38  5  P r e p a r a t i o n of 2-Methylisoxazolin-5-ones 103 R=Me E v a l u a t i o n o f B a s e s f o r D e p r o t o n a t i n g 2,3,4T r i m e t h y l i s o x a z o l i n - 5 - o n e (114) . .  Rules  r  6 7 8 9 10 11  12 13  57 65  Reaction of 2,3,4-Trimethylisoxazolin-5-one (114) W i t h S i m p l e E l e c t r o p h i l e s  72  A l k y l a t i o n of 2,3,4-Trimethylisoxazolin-5-one (114) W i t h U n u s u a l E l e c t r o p h i l e s  81  The R e d u c t i o n o f U n s a t u r a t e d V a r i o u s Reducing Agents  Ketone  C y c l i z a t i o n of; 2 - P y r i d i n e t h i o l cj-Hydroxycarboxylic Acids P r e l i m i n a r y Study of 6-Keto E s t e r H a l i d e s  163  108 E s t e r s of 160  the P r e p a r a t i o n o f 255  P r e p a r a t i o n o f Long C h a i n B r o m i d e s 262 Attempted C y c l i z a t i o n B r o m i d e s 262  of  vii  With  183  B-Keto E s t e r 192 B  - K  eto  Ester 213  L I S T OF  ABBREVIATIONS  DIBAL  = diisobutylaluminum  DBN  = 1 , 5 - d i a z a b i c y c l o [4 .3 . (3] non-5-ene  DMF  = dimethyIformamide  DMSO  = dimethyl sulfoxide  ether  = ethyl  Im CO  = N,N-carbonyIdiimidazole  IR  = infrared  LDA  = lithium  MsCl  = methanesulfonyl  NCS  = N-chlorosuccinimide  NMR  = proton  2  hydride  ether  diisopropylamide  nuclear  chloride magnetic  resonance  pyridine  py RT  = room  THF  = tetrahydrofuran  TLC  = thin  TMS  = trimethylsilyl  p_-TsOH  = para-toluenesulfonic  VPC  = vapour phase chromatography  Abbreviations  This for  temperature layer  for m u l t i p l i c i t i e s  s  = s inglet  d  = doublet  t  = tr i p l e t  q  = quartet  dd  = doublet  bs  broad  m  multiplet  t h e s i s has Authors",  chromatography  of  o f NMR  sign  doublets  singlet  been w r i t t e n  published  Washington, D.C,  acid  by  i n conformance with  the A m e r i c a n  1978 .  viii  Chemical  the  "Handbook  Society;  ACKNOWLEDGEMENTS  I would Weiler of  like  to express  my a p p r e c i a t i o n t o P r o f e s s o r  f o r h i s e n c o u r a g e m e n t and g u i d a n c e  throughout  t h i s work, and f o r h i s a s s i s t a n c e d u r i n g  this  Larry  the course  the preparation of  thesis. I am i n d e b t e d  Scheffer,  and P r o f e s s o r  manuscript The  to Professor  of this  efficient  spectroscopy,  G.S. B a t e s ,  P. L e g z d i n s  f o r reading  t h e s i s and p r o v i d i n g cooperation  P r o f e s s o r J.R. through the  invaluable  o f the s t a f f  suggestions.  o f t h e NMR,  mass  and m i c r o a n a l y t i c a l s e r v i c e s i s g r a t e f u l l y  acknowledged. Finally, for  their  out  the course  I wish  patience, o f my  t o extend constant  a special  thanks  t o my  e n c o u r a g e m e n t and s u p p o r t  education.  ix  parents through-  1  GENERAL  INTRODUCTION  One o f t h e most e x c i t i n g chemistry  lies  compounds. of  their  i n the t o t a l  and c h a l l e n g i n g a r e a s  synthesis of n a t u r a l l y occurring  These n a t u r a l p r o d u c t s  biological  activity  a t other  skill  and i n g e n u i t y o f t h e o r g a n i c  it  there  the  because  elled  broken  apart, piece  e a c h component back  synthetic organic fore  plan  r e a c t i o n s and t h e i r  critical  provides stantly  i s i n hand.  The  past  acceleration  by  results  t o the  in designing  a synthesis,  The t a r g e t m o l e c u l e i s i n s u c h a way  reasonable  assurance  framework h a s been  m a t e r i a l and p r o p o s a l s  A most scope  thorough  for this  These  that of  unravmade t o  t h a t the  knowledge o f  and l i m i t a t i o n s  process,  and i m p r o v e d  twenty  a challenge  chemist.  with  the t o o l s f o r s y n t h e s i s .  increasingly d i f f i c u l t  because  structure,  t o the t a r g e t molecule,  t o the p l a n n i n g  re-examined  of their  by p i e c e ,  I t i s when t h e m o l e c u l a r  t o an a c c e s s i b l e s t a r t i n g  rejoin  offer  the problem"backwards.  f r a g m e n t s c a n be r e a s s e m b l e d  success.  The  they  i s any key t o s u c c e s s  i s t o work  methodically  are often prepared  o r as p r o o f  while  If  times  i n organic  i s there-  knowledge  t o o l s must be c o n -  to provide  solutions for  tasks.  to t h i r t y  years  have s e e n  a tremendous  i n t h e d e v e l o p m e n t o f new s y n t h e t i c m e t h o d s . o f t h i s e x p l o s i v e g r o w t h have been made  the p r e p a r a t i o n  of n a t u r a l products  and n o v e l  apparent  organic  2  compounds o f include sin  the  increasing  complexity.  A few  s y n t h e s i s of g i b b e r e l l i c  acid  recent  examples  ( 1 ) ^ and  cytochala-  B (2) . 2  Z,R = H  1  The along  d e v e l o p m e n t o f new  two  involves certain  pathways. the  The  systematic  s y n t h e t i c methods has  first study  and of  more c l a s s i c a l  the  evolved approach  fundamental chemistry  c l a s s e s o f o r g a n i c compounds.  Some e x a m p l e s  of  include  3 the  study  o f organomagnesium compounds by G r i g n a r d  r e c e n t l y , work by Brown on  the  The  i n which c e r t a i n  second  tions, primary allows of  approach  i s one  chemistry  n o t f e a s i b l e by p r e - e x i s t i n g goal of  research.  transformation of  aldehydes  An  the n o r m a l l y  the c o r r e s p o n d i n g  dithioacetals  3  electrophilic through  (equations  .  s y n t h e t i c opera-  i s a process  centre  more 4  of organoboranes  r e a c t i o n s , become  example  into a nucleophilic  and  the  which carbon  formation  1 and  2).  of  3  V  Reagents which t e m p o r a r i l y reverse tivity  reac-  o f an atom i n a f u n c t i o n a l g r o u p a r e t e r m e d umpolung  reagents^ the  the c h a r a c t e r i s t i c  from  the corresponding  German word m e a n i n g  "change  polarity". For  a number o f y e a r s o u r l a b o r a t o r y h a s been  g a t i n g the chemistry of B-keto e s t e r s . from ester  a desire to functionalize  4_ i n an a t t e m p t 6 7 r e s i s t o m y c i n (5) ' .  This  the y carbon  investi-  interest  stemmed  atom i n a  B-keto  to synthesize acetogenins,  f o r example  8 E a r l y work by G e u t h e r anion  i n 1863  had  shown t h a t t h e mono-  1_ o f e t h y l a c e t o a c e t a t e c o u l d be g e n e r a t e d  ethoxide  0  i n anhydrous e t h a n o l  (equation 3).  0  0  however, f o r W i s l i c e n u s  3  i n 1877  anion to  t h i s author  7 f o r the f i r s t  sodium  I t remained,  0  t o r e p o r t the f i r s t  study of the p r o p e r t i e s of e t h y l a c e t o a c e t a t e ticular,  using  {6).  extensive In  par-  demonstrated the n u c l e o p h i l i c i t y of t i m e , by  i t s reaction with  form e t h y l 2 - e t h y l a c e t o a c e t a t e  (8_) .  This study  the  iodoethane provided  0  0  0  EtI  0  OEt  OEt  1 the  impetus  over  sixty  f o r o t h e r w o r k e r s , and y e a r s d u r i n g which  compounds and utilized  1 0  their  chapter  1958 when Hauser  the r e a c t i o n s o f g - d i c a r b o n y l  monoanions were e x p l o r e d  in  ft-dicarbonyl  of 1-phenylbutane-1,3-dione  with potassium  amide i n l i q u i d one  t h e compounds IC) and  t h a t the  (9) and  by t r e a t i n g  reacted r a p i d l y with  and gave  and e x t e n s i v e l y  c h e m i s t r y was  and H a r r i s o b s e r v e d  (11) c o u l d be g e n e r a t e d  salts  f o l l o w e d a p e r i o d of  .  A new  salts  there  opened  in  dipotassium  pentane-2,4-dione  t h e B - d i c a r b o n y l compound  ammonia .  These  11  dipotassium  e q u i v a l e n t of benzyl 1_2 i n 77 and  chloride  60% y i e l d  respec-  tively .  0  0  2,R=C H 6  2KNH  5  C H CH Cl 6  5  2  0  0  ll,R=Me  IQ,R=CH 6  12, R= Me  5  6  Compound not  t o be  10_  w  a  shown by a m o l e c u l a r w e i g h t d e t e r m i n a t i o n  s  a dibenzylated  p o i n t method n o t t o be which  could  chloride.  and  by  0  the mixed  structure  was  finally  13 and b e n z y l  c o n f i r m e d as 10  0  0  C H AA  * 6 5 C  B  H  C H  2  C l  *  C ^6  c l e a v a g e t o form acetophenone  pendent  synthesis  phenone  (15)  involving  (1J5), and  the a c y l a t i o n  with methyl hydrocinnamate  o  jt C  o f 10  6 5  0 II  2  2) C H C H C H C 0 0 M e  H  6  5  2  2  6 5 H  by an  inde-  of aceto-  (]Jj) ( e q u a t i o n  1) NaNH , E t 0 2  by  0  C  alkaline  melting  2-benzyl-l-phenylbutane-1,3-dione (14),  be p r e p a r e d f r o m t h e monoanion The  6  derivative  4) .  0 jf  C g H r / ^ ^ ^ C ^  (A)  16  ID.  15 A measure o f t h e r e a c t i v i t y b a n i o n s may with  be  seen by c o m p a r i s o n  of these d i p o t a s s i u m c a r of t h e i r  those o f the c o r r e s p o n d i n g monoanions.  rates The  of  alkylation  o f m o n o a n i o n s o f 3 - d i k e t o n e s p r o c e e d s s l o w l y , even vated at  low  t e m p e r a t u r e s , w h i l e the d i a n i o n temperatures.  This  result  salts  react  reaction  at  ele-  rapidly  i s consistent with  resonance  7  stabilization adjacent  arguments.  carbonyl  The  groups.  In  must s t a b i l i z e two n e g a t i v e expected  t o be  0  0  Scheme 1;  lated  >  0  0"  0"  0"  communication  further interest  by  carbonyl  both  groups  l a t t e r would be  (Scheme  1).  "0  0  R-  Resonance h y b r i d s B-diketones  initial  the  Hence the  a more r e a c t i v e s p e c i e s  <  The  is stabilized  the d i a n i o n  charges.  0  0  monoanion  f o r mono- and  by H a u s e r  i n the c h e m i s t r y  and of  dianions  Harris  of  stimu-  B-dicarbonyl  12 13 In p a r t i c u l a r , work on t h e i r a l k y l a t i o n ' , as 14 11 aldol and C l a i s e n c o n d e n s a t i o n s was c o n d u c t e d and  dianions. well  as  15 the c h e m i s t r y  extended 17 B-keto l a c t o n e s , and Most o f  this  B-keto a l d e h y d e s 18 — 21 c a r b o n y l compounds  t o the d i a n i o n s other  r e s e a r c h was  related  carried  out  of  by H a u s e r  and  coworkers, 22  and  the  relevant literature  The dianions potassium  (until  1966)  has  been  reviewed  i n v e s t i g a t i o n of  B~keto e s t e r s i n d i c a t e d t h a t  could  by u s i n g two e q u i v a l e n t s 23 ammonia . A l k y l a t i o n o f the  a l s o be  prepared  amide i n l i q u i d  16 ' ,  their of  8  dianion  17 o f e t h y l a c e t o a c e t a t e  b r o m i d e gave t h e d e s i r e d p r o d u c t s 29%  yield  respectively, while  18_, h o w e v e r , i n o n l y  a l d o l condensation with  the 6 - h y d r o x y - B - k e t o e s t e r  phenone a f f o r d e d  0  w i t h m e t h y l i o d i d e and e t h y l  (  0  0  R-X  OEt  OEt  17  0  benzo-  19 i n 5 0 % y i e l d .  0  AA  37 and  18a,R=Me 18b. R=Et HO  0 'OEt  C  0  0 OEt  6 5' H  C  6 5 H  12  No  i m p r o v e m e n t i n y i e l d s was o b s e r v e d by v a r y i n g  dianion generation  or a l k y l a t i o n .  alkylations with n-butyl  the time f o r  In a d d i t i o n , attempted  bromide and b e n z y l  c h l o r i d e were  unsuccessful. These w o r k e r s were a b l e decompose a p p r e c i a b l y  t o show t h a t d i a n i o n  under t h e r e a c t i o n c o n d i t i o n s and t h e r e -  fore a t t r i b u t e d the low y i e l d s t o incomplete the  g-keto e s t e r  leave  appreciable  17_ d o e s n o t  to i t s dianion.  This,  conversion of  i t was f e l t ,  would  amounts o f amide i o n i n t h e r e a c t i o n m i x -  t u r e t o compete f o r t h e e l e c t r o p h i l i c  reagents.  9  In tomycin Y carbon  studies  i n our l a b o r a t o r y  (5_) , as s t a t e d e a r l i e r , atom o f a g - k e t o e s t e r  HO  0  on the s y n t h e s i s  a method  of r e s i s -  t o f u n c t i o n a l i z e the  was r e q u i r e d .  The  generation  OH  L of  the d i a n i o n  _17 by means o f p o t a s s i u m  ammonia a p p e a r e d , however, t o impose the  reactions  limited low  o f g-keto e s t e r s .  (-33° or l o w e r ) ,  m i g h t be c o m p l i c a t e d  by r e a c t i o n  r e a g e n t s or p r o d u c t s . have been employed 23 acetoacetate ability the  search  abstracting  f o r an a l t e r n a t e ability  .  restrictions  reactions  at a reasonable  o f the s o l v e n t  on  would be rate at  the r e a c t i o n s ammonia  with  and 1 , 2 - d i m e t h o x y e t h a n e  o f the d i a n i o n  24 ' , but t e t r a h y d r o f u r a n 25  for alkyllithiums  in liquid  and s e c o n d l y ,  E t h y l ether  for reactions  severe  Firstly,  t o t h o s e w h i c h would p r o c e e d  temperature  amide  What  _17 o f e t h y l  has a b e t t e r remained,  base p o s s e s s i n g  and low n u c l e o p h i l i c i t y .  solvating  therefore,  a high  proton  was  10  It  i s w e l l known t h a t a c a r b o n y l  from n u c l e o p h i l i c a t t a c k For of  example,  selective  B-keto e s t e r  by f o r m a t i o n  conversion  g r o u p may be p r o t e c t e d of i t s enolate  o f the e s t e r  anion.  functionality  20_ i n t o an a l c o h o l was a c h i e v e d  by s e q u e n t i a l 26  treatment  o f 2_0 w i t h  (equation  5) .  sodium h y d r i d e  and e x c e s s  methyllithium  1) NaH,THF  —  5  2) xs MeLi 20.  Treating  methyl acetoacetate  (21) w i t h  o f n - b u t y l l i t h i u m , however, y i e l d e d c a r b o n y l only  27  .  two e q u i v a l e n t s addition  . • In a s u b s e q u e n t c o m m u n i c a t i o n , B r i e g e r  0  products  and S p e n c e r  0  AA  OMe  21  were a b l e  t o show t h a t i n t h e r e a c t i o n o f g - k e t o e s t e r s  alkyllithiums  the p r i n c i p a l  products  were k e t o n e s ,  with  even i n  28 the  presence  of excess  organolithium  reagent  .  Therefore,  the  r e a c t i o n o f n - b u t y l l i t h i u m (three e q u i v a l e n t s )  with  ethyl  11  2-n-butylacetoacetate  (22)  product  Careful examination  products  i n 24% y i e l d .  gave 5-decanone  l e d t o the c o n c l u s i o n t h a t ,  (23_) as t h e m a j o r of the  reaction  i n the case of  B-keto  e s t e r s , the e s t e r c a r b o n y l group i s a t t a c k e d p r e f e r e n t i a l l y with formation of a B-diketone. further  This B-diketone  t o g i v e the f i n a l p r o d u c t ketones  intermediate addition product.  then r e a c t s  by c l e a v a g e o f  T h i s c o n c l u s i o n was  by t h e i s o l a t i o n o f 2 - h e x a n o n e , 2 - h e p t a n o n e , and from  the r e a c t i o n  supported  5-nonanone  mixture.  S t u d i e s conducted t h e d i a n i o n 25  of  by H a u s e r and  phenylacetone  was  coworkers  had  shown t h a t  r e a d i l y produced v i a 29  t h e m o n o a n i o n 2_4 by d e p r o t o n a t i o n w i t h n - b u t y l l i t h i u m r e s u l t suggested  the  t h a t g e n e r a t i o n of the monoanion o f  .  methyl  o  n-BuLi THF  Ik  C  H 6  This  Ok  5  25.  12  acetoacetate  (21)  the d i f f i c u l t y  and  presented  methyl acetoacetate furan  gave  s u b s e q u e n t m e t a l l a t i o n would by c a r b o n y l  (23.) w i t h  the monoanion  26,  addition.  sodium h y d r i d e  surmount:  Treatment  of  in tetrahydro-  w h i c h upon m e t a l l a t i o n w i t h 27  n-butyllithium  0  d i d , in f a c t ,  give  0  0  0  II  jf  NQH^  ^ ^ ^ O M e  THF  II  of  the  tion  mixture  acid  in deuterium  at both  0.03  n-BuLi  the  d i a n i o n was  with  a and  a solution  0  » 1 / V ^ O M e  deuterium  analysis  21  confirmed  (equation  quenching  of deuterated  the  reac-  trifluoroacetic incorporation  y positions.  a t the  The  removed by  methyl acetoacetate at  by  o x i d e , w h i c h gave d e u t e r i u m  i n a d d i t i o n , be  resulting  2_7  0  2SL  Formation  The  II  ^NrN)Me  21  could,  the d i a n i o n i c s p e c i e s  the 6).  y position  deuterium  exchange was by NMR  found and  a  i n aqueous to c o n t a i n  carbon base. 0.96  ±  mass s p e c t r o s c o p i c  13  The rapidly  dianion  and i n h i g h  temperatures NMR  27. c o u l d  the r a t e  and mass s p e c t r a  alkylation  yield  be m o n o a l k y l a t e d a t 0°C  (Table  I)  o f the i s o l a t e d products cleanly  o f the crude  failed  for either  lated  The  indicated  that  reaction  mixtures  d i a l k y l a t e d or 0 - a l k y -  products. This  tuted  markedly.  a t t h e y p o s i t i o n , and f u r -  thermore, s p e c t r a l a n a l y s i s any e v i d e n c e  carbon  , b u t a t lower  of a l k y l a t i o n diminished  had o c c u r r e d  to give  a t the y  procedure  g-keto e s t e r s .  methyl acetoacetate then r e g e n e r a t e n-butyllithium disubstituted  also permitted Therefore,  the a l k y l a t i o n o f s u b s t i i t was p o s s i b l e  (2_1) , g e n e r a t e  the d i a n i o n  using  the d i a n i o n  to s t a r t  2_7 and a l k y l a t e ,  a second e q u i v a l e n t  and add a s e c o n d a l k y l a t i n g a g e n t  with  of y,y-  to yield  g - k e t o e s t e r s 29 (Scheme 2 and T a b l e  I ) . In  1) n-BuLi 2) R'-X  0  R Scheme  2:  Preparation  o f y,y-disubstituted  0  21 g-keto  esters  Table  I.  A l k y l a t i o n o f L i t h i u m Sodium M e t h y l Tetrahydrofuran^7  0  0  0  1) N a H . T H F 2) a - B u L i OMe  22  HI  R H  CH  H  C H  5  X  Yield  I  81  Br  84  H  (CH ) CH  I  73  H  n-C.HQ. — 4 9 CH 2 —CHCH2  Br  72  Br  83  Cl  81  Br  77  Cl  62  Cl  76  I  86  3  H 4  n-C H 4  CH 6 5  9  g  C H  2  H  C H  2  C-H _CH ~ 6 5 2 C  3  2  6 5 2 CH =CHCH C  H-C H  a.  3  2  H  H  0  R'-X  3)  23.  C  Acetoacetate  6 5 CH H  C H  3  2  2  (48)  The y i e l d i n p a r e n t h e s e s r e f e r s t o t h a t o b t a i n e d by successive treatment of methyl acetoacetate with n - b u t y l b r o m i d e and b e n z y l c h l o r i d e w i t h o u t i s o l a t i o n of the i n t e r m e d i a t e m o n o a l k y l a t e d p r o d u c t .  15  general,  however, h i g h e r  mediate monoalkylated prior  to performing  27  could  a l s o be  product  the  A more t h o r o u g h  y i e l d s were o b t a i n e d 2j3 was  second  study"^  alkylation  later  generated using  diisopropylamide  (3_0)  or  isolated  (3_1) , the  alkylation ether,  of  found  tetrahydrofuran,  methylphosphoramide.  the of  a d d i t i o n of these  a r p o o n ' base  .  In a d d i t i o n ,  1,2-dimethoxyethane,  In  and  dianion  of l i t h i u m  to proceed e q u a l l y w e l l  some i n s t a n c e s soluble  hexamethylphosphoramide  dianions  t h a t the  31  B-keto e s t e r s were n o t  complex  purified  l i t h i u m 2,2, 6,6 , - t e t r a m e t h y l p i p e r -  s o - c a l l e d 'H  2_7 was  inter-  I).  equivalents  + idide  and  (Table  revealed  two  i f the  the  and  where the in  the  in e t h y l hexadianions  of  tetrahydrofuran,  l e d to d i s s o l u t i o n  subsequent a l k y l a t i o n  then  proceeded  normally.  31  2£L The  simplicity  and  rv-buty H i t h i u m p r o c e d u r e B - k e t o e s t e r s has sis  of  jasmone  versatility i n the  of  preparation  been d e m o n s t r a t e d by  (3_2)  in greater  than  40%  32 methyl acetoacetate  (2_1)  the  (Scheme 3) .  the  sodium h y d r i d e of  y-substituted  efficient  overall  -  yield  synthefrom  16  0  0  1) K H , THF OMe 2) EtCECCH Br' 2  0  0  ^ V ^ O M e  21  ^•CECEt H . 2  Pd-BaSO  0  0  ==y  1) NaH, THF OMe 2) n-BuLi s^$ TMSCECCH Br  0  0  2  C TMS HgO.THF H2S0 H 0 4|  0  2  0 OMe  NaOH, H 0 2  32  Scheme 3;  Synthesis  o f jasmone  (32)  32  A  17  The  extension  of  this  procedure  t o the  33  via aldol  type  6-hydroxy B-keto e s t e r s (equation  7),  B-keto e s t e r and  these  0  and  r e s u l t s are  34  (equation  condensations  3_4 v i a the  8),  summarized  0  of 33  Br<5-diketo e s t e r s  dianions  preparation  has  a l s o been  in Tables  0  acylation  I I and  HO  examined  III  0  of  35  0  R  OMe  (7)  R 27  33  0  0  0 R  OMe  0  0  OR'  27  In that  0  3A  summary, p r e v i o u s work  the  sodium h y d r i d e  procedure  a B-keto ester  of  the  dianion  lent  to  the  preparation  of  of  Indeed, s e v e r a l  applications  total  of  natural  .  Nevertheless,  synthesis  laboratories  - n-butyllithium  generation route  i n our  of  products  shown  for  the  p r o v i d e s an  y-substituted this  has  synthetic  excel-  B-keto  esters.  method  in  have r e c e n t l y  the  appeared  in  36 the  literature  investigations use  of  that  B-keto ester  certain  i t was  also clear  l i m i t a t i o n s were  dianions.  The  from  inherent  utilization  of  a  in  these the  protected  A l d o l R e a c t i o n s o f L i t h i u m Sodium M e t h y l acetate i n Tetrahydrofuran35  0  0  Me  HO  00 23  R"  Yield  CH  26  3  CH CH 3  73  2  H- 4 9  36  E- 4 9  82  C  H  C  H  89  6 5 o-CH-jOC^H. — 3 6 4 C  H  2,3-(CH 0) CgH 3  2  2-furyl CH 3  2  -(CH ) 2  5  ~(CH ) 6 5 o-CH 0C H. — 3 6 4 6 5 2  C  C  4  H  o  c  H  68 3  68 70 56  3  CH CH  73  63 25 77 79 93  Aceto-  (%)  OMe  Table  I I I . Acylation  0  0  o f L i t h i u m Sodium M e t h y l  0  ^ ^ ^ O M e *  0  R/^OR'  Acetoacetate  0  ^ R / ' ^ ^ ^  27  34  CH  3  H B" 3 7 n-C H C  H  3  6  3  71  CH  3  69  CH  3  67  3  H  3  CH  CH CH  7  6 5 £-CH OC H C  Yield  RV  R  4  0  2  33  CH  3  37  CH  3  42  (%)  B - k e t o e s t e r i n an e f f o r t fore  t o overcome  these  p r o b l e m s was  there  considered. For  many y e a r s  36 may be p r e p a r e d  i t h a s been known t h a t by t h e c o n d e n s a t i o n  N-alkylhydroxylamine  hydrochlorides  isoxazolin-5-ones  o f B-keto e s t e r s  with  3_5 i n t h e p r e s e n c e o f a  37 base, such as p y r i d i n e  0  (equation  RNHOH-HCl  h o w e v e r , h a s been r e p o r t e d  Pyridine  R  '  on t h e c h e m i s t r y  We t h e r e f o r e became i n t r i g u e d monoanion o f i s o x a z o l i n - 5 - o n e s  (9)  o f these  by t h e p o s s i b i l i t y o f type  compounds  that the  3_7 may p r o v i d e  perhaps complimentary B-keto e s t e r d i a n i o n  (equation  work,  0 OMe  and  9 ) . Very l i t t l e  a new  equivalent  10.) .  0  Base  0 R"  N — 0 (10)  21  Part I of this  t h e s i s examines the p r e p a r a t i o n  and c h e m i s -  t r y o f m o n o a n i o n 3_7 and how i t s r e a c t i v i t y p a r a l l e l s , and i n some c a s e s d i f f e r s f r o m , t h a t o f B - k e t o e s t e r The tion large  f i n a l portion of this  thesis deals with  o f B - k e t o e s t e r s o f t y p e 38 and t h e i r ring  dianions. the prepara-  cyclization  t o form  B - k e t o e s t e r s 39, w i t h a v i e w t o w a r d s t h e s y n t h e s i s  of m a c r o l i d e s .  The g e n e r a l  philosophy  i s o u t l i n e d i n equation  11-  0  0  X-CH (CH ) 2  2  n  (CH ) 2  39  n  22  SECTION I CHEMISTRY OF THE ANIONS FROM ISOXAZOLIN-5-ONES  INTRODUCTION The ledge  utility  o f a new s y n t h e t i c method depends upon  of not only  tions.  This  the scope o f the p r o c e s s  allows  the o r g a n i c  any  new method i n o r d e r  the  s y n t h e s i s o f complex  chemist  but a l s o i t s l i m i t a -  to c r i t i c a l l y  thesis. during  Several  molecules.  limitations,  in this  ester dianions evident  regard,  lies  ketone  section of this uncovered  One o f t h e major  i n the high  reactivity  This  f o r products  o f B-keto  i s particularly  reaction of dianion  (4_0) and c y c l o h e x e n - 2 - o n e  are observed,  chemistry  chemistry.  towards e l e c t r o p h i l e s .  no e v i d e n c e  addition  Introduction  however, have been  i n the attempted M i c h a e l  methyl v i n y l cases,  i n the General  the development o f t h i s  problems,  evaluate  t o e s t a b l i s h i t s g e n e r a l i t y f o r use i n  E l e m e n t s o f t h e s c o p e o f B-keto e s t e r d i a n i o n have been d e s c r i b e d  know-  corresponding  i . e . 4_1 and J U ; i n s t e a d  (4_3) .  2_7 w i t h In b o t h  to conjugate the a l d o l p r o -  35 ducts  42 and 45 a r e o b t a i n e d  .  Indeed,  i t has been  generally  23  24  found  that  t h e more r e a c t i v e t h e n u c l e o p h i l e  employed,  the l e s s  38 conjugate a d d i t i o n The trated  reactivity  i s observed o f B-keto e s t e r d i a n i o n s  i s also  illus-  v i o l e n t r e a c t i o n with a c y l h a l i d e s t o give a 27 mixture of products (equation 1 2 ) . T h i s r e s u l t l e d t o the c o n s i d e r a t i o n o f m i l d e r a c y l a t i n g a g e n t s s u c h as e s t e r s f o r t h e 34 p r e p a r a t i o n o f t r i c a r b o n y l compounds (equation 13).  0  XX  by t h e i r  0  0 OMe  mixture of products (12)  RAVCI  27 0  0  0 OMe  R  0  OMe  postulated  of phenolic  arose  ( 1 3 )  34  Interest  gested  0  OR'  27  the  0  i n the p r e p a r a t i o n intermediacy  from  o f such s p e c i e s  natural products.  the p o l y c a r b o n y l  origin  the o b s e r v a t i o n  o f B - p o l y k e t o n e s stems  The i n i t i a l  i n the b i o s y n t h e s i s r e p o r t which  o f some p h e n o l i c  t h a t heptane  from  sug-  compounds  2,4,6-trione  (4 6)  39 cyclizes  to o r c i n o l  (Al_) under  acidic  conditions  .  I t was  25  0  0  0  H  47  this  observation,  which  led  to  later  confirmed  formulation  of  the  by  Birch  40  polyacetate  and  Bethel  route  to  41  ,  phenolic  compounds^. 34 Initial dianion esters  2_7  reacts  3_4.  the  by  Huckin  smoothly  However,  satisfactory of  efforts  the  (30-40%)  complications  esters  this  of  more  sary  to  preserve  deal  of  experimentation,  i t was  21_ w i t h  equivalent  half  the  more  during the  one  the  of  base,  of  the  r e a c t i o n was  species. found  and  provided  8,6-diketo  in  reaction  diketo  esters  the  ester,  finally  simple  of  that  of  of  yields  Following  the  of  dianion  of  addition  £8  remained  low.  for 3 4  yields  with  of  one  procedure  2_7  addi-  great  remaining  i n good  one  neces-  reaction then  a convenient  esters  the  a  not  transfer  course  preparation  the  proton  therefore  ester  esters  doubt  and  of  the  No  were  2_7  equivalent  Nevertheless,  3,6-diketo  condensations  involved  that  dianion  dianionic  half  equivalent  to  give  shown  simplicity.  reaction  tion  one  3_4  their  had  to  y i e l d s in these  the  base  of  Weiler  from  dianion  monoanion  with  despite in  and  .  aromatic  26  Reinvestigation  o f the crude products revealed  ponding c a r b o x y l i c amounts.  4_9 were a l s o o b t a i n e d  acids  In a d d i t i o n ,  that  these c a r b o x y l i c  the c o r r e s -  in significant  a c i d p r o d u c t s were  22  only  48, R=Me 4SL R=H  detected  i n condensations  r e s u l t was c o n s i s t e n t c o w o r k e r s who r e p o r t e d ethyl in  acetoacetate  i n v o l v i n g aromatic e s t e r s .  with  the e a r l i e r  that  f i n d i n g s o f W o l f e and  i n the attempted  aroylation of  with methyl benzoate using  1,2-dime t h o x y e t h a n e o n l y  This  the c a r b o x y l i c  sodium 4J3,  acid  hydride Ar=CgH^,  43 could  be i s o l a t e d  e v e r , remain The paration  .  The mechanisms o f t h e s e  hydrolyses,  how-  obscure.  a p p l i c a t i o n of this of polycarbonyl  a c y l a t i o n procedure  t o the p r e -  compounds h a s been d e s c r i b e d  by H a r r i s  44 and  Murray  philes, of  such  They have  to give  o f the d i a n i o n  monoanion o f e t h y l  carbonyl  found  that very  powerful  a s d i - and t r i a n i o n s , r e a c t w i t h  B-keto e s t e r s  densation the  .  compound  5_2.  acylated  products.  nucleo-  t h e monoanion  For example,  con-  5j0 o f 1 - p h e n y l - l , 3 - b u t a n e d i o n e w i t h . benzoylacetate  Harris  (5_1)  gives  the t e t r a -  and c o w o r k e r s h a v e , i n f a c t ,  27  0  0 -  0 -  C H 6  this  51  approach  i n the s y n t h e s i s o f l i n e a r  as many as e i g h t k e t o - g r o u p s  A similar achieved dianion  i n our  laboratory.  densation  i s used,  0 1  ^ ^  B-polyketones  45 '  of methyl acetoacetate  has a l s o been  I f , i n the g e n e r a t i o n o f  of methyl acetoacetate  n-butyllithium  0  acylation  0  £2  44 containing  0  O E t ^ C e H s - ^  5  50  used  0  0  only one-half  equivalent of  the B - k e t o e s t e r undergoes  and m e t h y l o r s e l l i n a t e  the  (5_4) i s o b t a i n e d  self-con( e q u a t i o n 14)  0 OMe  OMe 27  26  53 (14)  COOMe  34  28  Isolation effected  of by  the  quenching  phosphate b u f f e r conversion This who  of  (pH  the  t r i k e t o e s t e r _53 may  result  6.5).  was  a 59%  T h i s m a t e r i a l undergoes  a 10:1  confirmed  yield  also  r e a c t i o n mixture c a r e f u l l y  to methyl o r s e l l i n a t e  obtained  tion  intermediate  of  (5_4) on  by  m i x t u r e o f d i - and  with  a  spontaneous  standing.  H a r r i s and  triketo  be  ester  his  coworkers,  5_3 from  monolithium  the  salts  reac-  of  methyl  46 acetoacetate activated yield. acid  silica  gel  this  study,  In  (58_)  i n te t r a h y d r o f u r a n  and  be  21_ w i t h  expected  cyclization would  an  the  to g i v e  .  For  5_3 t h e n c y c l i z e d  the  was  ionized  of  81%  B-keto a l d e h y d e s  51_ and  condensation  acetoacetaldehyde ester  l o s s of  Nevertheless,  6-methylsalicylate  in  a l s o conducted using  hydroxy-diketo  to cyclohexanone  (_54)  (5_9) was  only  5_6, two  by  would  upon  moles o f  a trace  obtained  of  (5_5)  which  .  Instead,  i t was  found  that  the  with  water  (2.5%) this  46 approach  on  to prepare 6 - m e t h y l s a l i c y l i c  example, a l d o l  sodium s a l t  a f f o r d p h e n o l _59_.  of methyl  attempt  r e a c t i o n of 46  electrophiles  dianion  Ester  to g i v e methyl o r s e l l i n a t e  related metabolites  h i t h e r t o unexplored strong  .  self-condensation,  29  0  0  0 0  0  0 H 0 0 OMe  Na* 55  27  56  OH  6c  -2H 0  OMe  2  58,R=H 53,R=Me  c f . equation 14, predominated produced methyl o r s e l l i n a t e  and the c y c l i z a t i o n  (5_4) .  conditions  A s i m i l a r outcome has  occurred upon treatment of methyl a c e t o a c e t a t e d i a n i o n with the 46 monoanion of e t h y l b e n z o y l a c e t a t e to i n d i c a t e  .  These experiments  that d i a n i o n 21_ i s a s u f f i c i e n t l y  appear  strong base to  deprotonate the monoanion of acetoacetaldehyde.  The  resulting  monoanion of the keto e s t e r can then r e a c t with r e s i d u a l d i a n i o n 21_ to i n e v i t a b l y give methyl o r s e l l i n a t e equation  (5_4) as per  14.  Further work has revealed that t h i s problem can be  eli-  minated by the use of 3-keto e s t e r s having more bulky alkoxy groups which hinder n u c l e o p h i l i c attack on the e s t e r  group.  30  For  example, c o n d e n s a t i o n  (60)  with  the monoanion  satisfactorily cyclization  0  to give  and  of  t-butyl acetoacetate  5_5 o f a c e t o a c e t a l d e h y d e  dianion  proceeds  t-butyl 6-methylsalicylate  (6_1)  upon  dehydration^.  0  0  0  AAH  0C(CH )  ^  3  >  fil, S u b s e q u e n t l y , H a r r i s and problem of  self  Hubbard have r e p o r t e d  condensation  may  a l s o be  R= C ( C H ) 3  that  alleviated  by  3  the  using  47 the  dianion  of  a B-keto amide  acetoacetamide  (62)  with  amide a t - 2 0 ° C , or one by  one  equivalent  0  two  .  Treatment of  equivalents  equivalent  of  sodium h y d r i d e  0  0 NMe  followed  NaH, n-Buii  2  the  dianion  0  J\  >  fi  A ^ r ^ N M e  62  2  61  condensation  of d i a n i o n  acetoacetate  gave  taminated  e i t h e r the  by  lithium diisopropyl-  o f n - b u t y l l i t h i u m a t 0°C a f f o r d e d  2 L D A or  The  of  N,N-dimethyl  the  63_ w i t h  triketo  the  amide 6_4  triketo ester  monoanion i n 56%  26^ o f  yield,  5_3 or m e t h y l  methyl  uncon-  orsellinate  63.  31  (54).  Similarly,  the  reaction  of d i a n i o n £3 with methyl  z o a t e gave  the d i k e t o amide 6_5 i n 88%  any  acid.  diketo  0  yield,  u n c o n t a m i n a t e d by  0 0  0  ben-  0  0  0  OMg  0  26  NMe-  0  SI  0  0  ^ > AXX  c  ,  C00Me  CH 6 5 C  NMe  H  1  £5  In g e n e r a l , the found  t o be s i g n i f i c a n t l y  triketo esters. the  triketo  transition  I t was state  dimethylamides,  amides p r e p a r e d  more s t a b l e  suggested  retard  thereby  than  that  aldol  stabilizing  in this  the  steric  were  corresponding interactions  cyclization the  study  in  o f the N,N-  initially  formed  acy-  47 lated  products A third  a desire  difficulty  to prepare  8-keto e s t e r shown t h a t  i n the c h e m i s t r y o f d i a n i o n s a r o s e  ring  dianion.  Earlier  the a l k y l a t i o n  p r o p a n e , o r one  compounds by t h e a l k y l a t i o n work  i n our  of a  l a b o r a t o r y had  o f d i a n i o n 2_7 w i t h e x c e s s  e q u i v a l e n t of  from  1,3-dibromo-  1 , 3 - d i b r o m o p r o p a n e under  high  32  dilution  c o n d i t i o n s gave m e t h y l  (6j6) .  The  3 5  extension  of  this  2-oxocyclohexanecarboxylate  principle  t o the  preparation  been  extensively  of  OH 67  The  synthesis  of p r o s t a g l a n d i n s  has  49 studied of  the  over  the  approaches  past  ten  to t h e i r  a s u i t a b l e five-membered elaborated use  of  bility  an  by  the  to f i f t e e n synthesis  ring  a d d i t i o n of  intramolecular  of employing  an  years  .  involve  the  compound, w h i c h the  dianion  two  Generally,  alkylation  a l t e r n a t e approach  formation  is  side chain  of  subsequently units.  offers  t o the  most  the  The possi-  synthesis  of  33  prostaglandins, in  i n which  the c y c l o p e n t a n e  the s y n t h e t i c sequence.  synthesis  The key s t e p  i s o u t l i n e d i n equation  0  ring  15.  i s formed  in this  late  proposed  The y a l k y l a t i o n o f  0 0  0 (15) C  68  dianion at  5 11 H  69  2_7 w i t h  compound  (68_) , f o l l o w e d  t h e a - c a r b o n would g i v e  m e d i a t e has a l r e a d y  by i n t e r n a l  cyclopentanone  been u s e d  i n a number  6_9.  This  cyclization key  inter-  of syntheses of  pros-  taglandms Unfortunately, pound  7_0 f a i l e d  instead  only  compound ditions  48  to give  the y  could  the r e a c t i o n of d i a n i o n  - a l  the d e s i r e d c y c l o p e n t a n o n e  kylated  product  n o t be c y c l i z e d  This  result  21_ w i t h  was  model com71. and  7_2 was o b t a i n e d .  t o 71 under  This  a v a r i e t y of con-  further confirmed  by t h e f a i l u r e  34  to obtain  other  zations.  For  hydrin,  only  types of  example, the  cyclopentane  i n the  O-cyclized  reaction compound  rings of  in related  2_7 w i t h  73_ c o u l d  be  cycli-  epichloroisolated  5 1  .  COOMe  0  0  0 OMe  27  A possible  73  explanation  for  the  failure  undergo c y c l i z a t i o n to cyclopentanone gested  by  Baldwin  and  coworkers  52  of  these  systems  derivatives  has  to  been  sug-  35  Recently,  Baldwin  has  reported  a study  of  the  ring c l o -  52a sures the  of  ketobromide  lithium was  a number o f  enolate  7_4 was _75.  the e n o l e t h e r  bromide  ketone e n o l a t e s converted  In b o t h  the  In  into either  cases,  7_6> whereas under  7_7 y i e l d e d o n l y  .  the  this  investigation,  i t s potassium  sole reaction  the  cyclohexanone  product  same c o n d i t i o n s 78.  or  keto-  36  Baldwin these of  two  the  cyclizations  alkylation  anion. the  suggests  Alkylation  electrophile  whereas oxygen the e n o l a t e .  of  the  to  sterically  results  from s t e r e o e l e c t r o n i c c o n t r o l  the  ambident n u c l e o p h i l e  i o n 79.  of  alkylation  t o the  plane  i n the c a s e  i t s approach  i n the  plane  six-membered  ring  approach  formation has  the  On  of  approach  the  resulting  which  other is  in  a the  78.  predict  the  enolate  cyclizations,  important  75,  length enables  i n t o a s e t o f e m p i r i c a l r u l e s w h i c h may  an  plane  is d i f f i c u l t  t o c o r r e l a t e a number  ease of r i n g  of  enolate,  alkylation  results  relative  enolate  oxygen s i t e ,  J76.  enolate,  of cyclohexanone  been a b l e  site  carbon  extra chain  t o the  the  i n the  t o the  enol ether case,  of  of enolate  carbanion  f o r m a t i o n o f the  i . e . the  r e q u i r e s approach  t o the  near p e r p e n d i c u l a r  Baldwin  carbon  n  center  possible since  preferential  o  r e q u i r e s approach  Consequently,  i n the  hand, i n the  r e m a r k a b l e d i f f e r e n c e between  perpendicular  alkylating  compared results  of  t h a t the  of be  such used  forming  reactions.  In  factor  i s whether  the  to ketone  37  enolate  double  bond  i s e n d o c y c l i c or e x o c y c l i c  formed  ring.  carbon  center undergoing  trigonal role.  In a d d i t i o n ,  (trig)  tion  i s f a v o u r e d over  tion  17,  The can  failure  cyclization  At ate  6_9,  (dig),  appears  can  i l l u s t r a t e s that  by B a l d w i n  stage,  a s p e c i e s which  readily  1_4 i n e q u a t i o n  i t appeared  prepared  that  and  was  does not  required.  from m e t h y l  rules,  was  found  to f u l f i l l  these  important cycliza-  The  equa-  three  i n Table  IV. 7L  this  an e n d o c y c l i c e n o l a t e 16. the  than  involve The  key i n t e r m e d i -  the v e r y the  a c e t o a c e t a t e 21 and  criteria  80  stable  less  enamine 8_0,  H  21  (tet),  from  since  48 idine,  the  to cyclopentanone  t o form  i s more r e a c t i v e  esters  and  a r e summarized  be c o n s i d e r e d t o i n v o l v e  at  a 5-exo-tet  6-exo-tet.  i n terms o f B a l d w i n ' s  to t h a t o f ketone this  t o p l a y an  a 5-endo-trig c y c l i z a t i o n  favoured e n d o c y c l i z a t i o n be  i . e . tetrahedral  o f compound 7_2 t o c y c l i z e  monoanion o f g - k e t o  can  cyclization,  16  r u l e s proposed  be u n d e r s t o o d  similar  of h y b r i d i z a t i o n  6 - e n d o - t r i g i s f a v o u r e d over  empirical  newly  the n a t u r e  or d i g o n a l  Hence, e q u a t i o n  t o the  which pyrrol-  38  Table  Rule  Rule  Rule  IV.  1:  2:  3:  Baldwin's  Rules  52  T e t r a h e d r a l Systems a)  3 t o 7-Exo-Tet are a l l favoured  b)  5 t o 6-Endo-Tet  Trigonal  are disfavoured.  Systems  a)  3 to 7-Exo-Trig  b)  3 to 5-Endo-Trig 6 to 7-Endo-Trig  Digonal  processes  are a l l favoured  processes  are disfavoured; are f a v o u r e d .  Systems  a)  3 t o 4-Exo-Dig are d i s f a v o u r e d p r o c e s s e s ; 5 t o 7-Exo-Dig are f a v o u r e d  b)  3 t o 7-Endo-Dig  are  favoured.  39  A general procedure  for  the  y  has  been r e p o r t e d  bonyls at a l . ^ .  the  For  position  example, a d d i t i o n  of  the  pyrrolidine  by  introduction  •v-alkylated  enamine 8_0  of  methyl  alkylation  by  in  the  for  crude  p r o c e d u r e was near 18  the  Yoshimoto  n-butyllithium  of  methyl acetoacetate, or  and  to  a  benzyl chloride  73%  yield  et  solution followed  gave  the  respectively.  No  81  80 evidence  enaminocar-  of  iodide  e n a m i n e s 81. i n 81  of  either  a-  reaction found  position  or  product.  to  of  G-alkylated  be  the  In  addition,  insensitive new  product could  to  this  be  y-alkylation  substitution  carbon-carbon  detected  bond, e . g .  at  or  equation  54  1) LDA 2) Mel  0  The similar  ability fashion  of to  the that  (18)  0  anion of  of  enamine 8_0  a g-keto e s t e r  to  react  dianion  in  a  provided  40  two  important  longer tion  advantages.  available  of anion  cyclization  Firstly,  the  keto  for O-cyclization,  and  secondly,  8_2 c o u l d  (equation  be 19).  considered  g r o u p was  to proceed  Such a r i n g  forming  the  no cycliza-  via a  5-exo-  reaction i s  82  favoured  according  To  test  this  to Baldwin's hypothesis,  methyl acetoacetate lithium  a t -60°C  compound l e n t of was  7fJ.  allowed  lytic  71  IV.  the p y r r o l i d i n e  treated with  anion  o f 8_3 was  diisopropylamide,  to s t i r  workup, the 48  tanone  Table  one  enamine 8_0  e q u i v a l e n t of  i n t e t r a h y d r o f u r a n , f o l l o w e d by  The  lithium  was  rules,  overnight  product  generated then  the  the  a t room t e m p e r a t u r e .  obtained  was  the d e s i r e d  n-butyl-  model  u s i n g one reaction  of  equivamixture  On  hydro-  cyclopen-  41  0  1)n-BuLi OMe  2)MsO^<^<c]  fiQ  During  the c o u r s e  c o w o r k e r s employed glandin A 2 ^ ° .  of  this  investigations,  s t r a t e g y i n the step in this  study  ment o f enamine 8_4 w i t h  sodium amide  to give  69  after  hydrolysis.  OMe  and  i n v o l v e d the  i n our  2  C  84  treat-  cyclopentanone  Subsequent e x p e r i m e n t a t i o n  1) NaNH  Martel  s y n t h e s i s of p r o s t a -  key  a  The  these  £9  5 11 H  42  laboratory directly  illustrated  from  (equation  that  cyclopentanone  69_ may  be p r e p a r e d  the p y r r o l i d i n e enamine 80 o f m e t h y l a c e t o a c e t a t e  20).  However,  1) 2) 3) 4)  e f f o r t s t o e f f e c t a more  n-BuLi M s O - ^ ^ ^ N ^ C ^ H 5 11 LDA n  H 0* 3  69  80 route tion  convergent  t o the p r o s t a g l a n d i n s of a t e t r a s u b s t i t u t e d  involving enamine  a l k y l a t i o n and c y c l i z a -  (equation  21) were  thwarted  o o •x—>  OMe  (21) C  5 11 H  48 because  of d i f f i c u l t i e s  preparation to  of t e t r a s u b s t i t u t e d  be d i f f i c u l t  substituents  i n f o r m i n g the d e s i r e d  due  interactions 55 bond  The p r o b l e m s e n c o u n t e r e d B-keto e s t e r  dianions  .  The  e n a m i n e s a r e , i n f a c t , known  to s t e r i c  on t h e d o u b l e  enamines  in certain  has l e d s e v e r a l  between  the c i s  applications  researchers  to  of consider  the use o f a p r o t e c t e d or  g-keto e s t e r s h o u l d  hidden  groups t i e d of  in  up i n such  the a- and Y - P  the  g-keto e s t e r e q u i v a l e n t .  reactivity a less  a way i-  o s l t l o n s  of the Y - P  o s  have b o t h  t h a t the d i f f e r e n t i a l  iti°  would  n  reactive nucleophile.  derivative  should  t h e k e t o n e and e s t e r  maintained,  s  The p r o t e c t e d  although  reactivity preferably  be d i m i n i s h e d  resulting  In a d d i t i o n , t h e p r o t e c t e d  be r e a d i l y c l e a v e d  back  t o a g-keto e s t e r  functionality. Recently, tion  Chan and B r o w n b r i d g e have r e p o r t e d  and r e a c t i v i t y  the p r e p a r a -  g-keto e s t e r d i a n i o n e q u i v a l e n t ,  o f a new  56 1 , 3 - b i s ( t r i m e t h y l s i l o x y ) - 1 - m e t h o x y b u t a - 1 , 3 - d i e n e (87) compound (21)  with  i s readily  prepared  b i s ( t r i m e t h y l s i l y l ) acetamide  3-trimethylsiloxycrotonate anion  by t r e a t i n g m e t h y l  o f 8_6 w i t h  lithium  trimethylchlorosilane.  (8_5) t o g i v e  diisopropylamide Judging  by i t s NMR  A  This  acetoacetate methyl  (8_6) , f o l l o w e d by g e n e r a t i o n  NTMS  21  .  and q u e n c h i n g  o f the with  s p e c t r u m , 87 was  OTMS  OTMS  85  1) LDA 2) TMSCl TMSO  OMe  found  to e x i s t  assigned  as  confirmed  as one  geometric  the E - i s o m e r .  by  i t s ready  isomer  The  w h i c h was  structure  hydrolysis  tentatively  o f 8_7 was  to methyl  further  acetoacetate  (21) . The can to  difference  be d e m o n s t r a t e d  by  their  i t s high r e a c t i v i t y ,  t o g i v e a number selective,  bromine  less  w i t h one  product  reactive  tetrachloride  example, M i c h a e l  -78°C  i n the p r e s e n c e  cyclized  product  d i a n i o n 21_  the d i a n i o n 2_7 r e a c t s w i t h  8_8,  On  the o t h e r  and  with  two  carbon  was  reaction of  89_  t o promote  o f 8_7 w i t h e t h y l  titanium tetrachloride  9fJ i n 74%  yield **. 5  bromine  to give  equivalents of  electrophiles,  necessary  Due  h a n d , 8_7 i s v e r y  e q u i v a l e n t of bromine  t o g i v e the a , y - d i b r o m o B - k e t o e s t e r  With other titanium  between 8_7 and  r e a c t i o n s with bromine.  of products.  reacting  the Y ~ b r o m i n a t e d  For  in reactivity  (Scheme 4 ) . activation reaction. acrylate gave  the  at  by  OH  *COOMe ^COOEt 90 k  0  TMSO  0 1  II  OMe  1Br  gsHsCHO  r ^ ^ ^ O M e  TiCl  )TMS  A  A  2.  Br  •CcH 6 5 n  OH  < ^ C O O E t , TiCl  87 2Br-  0  0 OMe  Br  Br  SI  Scheme 4; "  S e l e c t e d r e a c t i o n s of 1 , 3 - b i s ( t r i m e t h y l s i l o x y ) methoxybuta-l,3-diene ( 8 7 ) 5 6  46  The  reactivity  of g-keto e s t e r addition,  o f 8_7 a p p e a r s t o c o m p l i m e n t  dianions  8_7 p o s s e s s e s  of a l l i t s chemistry catalyzed  in several cases,  the  useful feature  Chan and  chemistry  Scheme 4. of  under e i t h e r n e u t r a l or  conditions.  the  the  In  generation  Lewis a c i d  B r o w n b r i d g e have  recently 57  applied  t h i s method  (equation  22),  in a novel  as w e l l  as  cycloaromatization  i n the  simple  reaction  preparation  of  oxabi-  58 cyclo  ring  The  systems  preparation  (equation  of  23).  a protected  been e n t e r t a i n e d  earlier  a good c a n d i d a t e  appeared  i n our t o be  g-diketone e q u i v a l e n t  laboratory.  In  i s o x a z o l e s e.g.  had  this  respect,  91..  Isoxazoles  are  easily  prepared  from g - d i k e t o n e s and  hydroxylamine  hydro-.  59 chloride  and  hydrogenolysis  o o  H  5  they can or  be  cleaved  hydrolysis^  AA  back  to 3-diketones  (equation  >  * NH OH-HCl 2  by  24).  6  5  JkJL il  1  (24) 0  N  D  C e ^ ^ ^ ^  >  2  H 0+  0  3  H  2^  H  3  ^ ^ ^ ^ ^  0 +  SL  il The anion  goal  of  C  6  H  5  of  that e a r l i e r  isoxazole  ° —  N  II  91  and  Q  S  e  ^ ^ ^  C  6  spond  5  ILIf  to g e n e r a t e  of  the  new  system, o v e r a l l ,  the  various e l e c t r o p h i l e s .  ^E * >  - ^ ^ -  C H 6  5  92.  hydrolysis  3-diketone  H  was  i t with  JYk  Base >.  O  research  react  21  Since  0'  93  isoxazole  93_ would  regenerate  isoxazole  anion  would  to a 1-phenyl-l,3-butanedione dianion  92  the  corre-  equivalent  50.  48  Unfortunately, isoxazole For  a l l attempts t o generate the anion o f  9_1 a t t h e d e s i r e d C-3 m e t h y l r e s u l t e d i n f a i l u r e .  e x a m p l e , t r e a t m e n t o f 9_1 w i t h  lithium, ing  followed  little  fifty  one e q u i v a l e n t  by d e u t e r i u m o x i d e  o r no d e u t e r a t i o n  of n-butyl-  gave a c r u d e p r o d u c t  show-  a t t h e C-3 m e t h y l and g r e a t e r  percent deuterium incorporation  a t C-4  than  (equation 25).  D  Similarly, greater with  u s e o f two e q u i v a l e n t s  than e i g h t y  little  The g e n e r a l  o f n - b u t y l l i t h i u m gave  percent deuterium incorporation  o r no i n c o r p o r a t i o n a t t h e d e s i r e d difficulty  i n deprotonating  C-3  a t C-4, methyl^ . 1  t h e C-3 m e t h y l o f 62  i s o x a z o l e s h a s been c o n f i r m e d by t h e r e p o r t o f K a s h i m a e t a l . that in  treatment of 3,5-dimethylisoxazole  liquid  alkylation  ammonia, f o l l o w e d a t t h e C-5 m e t h y l  (9_4) w i t h  s o d i u m amide  by a d d i t i o n o f m e t h y l i o d i d e only.  gives  49  0—N  1) N a N H , N H 2) Mel 2  I  3  25  24 In to its  order  to direct  d e p r o t o n a t i o n and e l e c t r o p h i l i c  t h e d e s i r e d C-3 m e t h y l , i s o x a z o l i u m s a l t 96.  treating  9_1 w i t h m e t h y l  dichloromethane.  capture  t h e i s o x a z o l e 9_1 was c o n v e r t e d T h i s was e a s i l y  accomplished  into  by  f l u o r o s u l f o n a t e ("Magic M e t h y l " )  in  The s t r a t e g y i n v o l v e d i n t h e u s e o f an  S0 F' 3  0— N  0  MeS0 F 3  CH Cl 2  2  N  CcHn  6 5 96  91  i s o x a z o l i u m s a l t was b a s e d upon e a r l i e r work on t h e c h e m i s t r y of  thiamine (97).  97  50  The mechanism  of a c t i o n of thiamine  of a great d e a l of research Breslow  found  pyruvic  acid  that  (97) was t h e s u b j e c t  i n t h e 1950's.  the thiamine  In t h i s  regard,  catalyzed decarboxylation  of  63 (9_8) p r o c e e d s by the r o u t e  i n d i c a t e d i n Scheme 5  -CO  Scheme 5;  Mechanism f o r t h i a m i n e pyruvic acid (98) 6 3  catalyzed decarboxylation  of  51  Decarboxylation mediate  9j9, w h i c h  effects.  is facilitated  is stabilized  This intermediate  by  has  by  the  both  formation  of  i n d u c t i v e and  a l s o been shown t o  inter-  resonance  participate  63 in  further reactions in biological Similarly  salt  9_6 would  dissolution  the c o n v e r s i o n lead  of  to a c t i v a t i o n  isoxazolium salt  sodium d e u t e r o x i d e was  completely  the C-4  could  of base.  be  problem, i n t h i s  and  those  in a d i l u t e showed  after  efforts  t h a t the and  no  three  of  C-3  alkylation  system  hours  to a l k y l a t e  in  the  products  .  These  to give products  yisoxazoles  100,  be  4H-isoxazolin-5-ones  C-3 bases.  formulated 101,  or  efforts  of a 3-keto  as  hydrox-  5-hydrox-  2H-isoxazolin-  37 5-ones 10_2  .  0  N  100  Some c o n t r o v e r s y  remained  N—0  101  i n the  in  l e d to con-  f o r the g e n e r a t i o n  w h i c h may  of  the  i s b e l i e v e d t o be  dianion equivalent. I t has l o n g been known t h a t 3 - k e t o e s t e r s r e a c t w i t h  ylamine  methyl  exchange  o f r e a c t i o n c o n d i t i o n s and  water-soluble  of a s i m i l a r  Indeed,  solution  o f Kashima e t a l . , d e s c r i b e d e a r l i e r ,  sideration ester  of  a variety  methyl.  immediately,  Nevertheless,  The  production  the C-3  d e t e c t e d even  using  the  of  oxide  almost  methyl f a i l e d principal  i s o x a z o l e 9_1 t o i t s i s o x a z o l i u m  9_6  i n deuterium  exchanged  proton  presence  of  systems  literature,  0  N  102  52  however, r e l a t i n g v a r i o u s R' and t o time u n t i l  t o the assignment  R""^'^. 1961, when  of s t r u c t u r a l  This discussion Katritzky  form f o r  reappeared  from  time  and B o u l t o n p u b l i s h e d 64  r e p o r t s on t h e t a u t o m e r i s m  o f s u c h h e t e r o a r o m a t i c compounds  In  and u l t r a v i o l e t  these s t u d i e s ,  well  infrared  as c h e m i c a l means, were u s e d  makeup  of s e v e r a l  exists  as a m i x t u r e  the t a u t o m e r i c  was f o u n d  and i n t h e s o l i d  to e x i s t state  3,4-dimethyli n aqueous  as t h e OH  3 - p h e n y l - i s o x a z o l i n - 5 - o n e (R'=CgH,-, o f t h e CH and NH f o r m s ,  i n a r a t i o depending  structures  form, R"=H)  101 and  upon t h e p o l a r i t y o f  solvent. I t was c l e a r  in  3  100, w h i l e  102 r e s p e c t i v e l y , the  (R'=R"=CH ),  chloroform solutions  structure  t o deduce  i s o x a z o l i n - 5 - o n e s . For example,  5-hydroxyisoxazole and  s p e c t r o s c o p y , as  structures  that  the presence  of a c i d i c  OH and NH  100-102 would n o t make s u c h compounds  as B - k e t o e s t e r  dianion  groups  suitable  e q u i v a l e n t s . R e p l a c e m e n t o f OH by OR  w o u l d , however, a l m o s t c e r t a i n l y  lead  back  t o the d i f f i c u l t i e s  encountered  i n t h e i s o x a z o l e work, i . e . d e p r o t o n a t i o n a t C-4  rather  a t t h e C-3 m e t h y l  of  than  an e n o l e t h e r w h i c h  the OH form c o u l d  pose  group.  In a d d i t i o n ,  was s u s c e p t i b l e problems  the presence  to hydrolysis  back t o  r e g a r d i n g t h e h a n d l i n g o f such  a compound. The  replacement  appealing restricted  o f NH by NR,  f o r two r e a s o n s . to a s i n g l e  on t h e o t h e r hand, would be  Firstly,  compound  t a u t o m e r i c form  thereby  103 would  be  simplifying  53  identification, pound  and s e c o n d l y ,  103 would be e x p e c t e d  analogy  with  the  the most a c i d i c  t o r e s i d e on the R' c h a i n  B-enamino e s t e r s 104.  104  103 compared w i t h  the c i s i n t e r a c t i o n s i n 104 Two  routes  involves cedure,  i s now  have been u t i l i z e d  isoxazolin-5-ones  by  An a d v a n t a g e o f t h e  103 isoxazolin-5-one  h y d r o g e n i n com-  o f type  the a l k y l a t i o n  103, R^H.  enamine  104  replaced  i s t h a t one o f  by a c h e m i c a l  bond.  f o r the p r e p a r a t i o n of The f i r s t  of isoxazolin-5-ones  of these  101.  This  routes pro-  however, o f t e n y i e l d s O - a l k y l d e r i v a t i v e s 105 o r m i x -  t u r e s o f N- and O - a l k y l d e r i v a t i v e s , t h e r e l a t i v e w h i c h depend on t h e s u b s t i t u e n t s R*  and R"  amounts o f  and sometimes on  65 the  reagent  101  employed  .  Nevertheless,  103  t h i s method  has been  105  54  used  i n the  synthesis  of  two  isoxazolin-5-one  natural  pro-  ducts The first er  natural  occurrence  recognized  i n 1969.  , while  gating  looking  a x i s o f pea  ing u l t r a v i o l e t  isoxazolin-5-one  that  for nucleic  seedlings,  spectra  These compounds were, to u l t r a v i o l e t the  with of  At  the  ring  time, V a n P a r i j s a n d  was  cowork-  7  ers  of  of  two  and  a-amino a c i d  spectral properties  of  very  106a  sensitive comparison  natural  isoxazolin-5-ones, as  promis-  properties.  After  the  elon-  the  and  products  structures  106b.  106a;  R=CH CH(NH )COOH, R'=R'=H  106b;  R= p-D-glucose, R=H, R"=CH CH(NH )COOH  2  2  2  s i x other  i s o l a t e d and the  t o be  dilute alkali.  compounds were e s t a b l i s h e d  and  i n the  products with  i n a d d i t i o n , found  synthetic N-substituted  Subsequently,  lings  found  having  irradiation  c h e m i c a l and  these  been  and  acid precursors  isoxazolin-5-one  characterized  chemistry  and  natural  f r o m pea  biology  of  and  this  2  products  sweet pea new  have  seed-  c l a s s of  plant  67 p r o d u c t s have been The  synthesis  alkylation  of  the  reviewed of  two  of  sodium s a l t  these n a t u r a l 107  of  p r o d u c t s by  isoxazolin-5-one  the has  also  55  been d e s c r i b e d by  these  isoxazolin-5-one acrylonitrile, ing  the  salt  bromide  while  107  (109)  (108)  with  workers was  the  66  .  Therefore,  prepared  from  glucoside  110  the  was  2-cyanoethyl-  salt  107  obtained  and  by  react-  2,3,4,6-tetraacetyl-a-glucopyranosyl  i n dry methanol.  The  two  products  were  produced,  0 H 108, R=CH CH CN 2  2  110. R= p-D-glucose AcO  I Br  AcO IQi  2) however, i n v e r y size  the  other  low  H 0  +  3  yields,  ca.  1%,  and  attempts  n a t u r a l i s o x a z o l i n - 5 - o n e s by  this  to  synthe-  procedure  have  been u n s u c c e s s f u l . The R^H,  second  route  i n v o l v e s the  esters  (equation  used  to prepare  isoxazolin-5-ones  reaction, of N-alkylhydroxylamine 26).  This procedure  provides  with  103, B-keto  the d e s i r e d  compounds 103 O-alkylated While for  these  i n good y i e l d  p y r i d i n e and  e t h a n o l are  reactions, pyridine usually For  example,  treatment  with N-methylhydroxylamine  in ethanol  the y i e l d  i s 0%,  AA ' 0Me  as  gives higher  hydrochloride  Table  (112)  (111)  any  the  this  ready  compounds has  yields  little  been r e p o r t e d .  of (21)  i n 60%  yield,  while  V  availability  method, v e r y  solvents  in pyridine  ^y,  0  H  in  Despite  concerning  suitable  MeNHOH-HO  2i  5-ones by  from  of methyl acetoacetate  2,3-dimethylisoxazolin-5-one  these  contamination  products. both  products.  gives  without  in of N - a l k y l a t e d work on  the  chemistry  T h i s l a c k of  isoxazolin-5-one chemistry  and  our  isoxazolin of  knowledge  interest  in  T a b l e V.  Preparation of 2-Methylisoxazolin-5-ones  103,  1Q3,R=Me Yields HL  HI  CH  H  3  H CH C  3  H  CH  3  C  6 5  C  6 5 H  0  3  37  21  CH  3  78  25  52  0  89  60  91  73  56  5.8  55  65  6 5  C  6 5  H  H  CH C  ethanol  CH  C  H  pyridine 50-60  H  6 5 H  in  (%) in  3  6 5 H  developing consider The pare  a new  B-keto e s t e r d i a n i o n  the study  o f these  equivalent  compounds.  a i m s , a t t h e commencement o f t h i s  a number  generation  of N-alkylisoxazolin-5-ones  o f the a n i o n s  an e v a l u a t i o n  of these  of the c h e m i s t r y  ones as a B - k e t o e s t e r  l e d us t o  dianion  work, were  and t o examine the  compounds.  o f the anion equivalent  to pre  Subsequently, of isoxazolin-5-  was  t o be e f f e c t e d  59  RESULTS AND  The  DISCUSSION  study  of isoxazolin-5-one  synthesis of isoxazolin-5-ones chosen  because  acyclic, lents  *N  their  cyclic,  anions  may  112-114•  began w i t h t h e  T h e s e compounds were  be c o n s i d e r e d  to represent  and s u b s t i t u t e d 3 - k e t o e s t e r d i a n i o n  respectively  equiva-  (Scheme 6 ) .  *N  0  chemistry  0  0  0  0  cA  0  0  0  ill  0  Scheme 6:  NJ  0  Isoxazolin-5-ones equ i v a l e n t s  0  0  as g - k e t o e s t e r d i a n i o n  60  The  preparation  accomplished  by  of  the  2,3-dimethylisoxazolin-5-one  r e a c t i o n of methyl a c e t o a c e t a t e  N-methylhydroxylamine h y d r o c h l o r i d e 100°C  6 5  .  Fractional distillation  0  (112)  (111)  of  (21)  was with  in p y r i d i n e at  the  crude  reaction  mixture  0  fl 11 A A A \ M e  •  MeNHOH-HCl  0  111"  21  gave  112  was  i n 57%  evident  yield.  from  g l e t s a t 6 2.16 (1H,  C-H).  product the  showed a b s o r p t i o n s  Sarlo et a l .  In  with  6  5  other  ring  and  that e x t r a c t i o n of with  of  the  of  this  desired  product  C=0  N - C H ) , and  spectrum of  and  and  C=C  1650  1  these  tarry  those  (115)  crude r e a c t i o n mixture,  distilled  typical  of  reported  by  f o r s u b s e q u e n t com-  authors  residue  have  obtained  g i v e s a s m a l l amount o f  compound was  ,  4.93  isoxazolin-5-ones.  112,  the d a r k  cm  the  sin-  stretching vibrations.  i n c l u d e d here  of  6  3  i n agreement w i t h  2,4-dicarbomethoxypyrrole formation  infrared  more complex  ligroin  (3H,  a t 1730  are  the p r e p a r a t i o n  tillation  6 3.30  a d d i t i o n , the  are  o f the  spectrum which d i s p l a y e d three 3  s p e c t r a l data  parison  formation  C-CH ),  isoxazolin-5-one  These De  i t s NMR  (3H,  In  The  6 5  .  Although  apparent no  from  e f f o r t was  reported after  dis-  1,3,5-trimethyl-  evidence  for  the  the NMR  spectrum  made t o  isolate  61  this  product.  M e c h a n i s t i c a l l y , t h e p y r r o l e 115 may  sidered  to arise  by the c o n d e n s a t i o n  enamine  116 w i t h  unreacted  Scheme 7:  o f the i n i t i a l l y  B-keto e s t e r  P o s s i b l e mechanism p y r r o l e 115  be  conformed  (Scheme 7 ) .  f o r the f o r m a t i o n  of  The p r e p a r a t i o n o f 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e was  similarly  acetoacetate (111)  effected (117) w i t h  in pyridine  6 4a  .  by the c o n d e n s a t i o n  of ethyl  N-methylhydroxylamine The NMR  s p e c t r u m o f the  (114)  2-methyl-  hydrochloride distilled  62  0  0 •  OEt  MeNHOH-HCl  111  117  product  displayed  corresponding The f a c i l e  three s i n g l e t s  t o t h e C-4, C-3  3.17  and N - m e t h y l g r o u p s r e s p e c t i v e l y .  be c o n t r a s t e d w i t h  isoxazolin-5-one  the d i f f i c u l t i e s  encountered  t h e s y n t h e s i s o f t e t r a s u b s t i t u t e d e n a m i n e s 118 f r o m t h e  corresponding  g - k e t o e s t e r s , as d i s c u s s e d  The s y n t h e s i s o f one  a t 6 1.73, 2.10, and  synthesis of a f u l l y substituted  s u c h a s 114 may in  0  2-methyl-3,4-tetramethyleneisoxazolin-5-  (113) h a s n o t been r e p o r t e d  i t was a n t i c i p a t e d t h a t t h i s similar  earlier.  i n the l i t e r a t u r e .  product  However,  c o u l d be p r e p a r e d  f a s h i o n t o t h a t o f compounds 112 and 114.  methyl 2-oxocyclohexanecarboxylate  in a  Accordingly,  (6_6) was p r e p a r e d  by t h e  68 method  o f D e s l o n g c h a m p s and c o w o r k e r s  (equation  2 7 ) , and  was  63  D N c t H , KH  OMe  (27)  2) (MeO)oCO  reacted  with  pyridine  0  N-methylhydroxylamine  (equation  28).  hydrochloride  The p r o d u c t ,  isolated  0 P y r i d m e  spectral  t o be homogeneous by TLC a n a l y s i s ,  these  the expected  anion  generation  s u b s t r a t e because a l l o w ready  113.  the d i s t i n c t  determination  nature  For t h i s  (114) was c h o s e n as o f i t s NMR  o f the e x t e n t  spectrum  and p o s i t i o n o f  deprotonation. An  ing  product  was u n d e r t a k e n .  purpose, 2,3,4-trimethylisoxazolin-5-one  any  and e x h i b i t e d  t h r e e compounds i n hand, an i n v e s t i g a t i o n o f  isoxazolin-5-one  would  (28)  HI  p r o p e r t i e s c o n s i s t e n t with  With  0  >  HI  66  the  i n 67% y i e l d ,  "NM  MeNHOH'HCl  was shown  (111) i n  e v a l u a t i o n o f b a s e s was  114 w i t h  t h e r e f o r e conducted  one e q u i v a l e n t o f base  by  treat-  i n t e t r a h y d r o f u r a n a t 0 C,  64  then  quenching  29).  The  the  results  reaction of  this  mixture  study  1) Base 0 2) Mel  with  are  iodomethane  summarized  ^  (equation  i n Table  VI.  o  I  l  29)  (  119 It the  i s . p a r t i c u l a r l y noteworthy  that n - b u t y l l i t h i u m deprotonates  i s o x a z o l i n - 5 - o n e a t - 7 8 ° C , w i t h no  the c a r b o n y l group o f the r i n g . a t low  evidence  In a d d i t i o n ,  anion  r e a c t s smoothly  temperature,  ester  d i a n i o n a l k y l a t i o n s which proceed  of a t t a c k  the  on  resulting  i n c o n t r a s t t o B-keto  o n l y s l o w l y under  these  conditions. The  s p e c t r a l d a t a f o r the crude  successful alkylations t h a t no d i a l k y l a t i o n , occurred. the C-3  (entries  4,  7,  O - a l k y l a t i o n o r C-4  Confirmation  m e t h y l was  2,  reaction mixtures and  10)  manifest  i n t h e NMR  had  spectra of  had  occurred the  a triplet  absence o f  m e t h y l a b s o r p t i o n a t <5  in  the  e x c l u s i v e formation  anions  appears  and  the 2.10  starting material.  The the  C-3  a t 6 1.18,  at  products,  w h i c h showed a q u a r t e t a t 6 2.45, the c h a r a c t e r i s t i c  the  indicated  alkylation  t h a t the c o n d e n s a t i o n  from  of -y-alkylated products  o f B-enamino e s t e r s 104  t o be  in c o n t r a s t with  the  and  from  isoxazolin-5-ones  recent results  of Smith  103 and  65  Table ~  VI. "  E v a l u a t i o n o f Bases f o r Deprotonating m e t h y l i s o x a z o l i n - 5 - o n e (114)  ^tJ  0  M  1) Base 0 2) Mel  2,3,4-Tri-  0  119  Yield  o f 119 (%)  E n t r y no.  Base  1  NaH  0  2  LDA  81  3  MeLi  4  n-BuLi  5  KH  0 (-78 C) W  74 0  6  (Me Si) NLi  7  (Me Si) NK  3  69  0  70  79  2  3  2  8  NaOMe  0  9  KOMe  0  /  C  6 5 H  -t - C KC H  10  6  71  5  py a)  Isolated  yields  o f p r o d u c t 119  71  66  R  ^ N — 0  R  0  Me  103  Scarborough  on  the a l k y l a t i o n  o f the a n i o n s o f B-keto  ester  72 enol esters and  121  .  were g e n e r a t e d  hydrofuran. and  methyl  tion  In t h i s  The  s t u d y , a n i o n s o f the e n o l e t h e r s using lithium diisopropylamide in  reaction  of  these anions w i t h n - p e n t y l  i o d i d e gave p r o d u c t s e x h i b i t i n g e x c l u s i v e  ( e q u a t i o n s 30  OEt  and  31).  120 tetraiodide  a-alkyla-  OEt  (30)  120 OEt  OEt  (31)  121 The of  such  n a t u r e o f the a v s y s e l e c t i v i t y systems i s not f u l l y  understood.  i n the  alkylation  P r e l i m i n a r y extended  73 Huckel  calculations  reveal,  however, t h a t  the  electron  67  density the in  i s higher  anions B-al  k c ,  electron  on  the y - c a r b o n  than  B-enamino e s t e r s and  of  xy-a / B  - U n s a t  urated  d e n s i t y on  on  a-carbon  in  isoxazolin-5-ones,  e s t e r s , e.g.  the a and  the  120  and  while  121,  the  y p o s i t i o n s a p p e a r s t o be  com-  parable . With may  be  formed three  the  generated,  t h a t the  a series  to determine  the  the  was  alkylation  Treatment of furan  used  114  a t 0°C,  deuterium  as  of  For the  of  isoxazolin-5-ones  anion  this  base  generation  purpose, l i t h i u m  since  i t gave  the  with  lithium  gave  diisopropylamide  quenching  the  diisobest  results  (114).  in tetrahydro-  r e a c t i o n mixture  the m o n o d e u t e r i o p r o d u c t  per-  for a l l  2,3,4-trimethylisoxazolin-5-one  f o l l o w e d by  oxide  anion  o f d e u t e r a t i o n e x p e r i m e n t s were  degree of  isoxazolin-5-ones.  propylamide in  knowledge  122  with  i n 78%  yield.  DLDAJHF, OC 0  D0  2)  2  HA  data. that had  The  s t r u c t u r e of  The  NMR  the  122  spectrum of  three-proton  been r e p l a c e d by  the  singlet a broad  tons.  In a d d i t i o n , the  parent  mass o f  128,  was  low  which  evident crude  i t s spectral  r e a c t i o n mixture  a t 6 2.10 signal  from  i n the  starting  integrating  resolution  the  material  t o c a . two  mass s p e c t r u m  i s c o n s i s t e n t with  revealed  pro-  showed  formula  for  a  68  122.  C a r e f u l examination  indicated  o f both  that deuterium  t h e NMR  and mass  spectra  i n c o r p o r a t i o n had o c c u r r e d  t o the  e x t e n t o f 95 ± 5%. Deuteration then  carried  furan  proton tion  out using  a t 0°C.  reaction  of 2,3-dimethylisoxazolin-5-one lithium diisopropylamide  I n v e s t i g a t i o n o f t h e NMR  mixture  singlet  again  revealed  a t 6 2.16 w i t h  in intensity  o f the v i n y l  t h e r m o r e , t h e low r e s o l u t i o n indicated  that starting  be  was  equivalent.  which c o u l d serve The  most l i k e l y  would  regenerate  o f 1:2:1.  Furproduct  candidate  compound  as a m e t h y l  c a p a c i t y was in this  cleavage  the parent  The  failure  s i n c e t h i s meant t h a t i t would  The u s e o f a d i f f e r e n t  in this  that ring  reduc-  i n c o r p o r a t i o n a t the d e s i r e d  was  (125),  accompanied  B-keto e s t e r 6  acetoacetate  isoxazolin-5-one  therefore  regard  dimethy1-4-carboethoxyisoxazolin-5-one anticipated  was a l s o e v i d e n t .  i n the r a t i o  a serious setback,  i m p r a c t i c a l t o use t h i s  dianion  however,a  mass s p e c t r u m o f t h e c r u d e  112 t o u n d e r g o c l e a n d e u t e r i u m  y-carbon  signal,  o f the t h r e e -  m a t e r i a l , as w e l l as mono- and d i d e u -  t e r i o p r o d u c t s were p r e s e n t , of  proton  in tetrahydro-  spectrum o f the crude  the replacement  a broad  (112) was  considered.  found  t o be 2,3-  s i n c e i t was  by d e c a r b o x y l a t i o n (equation  32).  The  (32)  COOEt  6  synthesis  o f 125 was a c c o m p l i s h e d  i n two s t e p s a c c o r d i n g t o  e q u a t i o n 33.  1)Mg, EtOH  0  MeNHOH-HCL OEt Pyridine  H C(C00Et) 2 2) CH3COCI 2  COOEt 125  124  123 Acylation  (33)  o f d i e t h y l malonate  (123) w i t h  acetyl  chloride 74  according  t o the procedure  d e s c r i b e d by T a r b e l l  gave d i e t h y l a c e t y l m a l o n a t e (124) i n 84% y i e l64c d. e s t i n g t o n o t e t h a t t h e s e w o r k e r s and o t h e r s the y i e l d  in this  high y i e l d  reaction  in this  and  spectral  for  this  data  case agree  t o be 53-55%.  those  I t i s interhave r e p o r t e d  The r e a s o n  i s n o t known, a l t h o u g h with  and P r i c e  for  the  a l l physical  reported i n the l i t e r a t u r e  74 compound  The  condensation  of diethyl  acetylmalonate  N-methylhydroxylamine h y d r o c h l o r i d e desired apparent glets  product from  125 i n 72% y i e l d  i t s NMR  spectrum  7 5  (111) i n p y r i d i n e  .  The s t r u c t u r e  which  showed  quartet-triplet  combination  b o e t h o x y g r o u p a t 6 4.25 and 6 1.32. spectrum  gave t h e  o f 125 was  three-proton  a t 6 2.51 (C-4 m e t h y l ) and 6 3.61 ( N - m e t h y l ) ,  the c h a r a c t e r i s t i c  red  (124) w i t h  sin-  as w e l l as  due t o t h e c a r -  In a d d i t i o n ,  the i n f r a -  o f t h e p r o d u c t d i s p l a y e d a b s o r p t i o n s a t 1750 and  70  1695  cm  a s s i g n a b l e t o t h e e s t e r and  1  stretching  the p r e p a r a t i o n o f  the d e g r e e o f a n i o n  125  g e n e r a t i o n was  however, t h a t the p r e s e n c e  i n hand, an examined.  of a carboethoxy  the y  carbon  more a c i d i c  Accordingly,  i t was  found  hydride  than  i o d i d e gave  g r o u p a t C-4  of  125  i n 85%  yield.  of  clear,  isoxazolin-5-one  that treatment  126  investigation I t was  in tetrahydrofuran-dimethyl sulfoxide  by m e t h y l  C=0  vibrations.  With  render  isoxazolin-5-one  with  would  114. sodium  a t 0°C,  Confirmation  followed that  1) NaH, THF-DMSO ^ Mel  alkylation from  the NMR  proton both C-3  spectrum  of  6 2.95  evidence  resolution  f o r the  and  the  facile  m/e  and  a three-proton  base, demonstrated  starting  of  of  that having  an  the  secured  126  was  at  6  two1.29,  characteristic  m a t e r i a l had  the p r o d u c t  125,  was  triplet  while  by e l e m e n t a l  alkylation  carbon  w h i c h e x h i b i t e d a new  formulation of  mass s p e c t r u m  peak a t 199 The  the p r o d u c t  c o u p l i n g c o n s t a n t s J = 6 Hz,  methyl a b s o r p t i o n of  parent  the  a t the d e s i r e d y  occurred  quartet at  with  Further low  had  disappeared.  provided  which  showed  by a  analysis.  using  sodium h y d r i d e  electron-withdrawing  as  the  71  g r o u p a t C-4 d o e s expected. ceeded  indeed  For t h i s  render  reason  i n good y i e l d ,  and b e c a u s e  e q u i v a l e n t appeared  earlier  problem with  lent  o u t by f i r s t  diisopropylamide oxide.  solution  t o the  resolution  mass s p e c t r u m o f t h e p r o d u c t  had  occurred  t o the e x t e n t  then  C a r e f u l examination  o f the  showed d e u t e r a t i o n  o f 95 ± 5%.  the i n c o r p o r a t i o n s t u d i e s now  o f the a l k y l a t i o n  equiva-  in tetrahydrofuran,  low  c o m p l e t e , an i n v e s -  of isoxazolin-5-one  with  electrophiles  chosen  f o r a l l s u b s e q u e n t work s i n c e i t was a n t i c i p a t e d chemistry  analogously. philes  could  initiated.  anions  simple  similar  was  acetoacetate  u s i n g one  deuterium  tigation  pro-  112.  quenching with  With  (equation  For t h i s purpose,  be p e r f o r m e d on t h e o t h e r  The r e s u l t s  as  2-methyl-3,4-tetramethyleneisoxa-  (113) was c a r r i e d  of lithium  the a l k y l a t i o n  t o be a p r a c t i c a l  isoxazolin-5-one  deuteration of  zolin-5-one  more a c i d i c  t h e use o f 125 as a m e t h y l  dianion  The  the y carbon  of this  34) a r e p r e s e n t e d  study  with  that  systems  carbon  i n Table V I I .  114 was  electro-  72  Table V I I .  A l k y l a t i o n of 2,3,4-Trimethylisoxazolin-5-one With Simple Electrophiles  V s  1)LDA,THF,0C 0  2)  N  0  RX  Compound Identification  R-X  127a  Mel  81  127b  EtI  67  127c  n-BuBr  80  127d  CH =CHCH Br  75  127e  (CH ) C=CHCH Br  75  127f  C H CH C1  52  a)  Yield  2  Yield of isolated  3  2  2  6  2  5  2  products.  (%)  (114)  73  0  0  1) LDAJHF, 0*C ^ R 0 2) RX  0  127  1U  The  alkylation  proceeded yield.  of  smoothly  o f 114 w i t h  simple  carbon  to g i v e the p r o d u c t s  from  their  NMR  i n the s t a r t i n g  the absence  a t 6 2.10, c h a r a c t e r i s t i c material.  ions i n their  Furthermore,  exhibited  parent  elemental  a n a l y s e s , w h i c h were c o n s i s t e n t  The  t o good  particularly  s p e c t r a w h i c h a l l showed  the t h r e e - p r o t o n s i n g l e t  C-3 m e t h y l  electrophiles  127 i n f a i r  The s t r u c t u r e s o f t h e s e p r o d u c t s were  apparent  (34)  ;  low r e s o l u t i o n  mass  with  formulae.  to a l d o l  lithium  d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n a t 0 ° C , f o l l o w e d by  N  0  the p r o d u c t  128  Treatment  and  condensations  gave  studied.  s p e c t r a , and  Claisen  benzaldehyde  was a l s o  a l l products  their  extension of isoxazolin-5-one chemistry  o f the  i n 71% y i e l d .  o f 114 w i t h  This  HO  product  0 0  114  128  74  was  found  analysis  t o be of  the  the p r o p o s e d  homogeneous by  TLC  recrystallized  m a t e r i a l was  formulation.  mass s p e c t r o s c o p y , adduct  indicated  of benzaldehyde  infrared  spectrum  3435, 1733  and  The  of  1640  and  molecular  and  an  128  d i s p l a y e d a d o u b l e t a t 6 2.82  at and  isoxazolin-5-one ring.  the y c a r b o n , a singlet The  aldehydes ing  attempted and  o f 114  One  Finally, due  condensation  not  to  while  the  o f an  3625, alcohol  spectrum  of  protons  the p r e s e n c e  with  aliphatic  For example,  gave  the  proton  protons.  o f 114  identified  by  one  t o the b e n z y l i c  successful.  readily  indicated  product  due  t o the a r o m a t i c  w h i l e mass s p e c t r o s c o p i c a n a l y s i s o f by p r e p a r a t i v e TLC  a one  the NMR  with  determined  t o the a l l y l i c  with cyclohexanone  s p o t was  weight,  the p r e s e n c e  condensation  was  i n agreement  showed a b s o r p t i o n s a t  a t 6 4.92  due  aldol  ketones  the anion  analysis.  a triplet  a t 6 7.29  elemental  i s o x a z o l i n - 5 - o n e 114,  indicating  1  and  the p r o d u c t was  the p r o d u c t cm  analysis,  two  s p o t s by  as s t a r t i n g  second of  the  treat-  spot  TLC  material,  isolated  cyclohexanone  129.  129  75  The material  presence 114  that proton one  and  a n i o n was  of  129  from  with  Aldol  i t s e l f would  of proton  isoxazolin-5-ones with  represents a l i m i t a t i o n  cussed one  above r e a c t i o n t o the  condensation  suggested  isoxazolin-5-  of  the a n i o n  t h e r e f o r e account  transfer  of  for formation  i n the use  d u r i n g an e x a m i n a t i o n  The  ability  128  may  be  i n the a l d o l  aliphatic  Possible solutions  anions with unusual  duct  i n the  starting  129.  problem  equivalents.  amounts o f b o t h  cyclohexanone  occurring.  the p r o d u c t The  product  transfer  cyclohexanone of  of s i g n i f i c a n t  aldehydes of  these  to prepare  contrasted with  (pg  purify  ketones  reagents  o f the r e a c t i o n  and  and  to t h i s problem  electrophiles  condensation  of  as d i a n i o n  will  be  dis-  isoxazolin-5-  80).  the a r o m a t i c  aldol  pro-  the o b s e r v a t i o n t h a t many 35  B-keto e s t e r  aromatic  For e x a m p l e ,  i n the a t t e m p t e d  130,  a l d o l products  t h r e e p r o d u c t s were  are  distillation  identified  by VPC  components were O - m e t h o x y a c e t o p h e n o n e of may  4-(2-methoxyphenyl)-pent-3-en-2-one be c o n s i d e r e d  to a r i s e  decarboxymethylation  thermally unstable of  analysis.  (131)  and  (132).  via a retro-aldol  process  respectively.  B-keto e s t e r  the These  and  The two  three isomers  products  a dehydration-  76  This e a r l i e r  work had a l s o shown t h a t d e h y d r a t i o n o f c r u d e  130 w i t h a n h y d r o u s h y d r o g e n gave  the u n s a t u r a t e d  the NMR cal  spectrum  shifts  chloride  keto e s t e r  o f the p r o d u c t  o f the v i n y l  protons  133.  in chloroform Careful  examination  and c o m p a r i s o n i n other  smoothly  with  styrenes  of  the chemi-  indicated 35  that  t h e isomer In  the p r e s e n t s t u d y ,  best dehydrated equation  r a t i o o f t h e p r o d u c t was  35.  the a r o m a t i c  2.3:1, E:Z aldol  u s i n g t h e two s t e p p r o c e d u r e  First,  product  128 was  outlined in  the a l c o h o l was c o n v e r t e d  into i t s  CH Cl ,A 2  Y  0  N  135  2  77  corresponding  mesylate  134  in quantitative  yield  by the p r o -  76 cedure was  o f C r o s s l a n d and S e r v i s  then  accomplished  .  by r e f l u x i n g  [1. 3 . (Tj non-5-ene , DBN,  Loss  of methanesulfonic  acid  134 w i t h 1 , 5 - d i a z a b i c y c l o -  (136) i n d i c h l o r o m e thane .  By  this  136 method,  the r e s u l t i n g  styrene  135 was  The s t r u c t u r e o f 135 was trum w h i c h  showed  stretching  vibration  In a d d i t i o n , spectrum posed  both  a t 1370 cm  the m o l e c u l a r  and e l e m e n t a l  6 1.98  1  i t s infrared  specS-0  i n the s t a r t i n g m a t e r i a l . w e i g h t d e r i v e d from  t h e mass  a n a l y s i s were c o n s i s t e n t w i t h  appeared  field  (100 MHz)  the p r o -  protons.  as an AB q u a r t e t w i t h of t h i s  The  two v i n y l  i t was  m e t r y 135  77  .  The f o r m a t i o n  assigned  . of a single  singlets  protons  J = 16 Hz.  apparent  135 c o n s i s t e d o f o n l y one g e o m e t r i c a l  the c o u p l i n g c o n s t a n t was  spec-  a t 6 7.36-7.66  a coupling constant  spectrum  NMR  three-proton  as w e l l as a m u l t i p l e t  t o the a r o m a t i c  the i n t e g r a t i o n  product  o f the h i g h  r e v e a l e d the expected  and 6 3.24,  corresponding  from  yield.  formulation.  trum o f t h e p r o d u c t  From  e v i d e n t from  i n 95%  the l o s s o f the c h a r a c t e r i s t i c mesylate  C a r e f u l examination  at  obtained  isomer,  t h a t the which  the t r a n s or E - g e o . isomer  . in this  reaction  78  JO  0  135  probably ring  r e f l e c t s the s t e r i c  and the h e t e r o c y c l i c  elimination. projections OMs.  This  ring  between  t h e benzene  i n the t r a n s i t i o n s t a t e f o r  be i l l u s t r a t e d  134a and 134b  The gauche  destabilizes  may  repulsion  by c o n s i d e r i n g  f o r the t r a n s  elimination  Newman o f H and  i n t e r a c t i o n between C^Hj. and H e t i n 134b  H  H  OMs 134a  OMs 134b  t h i s c o n f o r m a t i o n and t h e r e f o r e e l i m i n a t i o n  pro-  c e e d s v i a 134a t o g i v e t h e o b s e r v e d E - i s o m e r . An  i n v e s t i g a t i o n o f the C l a i s e n condensation o f i s o x a -  z o l i n - 5 - o n e a n i o n s was n e x t a t t e m p t e d by t r e a t i n g o f 114 w i t h m e t h y l b e n z o a t e  the anion  ( e q u a t i o n 3 6 ) . The s t r u c t u r e o f  79  0  1) L D A . T H F , 0°C  0  2)  C H COOMe 6  c H  5  6  0 (36)  0  5  137 137 was c l e a r  from  p l e t of signals and  a two-proton  i t s NMR  from  spectrum  5 7.47-8.06  singlet  a t 6 4.21, w h i c h  p r o t o n s a t the y c a r b o n .  tion  s p e c t r a were c o n s i s t e n t  and at  the i n f r a r e d 1700  spectrum  was  a s s i g n e d t o the  The low and h i g h with the proposed  displayed  a new  resolustructure  carbonyl absorption  - 1  benzoyl c h l o r i d e  t o p r e p a r e 137 by t h e a c y l a t i o n (138) p r o v e d  N,N-diisopropylbenzamide acylation  tion  multi-  cm .  An a t t e m p t  by  showed a b r o a d  due t o t h e a r o m a t i c p r o t o n s ,  methylene mass  which  37).  (139).  o f the c o n j u g a t e  The C l a i s e n  t o be f u t i l e  o f 114 w i t h  and i n s t e a d  This product c l e a r l y  acid  o f the amide base  6  138  arises (equa-  c o n d e n s a t i o n s o f 114 w i t h a l i p h a t i c  C H CON:  •  gave  5  139  acid  (37)  80  chlorides proton  and e s t e r s were a l s o u n s u c c e s s f u l .  transfer  was a g a i n stantial The  hampering  next  The  esters  the s u c c e s s o f t h i s  be c l a s s i f i e d 38).  as r e a c t i o n s  t o the anion  reaction,  were  facet of isoxazolin-5-one  (equation  in Table  the a l i p h a t i c  amounts o f s t a r t i n g m a t e r i a l  examined may philes  from  I t appeared  since  that  o f 114 sub-  recovered.  c h e m i s t r y which  was  with unusual e l e c t r o -  The r e s u l t s o f t h i s  s t u d y a r e summarized  VIII.  bromination  o f B-keto e s t e r  dianions  has been  found  78 to y i e l d  a plethora  of products  anion  o f 114 w i t h  5-one  140a i n 41% y i e l d .  on  the b a s i s  singlet  bromine  o f i t s NMR  .  However, t r e a t i n g t h e  a t -78°C gave  t h e y-bromo i s o x a z o l i n -  The s t r u c t u r e  o f 140a was  spectrum which d i s p l a y e d  a t 6 4.08 due t o t h e y m e t h y l e n e p r o t o n s .  established  a two-proton Additional  81  Table V I I I .  Reaction of 2,3,4-Trimethylisoxazolin-5-one (114) W i t h U n u s u a l Electrophiles  > — ?  1) LP A, THF, 0°C  A^y^o  2)  ^ — 0  EX  E  m  HA Compound Identification  E  X  140a  Br  Br  a)  a  140b  C  140c  (CH ) Si  140d  6 5 H  S e  3  C  6 5 H  C  S  S C  CH OOCCH  140f  BrCH CH CH  3  0  1  Yield 41 6  Cl  3  140e  Y i e l d of i s o l a t e d  \A^Y^O  2  0  products.  9  6 5 H  1  64 7  1  Br  58  Br  16  (%)  82  support high  f o r the  resolution One  of  140a  was  provided  this  by  both  low  and  mass m e a s u r e m e n t s .  s t r a t e g y i n the p r e p a r a t i o n o f  to convert use  formation  compound  as a W i t t i g  reagent  into  79  bromide  i t s phosphonium s a l t  The  • (CH)P 6  the  5  condensation  of  140a  was  141,  141  for  with  Br (C H ) R  — >  6  5  3  UOQ aliphatic  aldehydes  the u n s a t u r a t e d pared  v i a an  and  isoxazolin-5-ones  aldol  condensation  (C H LP 6  ketones would  0  5  then,  142  in turn,  provide  which c o u l d not  r o u t e , as d i s c u s s e d  pre-  earlier.  0  R  1) Base 2) RCOR'  be  1AZ  The  feasibility  somewhat i m p a i r e d bromination first  step  ation  of  of  the  the a n i o n  i n the  140a  by  of  was  this  p l a n , however, a p p e a r e d  r a t h e r poor o f 114.  scheme, an considered.  yield  Since  alternate  obtained  t h i s was  to in  only  pathway f o r t h e  be the  the prepar-  83  It are  has  long  been  s u s c e p t i b l e to f r e e r a d i c a l  3-methyl.thiophene refluxing of  known t h a t a l l y l i c  carbon  benzoyl  (143)  and  benzylic positions  halogenations.  reacts with  For  example,  N-bromosuccinimide  tetrachloride containing a catalytic  peroxide  to give  3-bromomethylthiophene  in amount  (144)  in  38 70-80% y i e l d  .  I t t h e r e f o r e seemed  likely  that  similar  CH Br 2  1AA  1A3 chemistry  m i g h t be  Treatment of and  a catalytic  tetrachloride  performed 114  with  on  one  isoxazolin-5-ones. e q u i v a l e n t of  amount o f b e n z o y l  gave  140a  i n 76%  N-Br  peroxide  yield.  6  5  CCL,  in refluxing  The  (C H C0-0-)  N-bromosuccinimide  crude r e a c t i o n  ^N  was  0  2  0  A 1A0a  11A product  carbon  then  dissolved in tetrahydrofuran  triphenylphosphine.  Almost  solid  Filtration  precipitated.  immediately o f the  and  treated  a flocculent, solid,  followed  with  white by  recrystallization colourless  from  crystals,  ether-methanol  mp  245-246°,in  •  (C H LP  gave 69%  141  as  overall  small,  yield  from  114.  0 Br  0  6  5  0 141  140a The which  s t r u c t u r e of  showed a d o u b l e t  protons, with coupling with  141  was  e v i d e n t from  a t 6 5.40,  assigned  a large coupling constant 3 1  P.  In a d d i t i o n ,  i t s NMR  spectrum  t o the  y methylene  J = 16 Hz  the C-4  methyl  due'to  at  6 1.18  was 77  also s p l i t Further mental  by p h o s p h o r u s w i t h  proof  Wittig  investigated earlier with  dimethyl 135  one  reaction  in order  work on  aldol  141  was  provided  o f 14_1 w i t h ben za l d e h y d e  to provide  some c o r r e l a t i o n  condensations.  Therefore,  e q u i v a l e n t of sodium h y d r i d e  sulfoxide,  i n 58%  Br'  f o r m u l a t i o n of  Hz  by  ele-  analysis.  The  141  f o r the  a coupling constant J = 3  yield.  N  f o l l o w e d by The  0  product  addition obtained  6  141  5  first  with  the  treatment  of  in tetrahydrofuranof benzaldehyde  in this  CgH  fashion  5  gave was  V N  P N a H , THF-DMSiD 2)C H CH0,A  was  0  135  identical  i n a l l r e s p e c t s t o the compound  In p a r t i c u l a r firmed  t h e NMR  spectrum  the p r e f e r e n t i a l  To d e m o n s t r a t e  the W i t t i g  aldehydes,  the  reaction was  could also  to a l i p h a t i c  hydride  in tetrahydrofuran-dimethyl sulfoxide, P r e p a r a t i v e TLC  141  o f the c r u d e  the u n s a t u r a t e d i s o x a z o l i n - 5 - o n e 145  con-  E-isomer.  applied  hexanal.  earlier.  o f the p r o d u c t once a g a i n  f o r m a t i o n of  that  prepared  treated  with  sodium  f o l l o w e d by  reaction  i n 64%  be  mixture  gave  yield.  145  141 The m/e  product  i n the  resolution revealed  low  resolution  the e x p e c t e d  singlets  NMR  data  the  reaction,  that  f o r both  suggests  isomer  acetone  that  mass s p e c t r u m The  NMR  protons  both double of  3:1.  o f 141  as w e l l  spectrum  ion at  as by  209  a high  o f the  product  a t 6 5.88-6.48 as w e l l  bond  C-methyl s i g n a l s . isomers  on  are  with a l i p h a t i c  likely  grounds.  ketones  was  with both cyclohexanone  in only recovered s t a r t i n g  in  clear  i t appears  steric  as The  formed  i t i s not  reaction,  should again p r e v a i l  reaction  a parent  Although  in this  however c o n d e n s a t i o n s  resulted  by  the N - m e t h y l and  predominates  Wittig  attempted,  characterized  vinyl  in a ratio  the E - i s o m e r The  was  mass measurement.  two  which  145  material.  and  Since  86  aldehydes reacted with possibly  141 o n l y  the use o f a h i g h e r  appropriate  t o condensations  in refluxing  boiling  tetrahydrofuran,  s o l v e n t may be more  involving  ketones.  The p r e p a r a t i o n o f compounds 140b and 140d was n e x t e x a m i n e d f o r two r e a s o n s . analogous r e a c t i o n s with  F i r s t , e a r l i e r work h a d shown t h e B-keto ester dianions  t o be  diffi-  78 cult  .  Secondly,  t h e use o f t h e p h e n y l t h i o and 80  groups as h a n d l e s f o r the f o r m a t i o n tained.  of o l e f i n s  This strategy i s outlined i n equation  E= C H S 6  phenylseleno was e n t e r -  39.  Therefore,  or  5  C H Se 6  alkylation followed  5  o f compounds 140b o r 140d w i t h an a l k y l h a l i d e ,  by o x i d a t i o n t o t h e c o r r e s p o n d i n g  selenoxide  and e l i m i n a t i o n would g i v e  s u l f o x i d e or  the d e s i r e d  unsaturated  isoxazolin-5-ones. The p r e p a r a t i o n o f 140b and 140d was a c h i e v e d alkylation disulfide  o f 114 w i t h p h e n y l s e l e n e n y l respectively.  by t h e  c h l o r i d e and d i p h e n y l  The s t r u c t u r e o f t h e p r o d u c t s  thus  o b t a i n e d was  secured  from  a two-proton  singlet  a t 6 3.66  140d,  w h i c h was  assigned  more, the m o l e c u l a r resolution  with  strated  t h a t these  anion  of  The synthesis  Y  - I T i e  and  thylene  the e l e m e n t a l these  at  be  both  the  for Further high  a n a l y s e s were  readily  by e q u a t i o n  <5 3.78  protons.  structures.  r e a c t s smoothly with  Having prepared  carbon  con-  demonand  that  electrophiles,  39  are p o t e n t i a l  routes  the e x t e n s i v e  investigation  of  isoxazolin-5-ones.  reasoning of  f o r 140b  compounds may  the pathways r e p r e s e n t e d to u n s a t u r a t e d  s p e c t r a which d i s p l a y e d  f o r m u l a t i o n d e r i v e d from  assignment of  114  NMR  t o the  mass s p e c t r a and  sistent  the  their  these  behind  unsaturated  i s o x a z o l i n - 5 - o n e s was  the  based  81 upon  the e a r l i e r  study, ethyl  w o r k e r s were a b l e  3-oxo-4-pentenoate  cess.  In p a r t i c u l a r ,  vinyl  k e t o n e had  latter tion  these  work o f N a z a r o v and  the  146,  .  to demonstrate i n a Robinson  reaction  known as  the  In  their  utility  annelation  o f an e n o l a t e w i t h  been c o n s i d e r a b l y i m p r o v e d  component w i t h  40) .  (146)  Zavyalow  by  of  pro-  methyl  replacing  the N a z a r o v r e a g e n t  the (equa  88  0  0 -OEt  0  0 OEt  +  (40)  COOEt  Wider  application  of both  146  3 - o x o - 4 - p e n t e n o a t e s h a s , however, their 146,  limited  accessibility.  f o r example,  (Scheme  8)  81  and s u b s t i t u t e d been g r e a t l y  The c l a s s i c a l  proceeded i n only  Several  7-9%  ethyl  hampered  synthesis  by  of  overall yield  a p p r o a c h e s have been d e s c r i b e d  for  89  Scheme 8:  C l a s s i c a l p r e p a r a t i o n of Nazarov reagent  146  90  the  preparation  of  14 6 and  substituted derivatives thereof, 82  but  a l l s u f f e r from a l a c k of g e n e r a l i t y  t o the was  synthesis of unsaturated  hoped  vide  the  that ring  cleavage  d e s i r e d Nazarov  .  T h i s problem  isoxazolin-5-ones,  of  these  reagents  since i t  d e r i v a t i v e s would  (equation  led  pro-  41).  (41)  OEt  During  the  the  synthesis  the  literature.  the  preparation  lined  of  course  this  The  key  feature  two  i n these  of a Y " " P h ° P h Y l s  42  go  and  new  o r  43  g  4  .  a t e c  F F  )Et 2) (EtO) P(0)"Na  have a p p e a r e d  in  involves  Wittig-type  0  +  to  B-keto e s t e r , as  3  The  NQH  approaches  studies  0 U  Br,  research,  s u b s t i t u t e d Nazarov reagents  in equations  0  of  [J  M 1  0  0 Br  H 0*  (C H ) POEt Et  0 (42)  3  6  N  condensation  Et  2  2  3)  out-  5  2  147  (C6H)  (43)  5  148  91  of  147  has  or  148  w i t h a r o m a t i c and  been f o u n d  the r e a c t i o n  to proceed  o f 148  with  aliphatic  aldehydes  i n v e r y good y i e l d s . two  For  e q u i v a l e n t s o f sodium  tetrahydrofuran-hexamethylphosphoramide,  and  ketones  example, hydride in  f o l l o w e d by  cyclo-  84 hexanone gave  ,„  L l  , §  149  ?  i n 85%  f  yield  1)2NaH,THF-HMPA  j}  [ l .  149  148  N e x t an  investigation  trimethylsilane stemmed f r o m  was  o f the r e a c t i o n  undertaken.  anticipation  the O - a l k y l a t e d compound  that 150  The  based  on  o f 114  interest  (equation 44).  with  in this  the p r o d u c t formed  chloroprocess  might  be  This expectation  150  114 was  H  the knowledge  t h a t upon q u e n c h i n g  enolate with c h l o r o t r i m e t h y l s i l a n e ,  O-silylated  a  ketone products  are  38 formed  exclusively  (equation 45).  The  O-silylated  5  product  92  150 m i g h t  then  react with various e l e c t r o p h i l e s CO  CfZ  sence tion  of Lewis a c i d s  to give products  lithium  treatment  140  (equa-  o f 114 w i t h one e q u i v a l e n t o f  d i i s o p r o p y l a m i d e i n t e t r a h y d r o f u r a n , f o l l o w e d by  chlorotrimethylsilane  gave a s i n g l e  The  p r o d u c t was a p p a r e n t  structure  of this  trum w h i c h showed s i n g l e t s (3H, C = C - C H ) , 6 2.09 3  compound  140c was  product  150.  formed  product  a t 6 0.31  (2H, C H S i ) ,  a b s e n c e o f any v i n y l  ated  o f type  46) .  Accordingly,  an  i n the p r e -  from 3  Clearly,  in preference  Further evidence  analysis.  i t s NMR  spec-  (9H, ( C H ) S i ) , 6 1.89  and 6 3.32  2  protons.  by TLC  3  (3H, N-CH ) and 3  the C - s i l y l a t e d  t o the d e s i r e d  0-silyl-  f o r the formation o f  93  compound vibration  tion  140c  was  i n the  provided infrared  The  possibility  but  was  hydrolyzed  workup and  vinyl  protons The  not  an NMR was  reason  1253  cm  was  during the  strong C-Si s t r e t c h i n g  indeed  formed  workup was  crude  spectrum  ^.  no  However,  evaporated  evidence  for exclusive C - s i l y l a t i o n however  in preparing  this  for  with-  any  unsaturated  olefination  route  in this  reaction is  compound d o e s appear isoxazolin-5-ones  85 Peterson  reac-  considered.  r e a c t i o n was  taken,  i n the  found.  w e l l understood,  potential  at  the  t h a t 150  when a s m a l l amount o f out  by  (equation  47).  by  t o have a  94  The  final  with unusual reaction of  a s p e c t o f the r e a c t i o n  of i s o x a z o l i n - 5 - o n e s  e l e c t r o p h i l e s w h i c h was i n v e s t i g a t e d  o f 114 w i t h d i f u n c t i o n a l  electrophiles.  the d i a n i o n o f methyl a c e t o a c e t a t e with methyl  had  earlier  (equation  0  been f o u n d  48).  to y i e l d  The a l k y l a t i o n  a complex m i x t u r e o f the a n i o n  i n v o l v e d the The  reaction  bromoacetate 7 of products  o f 114 w i t h  methyl  0 * BrCHUCOOMe  Me  b r o m o a c e t a t e was f o u n d uncontaminated  Mixture of (48) Products  L  to give  t h e e s t e r 140e i n 58% y i e l d ,  by any a c y l a t e d p r o d u c t s .  1) LDA, THF 2) BrCH C00Me  0  The s t r u c t u r e o f  >  2  M  e  0  0  C  KOe 140e  was e v i d e n t f r o m  proton and  singlet  i t s NMR  a t 6 3.74 a s s i g n e d  a four-proton multiplet  methylene p r o t o n s . provided  spectrum  by b o t h  which  showed a t h r e e -  t o the c a r b o m e t h o x y  protons  a t 6 2.50-2.92 due t o t h e a d j a c e n t  Further evidence  low and h i g h  f o r formula  resolution  140e was  mass m e a s u r e m e n t s .  The  alkylation  studied.  o f 114 w i t h  1 , 3 - d i b r o m o p r o p a n e was a l s o  P r e p a r a t i v e TLC o f t h e c r u d e  the d e s i r e d b r o m i d e  1 4 0 f , however,  r e a c t i o n mixture  i n only  gave  16% y i e l d .  1) LDA, T H F :Q  Confirmation  2) B r ( C H ) B r 2  f o r the formation  low  resolution  249  and 247 m/e, and f r o m  triplet  B r  .  o f 140f was o b t a i n e d  mass s p e c t r u m w h i c h e x h i b i t e d p a r e n t  a t 6 3.46  2  attempt  i t s NMR  (2H, C E ^ B r ) ,  C H - H e t ) , and a m u l t i p l e t An  >  3  to prepare  spectrum which  another  a t 6 1.6-2.1  triplet  a cyclobutane  2  ring  by one e q u i v a l e n t o f 1 , 3 - d i b r o m o p r o p a n e  A ^ A ^ O  two e q u i v a l e n t s o f l i t h i u m  2  was made by  followed  0 I  showed a  (4H, CH CH" ) .  114 w i t h  T  ions a t  a t 6 2.51 (2H,  treating  N  from i t s  diisopropylamide, ( e q u a t i o n 49)  D 2LDA,THF  (49)  2) B r t C H ^ B r *  1U  TLC  a n a l y s i s o f the crude  w h i c h were s u b s e q u e n t l y a l k e n e 127d.  r e a c t i o n mixture  identified  disclosed  as t h e b r o m i d e  two s p o t s  140f and t h e  96  1)2LDA,THF^ 0 2) BKCH )^Br  KOf  2  127d  IH  H a v i n g e x a m i n e d t h e r e a c t i o n o f 114 w i t h some u n u s u a l electrophiles, be  studied.  there  r e m a i n e d o n l y one o t h e r  Results secured  earlier  functionality to  i n our l a b o r a t o r y  shown t h a t t h e r e a c t i o n o f B - k e t o e s t e r d i a n i o n s w i t h proceeded smoothly t o give a l c o h o l s . TT_ w i t h p r o p y l e n e  the d i a n i o n 152  e x c l u s i v e l y (equation  0  0  Me  50).  the c y c l i c  0  treating  However, t h e B k e t o e s t e r _  0  0  OMe OH  a l c o h o l s were f o u n d t o be v e r y  epoxides  gave t h e s e c o n d a r y a l c o h o l  • A/  27  (equation  oxide  In p a r t i c u l a r ,  had  5 1  152  s e n s i t i v e t o a c i d and a f f o r d e d  f u r y l i d e n e s , e.g. 153, under m i l d a c i d c o n d i t i o n s 51)  51  The  u s e o f an i s o x a z o l i n - 5 - o n e  ring to  0  CHCOOMe  152  153  (51)  (50)  97  prevent tion  such  c y c l i z a t i o n was  o f 114 w i t h e p o x i d e s Treatment  the  alcohol  obvious,  was  and t h e r e f o r e  the a l k y l a -  examined.  o f t h e a n i o n o f 114 w i t h e t h y l e n e o x i d e  154  i n 30% y i e l d .  The s t r u c t u r e  o f 154  gave  was  1) L D A , T H F  A  2)  154  IH apparent  from  stretching  i t s infrared  vibration  mass s p e c t r a l  spectrum  a t 3400 c m . - 1  which d i s p l a y e d Furthermore,  a n a l y s e s were c o n s i s t e n t  with  an  0-H  b o t h NMR  and  the a s s i g n e d  structure. A similar alcohol  reaction  155, t h i s  o f 114 w i t h p r o p y l e n e  time  i n 41% y i e l d .  o x i d e gave t h e  The a l c o h o l  155 was  0  ULDAJHF, 0  A/  2)  OH  characterized spectrum.  by an O-H  In a d d i t i o n ,  secured  from  t h e NMR  doublet  a t 6 1.40  due  again  stretching  vibration  15& in i t s infrared  the d i r e c t i o n o f epoxide  spectrum  opening  was  o f t h e p r o d u c t , w h i c h showed a  t o the t e r m i n a l  methyl  o f the s i d e  chain  This concluded  the s t u d y  o f the c h e m i s t r y  isoxazolin-5-ones  and c o n s i d e r a t i o n was now  cleavage  heterocyclic  o f these  One o f t h e e a r l i e s t tuted  o f the anion o f  given  rings.  s t u d i e s o f the c l e a v a g e  isoxazolin-5-ones,was  t o the  r e p o r t e d by U l r i c h  of N-substi-  et a l . in  75a 1962  .  In t h i s work  i t was  N-methylisoxazolin-5-ones opening added  in dilute  base.  acetamide  t h a t C-3 u n s u b s t i t u t e d  undergo a remarkably  facile  F o r e x a m p l e , when compound  t o 5% s o d i u m h y d r o x i d e  immediate e x o t h e r m i c  found  reaction  (157) was o b t a i n e d  ring  156 was  or aqueous s o d i u m c a r b o n a t e ,  an  o c c u r r e d and c a r b o e t h o x y m e t h y l 75a i n 54% y i e l d . The key e l e m e n t  0  COOEt  15Z  156  of  this  tion  reaction  i s the a v a i l a b i l i t y  o f the h e t e r o c y c l e .  of a proton  F o r example,  a t the 3-posi  treatment  o f 2,3-  dimethyl-4-carboethoxyisoxazolin-5-one  (125) w i t h  hydroxide  starting  fifteen left  solution  minutes.  gave o n l y r e c o v e r e d In a d d i t i o n ,  5% s o d i u m  material after  i f the r e a c t i o n  mixture  was  overnight, only ester h y d r o l y s i s occurred  to give  2,3-  dimethyl-4-carboxyisoxazolin-5-one  (158)^  5 a  .  99  N  0  0  NaOH,HCL 2  0 COOEt 158  125  The  o b s e r v a t i o n t h a t C-3 u n s u b s t i t u t e d N - m e t h y l i s o x a z o l i n -  5-ones a r e r e a d i l y  h y d r o l y z e d by a l k a l i n e  s o l u t i o n s was  also  86 made by De S a r l o  and R e n z i  .  In t h e i r  w o r k e r s were a b l e  t o demonstrate  a l s o undergo r i n g  opening  sodium h y d r o x i d e  with  that  s t u d y , however,  these  3 - s u b s t i t u t e d compounds  on p r o l o n g e d  heating with  the formation o f ketones  dilute  (equation 52).  (52)  Since  a l l isoxazolin-5-ones prepared  substituted, used  i t was c l e a r  to regenerate The  procedure  cleavage  that  in this  t h e s i s were C-3  base h y d r o l y s i s  the B-keto e s t e r s  c o u l d n o t be  or t h e i r e q u i v a l e n t s .  of N-methylisoxazolin-5-ones  by a d i f f e r e n t  has a l s o been r e p o r t e d by De S a r l o e t a l . * ' . 5  In  100  this  study,  t h e s e w o r k e r s showed  N-methylisoxazolin-5-ones nickel  as c a t a l y s t  involves  the  of carbon  i n anhydrous a l c o h o l with  gave s e c o n d a r y  a b s o r p t i o n o f two  dioxide  the h y d r o g e n a t i o n  amines.  This  In a d d i t i o n ,  Raney  reaction  moles of hydrogen  (equation 53).  of  and  the  when  loss  the  Me  "NjJ R  that  0  I,  H -CO-  •  2  R  R  R 159  160b (53)  H  V  Me\  2  /H  R  R hydrogenation black  was  performed  as c a t a l y s t ,  compound  i n 95% 159  alcohol,  absorbed  with  palladium  o n l y one  mole o f  65 hydrogen  and  gave k e t o n e  mediate methylimine tion  transpired.  160b  These  161 was  .  In t h i s  case,  hydrolyzed before  results  demonstrated  the  inter-  further  that  reduc-  t h e N-0  bond  101  in  the  isoxazolin-5-one  intermediates  age tion one  of  of d i r e c t  be  use  i n the  s t r a t e g y i n v o l v e d i n the  isoxazolin-5-ones  of  may  the  salt.  in this  heterocyclic ring Previous  isoxazolium  cleaved,  however,  underwent f u r t h e r r e a c t i o n s t o y i e l d  w h i c h were n o t The  ring  salts  work  9j5 c o u l d  be  formation  o f the  b a s e d upon of  shown  prepared  by  methyl  f l u o r o s u l f o n a t e , as d i s c u s s e d  (equation  In  formation  the  o f an  3  C H 6  N  MeOSOoF  A A -c^clT 51  that  earlier^  isoxazolin-5-one  S0 F" 9  C H AA 5  26  salt  +  9 6  activa-  treating  isoxazoles with 54).  cleav-  an i s o x a z o l i n - 5 -  l a b o r a t o r y had  readily  products  study.  investigation t h e s i s was  by  i n our  present  the  «*)  1  102  by  this  procedure,  (equation verted  two p o s s i b l e p r o d u c t s  5 5 ) , however, i t was f e l t  could  be  t h a t both c o u l d  tetrachloride  methyl f l u o r o s u l f o n a t e i n carbon  gave no e v i d e n c e  f o r any s a l t  formation  when the s o l u t i o n was r e f l u x e d f o r l o n g  periods.  surprising  salt  not only  (equation  because  isoxazolium  reportedly  This  formation  even was i s so  5 4 ) , but a l s o because methyl f l u o r o s u l f o n a t e  + is  be c o n -  i n t o g-keto e s t e r s .  T r e a t m e n t o f 114 w i t h  facile  obtained  the s t r o n g e s t  source  87  o f Me  known  0 •>  Nevertheless, reagents  a l k y l a t i o n s with  were a l s o a t t e m p t e d .  other  No Reaction  powerful  electrophilic  However, t r e a t m e n t o f 114  with  g either  dimethyl  gave o n l y  s u l f a t e or t r i e t h y l o x o n i u m  recovered  starting  material.  tetrafluoroborate  The f a i l u r e  of the  103  latter  r e a g e n t i n t h i s r e a c t i o n may be c o n t r a s t e d w i t h i t s 38  f a c i l e conversion  o f amides i n t o  imino e s t e r s a l t s  (equation  56) .  C H CONEt • Et 0 BF "  (56) NEto • BF/  +  6  5  2  3  With the success zolin-5-ones cleavage  A  C  o f our i n i t i a l  65 H  strategy of using  now i n d o u b t , c o n s i d e r a t i o n was g i v e n  reactions.  The f i r s t  t o two o t h e r  a p p r o a c h w o u l d r e q u i r e a method  t o h y d r o g e n o l y z e t h e N-0 bond o f t h e i s o x a z o l i n - 5 - o n e under m i l d c o n d i t i o n s so t h a t t h e enamino a c i d c o u l d be i s o l a t e d  and c o n v e r t e d  to the B-keto e s t e r  0  (equation  57).  NHMe  The s e c o n d  DChhNo 2 )H  w o u l d be t o r e d u c e t h e c a r b o n y l  directly  hydrolyzed  possibility  0  2 ° R-  t h e n e i t h e r be  and o x i d i z e d t o t h e B - k e t o e s t e r o r h y d r o l y z e d t o a B-keto aldehyde  (57) OMe  group o f the i s o x a z o l i n - 5 - o n e  i n t o a l a c t o l - l i k e compound, w h i c h c o u l d  hydrolyzed  ring  intermediate  t o i t s e s t e r , then  R ^ Y  ring  isoxa-  (equation  58).  104  Many r e a g e n t s  a r e known t o e f f e c t  N-0 bond  hydrogenoly-  38 sis  .  The n a t u r e  o f the d e s i r e d  however, t h a t a m i l d  transformation  and s p e c i f i c method be u s e d w h i c h  l e a v e c a r b o n - c a r b o n d o u b l e bonds and c a r b o n y l Recently, method  Keck and c o w o r k e r s have r e p o r t e d  f o r the r e d u c t i v e c l e a v a g e  procedure,  required,  i t was f o u n d  intact.  a new and e f f i c i e n t 89  o f N-0 bonds  t h a t simple  groups  would  .  In t h i s  exposure o f the s u b s t r a t e s  105  t o e x c e s s a l u m i n u m amalgam i n a q u e o u s t e t r a h y d r o f u r a n  resulted  i n a l m o s t q u a n t i t a t i v e y i e l d s o f N-0  In  t i o n , under these amide c a r b o n y l  mild c o n d i t i o n s , carbon-carbon double  g r o u p s , and  found to s u r v i v e . i n 95%  yield  by  hydrogenolysis.  For  acid labile  functionalities  e x a m p l e , r e d u c t i o n o f 162  t h i s method  (equation  was  addibonds,  were  effected  59).  OH (59)  The the  a p p l i c a t i o n of  r e d u c t i o n of  recovery given  t h i s method i n t h e p r e s e n t  i s o x a z o l i n - 5 - o n e s , however, l e d o n l y  of s t a r t i n g m a t e r i a l .  t o t h e use  study  o f 6%  Consideration  was  to  to the  therefore  s o d i u m amalgam, w h i c h i s r e p o r t e d l y a 89  stronger the  reducing  r e a c t i o n o f 114  ing disodium rial  a g e n t t h a n a l u m i n u m amalgam  could  with  6%  .  However, i n  s o d i u m amalgam i n e t h a n o l  h y d r o g e n p h o s p h a t e as a b u f f e r , o n l y s t a r t i n g  be d e t e c t e d  e v e n upon p r o l o n g e d  exposure  No Reaction  Hi  containmate-  ( e q u a t i o n 60) .  (60)  106 In  fact,  a l l attempts  in this  study  to hydrogenolyze  t h e N-O 38  bond  i n i s o x a z o l i n - 5 - o n e s by u s i n g z i n c and ammonium c h l o r i d e 90 91 s u l f u r a t e d sodium b o r o h y d r i d e , diborane , and t i t a n i u m 92 tetrachloride-diisobutylaluminum hydride futile.  The p o s s i b i l i t y  (1:3)  proved  o f r e g e n e r a t i n g 3-keto a l d e h y d e s o r  B - k e t o e s t e r s by r e d u c t i o n o f t h e c a r b o n y l g r o u p 5-ones, a s o u t l i n e d  t o be  earlier  in isoxazolin-  ( e q u a t i o n 5 8 ) , was t h e r e f o r e  examined. Many r e a g e n t s oxygen d o u b l e selectivity the  bonds and much  exhibited  the r e d u c t i o n o f c a r b o n -  i s known o f t h e f u n c t i o n a l 93  by t h e s e  reagents  .  group  The u n i q u e n e s s  of  i s o x a z o l i n - 5 - o n e c a r b o n y l g r o u p would, however, u n d o u b t -  edly In  a r e known t o e f f e c t  require that a rather selective  these  (113)  studies,  was c h o s e n  overreduction ducts  than  reducing agent  be  found.  2-methyl-3,4-tetramethyleneisoxazolin-5-one a s t h e s u b s t r a t e because  r e d u c t i o n and i n d e e d  o f t h e compound would p r o v i d e l e s s v o l a t i l e  the o t h e r  pro-  simple i s o x a z o l i n - 5 - o n e s .  m A c c o r d i n g l y , compound 113 was t r e a t e d reducing analysis.  agents  with  a variety of  and the r e a c t i o n s f o l l o w e d by TLC and NMR  In t h e c a s e o f sodium b o r o h y d r i d e ,  sodium  107 bis(methoxyethoxy)aluminum aluminum h y d r i d e , l i t h i u m borane-methyl was a p p a r e n t agent.  c o m p l e x , no e v i d e n c e  e v e n upon p r o l o n g e d  hand, i n v a r i a b l y  exposure  a,B-unsaturated  of s e l e c t i v i t y ketones  lithium  f o r any r e d u c t i o n to excess  reducing  aluminum h y d r i d e , on  gave o v e r r e d u c e d  t o 1,2 and 1 , 4 - r e d u c t i o n  The p r o b l e m  tri-t-butoxy-  t r i - s - b u t y l a l u m i n u m h y d r i d e , and  The r e d u c t i o n o f 113 w i t h  the o t h e r ponding  sulfide  hydride, lithium  products  corres-  o f the i s o x a z o l i n - 5 - o n e . i n t h e 1,2 v s 1 , 4 - r e d u c t i o n o f  h a s been a d d r e s s e d  by Masamune and  94 coworkers  .  was o b s e r v e d lithium aluminum  In t h i s s t u d y , a r e m a r k a b l e  i n the r e d u c t i o n o f u n s a t u r a t e d  aluminum hydride  especially  s o l v e n t dependence  hydride.  In a d d i t i o n ,  to e f f e c t  almost  noteworthy  ketone  163 w i t h  the use o f d i i s o b u t y l -  e x c l u s i v e 1,2-reduction  was  (Table I X ) .  0 163  The  application  shown t h a t  results  the r e d u c t i o n o f 113 w i t h  gives mixtures hydrofuran.  o f these  i n t h e p r e s e n t s t u d y has lithium  o f p r o d u c t s whether c o n d u c t e d  aluminum  i n ether or t e t r a -  However, i n t h e r e d u c t i o n o f 113 w i t h  aluminum h y d r i d e  some i n t e r e s t i n g  results  hydride  have been  diisobutylobtained.  108  Table  IX.  The R e d u c t i o n o f U n s a t u r a t e d Reducing Agents"'*  Ketone  163 W i t h  Various  H 'OH  LAH,  .lEt 0,  25 C*  LAH,  THF, 0 C  2  78°C  4  A1H , 3  THF, 0 C  i.Bu AlH, 2  *  0  U  N a B H , EtOH,  C H , 0 C g  recovered  13  6  23% s t a r t i n g  0  28 100 0  26 0 100  86  10  4  98  0  1  material  109  Treatment of  113  with  hydride  in ether  ducts.  R e p e t i t i o n of  tetrachloride formed was  one  e q u i v a l e n t of  a t room t e m p e r a t u r e this  reaction  113  by NMR  a n a l y s i s which  showed  as w e l l as  m a t e r i a l a t <5 3.11,  In o r d e r  to d r i v e  this  treated with a t -23°C  acterized 6 2.84  by  and  two  reaction  in ether.  i t s NMR  The  spectrum  a t 6 1.33-2.00  material).  stretching  spectrum m/e  basis high was  of  displayed a parent corresponding these  resolution assigned  as  results  loss  and  cm  the  1  and  the  (4H)  product of  resolution  m/e  and  a base peak  dioxide.  formula  may  be  On  derived  164.  1M  multi-  absence  s t r u c t u r e of  —0  at  low  of carbon  164  char-  the  the m o l e c u l a r  product  1:1.  compound  to a  mass measurement, t h e The  of  6 2.14-2.45 of  Finally,  new  o b t a i n e d was  spectrum  i o n a t 155  t o the and  in a r a t i o  thus  (4H)  infrared  vibration.  of a  corresponding  the c y c l o h e x y l p r o t o n s  The  result  which d i s p l a y e d a s i n g l e t  showed a c a r b o n y l a b s o r p t i o n a t 1735 an O-H  This  was  diisobutylaluminum  product  ( c f 6 1.70-1.90  pro-  product  to completion,  equivalents of  the c o l l a p s e o f  starting  111  the  of  ice-carbon  the p r e s e n c e  starting  hydride  in  material.  o f the  was  plet  a t -23°C(dry  starting  N - m e t h y l a b s o r p t i o n a t 6 2.84 signal  gave o n l y m i x t u r e s  b a t h ) , however, r e v e a l e d t h a t a new  along with unreacted  clear  diisobutylaluminum  viewed  mass at  the from  the  product  as  arising  110  from a conjugate The  a d d i t i o n of hydride  susceptibility  a t c a r b o n 3 had cleavage  of  of  ion at carbon 3 of  isoxazolin-5-ones  113.  to n u c l e o p h i l i c attack  been s u g g e s t e d p r e v i o u s l y i n t h e h y d r o l y t i c  isoxazolin-5-ones^.  Ill  CONCLUSIONS  The  p r e p a r a t i o n o f a number o f  described The of  and  anion  reactivity 8-enamino The  g e n e r a t i o n o f t h e s e compounds  of these anions esters  electrophiles  and  Claisen  and  esters.  proceed  in fair are  provides unsaturated  yields.  The  The  particular, yield,  reaction  double  into  bond  a l s o conducted,  aldol  aldehydes  aromatic  aldol  i n these  and  s i n c e the  d i a n i o n s cannot  with  compounds  i n good y i e l d .  hexanol  in only  bromination Conversion reagent  and  p r o v i d e d a second  some  analogous  be e f f e c t e d .  bromine p r o c e e d s  i t s corresponding Wittig  benzaldehyde  while  car-  isoxazolin-5-ones with  d i r e c t N-bromosuccinimide  y-bromo p r o d u c t  compound  simple  to aromatic  resulting  the a n i o n o f  B-keto e s t e r  the  while  desired  with  of  e l e c t r o p h i l e s was  reactions with  the  occurs.  trans.  alkylation  unusual  those  isoxazolin-5-ones in excellent  g e o m e t r y o f t h e new  predominantly  t o good y i e l d s ,  limited  dehydration of  products  was  to p a r a l l e l  i s o x a z o l i n - 5 - o n e anions with  condensations The  appears  been  investigated.  in that exclusive y-alkylation  r e a c t i o n s of  bon  i s o x a z o l i n - 5 - o n e s has  fair  gave of  In  the  this  condensation  route  to  unsaturated isoxazolin-5-ones. The appear  r e a c t i o n s of  to p a r a l l e l  resulting  products  selectivity  isoxazolin-5-one anions with  those  of B-keto e s t e r  a r e more s t a b l e  observed  d i a n i o n s , however  to a c i d .  i n the r e a c t i o n  of  epoxides  these  In a d d i t i o n , anions  with  the the  112  d i f u n c t i o n a l e l e c t r o p h i l e s also provides t h e use  of B-keto e s t e r  The  cleavage  extremely  particular,  Various  has  been f o u n d t o  the  r e a c t i o n of  t i o n , f o l l o w e d by cleavage  has  approaches i n v o l v i n g i s o x a hydrogenolysis,  isoxazolin-5-ones with  been f o u n d t o i n v o l v e i n i t i a l  of  isoxazolin-5-ones been r e p o r t e d  methodology should  diisobutyl1,4-reduc-  to ketones,  i n the  amides,  literature  prove u s e f u l i n extending  H o w e v e r , t h e use  of  isoxazolin-5-one  and  heterocyclic  a p p r o a c h e s be rings.  c o n d u c t e d on  the  the  anions  cleavage  and  this  B-keto e s t e r d i a n i o n e q u i v a l e n t s r e q u i r e s t h a t f u r t h e r i n v o l v i n g new  In  further reductions.  s e c o n d a r y a m i n e s has  chemistry.  be  r e d u c t i o n have n o t p r o v e n s u c c e s s f u l t o d a t e .  aluminum h y d r i d e  present  isoxazolin-5-ones  s a l t formation, nitrogen-oxygen  carbonyl  The  dianions.  problematical.  zolin-5-one and  of  some a d v a n t a g e s o v e r  as study  of  these  113  EXPERIMENTAL  Unless  SECTION  otherwise  temperatures  are stated  were d e t e r m i n e d rected. Buchi in  specified  Kugelrohr  polystyrene.  thermostat.  recorded  Infrared  and a r e u n c o r by means o f a  s p e c t r a were  recorded  M o d e l 700 o r 710B  with  n u c l e a r magnetic  Chemical  standard.  shifts  t h e 1601 cm  resonance  band o f  1  s p e c t r a were  after  each  a r e r e p o r t e d on t h e 6 - s c a l e ,  The m u l t i p l i c i t y ,  signal.  on an A t l a s  coupling constants ( i f  peak a r e a a r e i n d i c a t e d Low  resolution  CH-4B mass  mass  spectrometer,  i n paren-  s p e c t r a were and h i g h  tion  mass measurements were o b t a i n e d u s i n g an AEI MS-9  mass  spectrometer.  ing  potential  given  spec-  as s o l v e n t and t e t r a m e t h y l s i l a n e as an  o b s e r v a b l e ) , and i n t e g r a t e d  recorded  were p e r f o r m e d  on P e r k i n - E l m e r  with deuterochloroform  theses  Melting points  on V a r i a n A s s o c i a t e d M o d e l T-60, HA-100, or XL-100  spectrometers.  internal  Centigrade.  and were c a l i b r a t e d  Proton  are i m p l i e d . A l l  hot stage microscope  distillations  chloroform solution  trophotometers,  i n degrees  on a K o f l e r  Kugelrohr  the f o l l o w i n g  A l l instruments  o f 70 eV.  Observed  i n t h e r e p o r t e d mass  the m e t a s t a b l e  were o p e r a t e d  metastable  peaks  s p e c t r a , and c a l c u l a t e d  peak r e s u l t i n g  from  a t an  resoluo r MS-50 ioniz-  (m*) a r e values for  the f r a g m e n t a t i o n  process 2 1  parentheses  after  c h r o m a t o g r a p h y was  t h e m*  values.  performed  High  pressure  liquid  on a W a t e r s A s s o c i a t e s  liquid  114  chromatograph  using a radial  able wavelength performed  ultraviolet  by Mr.  254+366  and  s u  PPli  e <  preparative  mesh ASTM was  3  thin  layer  employed  by E . M e r c k .  p l a t e s was  iodine  vapour  ratios  by volume  on  by d i s t i l l i n g  inch  stored  Methyllithium obtained solutions  light  bands  and/or  are expressed i n  Model  analyses  5830-A chromaor  3%  OV-101.  under  4A m o l e c u l a r  Dichloromethane  pentoxide.  o b t a i n e d by  refluxing  reduced  sieves.  diswas  Anhydrous over  barium  pressure Pyridine  and and  f r o m p o t a s s i u m h y d r o x i d e and  diiso-  then  hydroxide.  i n e t h e r and  from A l d r i c h  systems  aluminum h y d r i d e .  were d i s t i l l e d  over potassium  230-400 mesh  o f s p o t s or  c o l u m n s o f 3% OV-17  f o l l o w e d by d i s t i l l a t i o n  propylamine  100-200  Flash  G e l 60,  by u l t r a v i o l e t  from p h o s p h o r u s  activated  analytical  t e t r a h y d r o f u r a n were o b t a i n e d by  h e x a m e t h y l p h o s p h o r a m i d e was  s t o r a g e over  vari-  gel  (TLC), w h i l e  a Hewlett-Packard  Dry e t h y l e t h e r and  oxide,  a  Vapour-phase chromatographic  t o g r a p h u s i n g 6 f t x 1/8  dried  Silica  f o r both  Visualization  A l l solvent  (v/v).  lithium  used  using S i l i c a  accomplished  staining.  from  B.C.  chromatography  performed  were c o n d u c t e d  tillation  and  f o r column c h r o m a t o g r a p h y .  ASTM, s u p p l i e d  (VPC)  g e l column  E l e m e n t a l a n a l y s e s were  Vancouver  by E . Merck was  was  TLC  detector.  Columbia,  chromatography  on  silica  Peter Borda, M i c r o a n a l y s i s Laboratory, U n i -  v e r s i t y of B r i t i s h P F  pak  Chemical  were s t a n d a r d i z e d by  n-butyllithium Company, I n c . titration  i n hexane were The  against  alkyllithium a 1.0  M  115  solution as  of  indicator  t-butyl 95  Corporation) was  .  Sodium h y d r i d e  was  washed w i t h  a l c o h o l i n benzene u s i n g  weighed dry  (from A l f a  as a 50%  1,10-phenanthroline  . . . Division,  Ventron  d i s p e r s i o n i n m i n e r a l o i l and  t e t r a h y d r o f u r a n t o remove the o i l p r i o r  to  use. All  other  g r a d e and  used  procedures^. gen  or  reagents  argon  and  directly, Finally  s o l v e n t s were e i t h e r  or p u r i f i e d  according  a l l r e a c t i o n s were run  atmosphere.  of to  reagent literature  under  a dry  nitro-  116  Methyl  2-Oxocyclohexanecarboxylate  A 500-mL t h r e e - n e c k e d reflux  condenser,  nitrogen  inlet  mole) and (33.8 was  0.38  heated  mole) was  was  (14.7  hydride  mole)  and  Dimethyl  portion  f o r an  sulfate  and  bp  torr);  cm ,  I R 1765,  (m,8H),3.3  (m,  ( s , = 0.8H,  intensity)  156  1735  (100 mL).  (4 x 100  mL)  63-64°/1.4  = 0.2H, due  and  over  1680  due  and  1640  (lit. cm ; - 1  5%  8  aqueous  the  combined  bp NMR  t o the k e t o f o r m ) , 3.70  ( 2 5 ) , 124  ( 1 0 0 ) , 68  phase  magVacuum  o f 118  as  68°/0.8 6 1.4-2.5 ( s , 3H),  t o the e n o l f o r m ) ; mass s p e c t r u m  ( 6 2 ) , 125  the  The  (87%) 6  was  hydrochloric  pressure.  g  con-  workup,  anhydrous  reduced  torr  was  mixture  a d d i t i o n a l 0.5 h o u r . On  p r o d u c t gave 20.3  - 1  of  i n t r o d u c e d to  the r e a c t i o n  c o n c e n t r a t e d under  a colourless liquid:  suspension  of cyclohexanone  then  onto b r i n e  o f the c r u d e  the  f u n n e l and  i n o i l ) was  addition  with chloroform  0.47  A solution  i c e b a t h , quenched w i t h  poured  g;  carbonate  and  the a d d i t i o n  24.5%  of 1 hour,  (22.5  a  i n anhydrous t e t r a h y d r o f u r a n  through  The  with a  f u n n e l and  hydride  l a y e r s washed w i t h b r i n e , d r i e d  distillation  12.1  sodium  i n one  mg,  c o o l e d i n an  extracted  nesium  0.15  (ca.100  at reflux  was  equipped  with constant s t i r r i n g . g;  a period  (150 mL)  organic  added  the r e a c t i o n .  maintained  acid  with  added d r o p w i s e  over  mixture  charged  to r e f l u x  was  potassium  tinued  flask  pressure-equalized addition  was  cyclohexanone  initiate  bottom  d r y t e t r a h y d r o f u r a n (120 mL).  g;  (40 mL)  round  (118)  (33) and  m/e  (rel  55  (34).  117  2-Methyl-3,4-teframethyleneisoxazolin-5-one A 100-mL t h r e e - n e c k e d reflux  condenser,  nitrogen  with N-methylhydroxylamine dry p y r i d i n e (15.6 and  g;  the  0.10  On  until and tion was oil: 1.9 (rel  was  over  was  bp  heated  96  vacuum g i v i n g  ( 1 1 ) , 153  charged  3.11  and  (67%) 1640  temperature The  ( 1 0 0 ) , 152  carbonate  (3 x 100  ethereal  - 1  solu-  colourless 6  NMR  1.7-  mass s p e c t r u m  ( 2 5 ) , 127  mL)  the r e s i d u e  of a  cm ;  ( s , 3H);  (118)  a t 100° f o r  with ether  g  and  portion  pressure.  p r e s s u r e , and  10.4  IR 1738 4H),  i n one  The  a  mole)  aqueous p o t a s s i u m  reduced  (15),  m/e  125  (15). f o r CgH-^NO^ C,  62.73; H,  7.24;  N,  9.14.  Found: C,  62.58; H,  7.41;  N,  9.00.  was  followed,  2,3-Dimethylisoxazolin-5-one  starting  reduced  with saturated  (m,  0.12  c o o l e d t o room  magnesium s u l f a t e .  Anal. Calcd  The  was  anhydrous  154  septum was  on an o i l b a t h  removed under  2.14-2.45  with  2-cyclohexanonecarboxylate  then e x t r a c t e d  intensity)  ( 8 6 ) , and  a rubber  alkaline,  under  equipped  introduced v i a syringe  122-124°/0.2 t o r r ; 4H),  flask  h y d r o c h l o r i d e (10 g;  c o n c e n t r a t e d under  distilled  (m,  and  m i x t u r e was  treated  slightly  dried  inlet  workup, the m i x t u r e  the p y r i d i n e  r e s i d u e was  bottom  Methyl  mole) was  reaction  8 hours. and  (55 mL).  round  (113)  procedure  used  (112)  i n the p r e p a r a t i o n o f 113  from N-methylhydroxylamine  h y d r o c h l o r i d e (5.20  g;  118  61.9  mmole), e t h y l a c e t o a c e t a t e (20.6 g; 155 mmole) and d r y  pyridine  (35 mL).  gave  5.20 g  torr  (lit.  6 2.16 m/e  6  Fractional  d i s t i l l a t i o n o f the crude p r o d u c t  (74%) o f 112 as a c o l o u r l e s s 5  bp 8 8 - 8 9 ° / 0 . 2  ( s , 3H), 3.30  (rel intensity)  torr);  ( 1 0 0 ) , 96  2,3,4-Trimethylisoxazolin-5-one The  procedure used  ethyl  2-methylacetoacetate  pyridine  (50 mL).  to y i e l d  8.7 g  fied  39-40°); 3H),  ( 1 0 0 ) , 98  o f 113 was  bp 127-129°/5.0  t o r r , mp  NMR  (7) and 56  6 1.73 m/e  followed  (10 g; 0.12 m o l e ) , anhydrous  The c r u d e p r o d u c t was f r a c t i o n a l l y  ( s , 3H); mass s p e c t r u m  Anal. Calcd  spectrum  (114 )  (13.2 g ; 0.10 mole) and  - 1  NMR  (7) and 57 ( 3 1 ) .  hydrochloride  IR 1720 and 1640 c m ;  and 3.17  ( s , I H ) , mass  (69%) o f 114 as a c o l o u r l e s s  on c o o l i n g :  82-84°/0.05 1  i n the p r e p a r a t i o n  u s i n g N-methylhydroxylamine  bp  IR 1725 and 1645 cm" ;  ( s , 3H) , and 4.93 113  oil:  distilled  o i l , which 39-40°  solidi-  (lit.  6  4  a  ( s , 3H), 2.10 ( s ,  (rel intensity)  127  (17) .  f o r C g H N 0 : C, 56.68; H, 7.13; N, 11.02. 9  mp  2  F o u n d : C, 56.48; H, 7.24; N, 11.00.  119  Base Dependency S t u d i e s o f I s o x a z o l i n - 5 - o n e 2,4-Dimethyl-3-ethylisoxazolin-5-one  a)  Via lithium A solution  tetrahydrofuran round with  bottom  water b a t h (1.57 pale  mL;  of diisopropylamine  equipped  spetum.  with  was c o o l e d  solution  was s t i r r e d  t o 0 ° i n an i c e i n hexane  The c o l o u r l e s s t o  (114) (200 mg;  1.57 mmole) i n t e t r a -  (3 mL) was i n t r o d u c e d s l o w l y v i a s y r i n g e .  a final  10 m i n u t e s  chloric  acid  with ether  15 m i n u t e s ,  to complete  (5 mL) was added  (3 x 10 mL).  then  washed w i t h w a t e r  sium  sulfate.  180 mg  methyl  iodide  mixture  the r e a c t i o n .  The combined  TLC ( s i l i c a  80-82°/1.3  torr;  J = 7 H z ) , 1.74  hydro-  was e x t r a c t e d  over  product  a n h y d r o u s magner e d u c e d p r e s s u r e gave  was p u r i f i e d  g e l , 3:1 e t h y l e t h e r - c h l o r o f o r m )  (81%) o f 127a:  Rf 0.40; bp  (Kugelrohr  IR 1722 and 1635 c m  ( s , 3H), 2.45  1.57  o r g a n i c e x t r a c t s were  (5 mL) and d r i e d  The c r u d e  stir-  to stand f o r  Dilute  and the r e a c t i o n  Upon  (199 mg;  allowed  Removal o f t h e s o l v e n t under  an amber o i l .  preparative  3H,  and s t o p p e r e d  f o r 10 m i n u t e s and 2 , 3 , 4 - t r i -  mmole) was added and t h e r e a c t i o n  tion)  two-necked  a nitrogen i n l e t  The f l a s k  f o r an a d d i t i o n a l  give  1.74 mmole) i n d r y  i n a 25-mL  1.47 mmole) was added d r o p w i s e .  hydrofuran  as  (176 mg;  (10 mL) was p r e p a r e d  methylisoxazolin-5-one  127a  (127a)  and n - b u t y l l i t h i u m a s a 1.0 M s o l u t i o n  yellow  ring  Generation  diisopropylamide  flask  a rubber  Anion  - 1  ;  NMR  by to  distilla6 1.18 ( t ,  ( q , 2H, J = 7 H z ) , and 3.14  120  (s,  3H); mass s p e c t r u m  and  70  m/e  (rel intensity)  141 ( 1 0 0 ) , 112 ( 1 6 ) ,  (22) .  Anal. Calcd  f o r C^H^NC^: C, 59.56; H, 7.85; N, 9.92. F o u n d : C, 59.30; H, 7.86; N, 9.96.  b)  V i a n.-butyllithium A 25-mL two-necked  nitrogen  inlet  round  bottom  flask  and s t o p p e r e d w i t h a r u b b e r  equipped  with a  septum was c h a r g e d  with a s o l u t i o n  o f 2 , 3 , 4 - t r i m e t h y l i s o x a z o l i n - 5 - o n e (114) (204  mg;  i n d r y t e t r a h y d r o f u r a n (10 mL).  1.61 mmole)  cooled  t o -78° i n a d r y i c e - a c e t o n e bath  a 1.56 M s o l u t i o n dropwise. stirred  Upon c o m p l e t e  f o r 1 hour  was t h e n  i n hexane  165 mg  spectral  V i a potassium Potassium  (367 mg; bottom  Methyl  over  properties  (365 mg;  and t h e r e a c t i o n  t o those  with a nitrogen  2.57 mmole) allowed to  o i l with  reported e a r l i e r .  h y d r i d e a s a 20.6% d i s p e r s i o n into  7 0  in mineral o i l  a 25-mL two-necked inlet  septum, and d r y t e t r a h y d r o f u r a n (10 mL) was  directly  into  flask.  round  and s t o p p e r e d w i t h  a rubber  the r e a c t i o n  was  Workup and p u r i f i c a t i o n  bis(trimethylsilyl)amide  equipped  mixture  (73%) o f 127a as a c o l o u r l e s s  1.88 mmole) was w e i g h e d  flask  1.87 mmole) was added  iodide  4 hours.  was  and n - b u t y l l i t h i u m as  the r e a c t i o n  i n t r o d u c e d i n one p o r t i o n  as above gave  c)  addition  at -78°.  warm t o room t e m p e r a t u r e  identical  (1.20 mL;  The f l a s k  distilled  The s u s p e n s i o n was c o o l e d t o  121  0°  i n an  i c e water  mg;  1.88  mmole) was  allowed the  to stand  (200  A  mg;  hour.  by  tion.  stirring  as  Alkylation  General  of  f o r an  r e a c t i o n mixture complete  was  formation  of  2,3,4-trimethylisoxazolin-5-one  and  the  r e a c t i o n was  iodide  (199  mg;  a d d i t i o n a l 1.25  purification  as  (3 mL)  above gave  identical  stirred  1.57  hour  was  then for  mmole),  completed 175  mg  spectral  1 fol-  the  (79%)  reac-  of  p r o p e r t i e s to  earlier.  2,3,4-trimethylisoxazolin-5-one  solution  tetrahydrofuran bottom  a rubber  of d i i s o p r o p y l a m i n e (10 mL)  flask.  as  added d r o p w i s e . stirred  f o r 15  The  The  (114)  (3 mL)  introduced  the  114  (1.0  alkylating  was  t o 0°  equivalents)  fitted i n an  i n hexane  via syringe. agent  (1.0  with  a nitrogen  i c e water b a t h , (1.1  equivalent)  yellow  to ensure complete equivalent)  i n dry  i n a 25-mL two-necked  c o l o u r l e s s to pale  minutes  of  (1.2  prepared  flask  a solution  a solution was  was  septum, c o o l e d  n-butyllithium  utes,  (303  procedure  A  round  the  to ensure  of  a c o l o u r l e s s o i l with  reported  and  mmole) i n t e t r a h y d r o f u r a n  via syringe  Workup and  those  and  minutes  I n t r o d u c t i o n of methyl  lowed  127a  added  solution  1.57  added d r o p w i s e  1,1,1,3,3,3-hexamethyldisilazane  slowly  f o r 45  amide b a s e .  (114)  bath,  base  i n anhydrous  was  and was  solution formation  was and  tetrahydrofuran  Upon s t i r r i n g  equivalent)  inlet  f o r 30  added and  minthe  122  reaction  mixture  m a t e r i a l was acid  was  consumed  (5 mL)  was  (3 x 10 mL).  water  (5 mL)  alkylated  and  the  by  over  under  oxide  pressure  mmole), 114  (1 mL).  The  (181  added.  organic layer  The (2 mL)  ether  then  Removal o f  the  amber o i l :  NMR  netic  the  crude  and  57  resonance  dried  6 1.73 m/e  (20).  (122)  according  was  over  M  1.43  t o the g e n e r a l  solution  and  was  deuterium  excess  oxide  2.07  ( b s , 2.OH)  (rel intensity) Mass s p e c t r a l indicated  and  1.57 (1.25 deuterium  (3 mL)  washed w i t h  pressure  129  product  was  were  deuterium  sulfate.  gave  122  and  ( 1 2 ) , 128  proton  pro-  to stand for  a n h y d r o u s magnesium reduced  mg;  i n hexane  allowed  separated,  ( s , 3H),  analysis  (159  mmole) and  mixture  (10 mL)  s o l v e n t under  mass s p e c t r u m (11)  mg;  resulting  then  3H);  with  sulfate.  gave  using diisopropylamine  10 m i n u t e s ,  oxide  e x t r a c t e d with  e x t r a c t s were washed  reduced  mmole), n - b u t y l l i t h i u m as a 1.26  99  mixture  a n h y d r o u s magnesium  prepared  for a l k y l a t i o n  1.57  starting  Dilute hydrochloric  2,3,4-Trimethylisoxazolin-5-one-di  cedure  until  Studies  T h i s compound was  mL;  TLC.  reaction  combined  dried  to stand  products.  Deuteration a)  judged  and  The  the e t h e r  allowed  as  added  ether  Removal o f  then  as  3.17  an (s,  (100),  n u c l e a r mag95  ± 5%  d-^.  123  2,3-Dimethylisoxazolin-5-one-di This  compound  t h a t o f compound  was p r e p a r e d  by a p r o c e d u r e  122 u s i n g d i i s o p r o p y l a m i n e  mmole), n - b u t y l l i t h i u m as a 1.20 M s o l u t i o n 2.85 mmole), Workup 3.27  112  (270 mg;  intensity)  (288 mg;  2.85  i n hexane  (2.43 mL;  2.39 mmole) and d e u t e r i u m o x i d e  as above gave an amber  ( s , 3H) and 4.93  analogous to  o i l : NMR  ( s , = 0.6H); mass  i n d i c a t e d 28% d , 48% d D  1  6 2.10  (1 mL).  ( b s , * 2.4H),  s p e c t r u m m/e ( r e l  and 24% d . 2  2-Methyl-3,4-te framethyleneisoxazolin-5-one-di The  r e a c t i o n was  described (131  mg;  hexane  out according  t o the p r o c e d u r e  f o r t h e p r e p a r a t i o n o f 122, u s i n g  diisopropylamine  1.42  mmole), n - b u t y l l i t h i u m as a 1.42 M s o l u t i o n i n  (1.00 mL;  deuterium oxide stand low  is  1.42 mmole), (1 mL).  f o r 15 m i n u t e s ,  oil:  (68)  carried  mass  and 97  95 ± 5%  Diethyl  then  1.29 mmole) and  mixture  worked up as u s u a l (rel  Mass s p e c t r a l  was a l l o w e d to give  i n t e n s i t y ) 154  a  to  yel-  (100) , 126  analysis indicates  product  d . 1  a c e t y l m a l o n a t e ( 124)  A 500-mL t h r e e - n e c k e d mechanical s t i r r e r , chloride  (200 mg;  The r e s u l t i n g  s p e c t r u m m/e  (12).  113  drying  reflux  tube,  round  bottom f l a s k  condenser  fitted  equipped with  with  and a p r e s s u r e - e q u a l i z e d  a  a  calcium  dropping  funnel  124  was  c h a r g e d w i t h magnesium  ethanol  (5 mL)  and  turnings  carbon  mL)  was  added c a u t i o u s l y  tion  of d i e t h y l malonate  nel  at  such a r a t e  reaction 3.0 in  ether  (25  reaction stir.  A  was  solved.  The  further layers  and  and  37.3  1610  acid  g  was  was  Hz), and 15.0 160  (lit. NMR  of 7  124 bp  3  75  a l l the  115  the  g;  0.22  mole) the  bath  dis-  aqueous  combined  layer  organic  a n h y d r o u s magnesium pressure  under water  J  to  i c e water  the  The  over  ( t , 6H,  (100)  fun-  additional  s o l i d s had  and  mL).  leaving  aspirator  liquid: IR  = 6 Hz),  3410, 2.17  pres-  bp 1720, (s,  (s,^0.5H),4.20(l,4H,J  ( s , ^ 0.5H); mass spectrumm/e (59),  mL)  an  i n an  110-115°/13 t o r r ) ;  6 1.30  (20  m i n u t e s and  a colourless  ( s , * 1.25H), 3.27  ( 8 ) , 133  for  15  under r e d u c e d  as  solu-  addition  (17.3  separated  (1 x  the  A  m a i n t a i n e d , and  cooled  Distillation  (84%)  1  through  to  ether  i t became t o o v i s c o u s  added u n t i l  layer  liquid.  cm" ;  1.75H), 2.30  (0.7),  suspension  stirring.  to r e f l u x  until  were added  mole), ethanol  acetyl chloride  with ether  127-128°/20 t o r r  -  of  then c o n c e n t r a t e d  yellow  s u r e gave  1645  allowed  were washed w i t h w a t e r , d r i e d  sulfate a pale  0.22  b o i l i n g was  refluxed  ethereal  extracted  g;  added d r o p w i s e o v e r  resultant  dilute sulfuric  rapid  then  m i x t u r e was  The  (35.2  that  solution mL)  with constant  added d r o p w i s e  m i x t u r e was  hours.  and  was  several  mL)  Dry  minutes anhydrous  (175  mL)  mole).  after  reaction  (25  0.22  (0.5  the  ether  g;  tetrachloride  initiate  and  and  (5.4  and  (rel intensity) 88  (24).  202  =  6  125  2,3-Dimethy1-4-carbe t h o x y i s o x a z o l i n - 5 - o n e  N-methylhydroxylamine and d i e t h y l duced  into  was f i t t e d pyridine  125  h y d r o c h l o r i d e (0.50 g; 6.0 mmole)  a c e t y l m a l o n a t e 124 a 25-mL two-necked with a nitrogen  (1.0 g ; 5.0 mmole) were round  inlet  bottom  flask.  and a r u b b e r  (7 mL) was added v i a s y r i n g e .  intro-  The f l a s k  septum, and d r y  The r e a c t i o n  mixture  was h e a t e d on an o i l b a t h a t 8 0 ° f o r 7 h o u r s ,  then c o o l e d t o  room t e m p e r a t u r e .  reduced  and  P y r i d i n e was removed under  the r e s i d u e was t r e a t e d  carbonate u n t i l  slightly  then e x t r a c t e d  with ether  magnesium s u l f a t e .  with  saturated  alkaline.  Removal o f t h e e t h e r under  f o l l o w e d by r e c r y s t a l l i z a t i o n  (72%)  o f 125 a s w h i t e  1750 and 1690 c m  3H),  3.61  (rel  intensity)  - 1  crystals: ;  NMR  ( s , 3H) and 4.25  mp 1 3 7 - 1 3 8 °  with  sodium  (12 mL). and  inlet  The f l a s k  a solution  round  (58 mg;  (lit.  pres-  gave 0.551 g 7  4  mp  138°);  ( q , 2H, J = 6 H z ) ; mass s p e c t r u m  m/e  (100) and 67 ( 3 5 ) .  bottom  flask  and s t o p p e r e d w i t h a r u b b e r  hydride  anhydrous  reduced  from m e t h a n o l  2-Methy1-3-ethy1-4-carbethoxyisoxazolin-5-one  nitrogen  over  was  6 1.32 ( t , 3H, J = 6 H z ) , 2.51 ( s ,  185 ( 3 1 ) , 140  A 25-mL two-necked  potassium  The aqueous s o l u t i o n  (3 x 50 mL) and d r i e d  sure,  IR  aqueous  pressure  (126)  equipped  with a  septum was c h a r g e d  1.20 mmole) and d r y t e t r a h y d r o f u r a n  was t h e n c o o l e d t o 0° i n an i c e water  o f 125 (185 mg; 1.00 mmole) i n 1:1  bath  126  tetrahydrofuran-dimethyl  sulfoxide  The  allowed  r e a c t i o n mixture  methyl  iodide  solution  was  was  (14 2 mg; stirred  f o r an  The  aqueous s o l u t i o n  was  mL)  and  organic  sulfate.  gave 126 on  were added  combined  as  silica  gel  oil.  gave  169  mg  the  s o l v e n t under  1750  and  1650  cm" ;  2H,  = 7 Hz),  3.60  ( s , 3H)  of  distillation) NMR  1  5  Calcd  and  = 1 1 7 . 6 ) , 82 for C H 9  as  cedure  compound was  for a l k y l a t i o n  mg;  mmole), 1.57  114  mmole).  (200 The  (10  4.23  separated.  ether  (2x5  a n h y d r o u s magreduced  pressure  chromatography  ether-ethyl  a white  ( q , 2H,  ( 4 2 ) , 153 (12)  and  ace-  solid:  6H),  2.90  152  mp IR (q,  J = 7 Hz); (100),  81  mL)  mass (24),  (13).  N 0 : C, 4  54.26; H,  6.57,  N,  7.03.  F o u n d : C,  54.11; H,  6.40;  N,  7.04.  1 3  prepared  (127b)  according  to  using diisopropylamine  mmole) n - b u t y l l i t h i u m as 1.74  Ether  column  (m,  then  the  137-140°/0.15 t o r r ;  2,4-Dimethy1-3-propylisoxazolin-5-one This  by  6 1.13-1.43  ( r e l i n t e n s i t y ) 199  (m*,^ ^-  126  and  layer  l a y e r s d r i e d over  (85%)  1765,  Anal.  organic  Purification  (Kugelrohr  117-118  introduced  f u r t h e r extracted with  6 2 - 6 3 ° ; bp  s p e c t r u m m/e  the  dropwise.  f o r 20 m i n u t e s ,  (100-200 mesh) u s i n g p e t r o l e u m  tate mixtures  J  and  Removal o f  a yellow  added  a d d i t i o n a l 2 hours.  water  the  was  to stand  mmole) was  and  nesium  (5 mL)  1.00  (3 mL)  mg;  a 1.56 1.57  resulting  M  solution  mmole), and mixture  was  the (176  general mg;  i n hexane  1.74 (1.12  ethyl iodide stirred  pro-  for  mL;  (245 30  127  m i n u t e s , then  workup gave  P r e p a r a t i v e TLC  of  ether-chloroform less o i l : torr;  IR  Rf  3.21  (2:1)  = 0.40;  1722  1.55-1.80  this  and  (m,  ( s , 3H);  bp  of crude  163  mg  cm" ;  NMR  1  ( s , 3H),  2.48  114  (200  mmole).  ( t , 2H,  98  (100),  127  (23).  9.26.  prepared  (176  1.74  solution  i n hexane  (1.10  mmole) and  n-butyl  bromide  mixture  was  gave  of  127c  ( t , 3H,  (s,  3H),  ( t , 2H,  m/e  (rel intensity)  127  (100),  183 and  mg;  P r e p a r a t i v e TLC  1.57 then of  ethyl ether-chloroform  torr;  J = 7 Hz),  1.23-1.65  (24).  mmole),  for 3 hours,  and  3.12  IR  Rf  1722 (m,  ( s , 3H);  ( 1 0 ) , 140  pro-  n-butyl-  1.74  (215  93-95°/1.2  ( 4 2 ) , 141 98  mL,  a colourless o i l :  J = 7 Hz)  general  mmole),  stirred  amber o i l .  as  distillation)  (11)  t o the  mg;  M  (80%)  (127c)  according  g e l with  99  and  N,  silica  2.39  155  Hz),  8.29;  resulting  6 0.88  J = 7.5  Hz),  61.99; H,  The  NMR  = 7.5  F o u n d : C,  c r u d e m a t e r i a l on  -1  J  9.03.  an  cm ;  87-90°/1.4  N,  1.57  (Kugelrohr  a colour-  8.44;  mg;  mg  as  with  61.91; H,  workup gave c r u d e 127c as  230  gel  127b  ( t , 3H,  amber o i l .  f o r C g H ^ N C ^ : C,  cedure u s i n g d i i s o p r o p y l a m i n e a 1.6  an  silica  (rel intensity)  = 1 0 4 . 1 ) , and  T h i s compound was  as  as  distillation)  2,4-Dimethyl-3-pentylisoxazolin-5-one  lithium  127b  of  6 1.04  mass s p e c t r u m m/e  Anal. Calcd  (67%)  (Kugelrohr  1.82  (m*,^3-  ( 7 9 ) , 104  mg  c r u d e m a t e r i a l on gave  1625  2H),  195  0.60; and 6H), mass  ( 3 3 ) , 128  this (3:1) bp  1630 1.72 spectrum (10),  128  Anal. Calcd  for C  l f J  H  N 0 : C, 65.54; H, 9.35; N,  7.64.  Found: C, 65.24; H, 9.44; N,  7.50.  1 7  2  2,4-Dimethyl-3-(3'-butenyl)isoxazolin-5-one T h i s compound  was  prepared  cedure u s i n g d i i s o p r o p y l a m i n e lithium 114  mmole).  The r e s u l t i n g  purified  cm" ; 1  195 mg  NMR  5.01-5.24 intensity) and  mixture  1.56 mmole), (1.10 mL;  (silica  stirred oil.  6 1.88  n-butyl-  1.72  The c r u d e  g e l , 3:1  92-95°/1.5 t o r r ;  ( s , 3H), 2.20-2.66  (m, 2H)  and 5.64-6.01  (100),  166  pro-  mmole), 1.56  f o r 10 m i n u t e s ,  (75%) o f 127d as a c o l o u r l e s s  distillation)  167  was  127d as a y e l l o w  by p r e p a r a t i v e TLC  (Kugelrohr  i n hexane  t o the g e n e r a l  1.56 mmole) and 3 - b r o m o - l - p r o p e n e (189 mg;  worked up t o g i v e  to give  (174 mg;  as a 1.56 M s o l u t i o n  (198 mg;  according  (127d)  product  then was  ether-chloroform) oil:  Rf 0.50;  IR 1725 and  (m, 4H), 3.21  bp  1632  ( s , 3H),  (m, I H ) ; mass s p e c t r u m m/e ( r e l  ( 7 ) , 127  ( 1 3 ) , 125  ( 2 9 ) , 96 ( 2 2 ) ,  81 ( 4 0 ) . Anal. Calcd  f o r C g H ^ N C ^ : C, 64.65; H,  7.84; N,  8.38.  Found: C, 64.38; H,  7.80; N,  8.61.  2,4-Dime t h y l - 3 - ( 4 me t h y l - 3 ' - p e n t e n y 1 ) i s o x a z o l i n - 5 - o n e 1  T h i s compound  was p r e p a r e d  cedure using d i i s o p r o p y l a m i n e lithium  as a.1.6  M solution  according (176 mg;  i n hexane  (127e)  t o the g e n e r a l  1.74  mmole),  (1.10 mL,  1.74  pro-  n-butylmmole),  129  114  (200  mg;  1.57  1.57  mmole).  then  worked up  duct  was  mmole) and  The  resulting  to give  purified  by  127e  t o g i v e 230  Rf  (Kugelrohr  and  bp  1629  cm" ; 1  2.14-2.54  (m,  4H),  mass s p e c t r u m m/e and  69  mg  was  3.15  stirred  as a y e l l o w  (75%)  of  ( s , 3H), ( s , 3H)  127e  The  f o r C-^H^NG^: ' C  F o u n d : C,  ( s , 3H),  T h i s compound was  prepared  cedure u s i n g d i i s o p r o p y l a m i n e lithium  as  (200  mmole).  a 1.56  ( 4 9 ) , 136  1722  (s,  3H),  Hz);  ( 2 4 ) , 127  67.66;  H  f  8.78;  67.79; H,  8.96;  (100),  (Kugelrohr NMR  127f  m a t e r i a l on of  mixture  was  as a y e l l o w silica  127f  distillation) 6 1.55  mg;  t o the  1.74  ( s , 3H),  as  oil.  g e l with  mL,  2.59-2.94  1.74 mg;  1.57 then  P r e p a r a t i v e TLC ether-chloroform  torr;  (m,  pro-  mmole),  f o r 3 hours,  a colourless o i l :  127-130°/2.3  7.17.  mmole), n - b u t y l -  (1.12  stirred  N,  general  b e n z y l c h l o r i d e (199  resulting  (52%)  (176  7.17.  (127f)  mmole) and  The  mg  according  N,  i n hexane  1.57  crude  gave 179  1  IR  J = 6  M solution  mg;  workup gave c r u d e  cm" ;  ether-  1.74  ( t , IH,  2,4-Dimethyl-3-(2'-phenethyl)isoxazolin-5-one  this  pro-  (71).  Anal. Calcd  114  minutes,  crude  g e l , 3:1  mg;  as a c o l o u r l e s s o i l :  5.08  195  (233  f o r 10  93-95°/1.4 t o r r ;  1.67  and  (rel intensity)  oil.  (silica  distillation)  6 1.57  NMR  mixture  p r e p a r a t i v e TLC  chloroform) 0.65;  3-methyl-l-bromo-2-butene  4H),  IR  of (3:1)  Rf  0.40;  bp  1722  and  1630  3.00  (s,  3H),  130  and  7.04-7.36  (100),  105  (m, 5H); mass s p e c t r u m m/e  ( r e lintensity)  (29) and 91 ( 9 8 ) .  Anal. Calcd  for C  1 3  H  1 5  N 0 : C, 71.87; H, 6.96; 2  F o u n d : C,  71.91; H,  6.92;  N,  6.45.  N,  6.46.  2, 4 - D i m e t h y 1 - 3 - ( 2 ' - h y d r o x y p h e n e t h y l ) i s o x a z o l i n - 5 - o n e  T h i s compound  was  prepared  cedure u s i n g d i isopropylamine lithium 114  a s a 1.6 M s o l u t i o n  (200 mg;  The r e s u l t i n g  1.57  was  3.16  NMR  ( 3 6 ) , 79  Anal. Calcd  t o the g e n e r a l  1.7.4 mmole), (1.09 mL;  oil.  1.57  f o r 1.5  6 1.57  ( s , 3H), 2.80  ( t , 2H, J = 6.5  H  i  92-94°;  233  Hz)  mmole).  hours,  gave 260 mg  Rf 0.35; mp  ( 4 8 ) , 55 c  mmole),  Preparative  from ether  pro-  n-butyl-  1.74  (167 mg;  to stand  ( r e lintensity)  for i 3  (128)  (71%) o f  IR 3625,  and 7.29 127  this  (5:1),  ( d , 2H, J =  (100),  then  TLC o f  g e l using ether-ethyl acetate  ( s , 4H), 4.92  mass s p e c t r u m m/e ( 9 6 ) , 81  allowed  crystals:  1733 and 1640 c m ; Hz),  i n hexane  by c r y s t a l l i z a t i o n  - 1  (176 mg;  128 as a y e l l o w  c r u d e m a t e r i a l on s i l i c a  128 as c o l o u r l e s s  according  mmole) and b e n z a l d e h y d e  mixture  worked up t o g i v e  followed  217  3435, 6.5  ( s , 5H);  (100),  107  ( 2 3 ) , and 53 ( 2 3 ) . N 5  0  3  :  c  >  F o u n d : C,  66.94; H, 6.48; 66.87; H,  6.47;  N, N,  6.00. 6.01.  131  2,4-Dimethy1-3-(2'-mesyloxyphenethyl)isoxazolin-5-one  A solution  o f compound  tetrahydrofuran round and  bottom  (10 mL)  flask.  stoppered with  i c e water  bath.  128  was  The  (133 mg;  prepared  flask  a rubber  was  upon  s t a n d i n g f o r 15 m i n u t e s ,  mg;  0.68  mmole) was  was  stirred  crystals  The  168  mg  mp  6 1.51  2.80  ( s , 3H),  128  (39)  and  and  Anal. Calcd  (3x5  mL),  1640  and  ( s , 5H);  ( 1 0 0 ) , 170  as a p a l e  1370  the  (330 mg;  1.06  colourNMR  - 1  (m,  mass s p e c t r u m  m/e  ( 2 2 ) , 141  2H), (rel  (46),  (23) . for  c  i 4  25-mL two-necked condenser  under  cm ;  H  i 7  N  0  S  :  5  c  »  54.01; H, 53.91; H,  5.50;  N,  5.47;  2,4-Dimethy1-3-(2'-phenylethenyl)isoxazolin-5-one  reflux  resulting  pure  3.08-3.35  ( 2 9 ) , 156  (78  mixture  then d r i e d  ( s , 3H),  F o u n d : C,  A  inlet  added  reaction  as a n a l y t i c a l l y  3.21  7.42  The  s t a n d i n g and  1730,  ( s , 3H),  ( 1 6 ) , 215  115  IR  mmole) was  t o g i v e 134  on  o f 134  94-95°;  ( t , IH, J = 7 Hz)  i n t e n s i t y ) ' 311  0.86  t h e n worked up  (95%)  with a nitrogen  methanesulfonyl chloride  o i l crystallized  less crystals:  5.70  fitted  introduced dropwise.  were washed w i t h e t h e r  vacuum g i v i n g  i n a 25-mL two-necked  T r i e t h y l a m i n e (87 mg;  f o r 1 hour  mmole) i n d r y  septum, t h e n c o o l e d t o 0 ° i n an  and  yellow o i l .  0.57  (134)  and  round  bottom  a nitrogen  mmole) and  inlet  anhydrous  flask was  dichloromethane  N,  4.44.  (135)  equipped charged  4.50.  with a  with (15  134 mL).  132  1, 5 - D i a z a b i c y c l o [ 4 . 3 . 0 ] n o n - 5 - e n e introduced The  and  the  r e a c t i o n was  acid  (5 mL)  with  water  was  r e a c t i o n mixture  cooled  (10 mL)  gave  13 5 as  m a t e r i a l on 217  mg  standing: torr; 3.24  mp  of  Rf  141  oil.  then  d r i e d over  s o l v e n t under  Preparative  TLC  (200  mmole). hours, product  this  (1:1)  crude gave  bp  (Kugelrohr  IR  7.01  1730  and  ( q , 2H,  J  distillation)  1650  cm ;  = 16  Hz),  NMR  - 1  and  ( r e l i n t e n s i t y ) 215 129  Calcd  (15)  for C  1 3  and H  105  a 1.57  M  resulting  7.36-7.66 170  purified  (m,  5H);  (17),  156  (14). 6.09;  N,  6.51.  F o u n d : C,  72.58; H,  6.14;  N,  6.41.  to give  according (352  mg;  (2.23  137  allowed as  an  p r e p a r a t i v e TLC  general  pro-  mmole), n - b u t y l -  methyl benzoate was  (137)  t o the  3.48  i n hexane  mixture  by  3H),  72.54; H,  mmole) and  worked up  (s,  2  solution  The  120-122°/0.18  6 1.98  (100),  on  N 0 : C,  1 3  prepared  1.57  was  of  pres-  0.85;  mg;  then  anhydrous  a c o l o u r l e s s o i l which c r y s t a l l i z e d  cedure using diisopropylamine  114  washed  reduced  gel using ether-ethyl acetate  T h i s compound was  as  hydrochloric  separated,  2,4-Dimethy1-3-benzoyImethylisoxazolin-5-one  lithium  5%  hours.  as  (14),  Anal.  and  then  135  mass s p e c t r u m m/e (14),  (10 mL),  mmole) was  refluxed for 4  o r g a n i c p h a s e was  brine  a yellow  46-47°;  ( s , 3H),  was  Removal o f t h e  silica  (95%)  The  and  mg ; 1.60  t o room t e m p e r a t u r e  added.  magnesium s u l f a t e . sure  (199  mL;  3.48  (214  mmole),  mg;  to stand  1.57 for 5  amber o i l . The (silica  gel,  5:1  crude  133  ether-ethyl solid: NMR  acetate)  Rf = 0.40; mp  6 1.80  ( 9 ) , 122  (57%) o f 137 as a w h i t e  IR 1735, 1700 and 1642  ( s , 3 H ) , 4.21  ( 4 6 ) , 105  Found:  cm ; - 1  ( s , 2H), 7.47-7.69  (m, 2H); mass s p e c t r u m m/e  High R e s o l u t i o n 231.0895.  207 mg  77.5-78.5°;  ( s , 3H), 3.24  3H) and 7.96-8.06 231  to give  (m,  (rel intensity)  (100) and 77 ( 4 6 ) .  Mass Measurement C a l c d  for C^2 i3 H  2  N 0  :  231.0894.  2,4-Dimethy1-3-bromomethylisoxazolin-5-one  (140a)  Procedure A T h i s compound was p r e p a r e d general one  procedure.  (114) was p r e p a r e d  (176  mg;  hexane  bath  as u s u a l  mixture  resulting  was  then  diisopropylamine  cooled  mixture  TLC o f t h i s  was a l l o w e d to give  to stand  (41%) o f 140a as a p a l e  yellow  - 1  205  NMR  <5 1.81  ( s , 2H); mass s p e c t r u m m/e  (100),  126  Preether-  R f 0.50; IR 1740 and 1645 c m ;  (100),  f o r 10 m i n u t e s ,  g e l using  oil:  207  dropwise.  140a as an amber o i l .  acetate  3H), and 4.08  The  ice-acetone  introduced  c r u d e m a t e r i a l on s i l i c a  (2:1) gave 133 mg  1.57 mmole).  t o -78° i n a d r y  ethyl  (s,  (200 mg;  (251 mg« 1.57 mmole) was  worked up as u s u a l  parative  a t 0° u s i n g  1.74 mmole) and 114  and b r o m i n e  then  of 2,3,4-trimethylisoxazolin-5-  1.74 mmole), n - b u t y l l i t h i u m as a 1.16 M s o l u t i o n i n  (1.50 mL;  reaction  The  The a n i o n  by a m o d i f i c a t i o n o f t h e  ( 6 8 ) , 81  ( s , 3H) , 3.23  (rel intensity)  ( 9 3 ) , and 53 ( 9 8 ) .  134  High  R e s o l u t i o n Mass Measurement C a l c d  206.9719, 204.9739.  Found:  206.9714,  f o r CgHglS^Br:  204.9734.  2,4-Dimethyl-3-bromomethylisoxazolin-5-one  Procedure  B  A 25-mL condenser mide  (ca. for  two-necked round  and a n i t r o g e n  (28 0 mg;  carbon  te-trachloride  (5 mL)  washed w i t h b r i n e sulfate. mg  (200 mg;  the s o l u t i o n  added.  with a  reflux  N-bromosuccini-  1.57 mmole) and d r y of benzoyl peroxide  m i x t u r e was  was c o o l e d t o room  refluxed tempera-  The o r g a n i c p h a s e was s e p a r a t e d ,  (5 mL), t h e n d r i e d  (76%) o f 140a a s a y e l l o w o i l , as t h o s e  with  A few c r y s t a l s  over  Removal o f t h e s o l v e n t u n d e r  properties  equipped  added and t h e r e a c t i o n  On workup,  and w a t e r  flask  was c h a r g e d  114  (10 mL) .  10 mg) was t h e n  bottom  inlet  1.57 mmole),  2 hours.  ture  (140a)  anhydrous  reduced  magnesium  p r e s s u r e gave 345  w h i c h had i d e n t i c a l  spectral  r e p o r t e d above.  2 , 4-Dime t h y l - 3 - ( p h e n y l s e l e n e n y l m e t h y l ) i s o x a z o l i n - 5 - o n e (140b)  This cedure  compound  for alkylation  n-butyllithium mmole), (307  was p r e p a r e d  mg;  114  u s i n g d i i s p p r o p y l a m i n e (176 mg;  a s a 1.57 M s o l u t i o n  (200 mg;  1.57 mmole).  1.5 h o u r s ,  a c c o r d i n g to the g e n e r a l pro-  1.57 mmole),  i n hexane  1.74  (1.11 mL\  mmole),  1.74  and p h e n y l s e l e n e n y l c h l o r i d e  The r e s u l t i n g  t h e n worked up t o a f f o r d  m i x t u r e was s t i r r e d f o r 140b a s an amber  oil.  135  Preparative ethyl Rf  TLC o f t h i s  acetate  0.75; mp  torr;  c r u d e m a t e r i a l on s i l i c a  (1:1) gave 271 mg  6 9 - 7 0 ° ; bp  ( s , 2H), and 7.06-7.57  intensity) ( 1 4 ) , 202  284  ( 1 1 ) , 283  ( 1 8 ) , 125  Anal. Calcd  6 1.40  H  1 2  ( 6 8 ) , 282  1 3  solid:  ( s , 3H), 3.12  ( s , 3H),  (m, 5H); mass s p e c t r u m m/e ( r e l  (68) and 81  for C  ether-  d i s t i l l a t i o n ) 110-112°/0.06  NMR  1  3.66  (61%) o f 140b as a w h i t e  (Kugelrohr  IR 1730 and 1625 cm" ;  g e l with  ( 5 ) , 281  ( 3 6 ) , 280  ( 1 4 ) , 279  (100).  N 0 S e : C, 51.07; H, 4.64; N,  4.97.  2  F o u n d : C, 51.26, H,  4.65; N,  4.97.  2 , 4-Dime t h y l - 3 - ( t r i m e t h y l s i l y l m e t h y l ) i s o x a z o l i n - 5 - o n e (140c)  T h i s compound  was  cedure f o r a l k y l a t i o n n-butyllithium mmole), (171  mg;  114  ethyl Rf  a s a 1.6 M s o l u t i o n  (200 mg;  then was  1.57  acetate)  2H)  and 3.32  184  ( 4 3 ) , 156  mixture  NMR  200 mg  distillation) 6  0.31  Found:  1.74  mmole),  1.74  stirred oil.  f o r 15  The  g e l , 1:1  97-99°/1.6 t o r r ;  ( s , 9H), 1.89  ( 8 9 ) , 96  199.1035.  was  (silica  crude  ether-  IR 1720,  ( s , 3H), 2.09 ( s ,  ( r e l i n t e n s i t y ) 199  (54) and 73  H i g h R e s o l u t i o n Mass Measurement C a l c d 199.1029.  (1.10 mL;  pro-  (64%) o f 140c as a c o l o u r l e s s o i l :  ( s , 3H); mass s p e c t r u m m/e ( 3 9 ) , 127  (176 mg;  140c a s a y e l l o w  by p r e p a r a t i v e TLC  (Kugelrohr 1  i n hexane  The r e s u l t i n g  to give  1620 and 1253 cm" ;  t o the g e n e r a l  mmole) and t r i m e t h y l c h l o r o s i l a n e  worked up t o g i v e  purified  0.70; bp  according  using diisopropylamine  1.57 mmole).  minutes, product  prepared  (100). for CgH^NC^Si:  (100),  136  2,4-Dimethyl-3-(phenylthiomethyl)isoxazolin-5-one  T h i s compound cedure  was p r e p a r e d  for alkylation  mmole),  (342 mg; hours,  114  bp  as a 1.45 M s o l u t i o n  (200 mg;  1.57 mmole).  262 mg  NMR  - 1  7.56  The r e s u l t i n g  mixture  by p r e p a r a t i v e TLC  (71%) o f 140d as a w h i t e  <$ 1.46  was  126 High  spectrum  (87) and 67-68  (silica  solid:  stirred  ( s , 3 H ) , 3.78  m/e  =  Found:  in  (176 mg;  hexane  methyl  was p r e p a r e d  235  1.74  bromoacetate  stirred  low  oil.  7.32-  (100) , 127  67.6). C^2 i3  by t h e m o d i f i c a t i o n  d e s c r i b e d f o r compound  (1.20 mL;  was  62-63°;  H  N 0  2  S ;  235.0667.  T h i s compound  amine  crude  ( s , 2H), and  2,4-Dimethy1-3-(3'-methylpropionate)isoxazolin-5-one  general procedure  The  IR 1725 and 1640  (rel intensity)  (m*, - ^ j ^  for 2  Rf 0.40; mp  R e s o l u t i o n Mass Measurement C a l c d f o r  235.0667.  (1.20 mL;  g e l ,ether) to  132-135°/0.1 t o r r ;  ( s , 3H), 3.22  (m, 5H); mass  (17),  i n hexane  1.57 mmole) and d i p h e n y l d i s u l f i d e  (Kugelrohr d i s t i l l a t i o n )  cm ;  1.74  t h e n worked up t o g i v e 140d as a y e l l o w o i l .  p r o d u c t was p u r i f i e d give  a c c o r d i n g t o the g e n e r a l p r o -  u s i n g d i i s o p r o p y l a m i n e (176 mg;  mmole), n - b u t y l l i t h i u m 1.74  (140d)  mmole), n - b u t y l l i t h i u m 1.74  mmole),  (240 mg;  f o r 2 hours,  The c r u d e  140a, u s i n g  114  o f the diisopropyl-  a s a 1.45 M  (200 mg;  1.57 mmole).  (140e)  solution  1.57 mmole) and  The r e s u l t i n g  t h e n worked up t o g i v e 140e as a  p r o d u c t was p u r i f i e d  mixture yel-  by p r e p a r a t i v e TLC  137  (silica oil:  to give  178 mg  Rf 0.40; bp ( K u g e l r o h r  1740 (s,  g e l , ether)  and 1650 c m  - 1  (57%) o f 140e a s a c o l o u r l e s s  distillation)  9 2 - 9 5 ° / 0 . 1 0 t o r r ; IR  ; NMR <S 1.83 ( s , 3 H ) , 2.50-2.92  3H) and 3.74 ( s , 3H); mass s p e c t r u m m/e  (100),  (m, 4 H ) ,  3.24  ( r e l i n t e n s i t y ) 199  168 ( 3 7 ) , 140 ( 3 1 ) , 127 ( 7 8 ) , 112 ( 2 9 ) , and 96 ( 2 5 ) .  H i g h R e s o l u t i o n Mass Measurement C a l c d f o r C^H^NO^: 199.0845.  Found:  199.0845.  2,4-Dimethyl-3-(4'-bromobutyl)isoxazolin-5-one  T h i s compound cedure  f o ralkylation  n-butyllithium mmole),  parative  using diisopropylamine  then  The r e s u l t i n g  i n hexane  mixture  worked up t o g i v e  TLC o f t h i s  crude  as s o l v e n t gave 60 mg  and  t o the g e n e r a l  pro-  (176 mg; 1.74 mmole), (1.30 mL« 1.74  114 (200 mg; 1.57 mmole) and 1 , 3 - d i b r o m o p r o p a n e (317  1 hour,  0.40;  according  as a 1.34 M s o l u t i o n  mg; 1.57 mmole). for  was p r e p a r e d  (14Of)  bp ( K u g e l r o h r  was a l l o w e d  1 4 0 f as a y e l l o w o i l .  m a t e r i a l on s i l i c a  g e l using  (16%) o f 1 4 0 f a s a c o l o u r l e s s  distillation)  t o stand  oil:  120-122°/0.25 t o r r ;  1645 cm" ; NMR 6 1.81 ( s , 3H), .1.60-2.10 1  Preether Rf  IR 1728  (m, 4 H ) , 2.51  (t,  2H, J = 7 H z ) , 3.24 ( s , 3H) and 3.46 ( t , 2H, J = 5 H z ) ; mass s p e c t r u m m/e (82), ( m  ( r e l intensity)  249 ( 3 7 ) , 247 ( 3 6 ) , 168 ( 1 0 0 ) , 153  140 ( 4 4 ) , 124 ( 4 0 ) , 114-115  *'T4ir  =  1 1 3  - )' 4  9  6  < >' 57  5 5  (m*, ^ y - = 1 1 4 . 3 ) ,  < °)' 5  a  n  d 5 3 ( 6 7 )  113-114  *  H i g h R e s o l u t i o n Mass Measurement C a l c d f o r C g H ^ N G ^ B r : 249.0187,  247.0208.  Found:  249.0186,  247.0211.  138  2 ,4-Dime t h y 1-3 -me t h y l t r i p h e n y i p h o s p h o n i u m i s o x a z o l i n - 5 - o n e  bromide  (141) A  25-mL two-necked  condenser  and  (412  mg;  1.57  tion  o f the  nitrogen  crude  p o r t i o n and  for  3 hours. ether  lization of  141  140a  then  The  was  dry  in tetrahydrofuran  the  mL)  precipitate  to give  141  as  1590  3.00  ( s , 3H),  cm" ;  NMR  1  5.40  Anal. Calcd  ((CD ) SO) 3  (dd,2H, J for C  2 4  H  2 3  = 16  was  mg  allowed  (69%  245-246°;  Hz)  IR  tetrahydrofuran bottom  flask  inlet.  A  dimethyl  of  solution sulfoxide  of  141  (3 mL)  tion  allowed  to stand  hyde  (68 mg?  0.64  from  114)  1735,  J  = 3  7.66-7.97  (m,  Hz), 15H).  4.95;  N,  2.99.  F o u n d : C,  61.33; H,  5.00;  N,  3.11.  (31 mg;  prepared a reflux (300  was  mg; then  followed  0.64  (135) mmole) i n d r y  i n a 25-mL two-necked condenser  0.64  and  by  round  a nitrogen  mmole) i n a n h y d r o u s  added d r o p w i s e and  f o r 15 m i n u t e s .  mmole),  Recrystal-  61.55, H,  2  was  equipped with  washed  N 0 P B r : C,  sodium h y d r i d e  (12 mL)  reflux  and  (KBr)  ime t h y i - 3 - ( 2 ' - p h e n y l e t h e n y l ) i s o x a z o l i n - 5 - o n e A suspension  solu-  to  overall  (d, 3H,  and  reflux  added i n  collected,  <5 1.18  2  A  a w h i t e powder.  507 mp  (10 mL).  was  was  a  triphenylphosphine  (3 mL)  r e a c t i o n mixture  small white c r y s t a l s :  and  equipped with  charged with  f r o m e t h e r - m e t h a n o l gave  as  flask  tetrahydrofuran  resulting  (3x5  1635  2,4-D  inlet  mmole) and  one  with  round b o t t o m  the  Introduction of heating  to  reflux  solu-  benzalde-  139  for  1.5 h o u r s c o m p l e t e d  gave 79 mg tral  the r e a c t i o n .  Workup  and  (58%) o f 135 as a c o l o u r l e s s o i l w i t h  p r o p e r t i e s as t h o s e  reported e a r l i e r  T h i s compound  0.64  135, u s i n g  (300 mg;  mmole) and h e x a n a l  t u r e was  refluxed  yellow s o l i d . gel  141  was p r e p a r e d  6 1.20-1.60  ( 6 7 ) , 166 High  209.1416.  mmole).  The r e s u l t i n g  m a t e r i a l on  (1:1) gave 86 mg  ( s , 3H), 2.1-2.4  (m, 2H); mass s p e c t r u m (17) and 138  m/e  - 1  (rel intensity)  (100). H  T h i s compound  114  15.7 mmole).  N  :  209.1413.  was p r e p a r e d  for alkylation  n-butyllithium mmole),  cm ;  (m, 2H), 3.17 ( s ,  2,4-Dimethyl-3-(3'-hydroxybutyl)isoxazolin-5-one  cedure  (64%) o f 145 a s  R e s o l u t i o n Mass Measurement C a l c d f o r C ^ 2 i 9 0 2 Found:  mix-  silica  IR 1725, 1660, 1625 and 1615  (m, 9H), 1.86  ( 2 7 ) , 153  (31 mg;  t h e n worked up t o g i v e 145 as a  ether  Rf 0.35;  described  sodium h y d r i d e  P r e p a r a t i v e TLC o f t h e c r u d e  3H) and 6.00-6.35 209  mmole), 0.64  f o r 4 hours,  a pale yellow o i l : NMR  0.64  spec-  (145)  by t h e same p r o c e d u r e  (64 mg;  using ether-petroleum  identical  (pg. 1 3 1 ) .  2,4-Dimethyl-3-(1'-heptenyl)isoxazolin-5-one  for  purification  a c c o r d i n g t o the g e n e r a l p r o -  using diisopropylamine  as a 1.09 M s o l u t i o n  (200 mg;  (176 mg;  i n hexane  mixture  was  1.74  (1.60 mL;  1.57 mmole) and p r o p y l e n e  The r e s u l t i n g  (154)  allowed  oxide  mmole),  1.74  (911 mg;  t o stand  for 3  140  hours, TLC  then  worked up t o g i v e  of this  gave  1635 c m (s,  c r u d e m a t e r i a l on s i l i c a  118 mg  (Kugelrohr - 1  154 a s a y e l l o w  oil.  g e l using  (41%) o f 154 a s a c o l o u r l e s s o i l : distillation)  ether  as s o l v e n t  Rf 0.15; bp  107-110°/0.15 t o r r ;  IR 3430, 1730 and  ; NMR 5 1.40 ( d , 3H, J = 6 H z ) , 1.58-1.89  (m, 2H),  1.89  3 H ) , 1.96 ( b s , I H ) , 2.61 ( t , 2H, J = 7 H z ) , 3.25 ( s , 3H) and  3.75-3.94 158  (m, I H ) ; mass s p e c t r u m m/e  ( 1 1 ) , 142 ( 4 4 ) , 112 (28) and 96 High R e s o l u t i o n  185.1051.  Found:  (rel intensity)  This cedure  Mass Measurement C a l c d  f o r C^H^NO^:  185.1049.  compound  mmole),  was p r e p a r e d  foralkylation  n-butyllithium  using  as a 1.43 M s o l u t i o n  The r e s u l t i n g  mixture  w o r k e d up t o g i v e  this  c r u d e m a t e r i a l on s i l i c a  gave 81 mg  - 1  oxide  (690 mg;  f o r 2.5 h o u r s ,  Preparative  TLC o f  g e l u s i n g e t h e r - e t h y l a c e t a t e (1:1)  (30%) o f 155 a s a c o l o u r l e s s o i l :  and 1640 c m  (1.22 mL#* 1.74  was s t i r r e d oil.  pro-  (176 mg; 1.74 mmole),  i n hexane  155 a s a y e l l o w  (lj>5_)  t o the general  diisopropylamine  then  1725  according  114 (200 mg; 1.57 mmole) and e t h y l e n e  15.7 mmole).  185 ( 2 5 ) ,  (100).  2 , 4-Dime t h y l - 3 - (3 ' - h y d r o x y p r o p y l ) i s o x a z o l i n - 5 - o n e  (t,  Preparative  Rf 0.40; IR 3450,  ; NMR 6 1.78 ( s , 3 H ) , 1.76-1.92  (m, 3 H ) ,  2.62  2H, J = 7 H z ) , 3.24 ( s , 3H) and 3.70 ( t , 2H, J = 6 H z ) ; mass  s p e c t r u m m/e  ( r e l intensity)  High R e s o l u t i o n 171.0895.  Found:  171 ( 3 7 ) , 127 ( 1 0 0 ) ,  Mass Measurement C a l c d  171.0894.  and 98  for CgH^2  N 0  3  :  (25).  141  Dihydro-2-methy1-3,4-tetramethyleneisoxazolin-5-one  A 100-mL two-necked r o u n d nitrogen with The  inlet  and s t o p p e r e d  a solution flask  bath  o f 113  was c o o l e d  mL;  hydride  introduced,  and t h e s o l u t i o n  hour.  give  then  over  was a l l o w e d  ( 2 1 ) , 81 High  155.0946.  (50 mL).  i n hexane  The r e s u l t i n g  to s t i r  mixture  (30 mL) was  f o r an a d d i -  a n h y d r o u s magnesium s u l f a t e .  was c o n c e n t r a t e d  80-82°/0.15  (m, 1 0 H ) , 2.90  mass s p e c t r u m  charged  tetrachloride  5% h y d r o c h l o r i c a c i d  m/e  torr;  ( 5 1 ) , 68  oil:  bp  The  (Kugelrohr  IR 1730 and 1635 c m  (m, I H ) , 2.75  (rel intensity)  155  - 1  ;  NMR 6  ( s , 3 H ) , and 3.13 ( 3 5 ) , 138  ( 1 4 ) , 112  ( 3 5 ) , and 67 ( 4 1 ) .  R e s o l u t i o n Mass Measurement C a l c d f o r CgH-j^NC^: Found:  155.0941.  water  and t h e r e s i d u e d i s t i l l e d t o  1.19 g (77%) o f 164 a s a c o l o u r l e s s  1.30-2.00  109  dried  solution  distillation)  septum was  The o r g a n i c phase was s e p a r a t e d , washed w i t h  b r i n e , then  ethereal  with a  a s a 1.0 M s o l u t i o n  20.0 mmole) was added d r o p w i s e . f o r 6 hours,  and  a rubber  equipped  t o -23° i n a d r y i c e - c a r b o n  was s t i r r e d  tional  with  flask  (1.53 g ; 10.0 mmole) i n e t h e r  and d i i s o b u t y l a l u m i n u m  (20.0  bottom  (164)  (m, I H ) ; (100),  142  SECTION I I LACTONE SYNTHESIS VIA B-KETO ESTER DIANION ALKYLATION  INTRODUCTION The  s y n t h e s i s o f medium and l a r g e  lactones  h a s been an o b j e c t o f i n t e r e s t  for  fifty  over  years.  This  interest  r i n g s or m a c r o c y c l i c to organic  chemists  stemmed f r o m  the d i s c o v e r y  of the p r e s e n c e o f p e n t a d e c a n o l i d e  (exaltolide)  97 by  Kerschbaum  (165)  and A - h e x a d e c a n o l i d e 7  t a b l e musk o i l s  (ambrettolide)  (166) i n t h e v e g e -  o f a n g e l i c a r o o t and a m b r e t t e  seed r e s p e c t i v e l y .  (CH ) . 2  8  C=0 (CH ) ^ 2  5  166  As  a result,  routes only  there  to these  ensued v i g o r o u s  and o t h e r  by t h e c h a l l e n g e  Several preparative  to uncover  synthetic  r e l a t e d compounds, prompted n o t  of preparing  t o n e s b u t a l s o by t h e i r  efforts  importance  techniques  the novel  macrocyclic  i n the f r a g r a n c e  were d e v e l o p e d  lac-  industry.  t o form  these  143  large  rings,  generally involving  cyclization  of  bifunctional  98 p r e c u r s o r s under The  next  high d i l u t i o n  conditions  major d e v e l o p m e n t  in t h i s  area occurred  in  1950  99 with  the  the  first  r e p o r t by  Brockmann  and  macrocylic a n t i b i o t i c ,  Actinomyces c u l t u r e .  Henkel  of  picromycin  Soon a f t e r w a r d s ,  the  the  isolation  (167),  from  isolation  of  an  from  167  Streptomyces c u l t u r e s of appeared (167)  t o be  was  chemical  reported  B  1 0 0  degradations  structures and  related  1 0 3  , and  antibiotics  i n s t r u c t u r e and  .  The  activity  to  elegant execution of  l e d t o the e l u c i d a t i o n  o f methymycin  (170)  s e v e r a l other  (168)  magnamycin A  1 0 1  ,  of  erythromycin  (171)  1 0 4  .  The  which picromycin  classical the A  term  gross (169)  1 0 2  'macrolide'  144  mycaminosyl  145  was  originally  otics  1  0  4  ,  3  which  containing  few  However, as  of  their  in  the  of  lactone  this  has  macrolide to  the  by  the  chiral  A.  resulted  Synthesis  need  of  be  ring  residues.  macrocyclic  has  gradually  a l l natural  comfound  products  of  1 0 5  Nevertheless,  i n t o an  new  methods  aliphatic  total In  i n the  synthesis  particular,  large-sized lactones  past of  interest  early for  moiety  large-sized lactones.  forthcoming  .  demonstration  i n tremendous  to devise  centers  i n the 8  now  more s u g a r  resulted  of m a c r o l i d e s .  antibiotics^ '  these w i l l  antibi-  lactone  compounds and  has  construction  formation  or  'macrolide'  novel  t o b o t h p r o b l e m s have been and  a large  encompassing  importance  synthesis  the  term  these  were hampered  methods f o r  one  c l a s s of  ring.  of  i n t r o d u c t i o n of  by  new  naturally occurring  the  context  clinical  total  efforts  b o n d s , and  number  isolation  this  characterized  increased,  a large The  the  are  i n a broader  with  to represent  double  the  pounds has use  coined  Solutions  ten  years,  a number  several  have been  and  of  approaches  reported  and  reviewed.  of m a c r o c y c l i c  lactones  via  (jj-halocarboxylic  and  one  acids This direct,  approach  syntheses  provided of  simple  the  first,  macrolides  such  of  the  most  as e x a l t o l i d e  98 (165)  and  ambrettolide  p o n d i n g w-bromo- or  (166)  .  iodo-alkanoic  C y c l i z a t i o n of acids  172  the  could  be  correseffected  146  by  heating  with  silver  mmole/day/liter taining 61).  of  potassium  By  oxide  solvent) carbonate  t h i s method, 10  122,  or of  by  slow a d d i t i o n  the  haloacid  or p o t a s s i u m  t o 18-membered  (e.g.  6.6  to a s o l v e n t  hydroxide  con-  (equation  lactones could  be  X=Br or I 98  obtained The sents  in fair  t o good  cyclization  the  however, two cedures.  associated  on  Many o f  provide  than  the new  precursors  the  newly  While c o n c e p t u a l l y the employment o f  a long chain  g r o u n d s due  b r i n g i n g i t s two rather  many o f  during  c l o s u r e of  entropy  with  intermolecular  ring  behind  formation.  problems a r i s e  First,  unfavourable  tion  of such open, l o n g c h a i n  guiding principle  methods f o r m a c r o l i d e  occurs.  yields  t o the  ends  developed simple, such  precursor  loss  together.  of  both  of  these  is  Secondly, often  s y n t h e t i c methods f o r m a c r o l i d e or  pro-  entropy  intramolecular cyclization  s o l u t i o n s t o one  repre-  problems.  forma-  I  147  B.  Synthesis  of m a c r o c y c l i c  lactones  v i a co-hydroxycar b o x y l i c  acids i)  By d i r e c t The  by  Stoll  tion  ester i f i c a t i o n  most d i r e c t  route  and Rouve  Solutions  acids  173. In t h i s  study  reported  esterificat h e use o f  ( e . g . 0.0002-0.0008 M) and c a t a l y s t s s u c h as  b e n z e n e s u l f on i c o r j o - t o l u e n e s u l f o n i c essential  l a c t o n e s , as  , i n v o l v e s the i n t r a m o l e c u l a r  of (jj-hydroxyalkanoic  dilute  to macrocyclic  (equation  acid  were  found  t o be  62).  173. The  synthesis  of l a c t o n e s with  atoms has been r e p o r t e d , the  case  of nonanolide  with  yields  as many as t w e n t y - f o u r ranging  ring  from c a . 1% f o r  (174) t o 87% f o r e x a l t o l i d e  (165)  1 0 6  .  148  0  165  174  Nevertheless, contaminated ation  has  effected yields  with  been the  by  this  By  direct  using  175  by  i s cumbersome  t r i m e r s , and  by  S c o t t and  lactonization  boron  trifluoride  polystyrene  of  and  polymers.  product  who  have  oj-hydroxy  acids  in  1  7  is  A recent  Naples ^ ,  etherate  b e a d s as  the  i n the  vari-  improved  presence  of  catalyst.  transesterification  This tones  dimers,  reported  unfunctionalized  ii)  procedure  approach the  (equation  i n v o l v e s the  internal 63).  An  preparation  transester if ication early  adaptation  of m a c r o c y l i c  o f oo-hydroxy  lac-  esters  of t h i s procedure  was  (63)  175  149  reported linear  by H i l l  and C a r o t h e r s  polyesters  176 under  x u o  ,  vacuum  who  found  that p y r o l y s i s of  a t c a . 270°C,  sence o f a c a t a l y s t , r e s u l t e d  i n the d i s t i l l a t i o n  and  v i a ester  dimeric  products obtained  0  0  o f monomeric  exchange (equation  ft  64).  =0 (64)  -0-  —0  -ft—0  i n the p r e -  1Z£ Pyrolysis in  of linear  t h i s manner  yields  ranging  polyesters  gave l a c t o n e s from a t r a c e  of to-hydroxyalkanoic  with  acids  11 t o 17-membered  (14-membered)  t o 90%  176  rings i n  (15-membered),  109 S u b s e q u e n t work  by S t o l l  phase p y r o l y s i s o f the e s t e r s (165) tion , lyst  i n y i e l d s o f c a . 50%.  and B o l l e 177 g e n e r a t e s  L2  17  17Za,R=H b,R=Me  t h a t gas  pentadecanolide  The a u t h o r s have p o s t u l a t e d  and s u b s e q u e n t d e p o l y m e r i z a t i o n _ . ... .. 108 surface in this reaction  HC00-(CH ) C00R 14  has shown  of polyesters  T i 0 or J> Zr0 , A 2  7  2  16£  forma-  on t h e c a t a -  150  Recent v a r i a t i o n s o f these tion  p r o c e d u r e s have f o u n d a p p l i c a -  i n the s y n t h e s i s o f m a c r o c y c l i c  ever,  t h e u s e o f t h i s method  lides  appears  which c o u l d  t o be p r e c l u d e d  alter  musk l a c t o n e s ' ' ' . 1  i n the s y n t h e s i s by t h e h i g h  How-  0  o f complex  reaction  macro-  temperatures  many o f t h e f u n c t i o n a l g r o u p s on t h e l a c t o n e  r ing. The using the  l a c t o n i z a t i o n of w-hydroxyesters  sodium a l k o x i d e s  cyclization  precursor 178  direct  with  h a s a l s o been  o f hydroxy methyl e s t e r  179 h a s been a c c o m p l i s h e d a dilute  t-amyl a l c o h o l  reported  1 1 1  toluene .  .  i n low y i e l d  s o l u t i o n o f sodium  to drive  F o r example,  178 t o t h e  zearalenone  by t r e a t i n g  t-amylate i n  The b y - p r o d u c t m e t h a n o l was  removed by d i s t i l l a t i o n  178  1 1 1  in solution  the r e a c t i o n t o  continuously completion.  179  151  iii)  By  carboxylic acid activation  The t o 179  desire  to perform c y c l i z a t i o n s ,  illustrated  the c o n s i d e r a t i o n  above, u s i n g  able d i l u t i o n The  intramolecular  l a c ton i z a t i o n of oj-hydroxy a c i d s their  trifluoroacetic  reaction with  the  with  h y d r o x y a c i d 181 boron t r i b r o m i d e  led  to  the  free  hydroxyl  yield  65).  the  suit-  conditions. 173  has  been  achieved,  phosgene-triethylamine  For  trifluoroacetic  to cleave 112  in varying  of  anhydride through the  (equation  (18 2)  attack  o c c u r s under r e l a t i v e l y m i l d  m i x e d a n h y d r i d e s 180  by  less forcing conditions  178  the newly a c t i v a t e d c a r b o x y l i c a c i d under  i n t h i s m a n n e r , by or w i t h  t h a t of  o f methods t o a c t i v a t e the c a r b o x y l i c a c i d .  In t h i s p r o c e d u r e , the f u n c t i o n a l i t y on  s u c h as  formation  of  example, treatment  anhydride,  a.r.yl e t h e r s ,  gave  of  followed zearalenone  152  )H  0'  1) (CF CO) 0 3  0 2)  ;  2  BBr  ;  3  HO'  MeO  involves  method  their conversion  f o r the a c t i v a t i o n o f c a r b o x y l i c to N-acylimidazolides  ment w i t h N N ' - c a r b o n y l d i i m i d a z o l e f  (18 3)  113  c o w o r k e r s have shown  be p r e p a r e d reaction  that  acids  184 by t r e a t -  R e c e n t l y , Masamune  183  and  0  182  181  An a l t e r n a t e  0  184  N-acylimidazolides  from p h e n y l or 2 , 2 , 2 - t r i f l u o r o e t h y l  with N - t r i m e t h y l s i l y l i m i d a z o l e  184 may esters  by t h e i r  (185) i n t h e p r e s e n c e o f  114 a c a t a l y t i c amount o f s o d i u m p h e n o x i d e  also  (equation 66).  153  N RCOOR' •  C H QNa 6  TMS-N  RCO-H'  5  (66)  185  R= A r y l , alkyl or cycloalkyl R= C H or C F C H 6  5  3  2  The c y c l i z a t i o n o f a c y l i m i d a z o l i d e s  184  i n d i l u t e s o l u t i o n by t h e i r t r e a t m e n t w i t h base.  For example,  catalytic 187  1 1 5  the r e a c t i o n  has been  a catalytic  of imidazolide  amount o f s o d i u m t - a m y l a t e gave  effected  the  amount o f  186 w i t h  a  tridecanolide  .  OCOCH3 1-AmONa —  r"  ^0  > •  0^0 18£ Carboxyl a c t i v a t i o n v i a imidazolide been e m p l o y e d phorin  (189).  by C o l v i n This  et a l .  antifungal  1  1  6  formation  has  in their synthesis  also  o f pyreno-  and c y t o s t a t i c d i l a c t o n e  was  154  prepared  by  the  c y c l i z a t i o n of  amount o f  1, 5 - d i a z a b i c y c l o Q  solution,  followed  by  imidazolide  188  . 3 . <5] non-5-ene  h y d r o l y s i s of  the  with  (DBN)  a catalytic  in d i l u t e  dithioketals.  1) DBN 2) NCS,AgN0  3  188 An  analogous  accomplished dinium  67)  1  1  7  .  iodide This  by  lactonization  carboxyl  (190)  of  activation  i n the  presence  oj-hydroxy with of  a c i d s has  been  1-methy1-2-chloropyri-  triethylamine  r e a c t i o n proceeds v i a formation  of  the  (equation pyridinium  192  155  intermediate  191,  followed  hydroxyl  function to give  Lactones  with  fashion  up  by n u c l e o p h i l i c a t t a c k the  lactone  and  the  of  the  2-pyridone  t o s i x t e e n members have been p r e p a r e d  in r e f l u x i n g dichloromethane  or  192.  in  this  use  of  acetonitrile.  118 Recently,  Bartlett  and  Green  t h i s procedure  in their  s y n t h e s i s of  slow a d d i t i o n o f hydroxy a c i d ing  solution  (194) in  37%  i n 3:1 yield  of  as  a mixture  of  methoxymethyl ether A  A  the  (196).  o f C-15  epimers.  sodium b o r o h y d r i d e ,  (196).  H 196  with  The  t r i e t h y l a m i n e to a  reflux-  tetrafluoroborate  d i c h l o r o m e t h a n e - a c e t o n i t r i l e gave compound  function with  brefeldin  and  brefeldin  l-methyl-2-chloropyridinium  ketone the  193  have r e p o r t e d  Reduction  followed  trifluoroacetic  19 5  of  the  by h y d r o l y s i s  acid  gave  156  iv)  By h y d r o x y l A new  activation  s t r a t e g y f o r the r i n g  c l o s u r e o f to-hydroxy a c i d s  has  119 been  reported  function  temperature e f f e c t s carboxylate  , wherein  the c a r b o x y l a t e  the  anion  hydroxyl a c t s as t h e  I n t h i s method, the r e a c t i o n o f t h e h y d r o x y  triphenylphosphine  C  et a l .  i s a c t i v a t e d and  nucleophile. with  by K u r i h a r a  197.  and d i e t h y l a z o d i c a r b o x y l a t e  ring  c l o s u r e v i a the  acid  a t room  alkoxyphosphonium  T h i s p r o c e d u r e has been  a p p l i e d by W h i t e  and  CH OH 2  COOH  • EtOOC-N=N-COOEf  (^J=0  (C H ) P 6  5  3  CH -0-PR 2  + R  3  P  >(Et00C-NH-h  00"''  "  0  3  197  coworkers tion  in their  o f the h y d r o x y  azodicarboxylate  synthesis of vermiculine  acid  provided  198  with  (199) .  triphenylphosphine  vermiculine  (199)  i n 15%  Cycliza-  and yield.  diethyl  157  (Et00C-N^ (C H ) P 6  5  9  ^>  0:  3  HOOC 0' 199  198  A similar  a p p r o a c h h a s a l s o been  reported  i n the s y n t h e s i s  121 of pyrenophorin hydroxy a c i d diethyl  (189) by G e r l a c h  200 was d i m e r i z e d  azodicarboxylate.  groups then  et a l .  using  (189).  (C H ) P 6  2)  5  3  p_-TsOH Me C0 2  2QD.  c a s e , the  t r i p h e n y l p h o s p h i n e and  1) ( E t 0 0 C - N ± o H  In t h i s  H y d r o l y s i s o f the k e t a l p r o t e c t i n g  gave p y r e n o p h o r i n  °°  .  J  158  v)  By a c t i v a t i o n This  s t r a t e g y arose  activation mit  rapid  providing  o f both  o f both  from  the b e l i e f  that  groups  simultaneous  t h e c a r b o x y l and h y d r o x y l g r o u p s would  cyclization access  t h e c a r b o x y l and h y d r o x y l  per-  under e v e n m i l d e r c o n d i t i o n s , t h e r e b y  t o complex, p o l y f u n c t i o n a l  lactones.  Corey  122 and  Nicolaou  activation" derivative  e n v i s i o n e d t h a t one way would  be t o u t i l i z e  w h i c h would  favour  group t o the c a r b o x y l i c a c i d for  the case  such  "double  an a p p r o p r i a t e c a r b o x y l i c a c i d  proton oxygen.  of 2-pyridinethiol  to e f f e c t  transfer This  from  the h y d r o x y l  idea i s i l l u s t r a t e d  e s t e r s 202 i n Scheme 9. The  201  202  M  H 205 Scheme 9;  201  204  Lactone formation v i a double 2-pyridinethiol esters.  activation  using  159  key  element  -ofi this  b a s i c n i t r o g e n of from  the  tion  of  scheme  the p y r i d i n e  nucleus  i n the p r o t o n  h y d r o x y l g r o u p t o c a r b o n y l oxygen the d i p o l a r  i n t e r m e d i a t e 203  an e l e c t r o s t a t i c  attraction,  and  with concomitant  elimination  of  high d i l u t i o n comparable reacting  techniques  p a t h may  i n 202.  t o 204  provides  feasible  transfer Cycliza-  the d e s i r e d  two  by  lactone  The  a requirement, with  the  is facilitated  2 - p y r i d t h i o n e 205.  is clearly  a l s o be  of  i n v o l v e s the p a r t i c i p a t i o n  use  of  since a  molecules  of  202  intermolecularly.  Accordingly,  the  2-pyridinethiol esters  202  were  prepared  123 by  t h e method d e v e l o p e d  by Mukaiyama  disulfide  (201)  i n the p r e s e n c e  resulting  thiol  e s t e r s were t h e n  dilution in  fair  cyclic  c o n d i t i o n s and t o good y i e l d  dilactones  208  , employing  o f t r i p h e n y l p h o s p h i n e . The heated  tion"  i n x y l e n e under  gave t h e c o r r e s p o n d i n g  lactones  high 207  t o g e t h e r w i t h v a r y i n g amounts o f m a c r o (Table X).  206  In a s u b s e q u e n t  di(2-pyridyl)  207  study  mechanism p r o p o s e d  , evidence  i n Scheme 9 was  f o r the  208  "double  obtained.  activa-  Thus,  the  160  Table  X.  C y c l i z a t i o n of 2 - P y r i d i n e t h i o l carboxylic Acids  Esters  o f w-Hydroxy-  1 2 5  •OH  1)(C H ) P 6  (CH^OOH  2 )  X  y  5  l  e  n  3  e t  (fjl  /-^o  ^cocv  X^J  00C  1  L  2GZ  206 Solvent  n  208 208  207 Isolated Y i e l d (%)  -  Isolated Y i e l d (%)  71  7  xylene  8  41  10  xylene  47  30  11  xylene  66  7  12  xylene  68  6  14  xylene  80  5  5  benzene  7  161  rate  of c y c l i z a t i o n  209a  of 16-hydroxyhexadecanoic  to hexadecanolide  found  t o be i n f l u e n c e d  triphenylphosphine thione or a c e t i c zation  by t h e a d d i t i o n  acid.  ester  by a c i d ,  i n the r e a c t i o n  HO(CH ) COS-^ 1 5  of triphenylphosphine,  triethylamine,  These r e s u l t s  was n o t c a t a l y z e d  2  thiol  (210) i n r e f l u x i n g benzene was n o t  oxide,  taminants present  acid  triamylamine,  indicated  that  2-pyrid-  the c y c l i -  b a s e , or any o f t h e c o n mixture.  F u r t h e r m o r e , the  (CH ) 2  N  C=0  15  209a  thiol  esters  2fJ9b.and 2 0 9 c . w h i c h c a n n o t f o r m h y d r o g e n  intermediates  were  found n o t t o c y c l i z e  heating.  HO(CH ) COS  HO(CH ) COS  209b  209c  2  The  2  15  utility  of macrocyclic  of 2-pyridinethiol  lactones  of several  complex  esters  15  i n the s y n t h e s i s  h a s been d e m o n s t r a t e d  c o w o r k e r s who, i n r e c e n t sis  on  years,  by C o r e y a n d  have s u c c e e d e d  ,105b,127 macrolides"  bonded  For  i n t h e syntheexample, i n  162  the  synthesis of zearalenone  a c c o m p l i s h e d by f i r s t di (2-pyridyl)  treating  disulfide  then h e a t i n g the  ( 1 8 2 ) , t h e k e y l a c t o n i z a t i o n was the  i n the  hydroxy acid  211 w i t h  presence o f triphenylphosphine,  r e s u l t i n g t h i o l ester  in dilute  benzene.  H y d r o l y s i s o f t h e k e t a l and t e t r a h y d r o p y r a n y l e t h e r  protecting  122 g r o u p s gave z e a r a l e n o n e  (18 2)  i n 75% y i e l d  I n an e f f o r t t o m a x i m i z e t h e the  double a c t i v a t i o n method, the  overall  e f f i c i e n c y o f c y c l i z a t i o n by u s e o f a number o f o t h e r 126  heterocyclic  d i s u l f i d e s was a l s o  212-214 were f o u n d than the  t o be l e s s e f f e c t i v e  di-2-pyridyl  derivative.  212a;X=NMe,R = H b X=0 , R = H C ; X = S , R=H d X = S , R=N0  213  ;  ;  investigated  2  .  Disulfides  i npromoting c y c l i z a t i o n  On t h e  o t h e r hand, use o f  2K  163  the  imidazolyl disulfide  215  was  shown t o e x h i b i t e x c e p t i o n a l  promise, since l a c t o n i z a t i o n employing t h i s reagent could effected very when 215,  r a p i d l y e v e n a t room t e m p e r a t u r e .  triphenylphosphine,  were a l l o w e d  and  (210)  example,  16-hydroxyhexadecanoic a c i d  t o r e a c t i n benzene s o l u t i o n ,  hexadecanolide  For  be  c o u l d be d e t e c t e d  the  by VPC  formation  of  analysis after 12 6  o n l y t e n m i n u t e s , i n y i e l d s o f 20-37%  (equation  68)  (68)  215 H o w e v e r , s u b s e q u e n t t o t h i s p e r i o d no occurred  e i t h e r upon p r o l o n g e d  y i e l d s were l a t e r N-acyl  derivative stituted  217,  exposure or h e a t i n g .  f o u n d t o be due  d e r i v a t i v e 216 and  imidazole  further lactone  to competitive  a t the expense o f the  r i n g which would h i n d e r  \COR 216  211  low of  S-acyl  of a sub-  formation  I  These  formation  required  t h i s r e s u l t s u g g e s t e d t h e use  formation  of  216.  164  I n d e e d , the  disulfides  strategically superior  placed  218  219,  to suppress  to a l l reagents  from u)-hydroxy a c i d s .  and  hydroxyhexadecanoic a c i d  N - a c y l a t i o n , were f o u n d  f o r the  For  i n which a t - b u t y l group i s  formation  of  simple  e x a m p l e , the c y c l i z a t i o n  to hexadecanolide  to  be  lactones of  16-  (210), cf. equation  126 68, was  accomplished  i n 96%  yield  by  this  219  218  Recently,  method  C o r e y and  c o w o r k e r s have r e p o r t e d  the a p p l i c a t i o n  127 of  t h i s procedure  i n the  s y n t h e s i s of e r y t h r o n o l i d e A  (220)  128 and  B  (221)  .  the c o r r e s p o n d i n g p h o s p h i n e , by macrocyclic  The  key  lactonization  s t e p was  hydroxy a c i d s , d i s u l f i d e  heating  lactones  0  HoY[OH  in a dilute i n 30  and  50%  toluene  219  performed and  triphenyl-  s o l u t i o n and  yield respectively.  0  using  gave  the  165  A modification  of  the  Corey double  a c t i v a t i o n method  is  129 due  to Gerlach  (AgC10 tion  4  as  or  and  Thalmann  , who  found  that  AgBF^) a c t i v a t e s 2 - p y r i d i n e t h i o l e s t e r s  shown  i n 222.  The  undergo f a c i l e  solution.  by  a c t i v a t e d w-hydroxyalkanoic  ion complexaacids  222b  222a 222  silver  cyclization  This modification  a t room t e m p e r a t u r e  has  found  i n benzene  applications in  the  130 synthesis in  the  of  cyclization  plished  (224)  a number o f m a c r o c y c l i c  synthesis  (224),  tion.  of  using  the of  silver  in greater  p l a n t growth  the  hydroxy  perchlorate  Hydrogenolysis than  lactones  of 50%  the  yield  inhibitor  thiol  ester  in a dilute  benzyl  ether  overall  accom-  acetonitrile  solu-  lasiodiplodin  A  3  2  was  .  CH CN,A  C H CH 0  example,  OMe 0 1)AgCl0  5  223  gave 1 3 0 0  For  lasiodiplodin  OH  OMe  6  .  2)H ,Pd-C  >  HO  2  221  22k  166  A  similar  a p p r o a c h has  a l s o been r e p o r t e d by Masamune  and  131 coworkers  , involving  o f w-hydroxy a c i d s , sulfonate pared  could  225 be  mercuric  thiolates  225  (226),  (equation prepared  imidazoles  The  227  69)  1 3 1 a  '  acid or  b  .  chlorides  by  70)  >  reaction  1  1  3  of '  1  3  1  or  with the  the  .  Cyclization  phos-  thiolate  thiol  esters  228  acyl  of  the  RCOSR  RCOOH  > RC00P0(0Et) (EtO) POCl  2  2  RCOOH  ^  RCO.-N  RSH  ^  228  RCOSR  \=l  228  227  resulting  RSTl  /  ,  thiol esters  (69)  22£  226  under  with  with d i e t h y l  corresponding  c  pre-  reaction  the  RCOCl  methane-  c o u l d be  by  treatment  Alternatively,  via thiolysis  (equation  benzenethiol esters  e s t e r s 228  f o l l o w e d by 1 3 2  and  trifluoroacetate  thiol  the c o r r e s p o n d i n g  phor o c h l o r i d a t e salt  and  as c a t a l y s t s .  from  thallous  t-butylthiol  with mercury  v e r y m i l d cond i t i o n s .  salts  Subsequent  furnished lactones  s t u d i e s have r e v e a l e d  (70)  167  the  metal-catalyzed  coordination t i o n 71)  lactonization  of the a l c o h o l  proceeds p r i m a r i l y  and t h e s u l f u r  through  t o the metal  (equa-  131b  (71)  The  utility  o f t h i s t e c h n i q u e h a s been d e m o n s t r a t e d  i n the  131 s y n t h e s i s o f methymycin The  (173) by Masamune and c o w o r k e r s  k e y c y c l i z a t i o n s t e p was e f f e c t e d  t h i o l ester  by e x p o s u r e o f t h e h y d r o x y  229 t o m e r c u r i c t r i f l u o r o a c e t a t e  and g a v e , a f t e r  in acetonitrile  removal of the t - b u t y l d i m e t h y l s i l y l  group, methynolide  ( 1 7 3 , R=H)  i n 20-30% y i e l d .  0  0  H CH CN 3  1Z1  protecting  168  A p o s s i b l e disadvantage eTectrophilicity ever,  of mercury  i n most c a s e s  sulfur  exceeds  deficient  the  according  By  t o the  r i n g s has simple  ring  toward o r d i n a r y  only 230  i n the was  230  with  desired  1 0 5 a  of carbon-carbon  (II) or  in  the  attempted  silver  toward  cyclization found  to  applied with  of  trifluoroacetate,  described  earlier,  double  bonds  some s u c c e s s  t o the  this  respect,  b i c y c l i c enol ethers  with  the  proven  t o be  very  gave  .  In  f u s i o n has  lactones.  be  Nevertheless,  c o n c e p t o f c l e a v i n g b i c y c l i c compounds t o c r e a t e been  How-  electron  t h i s problem  procedure of Gerlach  macrocyclic  cleavage  ester  (2^) as  cleavage  The  r e a c t i v i t y of mercury  seco-acid  thiol  lies  reactive alkenes.  to a successful l a c t o n i z a t i o n .  cytochalasin-B vi)  procedure  ( I I ) toward  its reactivity  of c y t o c h a l a s a n - B  treating  the  d o u b l e b o n d s , and  detrimental  to t h i s  synthesis the  since  of  oxidative  d o u b l e bond  valuable,  large  this  at  the  reaction  169  generates a large step  (equation  r i n g and a l a c t o n e  72).  functionality in a single  These o x i d a t i o n s  may  be p e r f o r m e d  using  0 (CH ) 2  [0]  2'm  n  (  7  2  )  0  m-chloroperbenzoic  a c i d , chromic  a c i d , hydrogen p e r o x i d e or  133 ozone This number  procedure  o f medium  has been a p p l i e d  and l a r g e  i n the s y n t h e s i s  r i n g keto l a c t o n e s .  of a  F o r example,  oxidation tone  o f 231 w i t h m - c h l o r o p e r b e n z o i c a c i d gave t h e k e t o l a c 134 232 i n s a t i s f a c t o r y y i e l d . R e c e n t l y , Wakamatsu e t  mCPBA CH Cl 2  2  231  al. by  have d e s c r i b e d a slight  oxidation  232  the s y n t h e s i s  modification  of the b i c y c l i c  of this diol  o f d i p l o d i a l i d e C (235)  route.  233 gave  Lead  tetraacetate  the keto l a c t o n e  234  170  in nearly q u a n t i t a t i v e y i e l d , diplodialide vii)  By  C  (235) by a s e r i e s o f  intramolecular  The p r e p a r a t i o n carbon-carbon of  bond  attention.  nition  This  of macrocyclic  formation interest  More  important,  preparation  of lactones  potentially  offers  design  c o n v e r g e n t scheme may portions and  final  ring  closure.  have been d e v e l o p e d  formation  l a c t o n e s by  has p a r t i a l l y  however, was  intramolecular  a r i s e n out of s u c h bond  the r e a l i z a t i o n  v i a carbon-carbon  bond  recogforma-  t h a t the  in synthetic  For example, a  i n w h i c h t h e a l c o h o l and a c i d  independently, Accordingly, will  deal  formation  degree of f l e x i b i l i t y  lactonization routes.  and t h e s e  into  has r e c e n t l y commanded a g r e a t  be e m p l o y e d  are synthesized  bond  a v a i l a b l e to e f f e c t  a greater  than c o n v e n t i o n a l  then c o n v e r t e d  steps.  carbon-carbon  o f t h e many methods  tions.  w h i c h was  now  prior  to ester i f i c a t i o n  a number o f p r o c e d u r e s be  reviewed.  171  The o f an  first  approach  involves  activated phenylthio  the  intramolecular alkylation  compound.  T h i s p r o c e d u r e has  been  136-138 u s e d by  Tsuji  and  coworkers  of  simple  of  recifeiolide  by  slow a d d i t i o n of  potassium  macrocyclic  lactones.  (237)  the  the  key  For  ring  phenylthio  synthesis  reduction  in  yield  e x a m p l e , i n the  c l o s u r e was i o d i d e 236  of  the 136  phenylthio  Verhoeven of  tion  lactones 73).  (237)  THF Ra-Ni  0^0  5  s i m i l a r a p p r o a c h has 137  stabilized  palladium(0)  sized  Raney  221  A conceptually  by  to a s o l u t i o n of  2  236  reaction  accomplished  overall  SC5H5 2)  and  synthesis  g r o u p gave r e c i f e i o l i d e  1) KN(TMS)  Trost  o f a number  bis(trimethylsilyl)amide in tetrahydrofuran.  nickel 60%  i n the  .  In  this  study,  anions with  c o m p l e x e s was under m i l d  been d e s c r i b e d  found  conditions  • intramolecular  the  allylic  acetates  to give and  by  catalyzed  medium- and  i n good y i e l d s  M e c h a n i s t i c a l l y , the r e a c t i o n i s b e l i e v e d  to  large(equa-  proceed  172  PdL  o=c  A  (73)  0=  9>  E = Electron withdrawing group L = Neutral ligand e.g. (C H ) P 6  5  v i a an i n i t i a l d i s s o c i a t i o n o f t h e p a l l a d i u m ( 0 )  3  catalyst,  f o l l o w e d b y f o r m a t i o n o f an a l l y l - p a l l a d i u m IT-complex 238 . Cyclization of this activated intermediate provides a n-olefin complex 239, which s u b s e q u e n t l y and  regenerated  catalyst  dissociates t o give the lactone  (Scheme 1 0 )  1 3 9 b  .  Pdl_  PdL  Pdl_  While 2  cyclization of  * 2L  2  OAc  238  PdL  239 Scheme 10  Mechanism proposed f o r p a l l a d i u m - c a t a l y z e d c y c l i z a tionsl39b.  173  238 a  may  and  be  e f f e c t e d at  the  b i n 238 , e x c l u s i v e c a r b o n - c a r b o n  a was the  theoretically  found  in a l l cases.  This  of  a six-membered  source of well  this  several example,  ring  at p o s i t i o n  noteworthy  formation,  is usually highly  regioselectivity  a p p l i c a t i o n of macrocyclic i n the  with  this  lactones  synthesis  f o r m i n g r e a c t i o n was  in  since  favoured.  forma-  The  i n these c y c l i z a t i o n s i s  of  procedure has  then  amount o f  and  the  a l s o been  by  synthesis  reported  not  slowly  adding  the  of  139b  (237) , the  t r e a t i n g the  For  key  allylic  ring acetate  resulting  anion  tetrakis(triphenylphosphine)palladium-  in refluxing tetrahydrofuran.  boxylation,  to  recifeiolide  performed  sodium h y d r i d e ,  to a c a t a l y t i c (0)  formation  as  understood. The  240  ring  bond  is particularly  c a s e of e x c l u s i v e eight-membered  tion  p o s i t i o n s denoted  subsequent  Ester  hydrolysis, decar-  s o d i u m amalgam r e d u c t i o n  of  the  sul-  140 fone gave r e c i f e i o l i d e  0  AcO  (237)  6  3) 240  yield  overall  1) NaH, THF ((C H ) P) Pd^ 2)  MeOOC  i n 63%  5  3  0  /t  Me^N* OAc" Na/Hg 237  174  a l t e r n a t e method f o r the  An lactones tion  1 4 1  0-d  i n v o l v e s t h e use o f an (equation  74).  0"—CHO  Base _bose  example,  sodium  by t h e g r o u p s o f S t o r k  Wittig  S  \^  1 4 z  lactones  i n 70% y i e l d  .  (74)  y\\  and N i c o l a o u " " " in yields  i n dimethoxyethane under h i g h ] 42  242  reac-  / ° ^ ~ > HH  0  of  t r e a t m e n t o f t h e a l d e h y d o p h o s p h o n a t e 241  hydride  t i o n s gave  ^ =C  Solvent  s y n t h e s i s o f 13 t o 18-membered For  intramolecular  macrocyclic  T h i s a p p r o a c h has r e c e n t l y been  PO(OR)-  demonstrated  c o n s t r u c t i o n of  dilution  4J  i n the  45-70%. with condi-  175  C.  The  present  The  availability  large  ring  approach o f new  l a c t o n e s has  methods f o r the c o n s t r u c t i o n o f  resulted  i n the  successful synthesis  o f a number o f n a t u r a l m a c r o c y c l i c l a c t o n e s . surveyed  procedures,  vantages  which p r e v e n t  most commonly high  low  reactive  high d i l u t i o n  which might c i r c u m v e n t at the  from  a variety  general use.  conditions.  and  search for  these d i f f i c u l t i e s ,  are  requirements  or c a t a l y s t s , The  of d i s a d -  These problems  f o r m a t i o n , and  reagents  the  for  par-  procedures  therefore,  remains  forefront of organic synthesis.  For  a number o f y e a r s , our  possibility  that  3-keto e s t e r alkylation  large  l a b o r a t o r y has  r i n g s may  dianion chemistry.  be  product  ( e x c e p t n=3).  gives a mixture  Early  244,  w i t h no  of  efforts  had  evidence  the  f o r any  N e v e r t h e l e s s , the c y c l i z a t i o n  2  shown  using that  acetoacetate with l , n -  t h e b r o m i d e 243  (CH )  27  explored  conveniently prepared  o f t h e d i a n i o n 2_7 o f m e t h y l  dibromoalkanes lated  their  y i e l d s , dimer  temperatures,  ticularly  however, s u f f e r  Most o f  and  cyclic  bisalky-  product  of bromides  243  (CH k  n  2  m  2hk  176  (n=4  o r 5) c o u l d  of sodium  be e f f e c t e d by t r e a t m e n t w i t h one e q u i v a l e n t  methoxide  0  2  at reflux  (equation 7 5 ) .  0  0 OMe  (CH )  i n methanol  0  A^NT^OMe  NaOMe MeOH,A  n  I Br  241  Cyclization and  o f t h e d i a n i o n o f 243 (n=4 o r 5) was a l s o  t h i s r e s u l t e d i n the formation  0  of c y c l i c  OMe 1)NaH,THF (CH ) 2  B - k e t o e s t e r s 245.  0  0  2)  LDA  (CH ) 2  >  attempted  0  n  V  n  I Br  The  2A5.  2A1  extension  o f t h e s e methods t o t h e p r e p a r a t i o n  of large  144 r i n g s , h o w e v e r , p r o v e d t o be f u t i l e Recently,  Yonemitsu  and c o w o r k e r s h a v e r e p o r t e d  a ver145  s a t i l e new method f o r t h e p r e p a r a t i o n  of B-keto e s t e r s  T h i s p r o c e s s i n v o l v e s t h e a c y l a t i o n o f Meldrum's a c i d  177  (246)  X 4 P  ,  2,2-dimethyl-1,3-dioxane-4,6-dione, with  to i n i t i a l l y of  provide  the a c y l Meldrums' a c i d s  these d e r i v a t i v e s then a f f o r d s  carbon d i o x i d e  prepared utility cation  11).  A number o f B - k e t o e s t e r s  i n t h i s study i n y i e l d s ranging  i n natural product  synthesis  1 4 7  '  were  f r o m 6 9 - 9 2 % and t h e  1 4  in i t s appli-  ^.  i n t e r e s t i n t h i s p r o c e s s was s t i m u l a t e d  by t h e  reali-  t h a t a l c o h o l y s i s o f t h e a c y l Meldrum's a c i d 247 w i t h  l,n-hydroxyhalide ideally  76)  on t h e e s t e r c a r -  o f t h i s method h a s a l s o been d e m o n s t r a t e d  Our zation  (equation  Alcoholysis  B - k e t o e s t e r s , a c e t o n e and  through n u c l e o p h i l i c attack 145  bonyl group  247.  acid chlorides  248 w o u l d p r o v i d e  suited for ring closure  a B-keto ester  v i a the d i a n i o n  halide  method  a 249  (Scheme  178  Scheme 11;  This  Proposed plan formation.  strategy for macrocyclic  attractive alcohol allow  for s e v e r a l reasons.  and  a c y l Meldrum's a c i d  a convergent  lactone.  approach  Secondly,  while  6-keto e s t e r d i a n i o n s cular faster  thereby  cyclized cyclic  product  lactone  the  the  presence  would p e r m i t  ring.  portions  the  lactone  formation  would  preparation  independently  s y n t h e s i s of  a  rapidly,  t h e need  the  would  macrocyclic  the  c o n d i t i o n s may  be  of  intermolecular alkylation  appropriate  circumventing  Thirdly,  First,  t o the  8-keto  lactone  g e n e r a l l y occurs  e q u i v a l e n t under  tions.  for macrocyclic  be  of  intramoleeven  for high d i l u t i o n  of a 6-keto e s t e r moiety further elaboration of  condiin  the  the macro-  179  The  aim  of t h i s  s t u d y was  p r e p a r i n g B-keto ester  first  t o examine t h e  halides  249  feasibility  u s i n g the  of  chemistry  14 5 developed  by Y o n e m i t s u  and  compounds t o medium- and B-keto of  ester  reaction  would and this  large-ring  dianion chemistry. c o n d i t i o n s and  be c o n d u c t e d  limitations procedure  l a c t o n e s was  coworkers  with  of t h i s t o the  An  leaving  , then B-keto  cyclizing  lactones using  investigation g r o u p s on  o f the  these  a view towards e s t a b l i s h i n g process.  Finally,  s y n t h e s i s of simple  t o be s t u d i e d .  these  effects  cyclizations the  scope  the a p p l i c a t i o n macrocyclic  of  B-keto  180  RESULTS AND  DISCUSSION  A c c o r d i n g l y , our o f Meldtum's a c i d  investigation  began w i t h the  synthesis  (246) , 2 , 2 - d i m e t h y l - l , 3 - d i o x a n e - 4 , 6 - d i o n e , by 14 6  the  procedure o r i g i n a l l y  Treatment and  described  of malonic acid  sulfuric  acid  CH (COOH) 2  (250) w i t h a c e t i c  i n the c o l d  gave 246  • Me 2 C0  2  by Meldrum  f f  A  yield.  " " " Q ^  250  structure  6 1.78,  was  evident  from  s i n g l e t a t <S 3.57  while i t s infrared  stretching  vibration  peak a t 100  a t 1755  It  m/e  i s interesting  due  i t s NMR  and  0  cm  1  spectrum which  a six-proton  spectrum  trum o f the p r o d u c t e x h i b i t e d strong  The  246  o f 246  a two-proton  1908.  anhydride, acetone  i n 58%  >  in  .  displayed  s i n g l e t at a strong  Furthermore,  a p a r e n t i o n a t 144  t o the l o s s  to note  that  showed  of carbon  the o r i g i n a l  C=0  t h e mass s p e c m/e  and  a  dioxide. structure  146 proposed 251.  by Meldrum  This  v i e w was  experiments  was  actually  b a s e d on  indicated  that  acid  must r e m a i n  of 3 - l a c t o n i c  the o b s e r v a t i o n  the p r o d u c t was  and hence Meldrum c o n c l u d e d t h a t malonic  that  intact.  one  that  acid  titration  a monobasic  acid,  o f the c a r b o x y l g r o u p s  This  structural  assignment  of  181  •COOH  A 251 remained  i n the l i t e r a t u r e  Davidson  and B e r n h a r d  0  f o r over  demonstrated  forty  years,  before  t h a t the p r o d u c t  has s t r u c -  149 ture  246  (246),  pK  . a  5.1, may  stabilization ring  The s t r o n g  acidity  be a t t r i b u t e d  a s s o c i a t e d with  e x h i b i t e d by Meldrum's t o the s t r o n g  the planar  acid  resonance  1,3-dioxane-4,6-dione  252.  0  252  Meldrum's a c i d  (246) was  acylated with  acetyl chloride 14 5  and  two e q u i v a l e n t s o f p y r i d i n e i n d i c h l o r o m e t h a n e  a c e t y l Meldrum's a c i d  253  i n 85% y i e l d .  The f o r m a t i o n  to give o f 253  182  Me. 0.  •0  .OH .0  1) 2Pyridine CH Cl 2  2)  2  MeCOCl  246  was  c l e a r from  six-proton and  the  characterized  by  tions  cm  and  NMR  s i n g l e t at  a one-proton  at  253  1740  elemental  spectrum of 6 1.75,  s i n g l e t at  the  p r o d u c t w h i c h showed  a three-proton 6 15.0.  The  s i n g l e t at  p r o d u c t was  (C=0  stretch)  and  a n a l y s i s , w h i c h was  1665  cm  (C=C  - 1  consistent  with  2.67,  further  i t s i n f r a r e d spectrum, which d i s p l a y e d - 1  6  a  absorp-  stretch) ,  the  proposed  formulation. The  feasibility  of p r e p a r i n g  through a l c o h o l y s i s of  8-keto e s t e r  a c e t y l Meldrum's a c i d  halides  253  was  255  next 145  examined. it  was  Employing  found  equivalent gave the The XI.  that  of  t r e a t i n g 1.2  a haloalcohol  desired  r e s u l t s of The  a modification  facile  this  equivalents  254  B-keto e s t e r  of  of  253  in tetrahydrofuran  halides  preliminary  preparation  of Yonemitsu's procedure  255  study are  in very  with  one  at  reflux  good  summarized  B-keto e s t e r  chloride  in  yield. Table  255d  is  ,  183  Table XI.  P r e l i m i n a r y Study o f the P r e p a r a t i o n Ester Halides  X  Yield 255*  H  Br  68  3  H  Br  80  c  4  H  C l  d  5  CH  Compound Identification  n  254 R  a  2  b  Y i e l d s o f 255  1  o f B-Keto  3  r e f e r to y i e l d s  c i  of  1  5  0  79  1  5  1  85  distilled  184  -OH  0  ;0  0*  /  R  0  THF A  \)H  *R  X C C H ^ "  254  252  especially  noteworthy  since  255.  i t provides  an  excellent  intermedi-  135 ate  for  the  cyclization  synthesis and  of  (±)-diplodialide C  subsequent reduction  of  (235)  , via  the k e t o n e f u n c t i o n -  ality.  0  0 1) 2Base 2)  [H ] -  255d  The typical  reaction of  distillable by  TLC  rial  these  of  evidence  with  4-chloro-l-butanol  alcoholysis reactions,  product.  a n a l y s i s and  was  253  This  p r o d u c t was  in that found  e l e m e n t a l a n a l y s i s of  in f u l l  agreement w i t h  f o r : the  structure  the  255c was  the  (254c)  150  i t gave a  t o be  single  homogeneous  distilled  proposed  formula.  provided  by  the  was  mateFurther  infrared  spectrum 1720 cm  o f t h e p r o d u c t w h i c h showed a b s o r p t i o n s ,  1  typical  which e x h i b i t e d proton at  o f a B-keto e s t e r ,  a three-proton  s i n g l e t a t 6 3.43  6 3.50 The  was n e x t  analysis.  studied.  The a d d i t i o n  stretching vibration.  5.00-6.17  evidence  analysis, olefinic  the s t r u c t u r e B-keto e s t e r  by  an i n d e p e n d e n t  and  2-propen-l-ol  by mass  of t h i s  synthesis  This using  (256) ( e q u a t i o n  at 1  ( s , 2H) ,  and e l e m e n t a l  assigned  subsequently  as t h e confirmed  a c e t y l Meldrum's a c i d 77).  due t o  s p e c t r a l d a t a and  spectroscopy  was  spec-  spectrum o f the  ( s , 3H), 3.45  o f t h e p r o d u c t was  257.  by i t s i n f r a r e d  I n a d d i t i o n , t h e NMR  On t h e b a s i s  supplied  diiso-  gave a s i n g l e p r o d u c t by TLC  r e s o n a n c e s a t 6 1.24  (m, 3 H ) .  of lithium  a t 1650 cm  as w e l l  further  o f B-keto e s t e r  as an a b s o r p t i o n  1742 and 1715 cm  product displayed  v i a dianion  absorptions  the t y p i c a l  and  halides  B-keto e s t e r  trum w h i c h showed  a C=C  B-keto e s t e r  o f these  p r o d u c t was c h a r a c t e r i z e d  1  triplets  2  in tetrahydrofuran This  (CH^CO), a two-  and t w o - p r o t o n  255b t o a s o l u t i o n o f two e q u i v a l e n t s  propylamide  spectrum  (COOCH_ ) .  2  cyclization  formation bromide  (CH C1) and 6 4.13  and i t s NMR  s i n g l e t a t 6 2.26  (COCH^COO),  a t 1745 and  253  186  The f o r m a l l y a n a l o g o u s r e a c t i o n o f B - k e t o e s t e r 255c and 255d w i t h in  tetrahydrofuran,  two e q u i v a l e n t s however,  m a t e r i a l e v e n upon p r o l o n g e d formation methyl the  was  obtained  of l i t h i u m  gave o n l y exposure.  diisopropylamide  unreacted  starting  Confirmation  of  by the a d d i t i o n o f one e q u i v a l e n t  i o d i d e t o a s o l u t i o n o f the d i a n i o n  y - a l k y l a t e d product  chlorides  258  i n 75% y i e l d .  dianion of  o f 255c, w h i c h gave Evidence  that  187  0  0  1) 2LDA, THF 2)  Cl  Mel  25£  255c  alkylation the 6  NMR  had  i n d e e d o c c u r r e d a t the Y * *  spectrum  o f the p r o d u c t w h i c h  2.56,  a triplet  a t 6 1.09,  singlet  a t 6 2.26  due  material.  The  mass s p e c t r u m further  to the Y  -  m  k°  showed  the a b s e n c e e  t  n  y l  the q u e s t i o n o f d i a n i o n  it  appeared  to  the use  likely  that  of c h l o r i d e s  problem  would  be  methylphosphoramide,  leaving  t o use which  manifest in  a quartet  from  at  of a three-proton  t h e low  starting resolution  elemental analysis provided  f o r m a t i o n no  the d i f f i c u l t y as  was  p r o t o n s i n the  molecular weight d e r i v e d o f the p r o d u c t , and  n  e v i d e n c e f o r the f o r m a t i o n o f compound  With  this  and  c a r  258. longer i n doubt,  e n c o u n t e r e d was  groups.  a more p o l a r  One  method  solvent  i s known t o a c t i v a t e  linked to  solve  s u c h as  hexa-  carbanions  152 through s o l v a t i o n of  chloride  solution  o f two  a variety arising  255d  of their  metal counter ions  .  The  addition  i n tetrahydrofuran-hexamethylphosphoramide to a e q u i v a l e n t s o f l i t h i u m d i i s o p r o p y l a m i d e under  o f c o n d i t i o n s , however, gave m i x t u r e s o f p r o d u c t s  from e l i m i n a t i o n  and  dimerization processes.  188  A second better the in  s o l u t i o n was  leaving  groups  to c o n v e r t these c h l o r i d e s  s u c h as b r o m i d e s  treatment of 8-keto e s t e r r e f l u x i n g a c e t o n e gave  or  iodides.  the i o d i d e  259  i n 90%  the h a l i d e  the  p r o d u c t which  the  absence  the  starting material.  was  The under  was  o b t a i n e d from t h e NMR  showed a new  the low  conclusion  reaction  a t 6 3.18  Evidence  and  r e s o l u t i o n mass s p e c t r u m o f the p r o d u c t  an e l i m i n a t i o n  mixtures.  (CH^I)  of  F u r t h e r m o r e , the m o l e c u l a r w e i g h t  cyclization  was  spectrum  (CH^Cl) c h a r a c t e r i s t i c o f  w i t h the f o r m a t i o n o f the i o d i d e  attempted  from  triplet  a t 6 3.50  a v a r i e t y of c o n d i t i o n s .  resulting This  exchange  of a t r i p l e t  consistent  yield.  iodide  259  for  from  Accordingly,  c h l o r i d e 255c w i t h sodium  255c  derived  into  derived  of iodide Instead  259  proved  t o be  a predominance  p r o c e s s was  f r o m NMR  259.  found  analysis  of  futile 260  in a l l cases.  o f the c r u d e  A s t u d y o f m o l e c u l a r models r e v e a l e d  that  189  the  formation  intramolecular problem the ters  in  long  chain  78).  eight  to  dianion  these  in order  (equation  of  alkylation  cyclizations  halide to  eleven-membered  to  promote Careful  span the  would  appears five  be  to  lactones  very  difficult.  arise  successive  B-keto e s t e r  analysis  B-keto  indicated  from  the  planar  dianion this  to  sp  via The  need  of  cen-  alkylation be  possible  190  only  i n c a s e s where  equal  to seven The  halides was  79)  as  the  255b and  base  0  l e n g t h , n,  of o l e f i n i c  i n the  occurring  chain  was  greater  than  or  carbons.  formation  (equation  the  rather  attempted  cyclization  255c s u g g e s t e d  80).  This  of  that possibly  i n t r a m o l e c u l a r l y with  (equation  than d i m e r i c  the  0  B-keto e s t e r the  dianion  result  may  0  products  l o s s of  itself  reflect  the  H-X  acting rigid  0  (79)  0  0  -HX  geometrical lar,  the  requirements for  need  f o r a back  side  the  (80)  S 2 N  reaction  approach  to w i t h i n  .  In p a r t i c u 1.5-2.0 R  may  191  be c o n t r a s t e d w i t h  the r e l a t i v e l y  loose  transition  state require153  ments s u g g e s t e d In o r d e r  f o r intramolecular proton  to v e r i f y  that c y c l i z a t i o n  would  g-keto e s t e r h a l i d e s o f a p p r o p r i a t e c h a i n mine e x a c t l y a t what p o i n t e l i m i n a t i o n with c y c l i z a t i o n , bromides  transfer occur  with  l e n g t h and t o d e t e r -  becomes  the p r e p a r a t i o n of a s e r i e s  262, n = 5 - l l , was under t a k e n  indeed  competitive of g-keto e s t e r  ( T a b l e X I I ) . The  0  0  ™ > AAo-(CH ) Br F  •  Br(CH ) 0H 2  253  261  bromoalcohol  261g was o b t a i n e d  by c o n t i n u o u s  solution  o f the c o r r e s p o n d i n g  1 5 5 -  " " 1  6 0  .  H 0  4  8  %  n  two s t e p s .  acetyl the  from  a  263 i n 48% h y d r o g e n  "^-Solvent  >  H  0  (  C  H  2  ,  n  heated bro-  prepared  B  r  261  First,  cleavage  b r o m i d e and a c a t a l y t i c  bromoacetate  261b-f were  261a was c o n v e n i e n t l y  263  in  while  o f the p r o d u c t  diols  The b r o m o a l c o h o l  2  commercially,  extraction  (CH ) 0H  n  262.  prepared  mide  2  n  265  134  , then  of tetrahydropyran  264  amount o f z i n c c h l o r i d e h y d r o l y s i s of the e s t e r  with to give 154  192  Table  XII.  *  Preparation  o f Long C h a i n  B-Keto E s t e r  Y i e l d of 262* (%)  Compound Identification  261 n  a  D  74  b  ,155 b  86  Isolated  c  134,154  c  ?  156  d  8  157  e  9  158  f  10  g  l l  yields.  1 5 9  1  Bromides.  6  0  84 86 95 92 85  193  0  w  MeC00(c  264  which  bromoalcohols  proton  spectrum  triplets  a one-proton  a t 6 3. 62  singlet  deuterium oxide. played  0-H  low  parent  a l l exhibited  ions  alcohols  a t 164  alcoholysis 261  262  spectrum  m/e  smoothly  a t 3620 and  with r e l a t i v e  to give  in excellent yields  o f t h e s e compounds was  first  the  bromide  262g t o g i v e  structures. 261b  For  showed  two-  (CFj^Br) as w e l l exchanged  3450 cm  as  with dis-  ^, w h i l e  c o n t a i n e d the e x p e c t e d p a i r  the c y c l i z a t i o n examining  properties  o f the p r o d u c t  o f a c e t y l Meldrum's a c i d  proceeded  bromides  2  mass s p e c t r u m 162  6 3.44  (CH OH) w h i c h  vibrations  and  proposed  (CH^OH) and  infrared  stretching  spectral  of 6-bromo-l-hexanol  a t 6 2.32  The  resolution  The  ester  261  were i n a c c o r d a n c e w i t h t h e i r  e x a m p l e , t h e NMR  its  261 a  265  The  ^  m  intramolecular  i n t e n s i t i e s of 253  (Table X I I ) .  alkylation  the s i x t e e n - m e m b e r e d  B-keto A study of  initiated  o f B-keto  B-keto  1:1.  w i t h bromo-  the d e s i r e d  therefore  of  lactone  by  ester 266g.  194  0  0  2LDA THF Br(CH ) 2  1 l  262g  2£&g  C a r e f u l NMR a n a l y s i s of the crude r e a c t i o n product obtained from the a d d i t i o n of the bromide 262g to a s o l u t i o n c o n t a i n i n g two e q u i v a l e n t s of l i t h i u m d i i s o p r o p y l a m i d e in  tetrahydrofuran  r e v e a l e d the presence of two new compounds i n a d d i t i o n unreacted s t a r t i n g m a t e r i a l . the d e s i r e d c y c l i c  reduced i n t e n s i t y rial.  of  6 2.56  the Y  The minor product  the B-keto e s t e r  The major product appeared to be  B-keto l a c t o n e 266g as i n f e r r e d  sence of a new t r i p l e t at  olefin  to some  - m e t n  by the  pre-  (2H, CH COCH COO) and the 2  2  Y l protons of the s t a r t i n g  mate-  c o n s i s t e d of a very small amount of 267g.  In  an attempt to d r i v e  this  2£Zg reaction  to c o m p l e t i o n , the d i a n i o n was s t i r r e d  for  longer  p e r i o d s ; however again some s t a r t i n g m a t e r i a l was r e c o v e r e d .  195  The  use  of excess  gave a c r u d e  l i t h i u m d i i s o p r o p y l a m i d e , on  r e a c t i o n product  which appeared  the o t h e r  t o be  hand,  devoid  of  starting material. The obtained excess  from the  266g  r e a c t i o n of B-keto e s t e r bromide  262g  of  the  cyclic  lithium diisopropylamide  lematical. by  B-keto l a c t o n e  purification  Efforts  the d i f f i c u l t i e s  to u t i l i z e encountered  was TLC,  found  in v i s u a l i z i n g  (VPC)  sence  in a ratio  two  major p r o d u c t s  very  NMR  revealed  conditions. product poor  Finally,  reaction  These  a n a l y s i s i n d i c a t e d the of  5:1.  suggested  collection the  the c r u d e  t h a t an  VPC  reaction  267g  in very  investigation  c o n d i t i o n s leading to cleaner, product  f i r s t approach  alkylation  the  a d d i t i o n of p o l a r render  increase  to  VPC  decomposes under  to d i s t i l l  pre-  However,  o f compounds 266g and  results  the  tion.  attempts  spots.  of  formation  be e f f e c t e d .  The  would  product  gave o n l y m i x t u r e s  yields.  should  t h a t the  hampered  t h e TLC  s u b s e q u e n t s t u d i e s u s i n g VPC-mass s p e c t r o m e t r y , and  prob-•:  f o r example, were  Vapour p h a s e c h r o m a t o g r a p h i c of  t o be  with  the  The  process.  the Y "  c a r  s t u d i e d was In  the p r e s e n t  s o l v e n t s such '  relative  the e f f e c t  : , a n : L O n  as  case,  of s o l v e n t i t was  three e q u i v a l e n t s of  the  more n u c l e o p h i l i c  and  B - k e t o e s t e r bromide  lithium  that  hexamethylphosphoramide  p r o p o r t i o n of c y c l i z a t i o n  r e a c t i o n of  felt  on  diisopropylamide  hence  versus  elimina-  262g w i t h in  two  tetra-  h y d r o f u r a n - h e x a m e t h y l p h o s p h o r a m i d e , however, r e s u l t e d  only in  196  increased of  the  the  formation  cyclic  need  tem  solvent. tion  was  starting used A  as  dianion  therefore Under found  solvent  266g f o r m a t i o n .  t o be  very  s l o w and  were r e c o v e r e d .  only  unreacted  was  solvent  dianion One  expense  suggested  to achieve  method  using  to  more  deac-  solvent ether  dianion  sys-  as alkyla-  inevitably  large  amounts  Similarly,  when h e x a n e s were  m a t e r i a l was  between e t h e r also tested.  and  of  obtained.  tetrahydro-  However, use  gave m i x t u r e s o f c y c l i c  of  and  products.  A s e c o n d p o s s i b l e method between the  alkylation  employment o f  262g was  observation  repeated  starting  i s intermediate  1 , 2 - d i m e t h o x y e t h a n e as  the  267g a t the  t o employ a l e s s p o l a r  r e a c t i o n was  i n terms o f p o l a r i t y  olefinic  This  g-keto e s t e r  would be the  266g.  product  t h e s e c o n d i t i o n s , however, the  material  s o l v e n t which  furan  olefinic  the  g-keto lactone  the  and  the  g-keto lactone  to deactivate  selective tivate  of  therefore  low  and  to accentuate  e l i m i n a t i o n processes  temperatures.  added  the  The  to s o l u t i o n s of  difference would  involve  g-keto e s t e r  halide  two  equivalents  to three  197  of  lithium diisopropylamide  from 0°C run  to -98°C.  in i t s e n t i r e t y at  could  be  recovered.  initiated perature tably  a t low over  base  On  the  other  effect  reaction  hand, when the  reaction  s e v e r a l hours,  the  crude r e a c t i o n product  for  to d r i v e  these  the The  this  t o warm t o room  g-keto lactone use  of  reaction  up  was  the  key  to  266g  four  was tem-  ineviand  equivalents  to completion.  r e s u l t s at l e a s t suggested  reactivity  was  starting material  allowed  Never-  that modification  t o the  of  p r e f e r e n t i a l forma-  products.  alternate  dianion  the  ranging  and  of c y c l i c An  where  temperature, only  starting material.  dianion  tion  low  temperatures  temperature  failed  theless, the  conditions  showed e v i d e n c e o n l y  unreacted of  Under  at various  approach  reactivity  was  t o the  b a s e d on  o f m e t a l c o u n t e r i o n on  modification  previous  the  rate  of  g-keto  work c o n d u c t e d  of  a l k y l a t i o n of  ester on  the  ketone  38 enolates reaction  .  In  trend  i s changed  reflects  metal enolates, slower  i s the  retarded which  i t has  of metal e n o l a t e s  metal c a t i o n This  general,  even  tend  the  in that  rate  of  further  been  i s increased  from  degree the  more c o v a l e n t The  by  of  use  be  used  only  with  rate zinc  to  rate  of  the of and  the  potassium.  character  ion p a i r s .  highly  the  s u b s t a n t i a l l y as  of c o v a l e n t  reaction. the  that  l i t h i u m to sodium  t o f o r m even more t i g h t  e n o l a t e s can a g e n t4. s 38  found  of  these  i n t e r a c t i o n , the a l k y l a t i o n may magnesium These  be  enolates  metal  reactive alkylating  198  t h a t the r e a c t i v i t y of a B-keto e s t e r  T h i s work s u g g e s t e d d i a n i o n may while  be e n h a n c e d by f o r m a t i o n o f t h e d i p o t a s s i u m d i a n i o n ,  i t s r e a c t i v i t y may  o r magnesium examination  salts.  be m o d i f i e d by t h e a d d i t i o n o f z i n c  In order  t o t e s t t h i s h y p o t h e s i s , an  o f t h e e f f e c t o f c o u n t e r i o n on t h e i n t r a m o l e c u l a r  a l k y l a t i o n o f t h e B - k e t o e s t e r h a l i d e 262g was  conducted.  2£Zg The first  generation  attempted.  prepared  of  The  the d i p o t a s s i u m  monopotassium anion  using potassium  to generate  salt  hydride  as b a s e .  268,  of  M =M =K, 1  2  262g was  However  was  easily  a l l attempts  the dipotassium s a l t using potassium b i s ( t r i m e t h y l 70 (269) and p o t a s s i u m d i p h e n y l 2 - p y r i d y I m e t h i d e  silyl)amide 71 (270) proved  futile.  269  R e c e n t l y , P i e r r e and c o w o r k e r s h a v e  270  199  described  the m e t a l l a t i o n o f a s e r i e s  sium h y d r i d e  i n the p r e s e n c e  of  2.2.2  /  o f weak a c i d s by  potas-  271"161  cryptand  For  \  271  example, the d e p r o t o n a t i o n and  triphenylmethane  of diphenylmethane  (273) , p K  31.5,  =  was  ( 2 7 2 ) , pK  readily  33.4,  accomplished  a under no  these  c o n d i t i o n s , while  deprotonation  c o u l d be  i n the  observed.  absence of  These a u t h o r s  272  that  the  the  cryptand suggested  213  s t r o n g b a s i c i t y e x h i b i t e d by  potassium  presence  o f 2.2.2  from  crystal  surface of  cryptand  271  arises  hydride  activation  i n the  of  the  161 the p o t a s s i u m  hydride  by  the c r y p t a n d .  .  200  The  facile  potassium mise  hydride  f o r the  ester  deprotonation cryptand  two  Evidence  t h a t no d i a n i o n was  obtained  from  3-keto e s t e r  potassium  the  recovery  formed  r e a c t i o n mixture  With  the  availability  some  pro-  B-keto bromide  hydride  with  plan  and  the  p r e p a r a t i o n of  indirect  enolate  and  approach  a d d i t i o n of  methyl i o d i d e . base  capable  i n doubt, a r e t u r n  metal  through  e n o l a t e s was  zinc enolates  involving an  was  m a t e r i a l upon  of moderating d i a n i o n r e a c t i v i t y  direct  an  conditions  of a s t r o n g potassium  o f more c o v a l e n t l y l i n k e d the  these  starting  a B - k e t o e s t e r d i a n i o n now  of g e n e r a t i n g the o r i g i n a l  under  of unreacted  the  lithium  to o f f e r  with  i n t e t r a h y d r o f u r a n gave o n l y s t a r t i n g m a t e r i a l .  quenching  difficult,  (272)  of a d i p o t a s s i u m the  e q u i v a l e n t s of both  271  Although  appeared  However, t r e a t i n g  cryptand  formation  271  successful generation  dianion.  262g w i t h  and  of diphenylmethane  the  is  the  examined.  often  formation  anhydrous z i n c  to  salt  of  very the  provides  162 convenient  access  to these  g-keto e s t e r bromide a l e n t s of then  one  copious  lithium  the  262g ,was  Accordingly,  treated with  diisopropylamide  precipitate  formed  the c o u r s e  r e a c t i o n mixture  precipitate come was  .  two  to generate  and  found  the t o be  almost  immediately,  of  reaction.  the  resulted  recovery  i n the  of s t a r t i n g  independent of  the  equiv-  the d i a n i o n , added.  which  and A  failed  to  H y d r o l y t i c workup  dissolution material. time  the  to three  e q u i v a l e n t o f a n h y d r o u s z i n c c h l o r i d e was  dissolve during of  enolates  of  the  This  out-  o f r e a c t i o n as  well  201  as t h e amount o f l i t h i u m d i i s o p r o p y l a m i d e u s e d , and  suggested  that  stable  the o b s e r v e d p r e c i p i t a t e  zinc chelate  of a very  c o p p e r (I)  salts  reasoning  behind  the B - k e t o e s t e r  t o moderate  to a lesser  o f c o p p e r (I)  consist  274.  In an a t t e m p t tivity  may  e x t e n t , an  on  the a l k y l a t i o n  this  salts  investigation  approach  t o moderate  was  reac-  of the e f f e c t of  p r o c e s s was based  dianion  conducted.  on t h e known  the r e a c t i v i t y  The  tendency  of organolithium 163  reagents  in their  reactions with acid  RLi 0.5 Cul  chlorides  ( e q u a t i o n 81)  RCOR  (81)  RCOCl  RLi  Mixture of products  202  of B-keto ester  Generation of the dianion followed  by t h e a d d i t i o n  o f copper (I)  iodide  1 6 3  ,  copper  1 6 5  , and t r i - n - b u t y l p h o s p h i n e - c o p p e r  halide  262g a s u s u a l ,  s a l t s such as c o p p e r  copper bromide-dimethyl s u l f i d e c o m p l e x iodide  1 6 4  ,  methyl-  complex  1 6 6  ,  h o w e v e r , i n v a r i a b l y g a v e m i x t u r e s o f s t a r t i n g m a t e r i a l , and products derived An  alternate  directly tition  f r o m c y c l i z a t i o n and e l i m i n a t i o n approach which does n o t i n v o l v e  deals with  the e f f e c t o f l e a v i n g  b e t w e e n a l k y l a t i o n and e l i m i n a t i o n  processes. the d i a n i o n  g r o u p on t h e compereactions.  Several  y e a r s a g o , Bumgardner a d d r e s s e d a s i m i l a r p r o b l e m i n a cf  the e f f e c t o f l e a v i n g  report  g r o u p on t h e mode o f r e a c t i o n o f  3 - p h e n y l p r o p y l d e r i v a t i v e s 275 w i t h  s o d i u m amide i n l i q u i d  167 ammonia  (equation  82).  I n t h i s s t u d y , i t was f o u n d  ^  that  C H CH CH=CH 6  5  2  (82)  C H CH CH CH X 6  5  2  2  2  2  275  when t h e l e a v i n g g r o u p was b r o m i d e , e l i m i n a t i o n while  predominated,  when X=C1, a m i x t u r e o f c y c l i z a t i o n and e l i m i n a t i o n  observed.  More n o t e w o r t h y , h o w e v e r , was t h e o b s e r v a t i o n  was that  203  the use  o f t o s y l a t e and  only cyclopropane The  t i o n was  easily  277, w h i l e a s e c o n d  276.  6  5  2  2  The  s y n t h e s i s o f 277  utilizing  0  CeHgSfCH^H  1 (  278  s y n t h e s i s of the b e n z e n e s u l f o n a t e  Scheme 12.  problem  278.  0  277 The  The  candidate for cycliza-  0  C H S0 0(CH ) )  of pre-  s o l v e d by  the p h e n y t h i o B-keto e s t e r  deemed t o be  present  by t h e d i f f i c u l t y  trimethylammonium s a l t  by t o s y l a t e d e p r o t o n a t i o n was  the b e n z e n e s u l f o n a t e  t o the  of l i t h i u m d i i s o p r o p y l a m i d e  a t o s y l a t e g r o u p and  p a r i n g a B-keto e s t e r  posed  of these r e s u l t s  hampered by t h e a b i l i t y  deprotonate  gave  formation.  direct application  s t u d y was to  trimethylammonium l e a v i n g groups  was  277  initiated  i s outlined by  the  in  204  AcOH, H S O / 2  AcO(CH ) OH 2  H 0  1 Q  2  280  279  C H S0 CI 6  5  2  Pyridine HO(CH ) OSO C H 2  l 0  2  6  HCl 5  AcO(CH ) 2  MeOH  1 Q  OS0 C H 2  6  5  281  282  , THF,A  AA0  0  (CH ) 2  l 0  OSO C H 2  6  5  211 Scheme 12:  P r e p a r a t i o n o f B-keto e s t e r b e n z e n e s u l f o n a t e 277.  p r e p a r a t i o n o f 1 0 - a c e t o x y - l - d e c a n o l (280) f r o m (279)  i n 66% y i e l d  by t h e p r o c e d u r e  1,10-decanediol  d e s c r i b e d by B a b l e r and  168 Coghlan verted  .  The r e s u l t i n g  a c e t o x y a l c o h o l 280 was t h e n  con-  i n t o t h e a c e t o x y b e n z e n e s u l f o n a t e 281 i n 80% y i e l d  benzenesulfonyl chloride The  and p y r i d i n e .  p r o d u c t 281 was c h a r a c t e r i z e d by i t s NMR  which e x h i b i t e d  resonance  spectrum  a t 6 2.03 ( s , 3H, C H C O O ) , 4.00 3  using  205  (t,  4H, CH OAc 2  1.20-1.70  + C H O S 0 C H ) , 7.33-7.90 2  , while  parent  6  a s t r o n g C=0  which  The i n f r a r e d  stretching  i t s low r e s o l u t i o n  i o n a t 356 m/e,  (m, 5H, a r o m a t i c ) , and  5  (m, 16H, h y d r o c a r b o n ) .  product displayed cm"  2  spectrum  vibration  mass s p e c t r u m  i s consistent  o f the  a t 1725  showed a weak  with  the proposed  composition. Selective was r e a d i l y  hydrolysis  accomplished  v e n i e n t o f which methanol.  Evidence  the use o f h y d r o c h l o r i c  t h e NMR  a t 6 3.57  hydrolysis  spectrum  (CH_ OH) 2  2  2  6  5  as t h e  a t 6 2.03, c h a r a c t e r i s t i c o f  infrared  of the p r o d u c t d i s p l a y e d - 1  exhibited  p r o t o n s , as w e l l  i n the s t a r t i n g  a t 3625 and 3450 c m ,  group  (CH OS0 C H ) , a m u l t i -  the a c e t a t e g r o u p  vibrations  282  o f the a c e t a t e  o f the p r o d u c t which  and 6 4 .00  of a three-proton s i n g l e t  spectrum  acid in  benzenesulfonate  a t 6 7.18-7.90 due t o t h e a r o m a t i c  absence  281  yield.  f o r the s e l e c t i v e  was s e c u r e d f r o m  plet  involved  i n 72%  benzenesulfonate  by s e v e r a l m e t h o d s , t h e most c o n -  By t h i s method, t h e h y d r o x y  was p r e p a r e d  triplets  o f the acetoxy  material.  Furthermore, O-H  the  stretching  and t h e a b s e n c e  o f any c a r -  bonyl absorptions. The  p r e p a r a t i o n o f the B-keto  277 was c o m p l e t e d 253  with  ester  by the a l c o h o l y s i s  the a l c o h o l  282.  benzenesulfonate  o f a c e t y l Meldrum's a c i d  The r e s u l t a n t  p r o d u c t was o b t a i n e d  206  AA, 0  THF  ,  HO(CH ) 2  1 0  A OS0 C H ' 2  6  5  0  C H S0 0(CH ), 6  253  in  2  in full  accordance  structure.  preparation  of phenylthio  v e n i e n t l y c a r r i e d o u t i n two s t e p s ' , H0(CH,)„Br  0  277  and e x h i b i t e d s p e c t r a l d a t a  the assigned The  2  282  86% y i e l d  with  5  2NaH, T H F — C H SH 6  B-keto e s t e r  278 was c o n -  a s o u t l i n e d i n Scheme 1 3 .  >  H0(CH ) 2  1 1  SC H 6  5  5  2Mg  281 -OH  6 ^ 0  - ' THF  A  0 (C^^SCSHB  278 Scheme 1 3 :  In the f i r s t (261g)  1 6 0  Preparation  of phenylthio  step, the commercially  was t r e a t e d w i t h  B-keto e s t e r 278.  a v a i l a b l e 11-bromoundecanol  two e q u i v a l e n t s  o f sodium  hydride,  207  followed  by one e q u i v a l e n t o f t h i o p h e n o l .  obtained  i n 83% y i e l d ,  infrared  spectrum  3460 cm \ triplets plet  (CH OH) and 6 2.92 2  s y n t h e s i s o f B-keto e s t e r  the a l c o h o l y s i s  hydroxysulfide exhibited  283.  With  benzenesulfonate  the B-keto e s t e r 277 now  t h e s e compounds was  at  the c y c l i z e d  product  5  sulfide  278 was  sulfide  completed  253 w i t h t h e  i n 76% y i e l d with  again  the proposed  278 and B-keto e s t e r  conducted.  266f.  benzenesulfonate  277 w i t h  diisopropylamide in tetrahydrofuran  t o give a mixture  277  6  i n hand, a study o f the c y c l i z a t i o n  equivalents of lithium 0°C was f o u n d  exhibited  protons.  accordance  Treatment o f the B-keto e s t e r two  2  The p r o d u c t o b t a i n e d in full  spectrum  ( C H S C H ) , and a m u l t i -  o f a c e t y l Meldrum's a c i d  s p e c t r a l data  structure.  of  o f an a l c o h o l , and i t s NMR  a t 6 3.64  The  had a b s o r p t i o n s a t 3620 and  a t 6 7.10-7.40 due t o t h e a r o m a t i c The  by  was homogeneous by TLC a n a l y s i s .  o f the p r o d u c t  typical  The p r o d u c t 283,  of starting  A l l attempts  m a t e r i a l and  to drive  this  266f  reaction  208  to completion  using  more b a s e , and  longer  r e a c t i o n times,  futile.  In p a r t i c u l a r ,  of  lithium  diisopropylamide  l e d t o the  cleavage  of  the  apparent  the  use  formation  three  o r more  of  the  a t room  ful.  2  2  attempted  HO(CH ) " 2  starting  the  lithium  material.  xx 5  the  g-keto e s t e r s u l f i d e  r e a c t i o n of  266g was  sulfide  diisopropylamide may  be  278  also with  gave o n l y  2  11  m  278  unsuccessthree  unreacted  contrasted with  0  C H S(CH ) 5  of  B-keto lactone  This result  0  10  284  cyclization  example,  e q u i v a l e n t s of  via  3LDA THF  10  sixteen-membered For  temper-  a l c o h o l 284  277  t o the  equivalents  0  C H SO O(CH )  The  to  group.  xx, 5  of  in tetrahydrofuran  benzenesulfonate  0  6  temperatures,  a l t e r n a t e s o l v e n t s y s t e m s , however, p r o v e d  be  ature  higher  31-DA^THF^ •(CH^  2m  the  work  209  of J u l i a the  and c o w o r k e r s " 1  intramolecular  on t h e e f f e c t  alkylation  I n t h i s s t u d y , i t was f o u n d  o f l e a v i n g g r o u p on  o f a l k e n e 28J5 t o c y c l o p r o p a n e 2 8 6 .  that cyclization  was b e s t  and e l i m i n a t i o n was m i n i m i z e d when t h e l e a v i n g g r o u p  performed X=CgH^S  was u s e d . The mize  lack of success encountered  the c o n d i t i o n s  i n the attempt  f o r 8-keto e s t e r d i a n i o n  to opti-  cyclization  led to B-keto  a r e e v a l u a t i o n o f the o r i g i n a l procedure  found t o e f f e c t  lactone  In p a r t i c u l a r , the  formation  (3LDA, THF, 0°->-R.T.).  d e v e l o p m e n t o f a method t o p u r i f y preparative  the r e s u l t i n g  p r o d u c t on a  s c a l e was t o be a c r u c i a l p a r t o f t h i s  reinvesti-  gation. Earlier tone  efforts  h a d shown t h e p u r i f i c a t i o n  266g by T L C , VPC, and d i s t i l l a t i o n  o f B-keto  t o be d i f f i c u l t .  lacA  t e c h n i q u e w h i c h h a s r e c e n t l y shown a g r e a t d e a l o f p r o m i s e i n  210  the  separation  of organic  compounds i n v o l v e s t h e u s e o f h i g h 170  pressure  l i q u i d chromatography  the p u r i f i c a t i o n  (HPLC)  o f B-keto l a c t o n e  .  266g on a s m a l l  f o u n d t o be r e a d i l y a c c o m p l i s h e d u s i n g sure l i q u i d chromatograph equipped w i t h ultraviolet detector. the  In the present  s c a l e was  an a n a l y t i c a l h i g h  HPLC t o f o l l o w  f o r c y c l i z a t i o n were  deter-  mined t o i n v o l v e t h e d r o p w i s e a d d i t i o n o f B-keto e s t e r 262g t o a s o l u t i o n c o n t a i n i n g diisopropylamide  three  these c o n d i t i o n s , the formation minimized t o l e s s than f i v e  0  equivalents  i n tetrahydrofuran  pres-  a v a r i a b l e wavelength  S u b s e q u e n t l y , by u s i n g  r e a c t i o n , the best conditions  case,  bromide  of lithium  (0.03 M s o l u t i o n ) .  of eliminated  Under  p r o d u c t 267g was  percent.  0 3LDA,THF  r  0°->RT ^r-(CH )  Br(CH ) " 2  2  267g  2£2g The  p u r i f i c a t i o n o f t h e sixteen-membered B-keto  266g on a l a r g e s c a l e was a c c o m p l i s h e d u s i n g pressure  liquid  chromatograph.  displayed  lactone  a preparatory  The p r o d u c t , o b t a i n e d  p u r i f i e d y i e l d , was c h a r a c t e r i z e d  by i t s . N M R s p e c t r u m w h i c h  s i g n a l s a t 6 4.22 ( t , 2H, COOCH_ ) , 3.46 ( s , 2H, 2  2  high  i n 49%  C 0 C H C 0 0 ) , 2.56 ( t , 2H, C H C O ) , a n d 1.20-1.80 (m, 20H, 2  9  l1  211  hydrocarbon).  The  infrared  a b s o r p t i o n s a t 1735 while  i t s low  parent cular  m/e,  cial  cm  Recently, ment o f a new  no  further  Still  and  technique 1 7 1  .  with  similar  moleThe  sublimation commer-  a l c o h o l s 288 ether)  o n l y one  on  mixed  For and  develop-  for preparative  a form  separa-  is called  of a i r pressure  been o p t i m i z e d  for  par-  e x a m p l e , the s e p a r a t i o n o f  289  a one  the  T h i s technique  is basically  separations.  acetate-petroleum achieved  higher  B - k e t o l a c t o n e 266g and  column c h r o m a t o g r a p h y w h i c h has  diastereomeric  the  expected  formation.  c o w o r k e r s have r e p o r t e d  chromatographic  rapid  o f any  ester,  287.  c h r o m a t o g r a p h y and  ticularly  of a 8-keto  t o dimer  i m p l i e d by  f o r the  showed  e x h i b i t e d the  indication  t i o n s w i t h moderate r e s o l u t i o n  driven  typical  mass s p e c t r u m  and  observed  exaltolide  flash  ^,  o f the p r o d u c t  fragments corresponding  a b s e n c e o f d i m e r was temperatures  1710  resolution  i o n a t 254 weight  and  spectrum  (ARf=0.09 i n 5%  gram s c a l e  fraction  (65 mg)  was  ethyl  easily  i n seven  minutes.  212  OH n B u  3  S n  '"  HBU3S1V''  nBu  289  288  The  application  of this  lactone  2 66g was f o u n d  desired  product  t e c h n i q u e t o the p u r i f i c a t i o n  t o be v e r y s a t i s f a c t o r y ,  in similar  yield  The  purification  using flash  far  more q u i c k l y  and r e q u i r e d  With  both  c h r o m a t o g r a p h y , however, much  less  using  flash  0  of this  ester  1  bromide  study are  the p r o d u c t s a l l b e i n g  chromatography " ". 17  available,  o f B-keto  The r e s u l t s  i n Table XIII, with  proceeded  solvent.  t h e m e t h o d o l o g y and t e c h n o l o g y now  n = 5 - l l , was c o n d u c t e d .  summarized  p r o v i d i n g the  t o t h a t o b t a i n e d u s i n g HPLC.  the s y s t e m a t i c s t u d y o f t h e c y c l i z a t i o n 262,  o f B-keto  purified  The p r o d u c t s o b t a i n e d f r o m t h e  0  0  0  0  0  3LDA, T H F 0°—* RT Br(CH ) 2  (CH )n  n  262  267  266  cyclization  o f B-keto e s t e r  spectral data similar lactones  (CH2)nZ2  2  bromides  2 6 2 f and 262e  exhibited  t o t h a t o f the sixteen-membered  266g d i s c u s s e d  earlier.  B-keto  213  Table  XIII.  Attempted C y c l i z a t i o n of 262, n = 5 - l l .  B-Keto E s t e r  Bromides  0  0  AA ^ C H  2  )  n  ^  267  *  Starting Material  262 n  Product(s) 266  %* 267  262g  11  49  f  10  45  e  9  43  d  8  41  c  7  57  b  6  45  a  5  41  Isolated yields. The NMR s p e c t r a o f the c r u d e r e a c t i o n mixtures suggest r e l a t i v e l y c l e a n product format i o n and t h e r e f o r e the m o d e r a t e y i e l d s p r o b a b l y r e f l e c t losses incurred during p u r i f i c a t i o n .  214  The was  attempted  typical  by f l a s h  agreement w i t h  of  the p r o d u c t  ^, w h i l e  mass s p e c t r u m  spectrum  that elimination  w h i c h were a s s i g n e d  integrating  two-proton  singlet  a c e t a t e group  3  o f the r e s u l t s  support  ring  The r a t i o n a l e  o n l y i n the p r e p a r a t i o n  of chain  The  observa-  elimination  l e n g t h on t h e  bromides v i a d i a n i o n f o r m a t i o n . the p o s s i b i l i t y  and t h e l i k e l i h o o d behind  f o r the  X I I I shows t h a t  B-keto l a c t o n e s .  the importance  model s t u d i e s r e v e a l  twelve-membered  i n Table  predominates  o f B-keto e s t e r  protons,  o f an a c e t o -  when t h e c h a i n l e n g t h n=9, and  demonstrates  a t 6 5.64-  product.  f o u r t e e n t o sixteen-membered of c y c l i z a t i o n  further  2  alkylation  i n the  a t <5 2.28 and a  a t 6 3.46, w h i c h a r e t y p i c a l  An e x a m i n a t i o n  rings.  parent  o f the t e r m i n a l o l e f i n i c  (CH COCH_ COOR) p r o v i d e d  intramolecular  of three  of a three-proton s i n g l e t  o f an e l i m i n a t i o n  cyclization  showed m u l t i p l e t s  to a total  t o the protons  The p r e s e n c e  Molecular  the expected  had o c c u r r e d was . m a n i f e s t  of the p r o d u c t , which  and 6 4.92-5.10  when n=8  exhibited  m/e.  Evidence  tion  formula.  m a t e r i a l was  showed a b s o r p t i o n s a t 1745 and 1715 cm  a t 198  of  The p r o -  spectrum  ion  formation  262c  The i n f r a r e d  low r e s o l u t i o n  group.  a n a l y s i s o f the d i s t i l l e d  the proposed  its  6.04  bromide  c h r o m a t o g r a p h y , was homogeneous by TLC  and e l e m e n t a l  in  NMR  o f B-keto e s t e r  o f t h e r e a c t i o n s w h i c h gave e l i m i n a t i o n .  duct, p u r i f i e d analysis,  cyclization  the f a i l u r e  of forming  of preparing  a  larger  o f B-keto e s t e r  215  bromides  262c and  ever, i t might for  the S 2 N  An  reflect  reaction,  alternate  B-keto l a c t o n e s examined.  262d  to c y c l i z e i s not w e l l the r i g i d  using  Meldrum's a c i d  through  earlier  Meldrum"s a c i d  requirements  190). of large  derivatives  was  (equation  alcoholysis 83).  The  ring  also  the key c y c l i z a t i o n s t e p  intramolecular  derivative  (pg  f o r the p r e p a r a t i o n  In t h i s a p p r o a c h ,  lactonization  t r a n s i t i o n state  as d i s c u s s e d  strategy  u n d e r s t o o d , how-  o f an  involves acyl  feasibility  of  (83)  266  290  this  strategy  Meldrum's a c i d  was 295  e x a m i n e d by p r e p a r i n g according  t o the  the h y d r o x y  route  outlined  acyl i n Scheme  14.  216  iBuMe SiCl imidazole * 9  HOKH^COOH  , i ^Si-O(CH ) 2  DMF  221  1 0  • I COOSi-f  222 NaOH H 0 2  Q 1) Im CO 2  -|-Si-O(CH ) COOH 2  1 0  m ^-(CH ) OSi—|2  9  0 HO  nBu^NF THF  ^-(CH ) 0H 2  9  295 Scheme 14:  The sion  Preparation  synthesis  o f the a l c o h o l  o f the c o m m e r c i a l l y  (291)  1 7 2  into  of hydroxy  the s i l y l  available ester  292  acyl  Meldrum's  acid  295 was  initiated  by  295,  conver-  11-hydroxyundecanoic acid i n 95% y i e l d  using  t-butyl173  dimethylchlorosilane The in  resulting 97% y i e l d  ester using  and  imidazole  292 was aqueous  i n dimethylformamide  then h y d r o l y z e d sodium  hydroxide.  to the a c i d  293  217  The p r o d u c t showed  singlets  methylsilyl  293 was c h a r a c t e r i z e d  a t 6 0.00 and 6 0.86, t y p i c a l  group,  (CH OSi),  as w e l l  exchanged  upon  2  triplets as a b r o a d  the a d d i t i o n  a t 6 2.34 signal  and a weak, b r o a d  1  typical acid.  Finally,  acid  a t 3550-2550  The  a t 1718  cm ^, w h i c h a r e  vibrations  of a  carboxylic from  and e l e m e n t a l  were c o n s i s t e n t  infrared  absorption  the molecular weight d e r i v e d  material  with  t h e low analysis  the f o r m a t i o n o f  293 .  The c o n v e r s i o n acyl  2  a t 6 10.13 (COOH) w h i c h  mass s p e c t r u m o f t h e p r o d u c t  the d i s t i l l e d  the  both  which  (CH COO) and 6 3.58  a strong  o f C=0 and 0-H s t r e t c h i n g  resolution of  signal  spectrum  of a t - b u t y l d i -  of deuterium oxide.  spectrum o f the p r o d u c t d i s p l a y e d cm  by i t s NMR  halide  o f the a c i d  was n e x t c o n s i d e r e d .  293 i n t o  i t s corresponding  R e c e n t l y Ryan and c o w o r k e r s  148 have r e p o r t e d t h e a c y l a t i o n o f Meldrum's a c i d (246) w i t h an . . . . 113 a c y l i m i d a z o l e d e r i v a t i v e 296 . Acyl imidazoles are generally  231  218  much more e a s i l y additional dioxide  into  advantage  and  sequence.  prepared  than  that  acyl  halides  the r e a c t i o n  suggests that  the a c y l Meldrum's a c i d Treatment  of  the a c i d  offer  by-products,  i m i d a z o l e , are compatible with This  and  the  carbon  t h e n e x t s t e p i n the  the c o n v e r s i o n o f the a c i d 294  293  may  be p e r f o r m e d  w i t h one  i n one  equivalent  293 step.  o f N ,N' -  113 carbonyldiimidazole the a d d i t i o n solution  (298)  of t h i s  containing  the d e s i r e d  reaction  mixture  the a n i o n 300  acylated  p r o d u c t 294  , I -f-Si-0(CH ) COOH 2  in dichloromethane  10  W  dichloromethane  o f Meldrum's a c i d i n 94%  7 L  provided  crude y i e l d .  Evidence  , I -|-Si-0(CH ) COIm  CH Cl ^ > N4- C0 1  to a  , f o l l o w e d by  2  2  10  2  299  298  (CH ) OSi-{2  9  294 for  t h e f o r m a t i o n o f 294  was  s e c u r e d from  the NMR  spectrum  of  t h e p r o d u c t w h i c h showed t r i p l e t s a t 6 3 .47 (2H, CH_ OSi) and OH 6 2.90 (2H, C = C - C H ) , s i n g l e t s a t 5 1.81 (6H, ( C H ) C ) , 2  2  6 0.97  (9H,  ( C H ) C - S i ) , and 3  3  3  6 0.10  (6H,  (CH ) Si), 3  2  2  as w e l l  as  219  a broad  m u l t i p l e t a t 6 1.27-1.83  support  was p r o v i d e d  (16H, h y d r o c a r b o n ) .  by t h e i n f r a r e d  which d i s p l a y e d s t r o n g  absorptions  which are c h a r a c t e r i s t i c  Further  spectrum o f the p r o d u c t  a t 1730, 1635 and 835 cm  o f C=0, C=C,  1  Si-0 stretching vibrations  respectively. The of  s y n t h e s i s o f t h e a l c o h o l 295 was c o m p l e t e d  the s i l y l  fluoride ether duct  ether  294 u s i n g  in tetrahydrofuran  1 7 4  g r o u p was e v i d e n t  from  which d i s p l a y e d a broad  absence o f a s t r o n g the  i n compound  starting  .  The c l e a v a g e  the i n f r a r e d O-H  In a d d i t i o n , t h e NMR  d i m e t h y l s i l y l g r o u p from t h e s t a r t i n g The  final  step  B-keto l a c t o n e the  i n the p r e p a r a t i o n  of the  silyl  spectrum o f the p r o -  absorption  was a l s o c o n s i s t e n t w i t h  cleavage  tetra-n-butylammonium  a t 3400 cm  Si-0 stretching vibration  material.  crude product  1 7 3  by  and t h e  1  a t 835 cm  1  in  spectrum o f the  the l o s s  o f the t - b u t y l -  material. o f the fourteen-membered  266e i n v o l v e d t h e i n t r a m o l e c u l a r a l c o h o l y s i s o f  h y d r o x y a c y l Meldrum's a c i d  295.  The major c o n c e r n  THF A  (CH ) 0H 2  225  9  266e  in  220  this cyclization tions  p r o c e s s was t o a v o i d  which could  appeared  l e a d t o dimer f o r m a t i o n .  reasonable  w o u l d be r e q u i r e d .  Accordingly,  p r o d u c t was p u r i f i e d  t o be i d e n t i c a l lactone  conditions  t h e a l c o h o l 295 was a d d e d tetrahydrofuran  solution.  t o t h e fourteen-membered  266e p r e p a r e d v i a t h e d i a n i o n m e t h o d .  0  The  0  1 0  291 of lactone  266e f r o m t h e h y d r o x y a c i d  B-keto  overall  HO(CH ) COOH  yield  very  b y f l a s h c h r o m a t o g r a p h y and was f o u n d  i n a l l respects  2  reac-  I t therefore  that the use o f high d i l u t i o n  s l o w l y over f i v e hours t o a r e f l u x i n g The  any i n t e r m o l e c u l a r  291 was 2 5 % .  221  CONCLUSIONS The p r e p a r a t i o n has been d e s c r i b e d B-keto e s t e r s  0  o f a s e r i e s o f B - k e t o e s t e r h a l i d e s 262  and t h e c y c l i z a t i o n  investigated.  0  Br(CH ) ' 2  The major p r o d u c t  0  AA„  of the d i a n i o n  o f these  obtained  when  0  0  0  Br(CH ) '  n  2  n  262 the  chain  l e n g t h n<5, was f o u n d  t o be o f t y p e  267  corresponding  t o t h e e l i m i n a t i o n o f H-X.  0  0  AX •(CH ) -22  n  267 The c y c l i z a t i o n three the  equivalents  desired  o f B-keto e s t e r  of lithium diisopropylamide  sixteen-membered  amount o f 267g.  b r o m i d e 262g, n = l l ,  B-keto l a c t o n e  A t t e m p t s t o improve  gave  using  predominantly  266g, p l u s  the s e l e c t i v i t y  a small  in this  222  r e a c t i o n by v a r y i n g t e m p e r a t u r e were The  unsuccessful.  preparation  i n an e f f o r t on  t h e s o l v e n t s y s t e m s , c o u n t e r i o n s , and  o f B - k e t o e s t e r s 277 a n d 278 was c o n d u c t e d  t o determine the p o s s i b l e e f f e c t s o f l e a v i n g groups  the c y c l i z a t i o n  process.  0  0  C H S0 0(CH ) 6  5  The a t t e m p t e d c y c l i z a t i o n  2  2  0  1 0  ^  5  277  The  side  2  n  278  B-keto e s t e r s , however, p r o v i d e d or u n d e s i r e d  0  C H S(CH ) 6  of these  only unreacted  starting  material  products.  p r e p a r a t i o n o f B-keto l a c t o n e s  266 was  subsequently  f o u n d t o be b e s t p e r f o r m e d by d r o p w i s e a d d i t i o n o f a B - k e t o e s t e r b r o m i d e 262 t o a s o l u t i o n c o n t a i n i n g t h r e e  equivalents  of  In p a r t i c u l a r ,  lithium  under these 267  diisopropylamide  i n tetrahydrofuran.  c o n d i t i o n s the formation  was f o u n d t o be m i n i m i z e d .  o f B-keto e s t e r  olefins  The a p p l i c a t i o n o f t h i s  pro-  cedure towards the c y c l i z a t i o n o f B-keto e s t e r bromides 262, n = 5 - l l , h a s shown t h a t B - k e t o l a c t o n e p r e d o m i n a t e s when t h e chain  l e n g t h n = 9 - l l , w h i l e e l i m i n a t i o n p r e v a i l s when n<8.  This trend appears t o r e f l e c t the geometric c o n s t r a i n t i n  223  cyclization tance  of  of chain Many o f  possess  the  planar  length  the  lactones  B-keto e s t e r d i a n i o n  i n overcoming  macrolide  fourteen  struction  of  discussed  earlier,  classical  l a c t o n i z a t i o n route.  ability  t o employ  synthesis is  of  the  effected.  alkylation addition,  this  approach  of  the  be  avoided  allow  B - k e t o l a c t o n e s was intramolecular  the  however, i s  the  before  cyclization ring  t o be  via  dianion  taken.  In  dilution  cyclization  that  the  t o the  also investigated. a l c o h o l y s i s of  as  t h a t of  macrocyclic  functionality  approach  con-  advantages that high  further elaboration of a second  The  bond f o r m a t i o n ,  convergent approach  i n the  to  i n v o l v i n g independent  acid portions  preparation  a B-keto l a c t o n e  Finally,  the  or more members.  Most i m p o r t a n t ,  t h i s method o f f e r s t h e  c o n d i t i o n s can  should  a l c o h o l and  The  found  s e v e r a l advantages over  a convergent  also allows  presence of  have been  such r i n g s v i a carbon-carbon presents  impor-  this constraint.  antibiotics  containing  and.the  an  step  i n the  and  the  product  ring. synthesis  of  large  This procedure  ring  involves  a c y l Meldrum's a c i d  290.  224  This the  s t r a t e g y was  s u c c e s s f u l l y employed  fourteen-membered  potential dianion  B-keto l a c t o n e  f o r the p r e p a r a t i o n  i n the s y n t h e s i s  266e, and a p p e a r s  o f B-keto l a c t o n e s  procedure i s u n s a t i s f a c t o r y .  of  to o f f e r  where t h e  225  EXPERIMENTAL SECTION General:  See  page  113.  2,2-Dimethyl-1,3-dioxane-4,6-dione A 250-mL E r l e n m e y e r bar  was  charged  (246)  containing  with malonic  acid  a large (52 g;  magnetic  0.50  stirring  mole) and  acetic  j anhydride was  (60 mL;  and  cooling.  most o f  Acetone  while c o o l i n g  i n the  filtered  by  allowed  then white  fridge  to a i r dry.  acetone  (110 mL),  w h i c h was  phorus pentoxide, dec);  IR 1790 and  mass s p e c t r u m  ( 2 0 ) , 69  m/e  wt  acid  filtered  dried 35 g  with  The  then  was  was  1  NMR  (rel intensity)  ( 4 0 ) , 59  93-94°  dissolved  gave a  6 1.78 144  (lit.  1  4  6  ( 3 5 ) , and  (100),  58 ( 3 4 ) .  material,  flocculent  over  ( s , 6 H ) , 3.57 ( 1 ) , 129  were  then  undissolved  Filtration  mp  allowed  (3 x 75 mL),  solid  slowly  crystals  i n a vacuum d e s s i c a t o r  (49%):  spontaneous  introduced  resultant  i c e water  constant  with  mixture  t o remove any  (220 mL).  suspension  dissolved  r e s u l t i n g white  1755 cm" ;  ( 7 2 ) , 61  (1.5 mL)  the r e a c t i o n  washed w i t h The  resulting  mole) was  overnight.  d i l u t e d w i t h water solid  0.55  the  acid  the m a l o n i c  (40 mL;  suction,  To  sulfuric  t o 20-25° and  to stand  72  mole).  added c o n c e n t r a t e d  stirring  in  0.60  phos-  94-95° ( s , 2H) ; 100  (88),  226  5-(1'-Hydroxye t h y l i d e n e ) - 2 , 2 - d i m e t h y l - 1 , 3 - d i o x a n e - 4 , 6 - d i o n e (253) A 250-mL t w o - n e c k e d nitrogen  inlet  and  with  (10.0  g;  The  246  solution  was  69.4  mmole) and  stirring  f o r 10 m i n u t e s ,  139  introduced dropwise  dichloromethane,  acid  (2 x 25 mL),  o f 253  prepared  by  6H),  2.67  intensity) 84  (55)  and  solution  was  186 69  i c e water i n one  (6.0 g;  recrystallization  ( s , 3H),  15.0  ( 4 7 ) , 171  1740  for 1 5%  then d r i e d  mL).  and  dry  Upon was  to  hour.  hydrochloric  over  anhydrous  reduced  pres-  f r o m e t h y l e t h e r gave  10.5g  An  and  analytical and  had  1665  the  cm ; - 1  ( 1 0 0 ) , 111  sample  for CgH^C^:  C,  51.61; H,  5.41.  Found:  C,  51.82; H,  5.22.  was  following NMR m/e  ( 1 6 ) , 85  (36).  Anal. Calcd  bath  allowed  ( b s , I H ) ; mass s p e c t r u m  ( 1 7 ) , 128  (150  76 mmole)  Removal o f the s o l v e n t under  IR  charged  portion.  washed w i t h  (2 x 50 mL),  83.5-84.5°;  with a  septum was  m i x t u r e was  s u b l i m a t i o n (60°/0.35 t o r r ) mp  equipped  t h e n a t room t e m p e r a t u r e  as a p a l e y e l l o w s o l i d .  properties: (s,  added  the r e a c t i o n  water  magnesium s u l f a t e .  i n an  acetyl chloride  and  The  (81%)  mmole) was  f o r 1 hour,  s u r e f o l l o w e d by  flask  dry dichloromethane  t h e n c o o l e d t o 0°  (10.99 g;  a t 0°  bottom  stoppered with a rubber  pyridine  stand  round  6  1.75  (rel (36),  227  4-Chloro-l-butanol A reflux  (254c)  250-mL t h r e e - n e c k e d condenser,  dropping  placed  mechanical  f u n n e l was  mole) and  g;  0.22  bottom  stirrer  charged  dry p y r i d i n e  i n a water  (26.4  round  and  0.22  bath maintained  a t 55°  added d r o p w i s e  sulfur  dioxide  v e n t e d down the d r a i n  hose.  On  workup, t h e r e a c t i o n  with ether  (3 x 100  mL).  5% h y d r o c h l o r i c  acid  then d r i e d  anhydrous  over  removed under tilled  67-69°/5.0 t o r r - 1  3.72  (m,  ( 1 4 ) , 90  NMR 4H);  The  5  0  The  temper-  f o r 1 hour  c o o l e d and  brine  as  rubber extracted  The  (50  m/e  with  mL),  solvent  was  the r e s i d u e f r a c t i o n a l l y  254c as a c o l o u r l e s s  (m,  ( 1 0 0 ) , 62  chloride  by means o f a  (50 mL),  84-85°/16  mass s p e c t r u m  ( 5 9 ) , 71  water  of  6 1.70-2.00  0.22 was  1 hour.  t o 80°  m i x t u r e was  p r e s s u r e and  1  flask  thionyl  magnesium s u l f a t e .  g,. (36%)  (lit.  and  raised  a  e t h e r e a l e x t r a c t s were washed  (50 mL),  reduced  t o g i v e 8.7  2950 c m ;  then  (20 g;  The  over  b a t h was  with  pressure-equalizing  mole).  a t u r e o f the water was  a  equipped  with 1,4-butanediol  (17.6g;  mole) was  flask  torr);  4H),  2.65  IR  3620, 3450  ( s , I H ) , and  (rel intensity)  ( 2 3 ) , 57  liquid;  ( 1 3 ) , 55  108  disbp  and  3.43-  ( 1 ) , 92  (78) and  29  (13).  6-Chloro-2-hexanone A one-liter a l a r g e magnetic with 5%  a solution  solution).  two-necked r o u n d  bottom  stirring  an  o f sodium The  flask  bar  and  addition  hypochlorite was  flask  equipped f u n n e l was  i n water  c o o l e d t o 0°  with  i n an  (400 mL  charged of a  i c e water  bath  228  and  1-methylcyclopentanol  chloride  (2.0 mL)  solution  of g l a c i a l  (10 g;  added d r o p w i s e . acetic  acid  (5 mL),was i n t r o d u c e d and stirred  0.10  f o r 5h h o u r s .  mole) i n c a r b o n  Upon c o m p l e t e  (40 mL)  the r e a c t i o n  The  o f t h e aqueous p h a s e  saturated  sodium  anhydrous  magnesium s u l f a t e .  filtration  left  tetrachloride The hours  carbon  then  saturated addition  carbonate  ready  aqueous sodium compound was  extracted  dried  over  under  reduced  4.0  (30%)  bp  g  torr  and  3.52  136  ( 0 . 2 5 ) , 134  ( t , 2H,  and  over  Removal o f the d r y i n g  agent  by  i n carbon  f o r the rearrangement  step.  solution  for  was  carbonate  refluxed  reduced  was  (25 mL)  solution.  (2 x 50 mL)  and  magnesium s u l f a t e .  55  (m,  ( l i t . 4H),  1  5  1  a  2.16  the  The  decomposed  aqueous  the e t h e r e a l  52.5-54°/2.3 t o r r ) ; 2.48  (58).  ( 6 ) , 99  m/e  ( 1 3 ) , 98  IR  ( t , 2H,  layer  solution  Removal o f t h e  J = 7 H z ) ; mass s p e c t r u m ( 0 . 7 5 ) , 118  Excess  resulting  then  as a c o l o u r l e s s  ( s , 3H),  1%  pressure.  added and  washed w i t h e t h e r  of 6-chloro-2-hexanone  6 1.60-1.90  (100)  dried  p r e s s u r e f o l l o w e d by vacuum d i s t i l l a t i o n  NMR  58  t h e n washed w i t h a and  bisulfite  with ether  anhydrous  64-66°/3.8  tetrachloride  (2 x 10 mL)  removed under  w i t h warm aqueous sodium was  (3 x 10 mL),  solution  tetrachloride  the s o l v e n t  tetrachloride  vigorously  1-methylcyclopentyl hypochlorite  solution,  a  separated g r e e n i s h - y e l l o w carbon  t e t r a c h l o r i d e L l a y e r w a s combined w i t h c a r b o n extracts  addition,  i n carbon mixture  tetra-  solvent gave  liquid: 1710  cm ; - 1  J = 7 Hz),  (rel intensity) ( 4 6 ) , 71  (21),  229  6-Chloro-2-hexanol A  50-mL two-necked  nitrogen  inlet  and  2-hexanone  (4.0  was  t o 0°  cooled  (1.13  (254d)  g;  allowed  the  g;  30 mmole) and  i n an  added was  f o r Ah  acid  solution  aqueous s o l u t i o n the c o m b i n e d and  brine  was  IR  of  was  The  (m,  6H),  7 Hz), 136 57  the c r u d e  (48) , 56  bp 1  ( s , IH,  3.50-3.90  ( 1 ) , 123  reduced  Upon  reaction  pressure  and  added c a u t i o u s l y t o t h e extracted with  and  the  ether  On 5%  78-79°/2.3  torr  NMR  ( d , 3H,  6 1.17  (m,  55  (70%)  ( l i t .  (100) .  102  D 0), 2  ( 1 7 ) , 85  5  1  b  3.50 m/e  hydroThe  25 mL) (20  and mL),  over under  Vacuum of  dis-  254d as  58°/l.l  J = 6 Hz),  I H ) ; mass s p e c t r u m  (100),  1  workup,  removed  liquid. g  was  residue.  dried  s o l v e n t was  complete  mixture  (4 x  was  254d as a y e l l o w  exchanged w i t h  ( 2 8 ) , 121 (46)  then  m a t e r i a l gave 2.8  3470 cm" ;  2.07  and  the  flask  borohydride  in portions.  ethereal solution  leaving  liquid:  3620 and  The  sodium  a  6-chloro-  o r g a n i c e x t r a c t s were washed w i t h w a t e r  pressure  colourless  with  (25 mL).  and  and  with  h o u r s a t room t e m p e r a t u r e .  then  (20 mL).  tillation  equipped  charged  bath  removed  a n h y d r o u s magnesium s u l f a t e reduced  was  slowly  t h e e t h a n o l was removed under chloric  flask  ethanol  i c e water  i c e bath  to stand  bottom  a g l a s s stopper  30 mmole) was  addition,  round  a  torr);  1.30-1.90  ( t , 2H,  J  =  (rel intensity)  ( 5 6 ) , 67  (53),  230  General  procedure  f o r the  A 50-mL s i n g l e - n e c k e d reflux  condenser  253  (1.2  and  dry  heated and  fitted  round  with  e q u i v a l e n t ) , the tetrahydrofuran  to reflux  bottom f l a s k  a nitrogen  appropriate  (25 mL).  f o r 4 hours,  then  The  solution then  solution  (1 x  15 mL),  d r i e d over  solvent  under  was  reduced  (1 x  pressure  15 mL)  (67%) IR  253  mmole). of  1755  J  (3.6  g;  1725  = 6 Hz)  cm" ;  NMR  and  4.40  1  2H,  m/e  ( r e l i n t e n s i t y ) 210  129  (52),  109  (100),  Calcd  the  according  the  107  6 2.27  ( 1 9 ) , 208 (100)  temperature  and  50  mL  sodium  brine  of bicarbonate  (1 x  10  mL),  Removal o f  t o the  the  general  2-bromoethanol  c r u d e m a t e r i a l gave bp  62-64°/0.18  ( s , 3H),  ( t , 2H,  was  crude g-keto e s t e r s .  mmole) and  of  with  (,2,55a)  a colourless liquid:  (t,  Anal.  19.4  Distillation  255a as and  t o room  and  a  equivalent)  r e a c t i o n mixture  saturated  gave  prepared  charged  (1.0  a n h y d r o u s magnesium s u l f a t e .  T h i s compound was  16.0  was  funnel containing  (2 '-Bromo-1 ' - e t h y l ) - 3 - o x o b u t a n o a t e  cedure u s i n g  inlet  cooled  washed w i t h  water  equipped with  alcohol  The  transferred to a separatory  ether.  252.  a l c o h o l y s i s of  J  3.46  = 6 Hz);  (19), 102  168  (30),  (59).  for CgHgO^r:  C,  34.47; H,  4.34.  Found:  C,  34.66; H,  4.29.  (1.99  2.27  g  torr;  ( s , 2H),  mass  pro-  3.48  spectrum 166  (29),  g;  231  (3'-Bromo-1'-propyl)-3-oxobutanoate  (25 5b)  T h i s compound was p r e p a r e d a c c o r d i n g t o t h e g e n e r a l p r o cedure u s i n g (742 mg;  (1.20 g; 6.45 mmole) and  5.34 mmole).  gave 953 mg 0.40  253  torr;  1.93-2.36  Vacuum d i s t i l l a t i o n  I R 1745, 1720 and 1663 c m ; (in, 2H) , 3.43  ( 3 2 ) , 206  190  (M*,2~f  122  ( 7 7 ) , 121  ( 2 4 ) , 204  ( 7 8 ) , 103  for C ^ ^ B r :  g; 1.6.0  mmole).  2.44 g  87-88°/0.18  = 187.5),  189-  (48),  (53) and 101 ( 3 5 ) .  C, 37.69; H,  4.97.  C, 37.65; H, 5.10.  (?^c)  253  (3. 60 g; 19.2  Vacuum d i s t i l l a t i o n  mmole) and 254c  o f t h e c r u d e mate-  (79%) o f 255c as a c o l o u r l e s s  torr;  I R 1745 and 1720 c m ;  NMR  - 1  4H),  2.26  4.13  ( t , 2H, J = 6 H z ) ; mass s p e c t r u m m/e  (9),  192  103  224 ( 3 2 ) ,  compound was p r e p a r e d a c c o r d i n g t o t h e g e n e r a l p r o -  for alcoholysis using  gave  (m*,  ( 7 3 ) , 102  (4 ' - C h l o r o - l ' - b u t y l ) - 3 - o x o b u t a n o a t e  rial  ( s , 2H) and 4.25  182 ( 7 8 ) , 180 ( 7 8 ) , 143 ( 1 0 0 ) , 123  Found:  (1.72  ( s , 3H),  (rel intensity)  ( 2 4 ) , 187-188  ( 4 8 ) , 120  Anal. Calcd  m/e  material  bp 8 0 - 8 2 ° /  6 2.27  ( t , 2H, J = 6 H z ) , 3.43  222  = 189 . 5 ) ,  liquid:  NMR  - 1  2H, J = 6 H z ) ; mass s p e c t r u m  cedure  o f the crude  (80%) o f 255b a s a c o l o u r l e s s  (t,  This  3-bromo-l-propanol  ( s , 3 H ) , 3.43  ( 1 8 ) , 157  (100) , and 102  ( s , 2 H ) , 3.50  ( 1 2 ) , 152 (53) .  ( 1 1 ) , 150  liquid:  bp  <S 1.70-1.90  (m,  ( t , 2H, J = 5.5 Hz) and ( r e l intensity)  ( 3 3 ) , 116  194  ( 1 7 ) , 115 ( 2 3 ) ,  232  Anal. Calcd  for CgH^O^Cl:  C, 49 .88 ; H,  6.80.  Found:  C, 49.82; H,  6.91.  (6'-Chloro-2'-hexyl)-3-oxobutanoate  T h i s compound cedure (2.80 rial  was  for alcoholysis g; 2.06 mmole).  gave 3.82  96-98°/0.20  g  u s i n g 253 Vacuum  222  distillation  o f the c r u d e  NMR  - 1  (m, 6H), 2.23  (0.70),  220  pro-  (4.62 g; 2.48 mmole) and 254d  IR 1740 and 1715 c m ;  2H, J = 6 Hz) and 4.77-5.07 intensity)  a c c o r d i n g t o the g e n e r a l  (85%) o f 255d as a c o l o u r l e s s  torr;  6 H z ) , 1.40-2.00  prepared  (255d)  ( s , 3H), 3.41  (m, I H ) ; mass ( 2 ) , 118  liquid:  6 1.27  matebp  ( d , 3H, J =  ( s , 2 H ) , 3.48 ( t ,  spectrum  ( 5 8 ) , 103  m/e ( r e l  ( 7 4 ) , and 85  (100) . Anal. Calcd for C ^ H ^ C ^ C l :  C, 54.42; H,  7.76.  Found:  C, 54.44; H,  7.79.  (2'-Propen-l'-yl)-3-oxobutanoate  T h i s compound  (257)  was p r e p a r e d  a c c o r d i n g t o the g e n e r a l  c e d u r e f o r a l c o h o l y s i s u s i n g 253  (2.40 g; 12.9 mmole) and  2-propene-l-ol the crude liquid: 6 2.24  (624 mg;  10.8  m a t e r i a l gave 1.37 bp 7 1 - 7 2 ° / 2 5 t o r r ;  ( s , 3H), 3.45  mmole). g  Vacuum  distillation  (90%) o f 257 a s a  of  colourless  IR 1742, 1715 and 1650 c m ;  ( s , 2H) , 4.57  pro-  - 1  ( d , 2H, J = 5 Hz) and  NMR  233  5.00-6.17 100  (m,  3H);  ( 1 5 ) , 84 Anal.  (100)  Calcd  Attempted  mass s p e c t r u m m/e and  58  ( r e l i n t e n s i t y ) 142  (100).  for C ^ g C ^ :  C,  59.14; H,  7.09.  Found:  C,  59.24; H,  7.16.  cyclization  (9),  of  (3'-bromo-1'-propyl)-3-oxobutanoate  (255b) A solution dry  tetrahydrofuran  round with  bottom  (1.55  flask  a rubber  water b a t h mL;  255b  2.20  (223  brine  The  water  (3 mL)  and  f o r 10  d r i e d over  was  ether  t o 0°  The  (5 mL)  i n hexane  a  above  solution  (3 mL)  to s t i r  was for  were a d d e d .  water  (2x5  purification  f o r compound  30 The  mL)  and  sulfate. gave 82.5  o i l which e x h i b i t e d i d e n t i c a l  reported  ice  c o l o u r l e s s to  a n h y d r o u s magnesium by  stoppered  i n an  m i n u t e s and  allowed  washed w i t h  solvent, followed  t o those  i n l e t and  M solution  added d r o p w i s e . stirred  mmole) i n  i n a 25-mL two-necked  cooled  1.43  2.20  mmole) i n t e t r a h y d r o f u r a n  a pale yellow  properties  f l a s k was  separated,  then  mg;  a nitrogen  r e a c t i o n mixture  p h a s e was  (5 mL),  of  was  (222  prepared  n - b u t y l l i t h i u m as a  mg ; 1.00  Removal o f t h e (58%)  The  mmole) was  m i n u t e s , then  was  equipped with  solution  introduced.  organic  (12 mL)  septum.  and  pale yellow of  of diisopropylamine  257.  mg  spectral  234  (4'-Chloro-1'-butyl)-3-oxopentanoate  A 25-mL two-necked nitrogen with  and s t o p p e r e d  diisopropylamine  furan and  inlet  round  (12 mL).  bottom f l a s k with  a rubber  The f l a s k  was c o o l e d  was then  formation  allowed  o f the base.  an a d d i t i o n a l  with methyl  was t r e a t e d w i t h then  diluted  the r e a c t i o n  (143 mg; l.QOmmole).  with ether  (25 mL).  (75%)  on s i l i c a  o f 2 58  distillation)  6 1.09 3.46  complete  stirring  On workup, t h e s o l u t i o n  solution  until  acidic  dried  was  over  anhydrous  reduced  P r e p a r a t i v e TLC o f t h i s  g e l u s i n g c h l o r o f o r m a s s o l v e n t gave  70-72°/0.13  torr;  ( t , 3H, J = 7 H z ) , 1.85  solu-  was quenched  The e t h e r e a l l a y e r  liquid:  2.20  (19 3 mg; 1.00mmole)  Removal o f t h e s o l v e n t u n d e r  as a c o l o u r l e s s  ( s , 2 H ) , 3.58  to pale yellow  mixture  (10 mL), then  s u r e gave 258 a s a y e l l o w o i l .  bath  (1.38 mL;  (3 mL) was i n t r o d u c e d and upon  s e p a r a t e d , washed w i t h w a t e r  material  o f 255c  5% h y d r o c h l o r i c a c i d  magnesium s u l f a t e .  charged  f o r 15 m i n u t e s t o e n s u r e  A solution  30 m i n u t e s  iodide  septum was  i n hexane  The c o l o u r l e s s  to stir  dry tetrahydrofuran  for  with a  t o 0° i n an i c e water  n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n  tion  equipped  (223 mg; 2.. 2.0 mmole) and d r y t e t r a h y d r o -  mmole) was added d r o p w i s e .  in  (258)  R f 0.41; bp  (q  ( t , 2H, J = 6 H z ) , and 4.20  ?  crude 155 mg  (Kugelrohr  IR 1745 and 1718 c m (m, 4 H ) , 2.56  pres-  - 1  ;  NMR  2H, J = 7 H z ) ,  ( t , 2H, J = 6 H z ) ;  235  mass s p e c t r u m 116  ( 8 ) , 98  m/e  (rel intensity)  ( 1 5 ) , 93  Anal. Calcd  (37)  and  208  91  for CgH^C^Cl:  C,  52.30; H,  7.32.  Found:  C,  52.30; H,  7.39.  100-mL two-necked  reflux (1.93  condenser g;  acetone for  10.0  ethereal  was  charged  (6.0 g;  mixture  was  reduced was  then d r i e d  p r e s s u r e and  ether  washed w i t h w a t e r  over anhydrous  2H),  (m, and  intensity) High 283.9910.  afforded  2.56  bp 9 6 - 1 0 0 ° / 0 . 2 5  1.77-1.92  40.0  4H), 4.12  284  2.25  torr;  IR  o f 259  1740 3.18  and  283.9902.  reflux  added.  as a 1720  ( t , 2H,  ( 8 2 ) , 103  and  brine Removal of  the  colourless cm ;  NMR  - 1  6  J = 7 Hz),  (75)  was  The  Distillation  J = 5 H z ) ; mass s p e c t r u m  ( 7 0 ) , 157  and  acetone  (3 x 20 mL)  R e s o l u t i o n Mass Measurement C a l c d Found:  to  magnesium s u l f a t e .  (90%)  ( s , 3H),  ( t , 2H,  ( 2 ) , 183  g  255c  mmole)  The  (50 mL)  with a  with  heated  the s o l v e n t g a v e 259 as a y e l l o w l i q u i d .  liquid:  equipped  t h e n c o o l e d t o room t e m p e r a t u r e .  crude m a t e r i a l  (s,  flask  inlet  iodide  reaction  (5),  (259)  bottom  a nitrogen  The  solution  (20 mL),  round  mmole), sodium  removed under  of  and  (50 mL).  20 h o u r s  ( 7 ) , 171  (100).  (4'-Iodo-1'-butyl)-3-oxobutanoate  A  ( 3 ) , 206  m/e  and  85  3.43  (rel (100).  for CgH^O^I:  236  5-Acetoxy-l-broinopentane A  50-mL two-necked  reflux zinc  condenser  chloride  mole). and  The  acetyl  and  ( c a . 20 mg)  flask  was  bromide  (7.99  stand  hour  f o r 0.5  diluted  bottom  and  g;  for 2 hours.  saturated  mL),  (20 mL),  then d r i e d  12  torr);  3.37  IR  NMR  - 1  J = 7 Hz)  and  trum m/e  (rel intensity)  (35),  ( 1 8 ) , 69  5-Bromo-l-pentanol A solution (150 mL)  over  reduced  was  210  ( 1 0 0 ) , 68  was  allowed  to  was  cooled was  washed  magnesium  (20  sulfate.  p r e s s u r e f o l l o w e d by 11.0  61  (m,  g  (88%)  (lit. 6H),  1  3  of  265  106-107°/  3  2.03  ( s , 3H),  J = 6 H z ) ; mass ( 0 . 5 ) , 150  vacuum  spec-  (35),  148  (45).  (261a)  o f 265  prepared  (10.8  g;  0.052 mole) i n d r y  methanol  i n a 250-mL s i n g l e - n e c k e d r o u n d inlet.  bonate  t h e n added  0.116  introduced dropwise.  anhydrous  f l a s k equipped with a n i t r o g e n (16 g;  bath  bicarbonate solution  ( 0 . 5 ) , 208 and  0.10  i c e water  organic layer  ( t , 2H,  (28)  g;  and  6 1.53-2.10 4.03  anhydrous  solution  bp 8 9 - 9 1 ° / 4 . 5 t o r r  cm ;  with  over  The  sodium  s o l v e n t under  1720  with a  t o room t e m p e r a t u r e  o f t h e c r u d e m a t e r i a l gave  ( t , 2H,  73  i n an  mixture  The  (100 mL).  liquid:  charged  0.065 mole) was  (20 mL),  as a c o l o u r l e s s  equipped  t e t r a h y d r o p y r a n (8.61  w i t h water  distillation  was  a t 0 ° , t h e n warmed  refluxed  Removal o f the  inlet  the r e a c t i o n  with chloroform  water  flask  t h e n c o o l e d t o 0°  addition,  and  round  a nitrogen  Upon c o m p l e t e  1 hour  (265)  mole) was  bottom  Anhydrous potassium in portions  and  carthe  237  resulting  suspension  temperature.  stirred  v i g o r o u s l y f o r 4 h o u r s a t room  Dilute hydrochloric acid  t u r e became a c i d i c acetate  was  (3 x 100  washed w i t h  and  mL).  water  was  added u n t i l  the  solution  was  The  combined  o r g a n i c e x t r a c t s were  (50 mL)  and  brine  extracted with  (50 mL),  then  a n h y d r o u s magnesium s u l f a t e .  Removal o f  reduced  by  vacuum d i s t i l l a t i o n  of  261a  pressure,  material bp  53-56°/0.20  3400 c m ;  NMR  - 1  D 0),  3.40  2  followed  gave 5.71  g  (66%)  torr  (lit.  1  5  (m,  J = 6 Hz)  6H),  and  s p e c t r u m m/e  ( r e l i n t e n s i t y ) 168  148  ( 5 ) , 135  88  ( 4 ) , 137 ( 2 ) , 86  and  55  ( 2 ) , 70  ( 5 ) , 122  ( 9 ) , 69  as  3.60  cedure  0.2 2.27 (t,  dried  over  of  the  crude  ( 1 ) , 120 68  IR  ( s , IH,  166  3620  exchanged  J =  6 Hz);  (0.1),  ( 1 ) , 109  ( 1 6 ) , 57  and  150  with  mass  (4),  ( 2 ) , 107  ( 1 0 ) , 56  (2),  (13)  (26).  T h i s compound was  gave  ethyl  s o l v e n t under  ( t , 2H,  (0.1),  (100),  mix-  a colourless liquid:  2.50  (5'-Bromo-1'-pentyl)-3-oxobutanoate  (1.67  the  75-76°/0.5 t o r r ) ;  4  6 1.30-2.03  ( t , 2H,  the  prepared  for a l c o h o l y s i s using g;  10.0  1.87  g  torr;  mmole). (74%)  IR  ( s , 3H), 2H,  1740, 3.40  J = 6 Hz);  of  253  (262a)  according (2.23  g;  Vacuum d i s t i l l a t i o n 262a as  1720  and  ( t , 2H,  t o the 12.0 of  general  mmole) and the  a colourless liquid: 1660  cm" ; 1  J = 7 Hz),  mass s p e c t r u m m/e  NMR 3.45  pro-  crude bp  6 1.50-2.00 ( s , 2H),  261a  material  98-99°/ (m,  and  ( r e l i n t e n s i t y ) 252  6H),  4.13 (0.6),  238  250  ( 0 . 6 ) , 210 ( 0 . 3 ) , 208 ( 0 . 3 ) , 171 ( 1 ) , 150 ( 7 ) , 148 ( 1 0 ) ,  103  ( 3 8 ) , 85 ( 3 3 ) , and 69  (100).  H i g h R e s o l u t i o n Mass M e a s u r e m e n t C a l c d 252.0184, 250.0205. General  Found:  252.0175,  from  (l,n)-diols  A s o l u t i o n of the d i o l liquid-liquid bath  solvent. layer  250.0205.  procedure f o r the p r e p a r a t i o n o f ( l , n ) bromoalcohols  (n=6-10)  oil  f o r CgH^^O^Br:  extractor.  while being  i n 48% HBr was p l a c e d  The s o l u t i o n was t h e n h e a t e d i n an  c o n t i n u o u s l y e x t r a c t e d w i t h an a p p r o p r i a t e  On w o r k u p , t h e s o l u t i o n was c o o l e d  separated,  washed w i t h  saturated  and t h e o r g a n i c  sodium b i c a r b o n a t e  t i o n , w a t e r , t h e n d r i e d o v e r a n h y d r o u s magnesium Removal o f t h e s o l v e n t under r e d u c e d p r e s s u r e bromoalcohols,  i n a 100-mL  w h i c h were f u r t h e r p u r i f i e d  solu-  sulfate.  gave t h e c r u d e  by vacuum  distilla-  tion . 6-Bromo-l-hexanol  (2J51fcO  T h i s compound was p r e p a r e d  according  cedure f o r bromoalcohol formation 50.9  using  mmole) a n d 4 8 % h y d r o c h l o r i c a c i d  t o the general  1,6-hexanediol (12 m L ) .  toluene  crude product  (50 mL) a s s o l v e n t .  (6.00 g;  The s o l u t i o n  was h e a t e d t o 75-80° and t h e e x t r a c t i o n was c o n t i n u e d hours u s i n g  pro-  f o r 39  D i s t i l l a t i o n of the  g a v e 5.16 g ( 5 6 % ) o f 261b a s a c o l o u r l e s s l i q u i d :  bp 59-62°/0.10 t o r r  (lit.  1  5  5  105-106°/5.0 t o r r ) ;  I R 3620 and  239  3450;  NMR  D 0),  3.43  2  spectrum (14),  6 1.30-2.00  (rel intensity)  ( 6 3 ) , 32  164  (16) and 55  7- B r o m o - l - h e p t a n o l  ( 6 ) , 162  formation  using  hours u s i n g toluene  bp  gave  - 1  NMR  4.85 g  ( 2 4 ) , 97  m/e  T h i s compound  using tilled  (7.0 g;  solution f o r 16  Distillation  o f the  1  5  6  lll-112°/4 t o r r ) ;  (m, 10H), 3.02  ( 4 8 ) , 68  195  I R 3640 and  ( s , IH, exchanged ( t , 2H, J = 7 H z ) ;  ( 1 ) , 193  (20) and 55  liquid:  ( 1 ) , 150 ( 2 4 ) ,  (100).  (2 6Id) was p r e p a r e d  f o r bromoalcohol  according  formation  t o 9 0 ° and t h e e x t r a c t i o n toluene  pro-  (47%) o f 261c a s a c o l o u r l e s s  41.2 mmole) and 48% h y d r o b r o m i c heated  The  was c o n t i n u e d  as s o l v e n t .  (rel intensity)  ( 2 2 ) , 69  8- B r o m o - l - o c t a n o l  cedure  (36 mL).  ( t , 2H, J = 6 Hz) and 3.60  2  mass s p e c t r u m  (lit.  6 1.30-2.00  w i t h D 0 ) , 3.37  148  (100 mL)  107-108°/4.0 t o r r  3450 c m ;  ( 1 4 ) , 134  1,7-heptanediol  t o 7 5 - 8 0 ° and t h e e x t r a c t i o n  product  ( 6 ) , 136  a c c o r d i n g t o the g e n e r a l  53.0 mmole) and 48% h y d r o b r o m i c a c i d  crude  ( t , 2H, J = 6 H z ) ; mass  (100).  was p r e p a r e d  f o r bromoalcohol  was h e a t e d  with  (261c)  T h i s compound cedure  ( s , IH, e x c h a n g e d  ( t , 2H, J = 7 Hz) and 3.63  m/e  83  (m, 8 H ) , 2.27  using  acid  1,8-octanediol  (6 mL).  The c r u d e  (45%) o f 26Id  pro-  (6.0 g;  The s o l u t i o n  was c o n t i n u e d  (100 mL)as s o l v e n t .  and gave 3.86 g  to the g e n e r a l  was  f o r 72 h o u r s  m a t e r i a l was  as a c o l o u r l e s s  dis-  liquid:  240  bp  95-100°/0.27  and  3450; NMR  D 0),  3.40  2  spectrum (14), 67  (lit.  1  6 1.10-2.00  5  7  bp 7 7 - 7 8 ° / 0 . 0 1  (m, 12H), 2.08  ( t , 2H, J = 7 Hz) and 3.58  m/e  150  torr  (rel intensity)  ( 1 4 ) , 148  ( 1 4 ) , 56  ( 1 4 ) , 111  ( 2 0 ) , and 55  9-Bromo-l-nonanol  192  torr);  IR 3620  ( s , IH, e x c h a n g e d  with  ( t , 2H, J = 6 H z ) ; mass  ( 3 ) , 190  ( 1 1 ) , 82  ( 3 ) , 164  ( 3 8 ) , 69  ( 1 4 ) , 162  ( 8 0 ) , 68 ( 3 4 ) ,  (100).  (261e)  T h i s compound was p r e p a r e d a c c o r d i n g t o t h e g e n e r a l p r o cedure  f o r bromoalcohol  formation using  37.4 mmole) and 48% h y d r o b r o m i c heated using  t o 9 0 ° and t h e e x t r a c t i o n toluene  tilled  3450; NMR D 0),  torr  8  bp 9 7 - 1 0 0 ° / 0 . 0 6  (m, 14H), 2.00  ( 1 1 ) , 137  ( 1 3 ) , 56  10-Bromo-l-decanol T h i s compound cedure  5  (rel intensity)  150 ( 1 1 ) , 148  The s o l u t i o n  (38%) o f 261e as a c o l o u r l e s s 1  206  was  hours  ( 3 5 ) , 135  torr);  dis-  liquid: IR 3630 and  ( s , IH, exchanged  with  ( t , 2H, J = 6 H z ) ; mass  ( 1 ) , 204  ( 1 6 ) , and 55  (6.0 g;  The c r u d e m a t e r i a l was  ( t , 2H, J = 7 H z ) , and 3.57  s p e c t r u m m/e  ( 2 0 ) , 57  (8 mL).  was c o n t i n u e d f o r 72  as s o l v e n t .  (lit.  6 1.27-2.00  3.35  2  68  (100 mL)  and gave 3.19 g  bp 9 2 - 9 4 ° / 0 . 0 6  (3),  acid  1,9-nonanediol  ( 1 ) , 169  ( 3 5 ) , 97  ( 3 ) , 167  ( 4 3 ) , 69 ( 8 0 ) ,  (100).  (261f) was p r e p a r e d a c c o r d i n g t o t h e g e n e r a l p r o -  f o r bromoalcohol  formation using  34.4 mmole) and 48% h y d r o b r o m i c  acid  1,10-decanediol  (27 mL).  (6.0 g;  The s o l u t i o n  was  241  heated  t o 9 0 - 9 5 ° and  using petroleum distillation bp  ether,  gave  115-117°/0.30  3445 cm" ;  NMR  with  3.37  1  D 0), 2  ( 3 ) , 164  ( 1 6 ) , 97  extraction  bp  5.33  (65%)  (lit.  6 1.33-2.00 ( t , 2H,  69  J  1  5  of  of  crude  16H),  A  ( 2 8 ) , 148  3:1  0.12  IR  torr;  (s,  3H),  2H,  J = 6.5  55  3.44  1740  ( 0 . 1 ) , 164  purified  1718  cm" ;  NMR  J = 7 Hz),  3.48  (Kugelrohr  mass s p e c t r u m m/e ( 3 ) , 103  by  ether  bp  ( 3 ) , 162  g;  w h i c h was  1  ( 1 ) , 192  (20)  and  t o the  for C  1 Q  H  1 7  13.3,  (3), 135  55  mmole)  (100).  (86%) TLC  p r e p a r a t i v e TLC and  gave  (m,  and  (rel intensity)  on  262b as  distillation)  ( s , 2H),  85  and  homogeneous by  6 1.30-1.96  (100),  pro-  g  266  ( 4 4 ) , 83  C,  45.30; H,  6.46.  Found:  C,  45.82; H,  6.70.  a  97-100°/  8H),  4.18  0 Br: 3  Hz);  general  (73). Anal. Calcd  and  (16),  r e m o v a l gave 2.53  0.75;  and  ( t , 2H,  Hz);  (2.47  ether-petroleum Rf  3625  (262b)  Solvent liquid  liquid:  J = 7  (.28), 137  ( 2 0 ) , 56  Vacuum  exchanged  ( t , 2H,  according  253  s m a l l sample was  liquid:  264  prepared  IR  ( s , IH,  ( 1 ) , 218  mmole).  colourless  3.10  ( 2 5 ) , 57  solvent.  torr);  220  ( 6 ) , 150  hours  a colourless  (rel intensity)  a yellow  gel using  as  3.58  ( 9 0 ) , 68  11.1  262b as  analysis. silica  g;  as  166-169°/10  9  (m,  for alcoholysis using  (2.00  mL)  and  T h i s compound was  261b  (100  261f  (6'-Bromo-1*-hexyl)-3-oxobutanoate  cedure  c o n t i n u e d f o r 65  = 7 Hz)  ( 6 ) , 162  (26),  was  100-115°,  g  torr  mass s p e c t r u m m/e 190  the  2.28  (t, (0.1),  (81),  and  242  H i g h R e s o l u t i o n Mass Measurement C a l c d 266.0341.  Found:  266.0346.  (7'-Bromo-1'-heptyl)-3-oxobutanoate  T h i s compound was cedure 261c of  crude  TLC.  A  gel Rf  g;  262c a s  0.81;  bp  and  3 a-4 4  ( t , 2H,  188  mmole).  as  1710  cm ;  ( 4 2 ) , 85  Solvent  Anal. Calcd  for  by  (20) c  and  H 1  1  1  9  ° 3  B  r  :  C  '  (1.0  g;  (86%) by  for alcoholysis  TLC  4.78  of  mmole).  crude  A  using  253  a yellow  small  on  (s,  ( t , 2H,  by  silica liquid: IR 3H), J = 7  (<0.1), 2.78  ( 1 ) , 135  4 7.42;  (<0.1),  ( 1 ) , 103  (100),  6.86.  H,  6.77.  (262d)  according (1.07  Evaporation  262d as  analysis.  prepared  (84%)  torr;  2.30  4.18  47.32; H,  C,  (8'-Bromo-1•-octyl)-3-oxobutanoate  T h i s compound was  g  a colourless  10H),  280  and  (70).  Found:  cedure  (m,  pro-  homogeneous  120-125°/0.50  ( 4 ) , 137 55  mmole)  p r e p a r a t i v e TLC  ( s , 2H) , and  ( 4 ) , 148  69  10.30  gave 262c as  3.49  general  w h i c h was  (rel intensity)  ( 2 ) , 150 (30),  g;  liquid  6 1.30-1.98  = 7 Hz),  t o the  r e m o v a l gave 2.02  distillation)  mass s p e c t r u m m/e ( 2 ) , 186  (1.92  purified  NMR  - 1  J  253  s o l v e n t and  (Kugelrohr  (262c)  according  a pale yellow  s m a l l sample was  1735  97  8.56  using ether  Hz);  prepared  for alcoholysis using  (1.67  f o r C^gH^O^Br:  of  the  liquid  sample was  g;  t o the 5.74  general  mmole) and  s o l v e n t gave  w h i c h was  purified  by  1.20  pro26Id g  homogeneous preparative  243  TLC on s i l i c a  g e l using  3:1  as a c o l o u r l e s s l i q u i d : 115-118°/0.40 12H) , 2.28 4.17  R f 0.77;  IR 1740  ( s , 3H), 3.43  and  bp  ( 0 . 2 ) , 213  ( 7 ) , 148  (19),  69  ( 7 ) , 137  ( 3 5 ) , and  Anal. Calcd  1713  cm" ;  H z ) , 3.47  (88%)  for C  ( 4 ) , 135  ( 4 ) , 111  ( 1 8 ) , 103  1 2  H  2 1  TLC on s i l i c a  C, 49.07;  H,  7.38.  Found:  C,  H,  7.35.  3  prepared  2.27  and  4.16  308  ( 0 . 1 ) , 306  (100),  85  85  (262e)  253  g e l using  3:1  t o the g e n e r a l  (1.0 g; 5.38  liquid,  w h i c h was  purified  ether-petroleum Rf 0.78;  IR 1735  ( s , 3H), 3.42  mmole) and  o f t h e s o l v e n t gave  A s m a l l sample was  110-113°/0.12 t o r r ;  (m, 14H),  49.29;  according  Evaporation  262e as a c o l o u r l e s s l i q u i d : tion)  (100),  0 Br:  262e a s a y e l l o w  by TLC a n a l y s i s .  ( 4 ) , 162 ( 4 ) ,  55 ( 2 1 ) .  mmole).  of crude  ( r e l i n t e n s i t y ) 294 ( 4 ) , 164  for a l c o h o l y s i s using  g; 4.48  (m,  ( s , 2H), and  ( 4 ) , 190  T h i s compound was  (1.0  262d  6 1.14-1.97  ( 3 ) , 192  1  cedure  and gave  distillation)  NMR  1  ( t , 2H, J = 7  (9 -Bromo-1 -nonyl)-3-oxobutanoate 1  ether  (Kugelrohr  ( t , 2H, J = 7 H z ) ; mass s p e c t r u m m/e  ( 0 . 2 ) , 292 150  torr;  ether-petroleum  and  bp  by  ether  cm" ; 1  ( 0 . 1 ) , 150  ( 1 8 ) , 83  ( 9 ) , 69  ( 1 ) , 148  ( 1 ) , 137  1.21  g  preparative and  NMR  ( t , 2H, J = 7 H z ) , 3.46  ( t , 2H, J = 7 H z ) ; mass s p e c t r u m m/e  261e  homogeneous  (Kugelrohr  1710  pro-  gave distilla6 1.30-1.96 ( s , 2H)  (rel intensity) ( 1 ) , 135  ( 2 1 ) , and 55 ( 1 9 ) .  ( 1 ) , 103  244  H i g h R e s o l u t i o n Mass Measurement C a l c d 308.0812, 306.0830.  Found:  cedure (2.0  g;  crude  9.0  mmole).  262f as  petroleum 0.79;  bp  and  1715  2H,  J  ether  cm ;  = 7 Hz),  ( 1 4 ) , 164  ( 4 6 ) , 103 and  54  and  (2.0 the  by  262f as  6 1.30-1.96  (m,  16H),  ( 0 . 1 ) , 320  ( 3 4 ) , 150  (88),  69  using  TLC  analysis.  3:1  ether-  liquid:  ( 9 9 ) , 57  IR  1740  3.46  J = 7 Hz); (0.1),  ( 6 7 ) , 148  Rf  ( s , 3H),  ( t , 2H,  (68),  ( 7 2 ) , 56  192 137  of  (t,  mass (13),  (44),  ( 8 2 ) , 55  135  (100)  (65) . for C  T h i s compound was  1 4  H  2 5  0 Br:  C,  52.34; H,  7.84.  Found:  C,  52.75; H,  8.09.  3  prepared  for alcoholysis using  bromo-l-undecanol g  261f  2.29  322  85  mmole) and  120-125°/0.12 t o r r ;  (rel intensity)  (100),  pro-  a colourless  4.17  162  B r :  general  homogeneous by  and  (36),  H  s o l v e n t g a v e 2.49 g ( 9 2 % )  (11'-Bromo-1'-undecyl)-3-oxobutanoate  2.26  11.1  ( s , 2H),  Anal. Calcd  cedure  t o the  p r e p a r a t i v e TLC  distillation)  3.48  g;  o i l , w h i c h was  gave  NMR  - 1  253  purified  (Kugelrohr  s p e c t r u m m/e  using  a yellow  ^3 23°3  (262f)  according  Removal o f  A s m a l l sample was  190  prepared  for alcoholysis  c  308.0814, 306.0832.  (10'-Bromo-1'-decyl)-3-oxobutanoate  T h i s compound was  for  (85%)  1 6 0  of crude  (2.00  g;  262g as  (262g)  according  253 7.97  (1.78  g;  mmole).  a yellow  t o the 9.57  general  mmole) and  pro11-  Workup as u s u a l  liquid,  which  was  gave  245  homogeneous by TLC a n a l y s i s . preparative colourless 140°/0.13 2.28  TLC u s i n g liquid:  torr;  A small  chloroform  sample was p u r i f i e d  as s o l v e n t and gave 262g a s a  Rf 0.40; bp ( K u g e l r o h r 1  2H, J = 6.5 H z ) ; mass s p e c t r u m m/e  334  ( 2 ) , 318  esters  ( 4 0 ) , 85  (100) and 69  forC  procedure  1 5  H  2 7  0 Br:  C, 53.73; H, 8.12.  Found:  C, 53.92; H, 8.08.  3  f o r the attempted  was p r e p a r e d  bottom f l a s k e q u i p p e d w i t h and a n i t r o g e n bath  of  cyclization  o f B-keto  yellow  i n a 200-mL t w o - n e c k e d  i n dry  round  a p r e s s u r e - e q u a l i z i n g dropping  inlet.  The f l a s k  was c o o l e d  was added d r o p w i s e .  s o l u t i o n was s t i r r e d  the B-keto e s t e r  bromide  was added d r o p w i s e .  fun-  t o 0 ° i n an i c e  over  The c o l o u r l e s s t o  f o r 10 m i n u t e s and a s o l u t i o n  (one e q u i v a l e n t )  i n tetrahydrofuran  The r e a c t i o n m i x t u r e was t h e n  5 h o u r s and t h e s o l u t i o n was s l o w l y temperature  (three e q u i v a l e n t s )  and n - b u t y l l i t h i u m a s a 1.6 M s o l u t i o n i n hexane  (three e q u i v a l e n t s ) pale  ( r e l i n t e n s i t y ) 336 ( 2 ) ,  262a-g  tetrahydrofuran  water  ( s , 2H), and 4.15  (100).  A s o l u t i o n of diisopropylamine  nel  (m, 18H) ,  ( 3 ) , 316 ( 3 ) , 255 ( 1 4 ) , 164 ( 2 6 ) , 162 ( 2 6 ) , 150  Anal. Calcd  General  6 1.25-1.95  ( t , 2H, J = 7 H z ) , 3.45  (t,  ( 4 0 ) , 148  d i s t i l l a t i o n ) 135-  IR 1740 and 1715 cm" ; NMR  ( s , 3 H ) , 3.43  by  this  a d d e d , and t h e o r g a n i c  allowed  t o warm t o room  p e r i o d . On workup, w a t e r p h a s e was s e p a r a t e d .  stirred for  and e t h e r  The o r g a n i c  were  246  e x t r a c t was washed w i t h magnesium., s u l f a t e . sure  gave t h e c r u d e  water, b r i n e , then  Removal o f t h e s o l v e n t under  cedure  according  t o the g e n e r a l  using diisopropylamine  mmole), n - b u t y l l i t h i u m a s a 1.6 M s o l u t i o n and 262a  (1.27 g; 5.00  column c h r o m a t o g r a p h y u s i n g  chloroform  o f 267a as a c o l o u r l e s s l i q u i d :  tion)  40-42°/0.20 t o r r ; (m, 4H), 2.28  Hz),  4.97-5.16  m/e  i n hexane  ( 6 ) , 103  15.0  (9.38  mL;  as e l u e n t gave 353  mg  (Kugelrohr 1  ( s , 3H), 3.46  pro-  by  bp  ( s , 2H), 4.19  (m, I H ) , and 5.64-7.03  NMR  6 1.63-  ( t , 2H, J = 7  (m, I H ) ; mass  ( 5 ) , 85  distilla-  ( 3 0 ) , 69  spectrum  ( 2 1 ) , 68  and 67 ( 3 5 ) . Anal. Calcd  f o r C H C> :  C, 63.51; H,  8.29.  Found:  C, 63.65; H,  8.30.  g  1 4  3  (5'-Hexen-l'-yl)-3-oxobutanoate T h i s compound cedure  was p r e p a r e d  for cyclization  (267b) according  12.0 mmole),  and 262b  t o the g e n e r a l  using diisopropylamine  mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n  flash  pres-  Purification  IR 1742, 1720 and 1645 cm" ;  ( r e l i n t e n s i t y ) 170  (100)  (1.52 g;  mmole).  (41%)  2.19  reduced  (267a)  was p r e p a r e d  for cyclization  15.0 mmole),  anhydrous  products.  (4'-Penten-l'-yl)-3-oxobutanoate  T h i s compound  d r i e d over  (1.06 g; 4.0 mmole).  chromatography u s i n g  petroleum  (1.21 g;  i n hexane  pro-  12.0  (7.50 mL;  Purification  ether-ethyl acetate  by (9:1)  247  as e l u e n t gave 331 mg 40-45°/0.20 t o r r ;  IR 1735, 1718 and 1645 c m ; (m, 2 H ) , 2.28  2H, J = 6 H z ) , 4.93-5.12  mass s p e c t r u m m/e 85  ( 4 3 ) , 82  67  ( 5 9 ) , 56  for C  H 1  0  i 6  O  ( 0 . 3 ) , 137  C, 65.36; H,  according  liquid:  bp  using diisopropylamine  1  2H) , 2.28 5.09  i n hexane  NMR  6 1.26-1.80  ( 2 5 ) , 68  198  ( 0 . 1 ) , 102  ( 5 9 ) , 67  Anal. Calcd  chromatog-  ether-ethyl  45-48°/0.23  torr;  (m, 6H), 1.94-2.12  ( s , 2H) , 4.16  (m, 2 H ) , and 5.63-7.03  Flash  (7.50 mL;  acetate  (57%) o f 267c as a c o l o u r l e s s  distillation)  ( s , 3H) , 3.45  intensity) 69  457 mg  pro-  (1.21 g ; 12.0  (1.12 g; 4.00 mmole).  (Kugelrohr  1718 and 1635 cm" ;  8.90.  t o the general  raphy o f the crude m a t e r i a l u s i n g petroleum as e l u e n t gave  ( 8 ) , 103 ( 1 0 ) ,  (267c)  mmole), n - b u t y l l i t h i u m as a 1.6 M s o l u t i o n  (9:1)  (m, I H ) ;  C, 65.19; H, 8.75.  : 3  T h i s compound was p r e p a r e d  12.0 mmole), and 262c  ( s , 2H), 4.18  (44) and 55 ( 8 5 ) .  (6'-Hepten-1'-yl)-3-oxobutanoate  for cyclization  6 1.26-1.80  (m, 2 H ) , and 5.64-7.04  Found:  cedure  ( s , 3 H ) , 3.46  ( r e l i n t e n s i t y ) 184  (100),  Anal. Calcd  NMR  - 1  (m, 4 H ) , 1.92-2.20 (t,  (45%) o f 267b as a c o l o u r l e s s l i q u i d : bp  IR 1735, (m,  ( t , 2H, J = 6 H z ) , 4.92-  (m, I H ) ; mass s p e c t r u m m/e ( r e l  ( 7 2 ) , 96  ( 6 9 ) , 56  ( 6 3 ) , 85  ( 2 8 ) , 55  ( 6 7 ) , 81 ( 4 1 ) ,  (100),  and 54 ( 7 4 ) .  for C^H^C^:  C, 66.64; H,  9.15.  Found:  C, 66.71; H,  9.25.  248  (7'-Octen-l'-yl)-3-oxobutanoate  T h i s compound  (267d)  was p r e p a r e d  cedure f o r c y c l i z a t i o n  using  according  t o the g e n e r a l  diisopropylamine  mmole), n - b u t y l l i t h i u m a s a 1.6 M s o l u t i o n 12.0 mmole), and 262d  (9:1)  as e l u e n t gave 348 mg  liquid:  bp  (Kugelrohr  1718, and 1650 cm" ; 2.28  ( s , 3H), 3.46  sity) 69  212  (100),  (0.1), 68  Anal.  103  Calcd  6 1.26-1.85  ( 8 7 ) , 95  for C  H  20°3  :  Found:  3-Oxotridecanolide This cedure  compound  e t h e r - e t h y l acetate  60-63°/0.4 t o r r ;  ( 1 1 ) , 56  ( 8 7 ) , 82  was p r e p a r e d  12.0 mmole), and 262e  - 1  NMR  ( 5 0 ) , 81 ( 5 8 ) ,  (79) and 55  C, 67.89; H,  9.50.  C, 67.94; H,  9.55.  according  (100).  t o the g e n e r a l  using diisopropylamine  (1.23 g; 4.0 mmole).  chromatography u s i n g  as e l u e n t gave 389 mg  cm ;  (rel inten-  (266e)  for cyclization  sublimation  (m, 2H),  ( t , 2H, J = 6 H z ) , 4.93-5.10  mmole), n - b u t y l l i t h i u m a s a 1.6 M s o l u t i o n  flash  IR 1740,  (m, 8H), 1.93-2.10  ( 2 0 ) , 85  ( 8 0 ) , 66 1 2  (7.5 mL;  chromatog-  (m, I H ) ; mass s p e c t r u m m/e  ( 8 4 ) , 67  12.0  (41%) o f 267d as a c o l o u r l e s s  ( s , 2H), 4.17  (m, 2H), and 5.66-7.04  Flash  petroleum  distillation)  NMR  1  i n hexane  (1.17 g; 4.0 mmole).  raphy o f the crude m a t e r i a l u s i n g  (1.21 g;  pro-  i n hexane  12.0  (7.5 mL;  Purification  ether-ethyl acetate  by (9:1)  (43%) o f 266e as a c o l o u r l e s s s e m i - s o l i d :  temperature  6 1.25-1.81  petroleum  (1.21 g;  pro-  103-105°/0.18 t o r r ;  (m, 16H), 2.61  IR 1750 and  1725  ( t , 2H, J = 7 H z ) , 3.44  249  (s,  2H) , and  intensity) ( 4 6 ) , 67  4.24  226  ( t , 2H,  ( 8 ) , 208  ( 2 9 ) , 56  Anal.  Calcd  J  = 5 Hz);  ( 6 ) , 124  ( 2 3 ) , and for C  H 1 3  55  22°3  ( 2 3 ) , 103  :  prepared  cedure f o r c y c l i z a t i o n  flash  262f  solid: and  bp  1718  Hz), m/e  (1.28  1  3.46  mg  NMR  ( s , 2H),  (100)  and  ( 3 1 ) , 81 54  69  C,  68.78; H,  9.8 4.  t o the  M solution 4.0  of  and  4.22  240  ( 2 0 ) , 69  g;  Purification  a colourless  18H),  ( t , 2H,  12.0  (7.5  J  2.57  ( 1 7 ) , 103  ( 3 3 ) , 68  ( t , 2H,  = 6 Hz);  by (9:1)  IR J  1742 =  7  mass s p e c t r u m  ( 1 9 ) , 96  ( 2 8 ) , 67  mL;  semi-  85-88°/0.l0 t o r r ;  (m,  pro-  ether-ethyl acetate  266f a s  ( 1 ) , 148  (1.21  i n hexane  mmole).  distillation)  general  (27),  (24), 56  83  (14),  55  (17).  Anal. Calcd  for  C  H 1 4  24°3  :  Found:  3-0xopentadecanolide T h i s compound was cedure  9.80.  petroleum  6 1.20-1.82  (rel intensity)  ( 1 9 ) , 82  g;  (45%)  (Kugelrohr  cm" ;  68.99; H,  according  a 1.6  chromatography using  as e l u e n t g a v e 432  C,  using diisopropylamine  mmole), n - b u t y l l i t h i u m as mmole), and  (36),  (266f)  T h i s compound was  12.0  ( 2 5 ) , 82  (rel  (100).  Found:  3-0xotetradecanolide  mass s p e c t r u m m/e  for cyclization  C  ' C,  6  9  -  9  6  '  H  '  10.07.  70.00; H,  10.14.  (266g) prepared  according  t o the  using diisopropylamine  general  (1.21  g;  pro12.0  250  mmole), n - b u t y l l i t h i u m 12.0  mmole), and  262g  as  (1.34  raphy  o f the crude  (7:1)  as e l u e n t gave 498  solid: 1710  M solution  g;  4.0  cm" ; 1  NMR  mg  6 1.20-1.80  ( s , 2H),  and  (rel  intensity)  i n hexane  mmole).  Flash  product using petroleum (49%)  s u b l i m a t i o n temperature  3.46  152  a 1.6  4.22  254  ether-ethyl acetate  o f 266g a s a c o l o u r l e s s  20H),  ( t , 2H,  2.56  ( t , 2H,  ( 2 2 ) , 219-220  2  10-Acetoxy-l-decanol A solution glacial liquid  acetic  (280)  extractor.  The  (250  mL)  filtered  40  hours.  (66%)  (3.91  The  g;  prepared was  acid  2.40  1725  219.3),  10.17.  (0.5 mL) 1:1  22.5  mmole) i n  cm" ; 1  liquid-  w i t h water  added and  the  s o l v e n t was  1,10-decanediol,  NMR  bp  mL),  resulting  cooled,  then d r i e d  Removal o f t h e s o l v e n t  liquid:  (180  hexane-cyclohexane  p r e s s u r e f o l l o w e d by vacuum d i s t i l l a t i o n  IR 3630, 3460, and  Hz), m/e  =  i n a 500-mL  diluted  extracting  carbonate.  o f 28 0 as a c o l o u r l e s s  ( s , 3H),  was  solution  t o remove u n r e a c t e d  anhydrous potassium reduced  70.65; H,  e x t r a c t e d continuously with over  and  1 6 8  (135 mL)  then c o n c e n t r a t e d s u l f u r i c mixture  C,  of 1,10-decanediol acid  1735  10.30.  3  Found:  semi-  J = 6.5  (m*, 4 j ~ -  ( 5 5 ) , 103 ( 1 0 0 ) , 95 ( 6 8 ) , and 55 ( 9 1 ) . Anal. Calcd for C H g 0 : C, 70.83; H, 1 5  IR  J = 5 H z ) ; mass s p e c t r u m o o c2  ( 2 6 ) , 236  mL;  chromatog-  110-113°/0.25 t o r r ;  (m,  (7.5  ( s , IH, exchanges w i t h DjO),  3.57  under  gave 3.24  118-120°/0.40  6 1.20-1.83  over  (m,  16H),  ( t , 2H,  g  torr; 2.02 J = 6  251  Hz),  and  sity)  4.00  216  ( t , 2H,  J = 6 Hz);  ( 2 . 5 ) , 186  ( 1 0 ) , 126  mass s p e c t r u m m/e  ( 2 4 ) , 110  ( 3 2 ) , 109  ( 2 2 ) , 96  ( 5 8 ) , 95  ( 5 0 ) , 83  ( 3 9 ) , 82  ( 9 7 ) , 81  ( 9 6 ) , 67  ( 7 3 ) , 57  ( 2 3 ) , 56  (30),  (100),  55  1-(10'-Acetoxydecyl)benzenesulfonate A s o l u t i o n of dine  (7 mL)  flask 0°  equipped  i n an  2.78  was  with  flask  and  ether  was  bath  placed  mL),  dropwise.  i n the  fridge and  phase was  water  a n h y d r o u s magnesium s u l f a t e .  the c r u d e m a t e r i a l on  vent bp  gave  663  mg  (Kugelrohr  6 1.20-1.70  and  7.33-7.90  ( 1 6 ) , 96 69  (m,  (m,  5H);  ( 6 2 ) , 95  of  ( 1 6 ) , 141  (58),  56  hydrochloric  (15 mL), the  liquid.  ( s , 3H),  then  Preparative as  IR  Rf  1725  ( t , 4H,  ( 9 6 ) , 110  ( 9 1 ) , 81 (100),  54  0.44; cm ; -1  J = 7  Hz)  356  (46),  ( 5 2 ) , 77 and  TLC  sol-  (rel intensity)  ( 1 7 ) , 138  ( 1 7 ) , 55  dried  s o l v e n t under  chloroform  4.00  mL)  sepa-  a colourless liquid:  ( 3 2 ) , 82  to mg;  (15  l a y e r was  180-185°/0.20 t o r r ;  2.03  bottom  (491  Water  dilute  Removal o f  gel using  as  pyri-  cooled  chloride  brine  a yellow  281  round  f l a s k was  organic  mass s p e c t r u m m/e  ( 4 2 ) , 83  ( 8 0 ) , 67  and  silica  16H),  ( 0 . 8 ) , 159  ( 5 1 ) , 68  as  distillation)  NMR  ( 0 . 8 ) , 313  (80%)  (53).  Upon c o m p l e t e a d d i t i o n ,  washed w i t h  over  gave 281  The  overnight.  the  (15 mL),  68  (61),  mmole) i n a n h y d r o u s  inlet.  (4 x  of  54  97  (281)  2.31  acid  reduced pressure  and  benzenesulfonyl  were added  organic  15  and  (23),  ( 6 1 ) , 69  i n a 25-mL s i n g l e - n e c k e d  introduced  (20 mL)  The  mg;  a nitrogen  i c e water  the  (500  prepared  mmole) was  rated.  280  (rel inten-  109  (83), (52).  252  Anal. Calcd  for C  l g  H gS0 :  C,  60.65; H,  7.92;  S,  8.99.  Found:  C,  60.36; H,  8.00;  S,  8.81.  2  5  1-(10'-Hydroxydecyl)benzenesulfonate  A solution (25 mL) flask acid  was  of  281  prepared  was  mg;  a nitrogen  introduced  and  h o u r s a t room  temperature.  On  under r e d u c e d  pressure  (25 mL).  The  and  (15 mL),  brine  ether  and  was  0.48; and  bp  3450 c m ;  NMR  - 1  with  D 0),  3.57  2  7.18-7.90 284  (Kugelrohr  (m,  ( 4 ) , 159  of  ( t , 2H,  5H);  J  as  3.5  (2 x  oil.  gel using  15  mL)  sulfate. Prepara-  1:1  180-185°/0.20 t o r r ;  (m,  138  with  chloro-  28 2 as a c o l o u r l e s s o i l :  = 6 Hz),  (26),  water  a yellow  silica  mass s p e c t r u m m/e  ( 9 4 ) , 141  for  a n h y d r o u s magnesium  distillation) 6 1.20-1.83  diluted  washed w i t h  d r i e d over  (72%)  continued  ether  t h i s c r u d e m a t e r i a l on mg  was  hydrochloric  r e s i d u e was  s o l v e n t gave 282  gave 446  bottom  removed  tive  form-ether  round  workup, the m e t h a n o l was  of  of  methanol  Concentrated  stirring  Evaporation TLC  mmole) i n d r y  inlet.  the  solution then  the  19.7  i n a 50-mL s i n g l e - n e c k e d  equipped with (2 mL)  (700  (282)  16H), 4.00  1.83  IR  ( s , IH,  ( t , 2H,  Rf  exchanged  J = 6 Hz),  ( r e l i n t e n s i t y ) 314  (64),  126  (53),  3625  110  and  (3),  (46),  98  ( 2 9 ) , 97  ( 2 6 ) , 96  ( 4 6 ) , 95  ( 3 6 ) , 83  ( 3 9 ) , 82  ( 8 5 ) , 81  (46),  77  ( 8 7 ) , 70  ( 2 8 ) , 69  (56),  ( 7 8 ) , 67  ( 5 8 ) , 57  (21),  (37),  55  (100),  54  ( 4 5 ) , and  Anal. Calcd  for C  51 l g  H  68  56  (21). 0 S: 4  C,  61.12; H,  8.33,  S,  10.20.  Found:  C,  61.20; H,  8.17;  S,  10.02.  2 6  253  (10'-Benzenesulfonoxy-1'-decyl)-3-oxobutanoate  T h i s compound was cedure  for alcoholysis using  (1.675 g; (80%)  5.11  mmole).  of''28 4 as  analysis. silica  A  liquid:  1.83  (m,  Hz),  4.07  Rf  16H),  138  (100),  110  IR  398  54 H  100-mL two-necked  charged  with  hydrofuran  S O  bath  and  reaction  thiophenol mixture  was  282 g TLC  p r e p a r a t i v e TLC  and  gave 1660  277  as  cm ;  4.00 (m,  ( 1 ) , 159  spectrum (10),  (36),  ( 5 l ) , 67  1.10-  J = 7  mass  ( 2 7 ) , 85  ( 5 3 ) , 68  6  ( t , 2H, 5H);  ( 0 . 9 ) , 356  a colour-  NMR  -1  on  83  (38),  6  :  C  round  addition  The  '  6  0  C,  *  2  8  '" ' H  7  « '"  60.68; H,  5 9  s  >  8.05.  7.70;  S,  7.79.  (283)  sodium h y d r i d e  (40 mL).  mmole) and  (29).  11-Phenythio-l-undecanol  pressure-equalizing  by  ( 4 7 ) , 95  Found:  A  pro-  homogeneous by  7.33-7.87 380  general  s o l v e n t gave 1.75  and  ( 5 4 ) , 69  for 2 0 3 0 C  6.13  ( s , 2H),  ( 1 9 ) , 96  ( 3 5 ) , 77  (93) , and  Anal. Calcd  the  1718  3.40  (0.7),  ( 3 4 ) , 97  ( 6 4 ) , 81  g;  purified  and  t o the  w h i c h was  1740,  J = 6 Hz)  (rel intensity)  (11), 55  liquid,  ( s , 3H),  m/e  (1.14  ether-chloroform  0.66,  2.23  ( t , 2H,  ( 4 8 ) , 82  253  s m a l l sample was 1:1  according  Removal o f  a yellow  gel using  less  56  prepared  (277)  f u n n e l and (960  flask  (1.10  g;  allowed  11-bromo-l-undecanol 2 6 1 g  1 6 0  bottom f l a s k ' e q u i p p e d  mg;  was  10.0  a nitrogen  20.0  cooled  inlet  mmole) and t o 0°  with  i n an  dry  a was tetra-  i c e water  mmole) added d r o p w i s e .  to stand  f o r 15 m i n u t e s ,  (2.51  10.0  g;  mmole) i n  then  The  254  tetrahydrofuran stirred  f o r an  hydrochloric the  organic  (10 mL)  was  introduced  a d d i t i o n a l 18  acid  (20 mL)  and  (25 mL),  brine  Removal o f  the  then  283  TLC as  on  silica  a white  cm" ;  NMR  with  D 0),  2.87  2  7.00-7.25 280  (m,  ( 5 0 ) , 123  Anal. Calcd  mL)  Rf  solution  reduced  0.55; (m,  mp  (20 mL),  18H),  1.43  3.57  mass s p e c t r u m m/e  for C  (100),  1 7  T h i s compound was  H  69  yellow  3.57  liquid  mmole). w h i c h was  sample was  purified  chloroform  as  crystallized  by  (25  mL)  sulfate. (83%) o f  by  prepara-  and  afforded  3620, 3460,  ( t , 2H,  exchanged  J = 6 Hz),  ( r e l i n t e n s i t y ) 281  ( 1 6 ) , and  55  and  and  (8),  (45).  C,  72.80; H,  10.06; S,  11.43.  Found:  C,  73.01; H,  10.21; S,  11.55.  prepared  according  253  (839  Workup gave  992  homogeneous by p r e p a r a t i v e TLC  s o l v e n t and on  with  2.31g  (1:1)  IR  and  SO:  2 g  cedure f o r a l c o h o l y s i s using g;  gave  ( s , IH,  (11'-Phenylthio-l'-undecyl)-3-oxobutanoate  (1.00  water  pressure  66-67°;  Dilute  washed  a n h y d r o u s magnesium  J = 7 Hz),  110  was  were a d d e d ,  gel using chloroform-ether  ( t , 2H,  (21),  (100  An a n a l y t i c a l sample was o b t a i n e d  6 1.20-1.66  5H);  solution  o r g a n i c p h a s e was  d r i e d over  solid:  1590  1  The  s o l v e n t under  28 3 as a w h i t e s o l i d . tive  ether  layer separated.  sodium b i c a r b o n a t e  the  h o u r s a t room t e m p e r a t u r e .  and  saturated  and  standing;  gave Rf  mg; mg TLC on  (278)  t o the 4.51  general  pro-  mmole) and  (76%)  of  278  analysis. silica  gel  as A  283 a  small  using  278  as  a colourless liquid  0.36;  mp  2 9 - 3 0 ° ; bp  which  (Kugelrohr  255  distillation) 1590  cm" ;  NMR  1  2H,  175-180°/0.20 t o r r ; <5 1.20-1.80  J = 7 Hz),  7.40  (m,  5H);  ( 5 0 ) , 280 69  3.43  ( s , 2H),  55  4.14  1715,  2.25  1655,  ( s , 3H),  ( t , 2H,  2.89  J = 6 Hz),  ( r e l i n t e n s i t y ) 365  ( 3 4 ) , 110  (100),  103  and  ( 2 3 ) , 85  (t,  and  7.10-  (12),  364  ( 2 0 ) , 83  (20),  (67).  Anal. Calcd  for C 1 3 2 ° 3 H  S  :  2  Found: t-Butyldimethylsilyl  A  1735,  18H),  mass s p e c t r u m m/e  ( 3 4 ) , 123  ( 3 4 ) , and  (m,  IR  C,  69.19; H,  8.93;  S,  8.80.  C,  69.36; H,  8.75;  S,  8.59.  11-t-butyldimethylsiloxyundecanoate  50-mL s i n g l e - n e c k  round  bottom  flask  equipped  (292)  with  a 172  nitrogen (1.52  inlet  g;  mmole),  7.50  was  The  (15 mL)  with  (2 x water  magnesium  20  bp  (2.55  2.28  ( t , 2H,  trum m/e  37.5  mmole), and was  and  (15 mL),  were a d d e d .  ether  and mL).  the  0.86  combined  brine  acid  (15 mL),  g  (95%)  IR  1710  ( s , 9H),  J = 7 Hz),  of  and  ( r e l i n t e n s i t y ) 430  and  then  835  f o r 72 The  hours,  then  organic  layer with  e x t r a c t s were washed d r i e d over  anhydrous by  as a c o l o u r l e s s cm" ; 1  0.90  ( s , 9H),  3.54  ( t , 2H,  ( 1 ) , 415  18.0  dimethylformamide  solvent, followed 292  g;  further extracted  organic  Removal o f the  gave 3.06  stirred  aqueous l a y e r was  The  154-156°/0.20 t o r r ; ( s , 6H),  g;  solution  sulfate.  0.20  11-hydroxyundecanoic  resulting  (15 mL),  distillation  with  mmole), t - b u t y l d i m e t h y l c h l o r o s i l a n e (2.70  separated,  ether  charged  imidazole  (15 mL). water  was  NMR  liquid:  6 0.00  1.10-1.69 J = 6 Hz);  ( 1 0 ) , 373  vacuum  (s,  (m,  16H),  mass  (100),  6H),  spec-  357  256  ( 4 9 ) , 241 73  ( 3 5 ) , 149  ( 3 6 ) , 147  ( 3 2 ) , 83  ( 2 0 ) , 81  ( 1 3 ) , 75 ( 9 7 ) ,  (94) , and 55 ( 2 3 ) . Anal.  Calcd  for C  2 3  H  5 0  O Si :  C, 64.12; H,  11.70.  Found:  C, 64.34; H,  11.60.  3  2  11-t-Butyldimethylsiloxyundecanoic  A 50-mL s i n g l e - n e c k 292  (3.13 g; 7.28  (25 mL). was  round bottom f l a s k  with  solution  dilute  was e x t r a c t e d w i t h  over  followed thick,  1  and  (m, 16H), 2.34 10.13  (3 x 20 mL)  water  6 0.00  then  and t h e o r g a n i c (15 mL),  then  Removal o f t h e s o l v e n t  gave 2.23 g  ( s , 6H), 0.86  ( t , 2H, J = 7 H z ) , 3.58  ( b s , I H ) ; mass s p e c t r u m m/e  solution  The aqueous l a y e r  (97%) o f 293 as a  bp 1 4 8 - 1 5 0 ° / 0 . 1 0 t o r r ;  NMR  with  f o r 4 hours,  (15 mL), b r i n e sulfate.  by vacuum d i s t i l l a t i o n  colourless o i l :  stirred  hydrochloric acid.  a n h y d r o u s magnesium  1718, and 845 cm" ; 1.72  was  e t h y l acetate  e x t r a c t s were washed w i t h dried  was c h a r g e d  mmole) and 10% s o d i u m h y d r o x i d e  The r e s u l t i n g  acidified  a c i d (293)  IR  3550-2550,  ( s , 9H),  1.20-  ( t , 2H, J = 6 H z ) ,  ( r e l i n t e n s i t y ) 316 ( 1 ) , 24] 2  283 (6),  ( 8 ) , 259 83  ( 2 0 ) , 241  ( 1 4 ) , 81  Anal.  Calcd  (100),  ( 1 1 ) , 75 for C  1 7  H  224-225  ( 2 9 ) , 73 0 Si: Found:  3 6  3  (m*,  = 2 2 4 . 3 ) , 149  ( 2 5 ) , and 55 ( 2 0 ) . C, 64.50; H, C, 64.57; H,  11.46. 11.35.  257  5 - (11' -t:-Bu t y l d i m e t h y l s i l o x y - 1 ' - h y d r o x y u n d e c y l i d e n e ) - 2 , 2 dimethy1-1,3-dioxane-4,6-dione  A 50-ml s i n g l e - n e c k r o u n d 293  bottom  flask  was c h a r g e d  (1.74 g; 4.18 mmole) and d i c h l o r o m e t h a n e  b o n y l d i i m i d a z o l e (981 mg; the r e a c t i o n  acid  and t h e r e a c t i o n  t h e combined  On workup,  dilute  hydrochloric  magnesium  flask  was c h a r g e d  ceased.  with  mixture  the dichloromethane  sulfate.  6 0.10 2.90  stirred  acid,  water,  into  (40 mL).  brine,  The c o n -  the second  gave  over  ( s , 9 H ) , 1.27-1.83  14 with  anhydrous  1.45 g (78%)  IR 1730, 1635, and 835 cm  ( t , 2H, J = 7 H z ) , and 3.47  flask  was washed  then d r i e d  Removal o f t h e s o l v e n t  ( s , 6H), 0.97  por-  f o r an a d d i t i o n a l  solution  A  Meldrum's  f o r 1 hour.  was t h e n s y r i n g e d  294 a s a y e l l o w s e m i - s o l i d :  6H),  gas e v o l u t i o n  m i x t u r e was s t i r r e d  reaction  hours.  NMR  flask  N,N-Car-  (1.07 g; 13.5 mmole) was i n t r o d u c e d i n a s i n g l e  t e n t s o f the f i r s t and  bottom  until  with  i n p o r t i o n s and  (246) (1.13 g; 6.07 mmole) and d i c h l o r o m e t h a n e  Pyridine tion  (30 mL).  6.05 mmole) was added  m i x t u r e was s t i r r e d  100-mL s i n g l e - n e c k r o u n d  of  (294)  1  ;  (m, 16H), 1.81 ( s ,  ( t , 2H, J = 6 H z ) .  5-(11'-Hydroxy-1'-hydroxyundecylidene)-2,2-dimethyl-1,3-dioxane4,6-dione  (295)  A 100-mL s i n g l e - n e c k r o u n d nitrogen  inlet  n-butylammonium hydrofuran  was c h a r g e d fluoride  (50 mL).  with  bottom 294  flask  equipped  (1.25 g; 2.83 mmole), t e t r a -  (1.85 g; 7.07 mmole),  The r e s u l t i n g  with a  solution  and d r y t e t r a -  was s t i r r e d  f o r 3.5  258  hours,  then  added.  The  mL)  brine  and  5%  hydrochloric acid  organic  (10 mL),  fate.  Removal o f  yellow  oil:  16H), Hz), (rel  1.73 and  IR  2.90  ( b s , 2H,  ( 1 5 ) , 86  ( 4 0 ) , 67  separated,  d r i e d over  and  1635  ( t , 2H,  ( 3 1 ) , 84  (98%)  J = 7 Hz),  311.18 58.  +  3-Oxotridecanolide To  furan  and  was  t u r e was  allowed  organic  phase was  (2 x 25 mL),  (100  a (m,  ( t , 2H,  J = 6  ( 1 2 ) , 126  (40),  75  (12),  (100),  ( 2 4 ) , and  f u n n e l and  295  t o c o o l and washed w i t h (2 x 25  The  m/e  72  55  100 (43),  (25).  0^^270,.  for  over  ether  a nitrogen  2.73  (75 mL)  brine  was  sodium  (25 mL),  Removal o f  inlet  heated  mmole) i n  5 hours.  saturated  mL),  equipped with  s o l v e n t was  (8 50 mg;  added d r o p w i s e  water  purification  as  0  ( 8 2 ) , 56  mL).  a n h y d r o u s magnesium s u l f a t e . by  295  sul-  D 2 ) ; mass s p e c t r u m  round bottom f l a s k  dropping  a s o l u t i o n of  (20 mL)  (10  311.18 58.  a 200-ml two-necked  tetrahydrofuran  reflux  water  (266e)  pressure-equalizing added  Found:  were  1.20-1.65  3.53  H i g h R e s o l u t i o n Mass Measurement C a l c d (M -OH):  of  6  NMR  - 1  ( 6 ) , 211  ( 5 9 ) , 58  (25 mL)  washed w i t h  cm ;  ( 4 8 ) , 77  ether  a n h y d r o u s magnesium  exchanged w i t h  ( 0 . 1 ) , 269  ( 3 0 ) , 61  and  s o l v e n t gave 8 66 mg  3400, 1735  ( s , 6H), 3.56  then  the  i n t e n s i t y ) 311  ( 1 4 ) , 98 71  l a y e r was  (15 mL)  the  The  was to  tetrahydror e a c t i o n mix-  introduced.  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S o c . , 94, Synthesis,  SPECTRAL  APPENDIX  273  274  275  122. •—i CO  z UJ I—  z °  '—' o _ in  d  I 50.0 1  D.O  100.0  150.0  200.0  M/E  250.0  300.0  350.0  400.0  450.0  276  M  00  279  282  283  RELATIVE 0.0  25.0  INTENSITY 50.0  15.0  100.0  00 00  292  MICROMETERS Um)  FREQUENCY (CM'I  RELATIVE IN' 25.0 _J  50.0 I  RELATIVE INTENSITY 0.0  25.0  50.0  75.0  100.0  to  o  o  u> o  0  306  0  AA-  0-(CH ) Br  262b l±J >  (X  2  6  0  309  0 0-(CH ) Br 2  9  2£2e  cc _la  'I  100.0  50.0  ' '  I • 250.0 1  200.0  150.0  M/E  300.0  350.0  MICROMETERS (om)  1600  1200  2400  2000  1800  I6O0  FREQUENCY (CM')  1400  1200  1000  400.0  450.0  311  315  AA„. 0  0  (CH ) CH=CH  ma CKrsi  2  6  2  0.3 J  RELATIVE INTENSITT  25.0 1  50.0 I  75.0 I  100.0  I  U)  co  

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