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Synthetic studies using B-keto esters Sum, Phaik-Eng 1976

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SYNTHETIC  STUDIES  USING  S-KETO  ESTERS  by  PHAIK-ENG B.Sc.,  Fu  Jen  SUM  University,  Taiwan  1972  THESIS THE  SUBMITTED  IN  REQUIREMENTS  PARTIAL FOR  MASTER  OF  THE  FULFILLMENT DEGREE  OF  SCIENCE  in  THE  FACULTY  OF  DEPARTMENT  We  accept to  THE  this  the  GRADUATE OF  UNIVERSITY  OF  August,  (cT)  CHEMISTRY  thesis  required  STUDIES  as  conforming  standard  BRITISH 1976  Paik-eng Sum, 1976  COLUMBIA  In  presenting  an  advanced  the I  Library  further  for  degree shall  agree  scholarly  by  his  of  this  written  thesis  in  at  University  make  that  it  thesis  for  partial  freely  permission  purposes  may  University  C H E  It  of  H  British  tij  of  is  British  available for  gain  dy  Columbia  for  extensive by  the  understood  permission.  of  fulfilment of  be g r a n t e d  financial  2075 W e s b r o o k P l a c e V a n c o u v e r , Canada V6T 1WS  Date  the  representatives.  Department  The  this  shall  reference  Head  be  requirements  Columbia,  copying  that  not  the  of  copying  agree  and  of my  I  this  that  study. thesis  Department or  for  or  publication  allowed without  my  ABSTRACT  The using of  one  dianions  equivalent  n-butyl1ithium  amide. was  The  reaction  studied.  acetate oxide  On  (55)  and  anion  with  was  (9_6)  these  precursors  in  the  Robinson  one-half  of  ethyl  single  step  acetoacetate ether.  to  type  methyl our  diisopropyl-  various methyl  acid,  a  epoxides aceto-  of  ethylene  tetrahydro-  cyclization  synthesized  these  This  by  (5_5_) w i t h  one  methyl  reaction.  or  of  treating  (12 0)  from  the  the  3-keto  a-ch1oromethy1 a  reagent  annelation.  by  dianions  provides  The  di-  convenient which  be  are  the  equivalent  of  easily lithio  very of  useful methyl  achieved sodio  chloromethyl  were  ether  preparation  5-ethoxy-3-oxohexanoate (130)  esters  methyl  preparation  could  treating  5-methoxy-3-oxohexanoate  dianion  sodio  the  equivalent  lithium with  with  generated  a-(tetrahydro-5-methy1-2-fury1i-  Nazarov's  synthesis  Similarly,  one  equivalents  from  ether  5 -methoxy-3-oxopentanoate a  been  oxide.  investigated.  the  of  lithio  treatment  alkylation  of  of  also  and  dianions  formed  was  have  hydride  Methyl  propylene  a-chloroethy1 also  9_5_,  esters  equivalents  and  alcohol.  The with  of  subsequent  intermediate acetate  sodium  two  one  acetate  dene)  of  g-keto  treatment  with  on  furylidene  or  of  prepared  in  methyl methyl  ( 1 2 9)  and  using  The internal alkanes  double  The  diketo  esters  mately  equal  compound methanol,  isolated  with  and  one  reaction  However,  equivalent  the i n t r a m o l e c u l a r  via their  compounds dianions  found  mono-halo on  with  compound  diffi-  in  of the  approxi-  mono-halo  in refluxing  at the a-carbon  esters  to the c y c l i c  dihalo-  rather  methoxide  cyclization  the  of the b i s 3 -  treatment  g-keto  using  t o be  a mixture  o f sodium  mono-halo  dianions  was  were  a y-alkylated  The  ring  of these  products  amounts.  achieved.  cyclized  of large  alkylation  i n a one-step  cult.  easily  synthesis  could  also S-keto  or spiro  esters.  130  R =  C H  129  R = C  2  3  H  5  was be  142a  -  TABLE  OF  V  -  CONTENTS  Page Abstract  Table  List  of  of  i i  Contents  v  Schemes  v i i  Acknowledgements  ix  Introduction  H i s t o r i c a l The  1  Background  Dianion  Reactions  Results  and  of  of  g-Dicarbonyl  Dianions  of  Compounds  g-Keto  Esters  3 21  Discussion  Reaction with Reaction with  of  of  Methyl  Acetoacetate  Epoxides of  Lithio  33 Sodio  Methyl  Acetoacetate  a-chloroether  Alkylation with  Dianion  of  the  38  Dianion  Dihaloalkanes  of  and  g-Keto  Esters  Dihaloalkenes  46  Experimental General Reaction with Reaction with  60 of  Sodio  Lithio  Methyl  Acetoacetate  Epoxides of  Sodio  61 Lithio  a-Chloro-ethyl  Methyl ether  Acetoacetate 63  -  Table  of  Contents  -  v i  -  cont'd .  Alkylation with Reaction  of  of  B-Keto  Esters  Sodio  Lithio  68 Methyl  Acetoacetate  Dihaloalkene  Dialkylation of  Dianion  Dihaloalkanes of  with  the  at  Methyl  the  Page  y-carbon  Acetoacetate  76 of  the  Dianion 80  Bibliography  83  Spectral  90  Appendix  -  List  vii -  of  Schemes Page  Scheme  I II  The  Alkylation  of  Disodio  2 ,4 - h e x a n e d i o n e  The  Alkylation  of  Dianions  of  g-Keto  Alde-  hydes III IV  13  Reaction  of  the  Dialkylation  Anion  of  of  Dianion  Dimethylnitrosamine of  Methyl  The  VI  The  22  Reaction of  of  Methyl  Reaction with  N i t r i l e s  with  the  Dianion  Acetoacetate  Synthesis idene)  VII  of  Ethyl  30  a-(tetrahydro-2-fury1-  Acetate of  35  Dianion  of  Methyl  Acetoacetate  Epoxides  36  VIII  The  Synthesis  of  Methyl  3-oxo-4-pentenoate  IX  The  Synthesis  of  Methyl  5-methoxy-4-methy1-3 -  oxopentanoate X  The  Synthesis g-Keto  XI  Reaction tate  XII  Medium  Ring  Size  Cyclic  Esters of  with  47  Sodio  Lithion  Methyl  Acetoace-  Dihaloalkanes  Tautomerization  48  of  Methyl  2-oxocyc1oheptane-  and  Methyl  2-oxocyc1ooctane-  carboxylate Configurations  39  42  of  carboxylate  XIII  18  Acetoace-  tate V  11  50 of  enolates  of  g-Keto  Ester  53  -  cheme  XIV  D i a l k y 1 at i o n at of  XV  The  Methyl  Synthesis propanoate  V 1 1 1  the  y-carbon  of  the  Dianion  Acetoacetate of Methyl  57 3-oxocyc1oalky158  Acknowledgements  I guidance  am  and  much kind  indebted  to  Dr.  encouragement  Larry  during  Weiler  the  f o r his  course  of  this  work .  I to  Frank  preparin g  would  W.  B.  this  also  Skinner  like  to  f o r  the  manuscript.  extend  my  helpful  sincere advice  he  thanks gave  i n  -  1 -  INTRODUCTION  In natural  compounds,  is  natural  a  main  alkaloids,  well  thetic  methods.  One i s  the  involves Of  the  more  be  of  creating  various  basic  most of  both  the  which  of  molecules.  methodology, method yield  l i e in of  that  the the  major a  many  have  is  effort  now  and  natural  been  without  molecular  the  Many  challenges  framework  carbon-carbon  particular  of  to  in  development  of  usefulness  up a of  process.  syn-  new  syn-  chem-  problem  stereochemistry. none  bonds,  s t e r e o s p e c i f i c i t y  synthetic  of  organic  synthesis,  building  e f f i c i e n t  these  The  and  of  generality,  routes  compounds  by  discovery  formation  the  such  and  synthesized  organic  of  of  including  insecticides  in  c r i t e r i a  synthe-  synthetic  a r c h i t e c t u r e .  proper  the  and  synthesized,  products  types  In  many  number  elegant  sequences.  fundamental  chemical  of  been  of  chemistry.  exciting  the  of  tremendous  organic  possible  alkylation organic  in  reaction  than  the  synthesis  compounds  e f f i c i e n t  synthetic  the  control  organic  synthetic,have  interest  not  decades,  prostaglandins,  controlled  would  five  Although  years,  terpenes,  or  been  more  recent  theses  ists  has  theme  pharmaceutical  and  novel  or  development,of s t i l l  four  chemists.  In  of  and  interest  organic  the  past  products  b i o l o g i c a l tic  the  is  i . e .  the  skeleton  new  synthetic  a  synthetic and  the  optimal  2 -  Alkylation been  known  fields  and  of organic  3-dicarbonyl been  fully  interests cient  i n our  which  reactions  difficult  3-diketone, while  3-keto  ester.  to  on  chosen  of  the  have  new  two  of  dianions  of  the  major  and  effi-  general of  3-keto  synthetic  because  carbonyl  i t is carbons  to achieve  carbonyl  of  yet  i n modern  easy  various  not  dianions  two  long  has  one  mainly  the  i t is relatively  e i t h e r one  been  the  useful  differentiate  use  reactions  develop  be  were  the  i t has  based  will  esters to  However,  fact,  compounds  application in  in alkylation In  hopefully  at  widespread  laboratory  B-Keto  specifically  3-dicarbonyl  synthesis.  exploited.  chemistry. usually  found  compounds  alkylation  esters,  a  have  using  groups  in  reaction in a  3  HISTORICAL  The  Dianion  of  tions  or  carbon  other  through  a c e t y l ace tone metal  be  very  In acetone  (1_)  potassium carbon the  i s  or  salts  halides.  alkyl  even  in  Hauser  salt at  react  with  and  were  p KNH  example, or  formed  which  a l k a l i can  often  solvents.  i f  converted  y-carbon  amide  that  benzoyl-  to  the  other  rather  salt  in  or  i s  d i -  carbon-  than  at  generated  liquid  ammonia.  benzyl  chloride,  the  give  only  y-alkylated  On  dipotas-  products.  observed.  p C H CH Cl 6  5  R-  2  -»  NH  when  an  reactions  alkylation  R ^ \ < \  2  a-methylene  of  not  reac-  metal,  These  dipotassium  equivalent  rapidly  is  f i r s t  terminal  the For  reported  is  potassium  o o ^ v ^ \  {2)  The  1  Harris  undergoes  the  group .  monoanion  refluxing  and  at  a l k a l i  with  the  one  an  a  Dialkylatiji'g' products  R  with  acetylacetone  diketone with  treated  alkylation  monoanions.  carbonate,  1958,  salt,  treatment sium  formation  condensation  the  undergo  of  a-methylene  from  can  the  slowly  or  compounds  condensations  alkylated  proceed  Compounds  carbon-carbon  (2^  alkoxide  then  BACKGROUND  g-Dicarbonyl  g-Dicarbonyl  -  CH  e  2  3  C H 6  1_  R  =  C  6  5  H  2-  R  =  C  6  H  5  JL  R  =  C  6  H  5  5 (1)  _2_  R = CH  3  U_  R - CH3  _6_  R = CH^  These the  reaction  with  many  been  observed  e s t e r s  3  '  5  addition  of  other  -  7  ,  the  to  functionalize been  31  dicarbanions  include  with  procedure  of  3-dicarbonyl  applied  to  with  ketones  a,3-unsaturated  3-keto  are  of  useful  compounds  Reactions  with  aromatic  carbon and  i n p r e d i c t i n g  3-dicarbonyl  agents.  alkylation  carboxylation  This  results  e l e c t r o p h i l i c  reactions  additions  also  alkylation  that  and  dioxide , 3  '  7  a l i p h a t i c  carbonyl  4  a l d e h y d e s  have  -  9  and  1,4-  compounds ' ' . 5  generating compounds aldehyde  at  7  9  the the  7_ a n d  32  dicarbanions y-position 3-keto  ester  to has 31 ' 2  5  Since when  1:1  ratio  the  alkylation  the  site  of  of  3-diketones  of  a l k a l i  using  of  the  of  diketones  or  metal  excess  less  than  The by  comparing  alkylation The  latter  whilst  high the  of  the  time  i s  a-position the  of  simple very  alkylation  base  with  a  of  employed, occur  the  complete at  the  employed. the  are  observed  at  monoanions  stoichiometric  during  of  not  must  alkylation  observed  halide  of  of  are  base  e s s e n t i a l l y  formation  the  a-position  dianion  reactions  Apparently  dianion  amount  is  the  substan-  y - p o s i t i o n .  r e a c t i v i t y  rate  proceeds  rapid  been  the  that  same  and  Treatment  aldehydes  affords  alkyl of  compound  ionization.  the  not  Y -p o s i t i o n  the  equivalents  g-keto  At  has  nuc1eophi1icity t i a l l y  two  amide  dianion.  when  dicarbonyl  secondary  of  even  a l k y l a t i o n s at  -  of  dianion  these  a l k y l a t i o n  monoanions slowly  dianions  even  to  can  be  shown  that  of  the  of  3-dicarbonyl  at  elevated  of  dianions  occurs  even  of  s t e r e o s p e c i f i c i t y  compounds.  temperatures at  low  temper-  ature .  A these  high  degree  dicarbanions  alkylation  disodium  salt  of  chloride  gave  e x c l u s i v e l y the  that  a  high  reaction  1  1  .  reactions.  1-pheny1-2,4-pentanedione  degree  of  erythro  asymmetric  appears  Treatment (8)  product  induction  also  with 9^  occurs  of  in  the  a-phenethyl  indicating during  the  9  The tion  of the diketone  liquid have  ammonia.  been  aldehydes sodium  2  pally  The  employed have  salt  ammonia '  may  dicarbanions of diketones  1 2  t o two  equivalents of a l k a l i  amides  of lithium,  in this  usually  been  of the keto .  b y means  sometimes  Keto  ester  reaction.  3  1 4  1  3  ,  been  3-keto  o f t h e mono-  amide  in  prepared  although  addi-  potassium  dianions of  to potassium  amide '  by  amide i n  and  by a d d i t i o n  d i a n i o n s have  satisfactory  sodium  The  prepared  aldehyde  of potassium be  are generated  sodium  liquid  princiamide  The show  certain  time  the  it  was  were the  distinct  yields  found  acetone  dicarbanions  (2)  of  that gave  found  to  disodium  differences  alkylated the  dilithioacetylacetone  to  be  to  obtain  only  0  complete  67-73%  1  after  alkylation  vary  6  .  produce  with  of  M  +  1 )  nBuBr  2)  H 0  In  salts  yields  example,  n-butyl  reaction  acetyl-  salts  than  either  alkylation  was  reported  period  disodioacety1 acetone  same  general,  of  the  bromide  metals  the  dilithium  lower  the  At  widely.  The  For  twice  a l k a l i  r e a c t i v i t y .  dipotassium  salts.  (10)  different  0  M  This  25%  and  and  dipotassium  of  in  r e s u l t s  slower  by  products  disodium  comparable  react or  generated  employed  (11).  o  0  (5) +  10  M = Li*  11  M=  Na  +  ( CH )  3  2  +  lack  of  r e a c t i v i t y  character  of  the  can  be  1ithium-carbon  explained bond  but  12  M =  Li  13  M =  Na  by  the  i t  only  higher  3  <25%  +  G 7-73 %  +  covalent  applies  to  8  alkylation found  to  esters (14)  reactions  be  and  very  disodio-  useful  ketones ' . 6  reacts  greater  because  with  than  s e l e c t i v e l y  6  ethyl  proton  and  8  these  d i l i t h i u m  f o r condensation For  example,  acetate  abstraction  salts  with  have  enolizable  di1ithio-benzoylace  rapidly from  and  the  d i p ot as s ioben zo y 1 ac et one  at  been  a  e s t e r , 6  (_3)  ionize  0  0  rate  much  while the  tone  the ester  .  0  OEt Li  (6)  Li 15  0  0  0  16  3  C  5  H  5  C 0 C H K C 0 C H  17  (7)  3  - 9 -  Many potassium When  the  salts  primary  ating  agents  yields  range  from  when  examples of  and  55%  isopropyl  secondary  of  aliphatic  alkylation  to  80%.  bromide (40 .  But  a  of  butyl  bromide  gave  yield  products  8-phenethyl  of  r e a c t i v i t y  78%  have  c h l o r i d e  been 1  of  of  yield  66%  ( l J J  produced  of t e r t i a r y  alkyl  g-diketones  c a n be  reported. as  was with  5 1  with  due  to  i s  halides  ( 1 1 ) ,  obtained of  dipotas-  achieved the  i n the  same  with  product  1  t-butyl the  alkyl-  usually  alkylation  alkylated  probably  6  and d i -  are used  disodioacety1acetone  Alkylation a  been  obtained  27%  i n the  disodioacetylacetone  agent.  or  only  6  disodium  also  halides  product  yield  ating  alkylated  1  the  disodioacety1acetone  of  However, i s used  of  (2_) h a v e  t h e monoa Iky1 a t i o n  sioacetylacetone alkylation  alkylation  acetyl acetone  i n the  of  of  5  a l k y l -  sec-  .  No  chloride  inherent  lack  i n displacement  reac-  tions .  Bis of  disodioacetylacetone  nona f u l l y  and  have  ethylene  chloride,  and  paration  of bis-diketones  7  with  bromides  Failures  1  .  deca-methylene  (_1JJ  been  1  7  have  been when  bromide .  through  d i h a l o a Ik ane s .  reported  ethylene 18_  synthesized  T r i ,  employed methylene  were  used  alkylation tetra,  successchloride,  i n the  pre-  10  -  ii 1  0  0  2  +  Na  B r ( C H J  ^  Na+  +  n  B r  •  n=  n  4, 9 or 10  3 >  11  0  0  0  0  11 The ions at  of  the  3-diketone  two  of  producing different  diketones atoms  two  Treatment  mixture of  the  the  both or  (1_9_) of  discussed  different mixture  at  through  groups  hydrogen  of  to  arises are  atoms.  with  two  dianions with  theoretically,  formation i n  by  carbon  example,  equivalents might  methyl  of  unsymmetrical  flanked For  only  g-diketones  least the  dicarban-  occur  unsymmetrical  situation  treated  reaction  alkylation  i s capable,  carbonyl  was two  of  products This  more  the  been  case  dianions  dianions.  one  of  already  isomeric  whenever  bearing  a  In  their  2,4-hexanedione amide,  has  y-position.  alkylation of  r e g i o s p e c i f i c i t y  be  iodide  when  of  sodium  formed gave  1  8  an  .  - 1 1 -  89:11  mixture  products  2_2_  of  the  methyl  2_1_  and  respectively.  Scheme I  89  :  11  the  methylene  alkylation  12  Alkylation similar  r e s u l t s  system,  alkylation  in  -which  1  8  .  dipotassiopropionylacetone  In  the  of  alkylation  (equation  of  case  their  had  of  diketones  dianions  occurred  at  gave  gave  with  c y c l i c  only  those  the  methyl  group  0  0  products 1  9  9) .  0  0  1)  2KNH  2  (9)  6 5 H  C H CH Cl  3)  H  6  5  2  +  23  n = 0  25  n=0  (62%)  2U  n = 1  26  n=1  (5o%)  The have has  2)  also been  halides dense  a l k y l a t i o n s of  been  reported ' 2  effected in  good  gradually  d i f f i c u l t y aldehydes  can to  with  y i e l d to be  more  1  1  3  >  g-keto 2  0  .  Alkylation  methyl, 2  .  give  The  n-butyl, products  by  are  converting  copper  through  at  the  n-octyl  t r i a c y 1 b en z en e s  overcome stable  aldehydes  chelates  y - p o s i t i o n  and  unstable  2_9. the 27.  The  dianions  benzyl and  con-  i s o l a t i o n  alkylated  keto-  13  -  Scheme 1 1  Q o KNH-  H  RX  0  0  Copper chelate  H R  27  H  +  COCH R• 9  ( RCH COCH CHO ) 2  RCH CO ^^COCH R l  ?  29  have  been  monosodium liquid  2  2  a-Formy1cyc1opentanone  and  converted  dianions  salts  ammonia  effected  28  with  2 1  to  with .  secondary one  equivalent  Alkylation  several  alkyl  of  a-formy1-eyelohexanone  of  these  h a l i d e s  2  1  by  treatment  potassium dianions  >  1  3  .  of  amide  have  in  been  their  14  Alkylation of  dianions  tion  occurs  were  also  only  at  give  poor  reported  to  anion  ethyl  the  of  ester  ammonia . 3  gave  hour. been  yields  Alkylation  Benzylation effected  products  s i g n i f i c a n t time  was  of  ethyl  i n low  y i e l d  these  i n yields  amide  o f  change  i n yields  varied  from  a  4  5  was  2  bromide 29%  res-  observed  minutes (_31_)  to  even an  has  also  .  0 2  and  of  l i q u i d  ethyl  37%  few  addition i n  disodioacetoacetate 1  The d i -  3  by  reac-  were  e s t e r s .  and  ? o OC H  a l k y l a t i o n  prepared  iodide  formation  reactions  of potassium methyl  the  the  alkylated  (_3_0) w a s  with  through  Although  of  equivalents  the reaction  esters  studied.  acetoacetate  two  No  3-keto  the y-position,  the y-alkylated  pectively. when  to  of  >  0 OC H  A  2  30  5  31  1) RX 2) H  Q R  +  0 •OC H 2  5  (10)  15  The may  be  the  ethyl  to  due  to  the  by  Thus  equation  useful  first  valents  other  dilithio  potassium  of or  functions  dianion  2  7  '  2  ,  8  of  and  ethylamide  2 9  ,  the  3 1  of  amide  3 4  the  of  s a l t s added  of  search  of  3 3  of  bases  The  ester  and  2  4  '  2  to  5  '  a  produce used  enough  in  to  2  .  6  low  3 0  (3_0)  than  be  was  the  When t w o  solution  i t appeared  other  the  bases  of to  corequi-  ethyl attack  desired  was  initiated.  nuc1eophi1icity in-  ,  as  lithium  lithium  dicyclohexylamide lithium  func-  i t should  solubility  generating  of  to  base  strong  d i a l k y l a m i n e s , such  and  converted  acetoacetate  diisopropylamide  '  the  also  ammonia.  ethyl  were  other  3 2  of  dianions  liquid  sodium  lithium  tetramethylpiperide  partially  reaction conditions  i t s greater  a  salts  ,  only  r e a c t i o n and  aminolysis  instead  thus  lithium  cyclohexylamide  the  in tetrahydrofuran,  application use  of  salt  the  of  alkylations  i s necessary.  than  of n - b u t y l 1 i t h i u m  carbonyl  be  i n these  non-nuc1eophi1ic,  formation  (30)  clude  to  be  acetoacetate  Recent  due  esters  s t u d i e d because  responding  may  for other  should  in solvents The  (3_0)  ion  8-keto  complete  obtained  temperature  search  of  (10)  to  low  amide  a  dianion  lead  the  results  acetoacetate  dianion  tion.  poor  bis  3 2  ,  di-  N-isopropyllithium  2,2,6,6-  (trimethy1si1y1)  . Of  a l l these  has  been  widely  has  used  lithium  used  bases,  i n the  only  lithium  preparation  diisopropylamide  to  of  diisopropylamide dianions.  generate  the  Creger  dianion  of  3 0  -  2-methylpropanoic in  alkylating  this  acid  16  -  (3_3) a n d  good  results  have  been  obtained  dianion.  UN  C0 H 2  CO-  HF  33  36  RX  R  C0 H  (1D  2  35  The dianion has  been  of  same  t o l u i c  achieved  base acid  has 3_6_,  also and  i n moderate  been  used  alkylation y i e l d  3  5  .  to of  The  generate  the  the methyl dianion  C0 H  of  group a  series  • C0 H  2  2  LiN  R  CH.  36  THF. R'X  R  X  CH R' 2  37  (12)  17  of  alkylacetic  acids  d i i s o p r o p y 1 amide, alkyl  halides  to  3_8  and  have  only  H 39  38  These  d i l i t h i o  hydes  and  salts  ketones  .  A  when  hydroxylamine. to  Seebach similar groups  to of  generate (4 5 ) amide very  with  that ethyl  an  and of  the  >  allowed  in  the  n-buty11ithiurn. used,  they  high  yield  of i t  were  of  to  amino  have  would  (_30_)  a c i d  3 6  .  (13)  to  or  appear  of  of  aldol that  alde-  9  could  also  0-methyl-  added  the  dianions.  a  some  d i f f i c u l t y ,  upon  the  in  the  carbonyl  attempts  to  dimethylnitrosamine  when  form  3  was  attack  during  with  a-a1ky1acry1ic  with  reported  However, able  condense  aminated  a-position  alkylated  4 0  R-C-C-OH  dehydration,  were  3  product  R' 40  nucleophilic  acetoacetate  anion  Hence  4  with  I  s o l u b i l i t y  Enders  the  was  obtained.  •  after  salts  react  lithium  0  Hexamethylphosphoramide increase  to  R'X  synthesis  these  shown  using  mono - a - a I k y 1 a t e d  also  give,  one-step  achieved  reactions  were  to  prepared  0  I  1  8  been  R-C=CC\_  >  9  3  been  /0~  RCH C-0H  be  have the  0 II  a c i d s  also  these  give  -  lithium  the  anion  products lithium  47  diisopropyl4_6  and  could  a be  diisopropyl-  -  -  18  Scheme III  1) nBuLi/THF >  • C = NOH  5  5  N-N=0  (C H ) C'  2) (C H ) CO  6  5  2  2  OH  48  49  N-N=0 45  Li N  >-N=0  C  6  H  5  °  H  O  ,  '  6  H  5 Y ^ N - N = 0 OH  46  amide  C  could  esters .  '  47  also  be u s e d  t o generate  thedianion  o f 3-keto  19  An amides  showed  employed of  i n v e s t i g a t i o n of  to  this  that  form  base  lates.  In  lithium  l i t h i o  could  was  also  amide  was  ethyl  hexanoate.  Mayo monoanion  of  protected  the  be  to  e_t_ a l  bis  have  then  treatment  gave  the  of  dianion  the 5_2_  a c e t a t e " ,  (5_0_)  monoanion  6  H  5  X  ^  i  J  M  N  H  2  C  6  hydride  the  esters  smoothly  monoanion to  i n i t i a l  5_4,  and  monoanion  was  approach quite  converted addition 5j4  gave  use  ester  eno-  enolate  of  metal  amide  with  the  which  attack  and  n-buty11ithium  yield.  nBuLi  C  o 6 5\A H  in  the 4  5  i n v e s t i g a t i o n of .  One  equivalent  methyl  acetoacetate  of  equivalent  one  (14)  52  s i m i l a r  the  the  was  generating  51  Our 3-keto  the  n u c l e o p h i l i c  5 \ A  H  other  f i r s t  0 \  amide  that  forming  a  lithium  N -isopropy 1 cyc1ohexy1-  solution  excellent  50  of  and  form  in  with  from  0 C  in  succeeded  group  in  to  lithium  bases  phenylacetone carbonyl  (trimethy1si1y1)  that  other  44  alky1 -s u b s t i t u t e d  extended  found  superior  other  ethyl  not  -  desired  dianion  (53)  of 5_5_.  dianion of  into  sodium i t s  n-butyl 1 ithium However,  -  Q  O  20  O  /A^C0 CH 2  NaH  A^/  3  -  nBuLi  C 0  2  C H  3 < 15)  -  ->  53 it  54  i s  u s e d  important  2  8  '  3-keto s a l t s  4  5  4  7  .  4  and  8  was  When  the  with  a  the  found  of  product  ium  the atoms  the  0  per  of  was  a  4 9  acetoacetate  both  3-keto  acetoacetate  the by  a-  and  y-  extraction  sodium  by  nmr  (5>_3)  (5_3)  and  mass  contained  deuterium  2  n B  ]  3)  51  u  positions. of  the  0.95  was  After  ±0.03  located  D 0 3  +  3  0  r ^ ^ 0 C H D  3  57  3  X  D 56  0 1) NaHC0  D  +  (16)  deuteronly  0  [ Y 0CH /  iso-  spectroscopy,  0  L i  acid,  showed  bicarbonate.  1) NaH 3  of  was  y-position.  0CH  not  phosphonium  trif1uoroacetic  of  this  dianion  acetoacetate  methyl  exchanged  found,  to  the  i s  .  deuterated  at  and  organometal1ic  generating  methyl  solution  molecule  of  applied  recovered  i t was  0  2) H 0  of  deuterium atom  methyl  of  phosphonate  the  with  excess  been  dianion  that  extraction,  that  recently  solution  a-deuterium  lated  in  has  that  procedure  3-keto  incorporation The  note  This  esters  quenched it  '  to  55  3  21  Reactions  of Dianions  Some been  involved  dianions give  reactions  investigated  study  3-Keto  previously  react  y-alkylated  Esters  of dianions  with  a  products  of  3-keto  reaction  range  good  y i e l d s  one  found  be  very  also  found  adding  an  was by  and  clearly  showed  alkylated  5  0  .  a  second that  the second  d i a n i o n  that  3  dependent  '  5  2  '  was  a l k y l a t i o n .  5  3  agent.  yields  isolated  and  reported  3  (17.)  this  i n  The again  were  could  previous  .  equivalent  the a l k y l a t i o n had higher  alkyla-  0  d i a l k y l a t e d products  additional  a l k y l a t i n g  However,  product  The  58  f o r the low y i e l d  It  lithium  y-carbon  .  to  0CH  temperature  this  These  R  RX  to alkylate  obtained  with  t o be  of the reasons  attempts  2  >  3)  f i r s t  agents  1) NaH / THF .  53  be  4  0  2) nBuLi  was  The  of a l k y l a t i n g  i n very  have  of the dianion.  0 0CH<  tion  esters  i n our laboratory.  the a l k y l a t i o n  could  0  of  of n-butyl-  spectral  i  evidence  occurred  found  and p u r i f i e d  could  at the  i f t h e mono-  before  proceeding  22  Scheme  at  0-25°  with  the  several no  These  reactions  C  were  and  in  a-alkylated  even  complete  a-alkylation hours  with  an  were  of  product  excess  of  found in  (3-keto  r e f l u x i n g was  IV  to  less  than  ester  solvents. detected  a l k y l a t i n g  proceed  which This  in  30  the  agent. •  very  min.  easily compared  t y p i c a l l y  required  could  explain  above  reaction  why  23  The were  also  were  a  3-keto  reactions  b r i e f l y  mixture esters  of  of  dianions  i n v e s t i g a t e d c y c l i c  (6_2_) .  The  -  5  1  .  alkylated ratio  of  with The  a,to-dihaloalkanes products  products these  two  depend  on  61  react  may  the  (n=3  fate with  \  of  only )  the  another  5  intermediate molecule  of  6_3_ a n d  a b i s  products  may  0  0  63  isolated  ( n=3  2  61_.  The  dianion  to  10)  intermediate give  24  3-keto  bis tion  to  give  products propane of  ester  could was  was  dibromo 3-keto  agent,  of  was  63_.  when  solution  could  be  with  only  also  i n almost  dianion  one-half  ester,  product  was  5_5_.  5  that  1  used  as  Higher  yields  dibromo  be  when the  both  1,3-dibromo-  equivalent would  cycliza-  of  of  i f excess  reported  1,10-dibromodecane  amounts  equivalent  obtained  the predominant I t was  Equal  one of  intramolecular  com-  of the  the b i s one-half  alkylating  3,16-dioxooctadecanedioate  quantitative  yield  and  no  c y c l i c  was  product  detected.  dibromomethane  evidence  f o r the  found.  However,  yield, the  a  b i s 3-keto  only  undergo  compound  while  6_2.  When no  to  product  ester  i t may  obtained  compound,  isolated was  be  added,  equivalent  or  cyclic  added  cyclized  pound  a  6_2  -  and  the  compound  ternal shown  aldol  cyclic a  spectral  was  indeed  employed  product  new  compound  and  of  or  i n the  alkylation,  the b i s 3-keto  was  analytical  the product  condensation  i n equation (19).  was  produced data  which  the expected  i n  ester reasonable  indicated  arises  from  intermediate  that an i n 6_4  -  0  25  -  0  0  0  were  also  65  The undergo to  aldol  yield  6 7 could urated  dianions type  of  reactions  <5-hydroxy-3-keto then  3-keto  be  3-keto '  with  5 5  esters  dehydrated  esters  5 4  esters  6_7_.  to the  ketones These  found  and  hydroxy  corresponding  6 8 .  CRR 68  to  aldehydes esters  y,S-unsat-  26  When pentanal  as  the  and (5J5)  acetate  the  dianion  side  of  reaction of  and  proton  the reaction  of  acetaldehyde, of methyl  transfer  i n these  was  cases  cyclopentanone  dianion  involving  were  transfer  dianions  have  from  also  suspected  since also  cyclopentanone.  aceto-  self-  formed  Similar been  i n  d i f f i -  reported  g-diketones  with  ketones  aldehydes ' . 6  In products s i l y l  aldol that  dianion the  were 4  thium  was  the  prior  to p u r i f i c a t i o n  some  treated was  with  other  at  0°  no  terminal  gave  and  aldol  on  to  be  r e a c t i o n  sodium  I t was 3  7  found  could  subsequent aldol  product  4  5  ketones  because  very  products  f o r example,  could  be The  the  trimethyl-  these  d i s t i l l a t i o n .  retro-  I t was  obtained aldol  temperature  found  when  the  reaction  of  dependent  .  hydride that  also  7_0  detected  and n - b u t y 1 1 i t h i u r n  two  lead  reaction  product  was  and  corresponding  formaldehyde.  than  terminal  the  product  found  d i i s o p r o p y 1 amide  the dianion  ion  aldol  also  to  decomposition,  alkylation  of  aldehydes  converted  investigated.  C  aromatic  f i r s t  i d e n t i f i a b l e  Bases were  of  decarboxymethylat  dianion was  5  case  underwent  and no  8  the  e t h e r  usually  as  amount  Proton  recovered.  the  and  large  was  products  during  with  a  condensation  culties  treated  cyclopentanone,  competing  reaction  was  equivalents  to with i n  complete  formation  benzophenone  76%  when  o f ' l i -  yield.  two  (69)  However,  equivalents  0  0  0 0C H 2  5  +  ph^  Q 0 OC H  ^Ph  2  Ph 31  69  lithium  suspected ate  the  this  successful 7  >  5  8  .  base  the  acylation  Wolfe  dianion the  7  might  5  0  were  5  not  be  used  strong  and  i t  was  enough  to  method  for  gener-  dianion.  Besides  5  "  hexamethyldisilylamide that  (21)  OH  "  of  5  of  a  dianion  reported of  the  e_t_ a l _ , h a v e 3  3-keto _3_1_  pentanoic  acid  depending  on  ester  with  methyl  (7_1_)  or  the  dianion  reported which  has the  7_2  in  condition.  to 48%  a  also f i r s t  involved  benzoate  pyrone  reaction  a l k y l a t i o n s ,  the  give and  been  the  developed  acylation  of  condensation  the of  5-pheny 1 - 3 ,5 -dioxo• 11%  r e s p e c t i v e l y  -  0  28  0  0 OC H 2  C H C0 CK 6  5  2  0  0  H o b  5  OH  31  71 OH  I  (22)  or C  6  0 ^ 0  5'  H  72  Early that  the  lently of  the  dianion  with  products  agents  were  dianion  3,6-diketo  0  investigation from  acyl was  halide  investigated, 5_5_ w i t h ester  73  in  at  laboratory  -78°  Hence, and  methyl  our  acetoacetate  even  obtained.  acetate  30-40%  C  less  i t was  (5_3_)  and  a  0° One  C  demonstrated reacted  complex  reactive  found  at  yield.  that  mixture  acylating treatment  smoothly of  vio-  of  gave  the, r e a s o n s  for  p o o  0 *0CHo  55  methyl  in  R  C  0  2  R  R-  '  R=R'=GH  3  0CH  73  ( 3  2  3  )  -  the  low  from to  yield  monoanion  improve  f i n a l l y  Using  gave  in  of  remaining  with  reaction  methyl  yield  and  of  (5_3)  also  has  previously  may  be  been  of  condensed amide  to  with give  6  gave  in  7_4_  of  the  base  from  methyl  ace-  3 , 5-dioxohexanomethyl  butanoate  using 1  of  i n v e s t i g a t e d  ethyl  (R  dianion  two =  methyl 5  0  .  acetoacetate equivalents  CgH , 5  R  =  E t ) ,  It (30) of but  0 R'CN  +  NaNH /NH 2  3  74  31 R -  one-half  esters.  with  the  b r i e f l y  enamine  with  yield.  with  that  1  5j>_  procedure  of  methyl  5_5_  67%  b e n z o n i t r i l e the  equivalent  dianion  been  dianion  dianion  n i t r i l e s  reported  of  transfer  convenient  equivalent  acetate the  reaction has  one  one-half  proton  most  addition  3,5-dioxooctanoate  acetoacetate  The  ester,  71%  The  0  5_5_.  be.the  reaction  procedure,  methyl  sodium  dianion  could  involved  (5_3)  (7_3)  to  reaction  yield  the  this  toacetate ate  of  this  7_3  the  equivalent and  in  -  29  C H 2  5  0  0  75  76  R  the  reaction  amide  i s complicated  i o n on  benzamidine  the n i t r i l e with  It  was  in  our  laboratory  75  formation.  n i t r i l e s (12 in  hours) 66%  (R  gave  to  some  was  found  to  product =  C5H5).  subsequent  avoid  be  to  the  sluggish  the method  dianion  and  hydroxypyr idone be  which The  thermally was  later  analogous  5_5  extended  7_8_ ( 2 9 % ) .  unstable identified  thermal  of the  the pyrimidone  complication  between  of the  condensation  give  using  attack  5 - am i n o - 3 - o x o - 5 - p h e n y 1 - 4 - e n o a t e  and  cyclic  (78)  found  nucleophilic  that  reaction  yield  enamine a  was  The  by  ester  found  could  -  and  the keto  then  30  and as  developed  of  pyrimidone  and  benzo-  reaction (7_7) The  converted  6  R = CH  5  conversion  of  77  R = C H  79  R:  6  3  OH  78 80  C H ) 6  5  to  hydroxypyridone  RCN R^C H  =  isolated  0  55  times  (R  Scheme V  0  75.  CH  3  5  enamine  31  to  cyclic  yama the  6 1  .  hydroxypyridone Treatment  expected  A of  ketones  anion  of  lithium  of dianion  enamine  f a c i l e has  gave  product  and  also  simple  new  been  g-keto  the  has  also  5_5_ w i t h (79)  method  (R  to  r e p o r t e d  esters  g-diketone  been  5  0  with  reported  acetonitrile =  CH )  i n 86%  3  achieve  .  Sugialso  gave  yield.  the C-acetyl at ion  Treatment  two  i n good  by  of the  equivalents  of  monomethyl-  yield.  (25)  (26)  Similarly, was  added  to  80%)  was  found  when  three  the monoanion t o be  equivalents  the major  the expected  o f me t h y 1 1 i t h i u r n  product  tertiary  (greater  alcohol  than  compound.  84  S3  33 -  DISCUSSION  Our reactions use  of  of  which  pounds  such  furylidene  as  some  with of  the  ester  6-keto  and  of  to  esters.  synthesize  quite  further  explore  the  We  able  make  were  medium-sized  d i f f i c u l t  precursors  several  to  other  new  to  of  to  ring  form.  com-  Other  Nazarov's  com-  reagent,  compounds  were  dianions.  Methyl  the  oxide.  8_5_ s e e m e d  was  Acetoacetate  with  a-(tetrahydro-2-furylidene)  treating  homologs  to  the  Dianion  ethylene  project  homolog  using  Methyl by  of  usually  compounds  of  prepared  this  reactions  were  prepared  Reaction  i n  dianions  dianion  pounds  also  aim  sodio  I t has  this  l i t h i o  been  compound  unlikely.  methyl  reported  Epoxides  acetate  (95)  acetoacetate  that  the  by  the  reduction  However,  the  furylidene  (5 5)  preparation  of  furan  acetate  (  be  obtained  y-butyrolactone  2 7  86  85  could  was  i n 87  5  z  24% .  yield  by  a  Reformatsky  reaction  with  )  34  /fir  M  C0 C H  k  2  2  C0 C H 2  5  8 7  2  5  88  (2ft)  C0 C H 2  2  5  8 6  Recently, compound  86  obtained  this  of  ethyl  acetoacetate  of  iodoethanol,  the  using  T.A.  our  compound  sulfonic  acid  to  method i n  to  34%  and  achieve  by  6  3  prepare by  the  a  preparation dianion.  treating  the  tetrahydropyranyl  aqueous  f i n a l l y the  reported  yield  (30_) w i t h  followed  tetrahydropyranyl  B r y s o n  ethanol  using  and  benzene  O-cyclization.  He  and  f i r s t  dianion  ether  acid  of  to  (THP) remove  p-toluene-  Scheme  We the  dianion  smooth with  an  found  of methyl  addition acid  that  to  gave  the the  on  VI  treatment  with  a c e t o a c e t a t e (53) epoxide cyclic  and  ethylene would  subsequent  furylidene  oxide  undergo treatment  9_5_ i n g o o d  yield.  Scheme  Q  Q  VII  0  •1) N a H / T H F OCH  2 3  Q  )nBuLi  OCH55  53  o  H  .0. ^CHC0 CH  R  2  11  R=H  ^2  R  =  C  H  .  +  OCH-  3  ^ O H R 95  R =H  9 6  R =CH-  Similarly, give in  70%  y i e l d .  The  i n i t i a l  using  showed  dianion  also  reacted  a - ( t e t r a h y d r 0 - 5-me  methyl  about  fied  the  alcohol  preparative  absorption  at  R=H  93  cm  product  - 1  propylene  thy1 -2-fury1idene)  t . l . c .  3550  with  The ,  9_4 ,  (R  =  i r spectrum  indicating  the  oxide  acetate  CH 3) , of  was  this  presence  to (96)  purialcohol of  -  the  hydroxyl  structure  group  a  (9_6_)  strong  sence for  an  was  2H,  6  and  in nmr  ably  due  the  mixture  cm"  and  1  ester  consistent  5  5.2  (t,  IH,  J  =  (s,  3H,  -0CH ),  5  3.2  6  3  1.35  (d,  compound  9_5_  with  those  the  of  formation the  former  of  more  the  3H, and  0.4  Hz,  C=CH),  was  authentic  _E  the  Further spectrum  t h e _E_ i s o m e r  and  indicating  1  nmr  (m,  2H, The  3  9_6  i r of  the  -CH ).  favorable  product  favoring  by  cm"  The  group.  supplied  at  to  1700  was  both  f e r e n t i a l  was  d i s t i l l a t i o n .  9_6_  and  2  1640  by  3  3.7  -CH -)  bond  spectrum  with  a-(tetrahydro-5-methy1 - 2-furylidene)  p u r i f i e d  at  structure  0-CH),  nmr  a g-unsaturated  absorptions  in  methyl  peak  of  the  -  94.  The acetate  and  37  _E  -CH -), 2  over  Z  6  the  orientation i s  of an  6  (m,  2.2  of  3  of  dipole  R = H  96  R = CH  3  =  equilibrium  R  = CH  3  86a  R = H  86b  R = CH  R'  3  prob-  moments  Z R  prei s  H  95  double  i t s i r  The  isomer  IH, (m,  the  isomer.  £  has  4.5  comparison 8_6_ .  pre-  which 5  compound  reaction  the  showed  evidence  geometry  by  96  R  38  Reaction  of  Lithio  Sodio  -  Methyl  Acetoacetate  with  a-chloro-  ether  Since fulness the  esters  annelation  type in  of  the  However,  ( 7-9% ) of  the a  of the  c l a s s i c a l major  Nazarov  and  Zavyalow  3-oxo-4-pentenoic a  construction  was  of  cyclic  (equation  strated.  below,  of  with  annelation  the  work  the  3-diketone  2 9 )  6  6  ,  and  tediousness  synthesis to  9_8,  f o r a  piperidone  deterrent  acid,  r i n g  and  of  106  low  5  ,  the  such i n  as  a  6  7  has  use-  9_7_ f o r  Robinson  Mannich  reaction  been  overall  ( o r 97),  i t s general  6  demon-  yield  outlined  u t i l i t y .  -  39  -  Scheme VIII  106  65  -  Stork synthesis Another been  of  and  106  reported  reported  an  Guthikonda  which  approach  to  by  40  have  8  p a r t i a l l y  the  and  developed  a l l e v i a t e s  synthesis  Pichat  increased  8  of  yield  in  the  the  compound  Beaucourt  8  9  .  an  improved  above  problems.  97_ h a s  Trost  preparation  0  also  and of  Kunz  2  2  CI  5  4  also  106.  C0 Si(CH )  C H 0  6  3  3  Li-^—H C0 C H 2  2  5  103  0  0  0  H 0  OCoH 2 5  2  0  2  OC H  ^  n  C  0  2  H O' b c  107  Later, precursor  to  annelation an  by  was  valents  of  in  .  THF  7 1  Heathcock  reaction,  e_t  i f acid  This  of  magnesium  7  0  ,  discovered  might  be  catalysis  used was  that  the  d i r e c t l y  used.  in  the  Therefore,  ethy1 - 5-ethoxy-3-oxopentanoate  substance  3-ethoxypropanoy1 the  al_  reagent  synthesis  devised.  t r e a t i n g  97  Nazarov's  a l t e r n a t i v e  ( 1 0 7)  (30)  5  salt  was  obtained  chloride  ( 1 0 3)  of  hydrogen  ethyl  i n  with  58% two  yield equi-  malonate  108  -  41  -  0  0 CI  C H 0 2  5  OMg  C H 0 2  5  0 t  2+  108  103  THF  0  0  C°C  OC H 2  s»  58 %  C  (31)  5  H 0-  2  5  107  We  found  3-oxopentanoate to  Nazarov's  synthesis. ( 5 3) the  with  ( 1 2 0)  reagent On  one  chloride  that  the  and  preparation  i t s homologs  could  be  easily  l i t h i o  equivalent  of  ch1 oromethyl  3-oxopentanoate purified  through  spectrum  of  this  ( 1 2 0)  i n  displaced 65%  12 0  to  yield.  preparative compound  sodio  column showed  in  methyl me t h y 1  give  This-  5-methoxy-  were  achieved  of  smoothly  methyl  which  treatment  was  of  precursors a  single  step  acetoacetate ether  methyl  compound  at  at  C,  5-methoxywas  chromatography. absorptions  -5°  6  easily Nmr 2.6  42 -  (m,  2H,  0CH CH C0), 2  2  5 3.35  C0CH C0), 2  6 3.35-3.80  and  6 5.2  (enol)  Further spectrum  evidence and  which  2H,  were  for this  CH 0),6 3  CH 0CH ), 3  6 3.7  2  consistent  structure  3.48  with  came  ( s , 2H, ( s , 3H ,  structure  from  0CH ) 3  12 0.  i t s i r , mass  microanalysis.  Another pentanoate  (m,  ( s , 3H,  homolog, methyl  ( 1 2 3) was  also  easily  Scheme  5-methoxy-4-methy1 - 3-oxoprepared.  IX  The  dianion  was  - 43 -  generated  as b e f o r e  and a l k y l a t e d w i t h  compound  121; the d i a n i o n  to  react  with  at  0° C t o -5° C f o r 45 m i n u t e s  yield.  12 2 was t h e n  one e q u i v a l e n t  The nmr s p e c t r u m  methyl  generated  of chloromethyl t o give  showed  a t C-5, m e t h y l e n e  methylene, The  absorption  presence an  methine  of saturated  absorption  hexanoate our  into  able  reaction.  a-chloroethyl following  also  - 1  (129) and methyl  dianion  way  methyl 7 2  a mixture  1  by p a s s i n g  the methyl  between  group  3  6 3.1-3.5 group  C-4,  two c a r b o n y l  groups,  showed t h e  and t h e e s t e r  group  has  . to prepare  methyl  5-ethoxy-3-oxo-  5-methoxy-3-oxohexanoate  (12 8)  were  anhydrous  of paraldehyde  ethyl  ether  first  and a b s o l u t e  (130)  i n the  c h l o r i d e gas  alcohol.  CI +  ROH  125  R = C H  126  R = CH  2  3  5  +  HCl  *  CH  ^0R  3  by  ( 1 2 7) a n d  prepared  hydrogen  0 CH ^  3H),  of the ester respectively.  a-Chloroethy1 ether  ether,  12 3 i n g o o d  (m,lH),  i n the i rspectrum  carbonyl  a t 1740 c m  We w e r e  group  and 0-methoxy  a t 1715 c m "  methyl  allowed  s i g n a l s a t 6 1.16 ( d ,  2H) a n d 6 3.75 ( s , 3H) i n d i c a t i n g  0-methoxy  and  compound  6 3.35 ( s , 3 H ) , 6 3.48 ( s , 2 H ) , 6 2 . 0 - 3 . 0 (m,  iodide to give  + H^  127  R = C H  128  R = CH  2  3  5  (33)  The smoothly  l i t h i o  with  sodio  a-chloroethyl  5-ethoxy-3-oxohexanoate ether in  ( 1 2 8)  to  moderate  a  give  yield.  synthesized  from  very  convenient  reagent.  The  absorption carbonyl meric around  at  6  protons  on  with found  a  and  with  ( 1 2 7)  to  a-chloroethyl  At  same  the  time,  127  R = C H  128  R= C H  2  of  12 9  f o r the  the  C H  130  R=  CH  (R  =  Et)  methylene  center.  the  group  2  In  show  group  Nazarov's a  complicated  between  addition a  providing  to  showed  5  3  thus  precursors  methyl  a l l be  R=  materials,  asymmetric ethoxy  would  methyl  (150)  129  3  of  compound  they  5  available  reacted  give  5-methoxy-3-oxohexanoate  preparation  complex  the  the  diastereo-  multiplet  3.8.  Recently, Robinson  ether  (5_5)  methyl  2.0-3.0  the  acetoacetate  ethyl  (129)  readily  nmr  and  6  methyl  Annelation  i t has  reactions  3-chloroketone that  the  also  13 2  g-chloroketo  been can  i n the  be  r e p o r t e d carried  presence  compound  7  could  of be  that  3  out an  the  d i r e c t l y acid.  easily  We obtained  -  in  almost  quantitative  hexanoate  (12 9)  by  s t i r r i n g  in  chloroform.  0  The  =  C  C H 2  R = CH  of  presence  carbonyl  mixture spectrum  with  hydrogen  of methyl  (130)  chloride  5-chloro-3-  to and  OCH3  ( 36)  134  3  the  due  5-ethoxy-3-oxo-  5-methoxy-3-oxohexanoate  5  (15 4)  3.0  methyl  HCI/CHC13  H  oxohexanoate  5  nmr  from  0  R  130  or methyl  the reaction  0  129  yield  45  showed  -CH--C1  a  multiplet  group  the methylene the asymmetric  and  group  a  at  doublet  between  center.  6  4.5 of  the  indicating doublets at  saturated  46  Alkylation and  of  the  Dianion  of  -  g-keto  esters  with  Dihaloalkanes  Dihaloalkenes  A have The  been  of  prepared  f i r s t  ketone  series  route  135  by  medium  ring  previously  r e p o r t e d  means  of  7  4  size  using  g-keto  several  involved  excess  cyclic  the  diethyl  esters  different  carboxy1 ation  carbonate  and  methods of  two  the equi-  0 (EtO) CO 2  C H 2  (37)  5  2 NaH  136  135  valents been 155  of  prepared was  1 5 7,  f i r s t  followed  hydrolysis  On with  sodium  one  and  hydride.  i n a  very  lengthy  converted by  a  treatment  equivalent  to  Michael  f i n a l l y  of  of  62  halogen  7  5  '  7  they 6  '  7  i t s corresponding type  reaction,  the  sodio  to  equal  containing  a  amounts compound  7  .  141  The  enamine  methyl  ketone compound  140.  acetoacetate  of  products  b i s g-keto were  also  expansion,  compound  mixture of  have  ring  give  l i t h i o  dihaloalkane,  approximately  the  r o u t e  hydrogenated  containing and  Alternatively,  ester  formed.  -  47  Scheme  If  only  formed has  one-half  exclusively  been  cyclic  found  3-keto  reaction when  equivalent  at  5 1  the  was  used  d i h a l o a l k a n e were  when  ester  be  obtained  a-carbon,  no  cyclic  as  the  or  6_2_  51  .  1,3-dibromopropane  could  1,4-dibromobutane  decane  X  the b i s 3-keto  that  ester  of  -  through  products  1,5-dibromopentane  alkylating  agent.  One  used,  i t  Although i t was  used,  a  intramolecular were or of  detected  1,10-dibromothe  reasons  48  Scheme  XI  62a B r ( C H  2  )  3  ( n=3  B r  55  Br(CH ) 2  141 c  n = 10  n  Br  62d  n = 10  )  4 9  for  the  absence  of  be  that  medium-sized  to  form  than  monohalo of  sodium  sign  of  lates that  hydride  with  the  equivalent  about  to  (n =  4) .  The  and  the  hours give  to  make  refluxing  methoxide  the  and  methanol due  nmr  (n  =  5)  to  the  a-carbon  r e a c t i v i t y  was  observed  of  the  the  methyl  the  was  followed  easily  by  a-carbon  thin  isolated.  compound  layer  While 141c  the  mixture  to  the  d i f f i c u l t y both  (n  no =  cyclic 10)  refluxed  spectrum  of  showed  complicated  i n  (n  5)  14 0 a  proceeded  absorption  at  addition,  4) 6  also  observed  this  i s  i n pro-  ring.  and  5)  sodium  methoxide  3.5  these  were  was  sodium  =  (14 0a)  with  13-membered (n  4)  ( 1 4 0 b ) (n =  product  with  forming  In  =  =  work.  methanol  we  f o r 14" h o u r s ,  compounds  C-2.  (n  fact  chromatography  Similarly,  141b  corre-  dianion  141a  2-oxocyc1ooctanecarboxy1 ate  at  the  i n refluxing  the  no  This  and  original  compound  at  hours,  observed.  i n  p u r i f i e d  equivalent  2 - o x o c y c l o h e p t a n e c a r b o x y 1a t e  monohalo  group  one  a-carbanion  methoxide  c y c l i z a t i o n  and  methine  with  d i f f i c u l t  i f the  of  monohalo  sodium  compound  a  Even  was  the  methanol.  treating  reflux  might  more  at  of  methyl  usually  compounds. to  reaction  f o r several  of  was  this  tetrahydrofuran  reaction  product  ring  allowed  treatment  12  smoothly  The  are  d i a l k y l a t i o n  one  bably  compounds  lack  with  when  ring  i n  on  by  in  C-alkylation  no  able  compounds  was  However,  for  cyclic  six-membered  compound  -  140b  assigned compounds  - 50  0 OCH-  OCH  NaOCH(  CH3OH  141 a  enolize low  CH ) 2  140a  n =5  140 b  n =5  140d  which  readily  absorption  to at  form 6  14 0 c  12.66  and  Scheme  0  and 5  12.34  n  140b  (38)  =4  have  a  very  respectively.  XII  P OCH'  140a  3  n  = 4  n  141b  0  OCH  140c  I40d  51  An the  O-cyclized  p u r i f i e d  valent and  of  monohalo  sodium  product  14 2  compound  141a  hydride  in  a  was  formed  (n  mixture  hexamethylphosphoramide.  Q  -  In  =  4)  of  by  treating  with  one  equi-  tetrahydrofuran  general  when  the  active  0 •O^CHC0 CH  T  NaH  2  3  (39)  THF/HMP 141a  methylene  n = 4  142  compounds  tion  competes  case  (a  involved  s i g n i f i c a n t l y  3-keto  ester  of  the  enol  Especially  in  the  presence  at  of  the  carbon  ambident  atom  The  for  product  Nmr  crude  of  the  14 2  enolate  could  product  is  oxygen  atom  showed  E_  the 142a  this  or  Z  rather  one  than  favoured.  bond  142b  predominantly  such  as  electronegative  usually  double  con-  high.  solvent  more  is  in  r e l a t i v e l y  the  anion)  be  as  O-alkyla-  equilibrium  aprotic  at  at  about  the  often  polar  ( i . e .  stereochemistry  O-cyclized  a  which  a l k y l a t i o n  anion  an  of  acidic,  C-alkylation,  in  tautomer  hexamethylphosphoramide,  r e l a t i v e l y  with  compound)  centration  atom  are  of  as  this  shown.  product.  5  2 -  C0 CH 2  U2a  The _E  E ( trans )  product isomer  3  was  U 2 b  characterized  (or trans) , which  hydrogen),  6  4.2  as  compound  showed  (-CH -0-),  6  2  < cis)  14 2 a ,  absorption  3.7  (-OCH )  at  and  3  i . e . the 5  6  5.25  3.2  (vinyl  (-CH 2  C = C-) .  The to  observed  be  due  the  as  i n compounds  conformation  more  of  conformations shaped, late  -9 5 the  with  a  most  form  of  stable  the  sion  w-shaped  was  9_6_.  14 3b 8  1  the  r e d E  8  2  .  isomer  Thus  the  142a.  though  i o n as free  conformer  w-shaped  termed  Since  could  isolated  anion  i n which  product  142  w-, the  moments to  the  possible  and  sickle-  u-shaped ligand  was  14 3 a ,  expected  solvent  solvate  appeared should  enof o r  dipole-dipole  aprotic  14 3 b  three  i n structure  strongly  conformer  due  bidentate  shown  polar  be  u-,  could  dipole  are  only  a  enolate  145b, a  as  product  of  also  There  serving  metal  minimized.  the  could  14 3 c  Even  of  cyclic  orientation  This  or  .  hexamethylphosphoramide cations,  i n the  intermediate.  capable  association  be  and  14 3 a ,  was  isomer  favourable  r e s p e c t i v e l y  143a  _E  the to  be  the to  repul-  such  as  metal  be trans  preferor  -  53  -  79,81  Scheme XIII  0_  0  R  143a  (  3  U3b  U-shaped)  R -  OCH  (W-shaped  ( CH ) Br 2  4  0_  OCH3  143c  )  ( sickle - shaped )  5 A  Reaction investigated. thesized  of  The  from  cis  dianion  cis  5_5  with  a  dihaloalkene  1,4-dich1 oro-2 -butene  1 , 4 - d i o 1 - 2 - b u t ene  OH  HO  -  NCS/  Me S 2  CH Cl 2  (144)  (>91  % ,  also  was  syn-  c i s );  in  C I  -CI  (40)  2  144  0  (145)  was  145  Q OCH,  +  55  Q  •ci  CI  145  0  Q  Q  OCH-  OCH-t-  (41) OCH-  CI 0 146  0 147  55  this  way,  we  were  2-butene  ( 14 5)  2-butene  ( 1 4 5)  isolated  products  alkylated mately  was bond  was  allowed were  compound  146  The  geometry  was  to  remain  observed. protons  approximately products  6  5.7  were  14 6  was  a  shown  have a  a  sodium  by  of  1 , 4 -d ich 1o ro dianion,  ester  bond  the  14 7  of  the  formed  This  very  was  of  the  the  interesting  double  spectrum  J  =  12  be  of  the  at  Hz.  thin  pure  refluxing could  approxi-  absorption  isolated  in  mono-  in  preparative  a-carbon  product  the  chlorbproduct,  nmr  constant by  methoxide  is  the  characteristic  separated  at  cis  isomerization  coupling  treatment  1,4-dichloro-  chloro-containing  double  was  only 14 8.  the  when  3-keto  This  achieved.  compound  bis  c i s  with  of  no  cyclization  ring  react  and  intramolecular The  a  about  easily  with  to  that  mixture  and  with  On  found  mainly  c i s,  which  chromatography. compound  obtain  It  amounts.  found  to  .  equal  o l e f i n i c  two  8 0  able  These layer  mono-chloro  methanol, easily  seven-membered because  one  might  56  expect  the  mono-chloro  displacement which  might  membered dicated  the  require  ring that  methylene at  reaction  to  ct-carbon  than  the  ease  in  the  group for  compound  to  that  formation geometry  at  the  C-8  was  carbanion  of  the  the  the of  14 8  was  The  presence  lowers  the  formed  this  seven-membered  double  bond  kept  f a r  apart  to  reach  C-8  was  from at  of  a l l ,  so  the  and  in  five-  double ring  this  the i t i s  only  the  anion  of  r e f l e c t  tran s ,  i n -  therefore,  this  may  seven-  c i s,  to  the  of  14 9  models  instead  ring  C-2  of  was  C-6;  strain  and  bond  closer  at  a l l y l i c  compound  molecular  was  group  an  formation  double  chloride  14 9.  undergo  £ive-membered  study  methine  the  would  than  cycloheptane  of  of  the  ring  of  the  A  compound  seven-membered  compared  If  ring  14 6  energy  geometry  next  ring  give  148.  group  membered a  to  compound  seven-membered  in  compound  less  i f the  -  the  bond as  the case.  methylene impossible methine  57 -  carbon  would  be  attacked  Dialkylation acetoacetate dianion  was  one-half  was f i r s t  hour  propylamide  at  was  Intramolecular methyl  also  0°C , added  the  the  anion  at  C-2.  y-carbon  of  the  investigated to  then to  i n the  react  one  with  regenerate  c y c l i z a t i o n  at  150a  some  and  was  (150b) used  15 0 b  as  were  b i s alkylation  could the  anion the  be  alkylating  obtained products.  Scheme XIV  of  methyl  way.  lithium at  The  y-carbon. to  Methyl  obtained  when Both  i n reasonable  yield  provides  give  3-oxo-3-  agent.  This  a  f o r  diiso-  the  y-carbon  (150a).  also  of  1,4-dibromobutane  the  occurred  dianion  following  equivalent  3-oxo-3-cyclopentylpropanoate  dibromopentane  with  at  allowed  cyc1ohexy1propanoate  pounds  by  1,5comalong  very  con-  -  venient and  method  15 0 b ,  this  when  procedure  sodium and  the  150  as  f o r the  ethoxide  or  resulting shown  preparation  compared methyl  58  with  or  ethyl  methoxide, product  i n Scheme  was  3  or C H 2  5  these  method  then  an  acyl  hydrolyzed  XV  compounds  r e p o r t e d  acetoacetate  XV.  Scheme  R = CH  the  of  to  7  8  .  150 In  i s treated halide give  was  wi add  compound  59  1 50  -  60  -  EXPERIMENTAL  General  Melting hot  stage  A l l  i r and  used  microscope, nmr  model 1601  nmr  The  700 cm  o n  using  were  the  6  scale  where  integrated  peak  The  with  areas after  an  using  lution  determinations mass  at  ionising  The  were  potential were  British  Columbia.  E.  Merck  and  was  the  grade  PF 54,  was  the  grade  finer  that  The  used  2  using  of  70  whilst than  200  are  as  that mesh  used  absorp-  coupling are  and  AEI  were  volts.  used  or  standard, constants,  were  ob-  high  reso-  MS-902  or  operated Elemental  Borda, was  H-  indicated  spectra  an  1  reported  internal  mass  Peter  layer  each  T-60  using  gel  the  model  electron  f o r thin  of  spectrometer,  s i l i c a  with  Varian  The  Mr.  Perkin-Elmer  The  instruments  by  each  band.  assignments  obtained Both  a  of  solvent  each  m u l t i p l i c i t y ,  mass  performed  of  beginning  positions  signal.  the  calibrated  a  Kofler  uncorrected.  assignment  either  a  solution,  after  proton  CH-4B  spectrometer.  microanalyses  The  on  are  teframethy1si1ane  and  Atlas  the  were  signal  each  tained  MS-50  and  on  i n  recorded  i n parentheses  indicated.  parentheses  an  were  recorded  points  at  polystyrene.  spectrometer.  except  in  of  determined  recorded  i n parentheses  indicated  spectra  HA-100  were  i r spectra  band  were  boiling  spectrophotometer,  - 1  i s  which  and  spectra  i s reported  spectrum.  t i  points,  University  obtained  from  chromatography ( t i c ) f o r column  ASTM.  chromatography  61  Tetrahydrofuran aluminium  Reaction  Methyl  of  hydride f i t t e d  for in  Sodio  a  a  was  100  50%  then  at  (9.0 was  (1.0  two  room  temperature.  from  yellow  quenched of  phases  with water  were  until  the  dried  over  removed of  resulting  1.0896  cap,  reaction  was an  added  5  ml  as  ten  dry  reaction  of  concentrated  with was  with  sulfate, under  product. reduced  to  The  sodium weakly  f i l t e r e d , reduced  pressure  for  (1.0  n i t r o -  g,  .0 22  was  2.4  s t i r r e d  M  solution  and  the  reac-  minutes.  Ethyl-  brought  to  changed  one-half acid  combined  hour,  plus organic  bicarbonate  and  It  and  solvents  the  (Kugel mm)  to  rohr)  caused  was  brine  basic.  pressure,  D i s t i l l a t i o n  with  mixture  hydrochloric  ether.  saturated  neutral  stirred  was  tetrahydrofuran  the  then  sodium  flask  a  color was  of  dropwise  of  Epoxides.  d i s t i l l e d  (2.64  The  of  g  mixture  additional  in  use.  with  flushed  acetoacetate  the  to  was  The  immediately  evaporation  o i l at  septum  lithium  (95)  was  magnesium  crude  (55)  solution  diluted  washed  prior  the  It  over  tetrahydrofuran  containing  mole)  mole)  and  of  acetate  n-Buty11ithium,  0.023  ml  mixture  by  .022  green. 5  and  C.  hours  Acetoacetate  Methyl  for  and  to  0°  refluxing  o i l dispersion).  stirred g,  added  i c e .  ml,  ml  s t i r r e r ,  dropwise  minutes  was  mineral  with  added  oxide  ml  magnetic  mixture  (64%)  by  of  Methyl  flask  hexane,  ml  Lithio  into  cooled  ene  5  minimum  50  with  ten  tion  a  Approximately  (as  and  mole)  for  dried  a-(tetrahydro-2-fury1idene)  d i r e c t l y  gen  hydride  was  give of the  then were  2.045 the product  g  -  to  sublime  on  the  were  i d e n t i f i e d  tate  (95_) , ir  (CDC1  and  5.35  mass 44(21),  3H, =  furylidene)  55(19),  in  the  (5.80  mineral  solution  in  (2.90  0.05  for  C  7  H  sodium  (C=C-C=0);  1  =  =  7.0  7.0  Hz, 2H,  Hz,  C=CH); 41(29),  42(26),  84(9),  43(32),  110(12),  C  59.15  H  7.04  found:  C  58.99  H  7.14  was  9_4  with  The  0.05  (32  ml,  which  (1.74  mixture  O  3  g,  mole),  by  bicarbonate  (2  sodium  were:  n-buty11ithium,  6.034  g  (69%)  of  was  oxalic  stirred ml),  for dried  as  methyl  (2.7  g),  as  1.6  a  propylene  i d e n t i f i e d mole)  50  procedure  hydride  gave  (SL6_)  a-(tetrahydro-2-  used  and  x  same  methyl  mole)  then  acetate  the  0.05  equivalent was  1 i d e n e)  reagents  o i l dispersion,  one  0  preparation of  g,  mole),  i  prepared  0.01  with  ( t , J  IH,  t h y 1- 2 - f ury  (9_5_) .  hexane  Compound  reaction  ace-  :  nmr.  the  crystals  (t, J  69(100),  (94),  treated  cm"  3.15  4.25  Hz,  0.4  3-oxo-7-hydroxy-heptanoate  was  ,  2  59(11),  compound  acetate  acetoacetate  g,  CH )  1640  ( r e l intensity)  a - ( t e t r a h y d r o - 5-me  57%  2H,  3  (t, J m/e  and  0CH ) ,  calculated  employed  a  white  142(24);  This  as  C=0)  (m,  (s,  spectrum  and  (ester  2.08  ppm  analysis  that  6  53(11),  111(63),  Methyl  )  3.65  2  2  3  The  C;  1710  3  bulb.  cc-(tetrahydro-2-furylidene)  methyl  39-41°  CH C=C),  CH 0)  d i s t i l l a t i n g  as  (CHC1 )  nmr 2H,  mp  62  of  by  not  methyl-  i t s i r  and  p u r i f i e d  acid 2h  oxide  in  C H C1  hours,  over  2  but  2  ;  washed  magnesium  M  63  sulfate, reduced  and  the  solvents  pressure  to  give  -  removed 1.4558  by  g  evaporation  (84%)  hydro-5-methy 1-2 -fury 1idene)  acetate  the  pressure  of  crude pure  product  compound  ir  (CHC1 )  CH )  ,  IH,  CH3CHO)  2  3.20  mass  8  H  1  2  0  3  (9_6_), b p  5  ( C DC 1 3)  2H,  :  reduced  1700  3  nmr  C  at  (ester  1.35  (m,  spectrum  43(17),  ppm  ( t , J  a)  high  amu,  low  124(20),  125(58),  Reaction  of  Lithio  oro-ethy1  Methyl  It  was  mineral  0.02  washed o i l .  cap,  flask  was  cooled  in  hydride, mole)  with After  tetrahydrofuran The  0.4  Hz,  Hz,  resolution 56(9),  127(9),  cm"  g  (46%)  (C=C-C=0);  1  CH 3) ,  3H,  (s,  156.0761  3H,  2.20  0CH ),  IH,  (m,  4.5  3  (m,  C = CH) ;  calculated  for  m/e; m/e  ( r e l  59(9),  140(5)  intensity)  69(100),  and  Acetoacetate  5-methoxy-3-oxopentanoate  g,  0.7196  of  82(15),  156(64).  (55)  with  ether  Sodium (1.0896  1640  3.70  Methyl  D i s t i l l a t i o n  gave  resolution  55(10),  a-(tetra-  mm);  7.0  =  found  101(32),  a-Ch1  =  2  53(6),  Sodio  J  methyl  (9_6) .  and  CH C=C),  b) 41(16),  C, ( 1 4 C=0)  (d,  2H,  and.5.2  156.0786  90°  of  under  (50  then ice  as  was  a  (120)  57%  weighed  mineral  o i l  into  oven  tetrahydrofuran decantation ml)  was  equipped and  of  flushed  a  with  to  dried  ml)  the  tetrahydrofuran, d i r e c t l y  magnetic  get  flask.  (10  d i s t i l l e d w i t h  an  dispersion,  r i d  into  the  s t i r r e r ,  nitrogen.  of  Methyl  fresh flask.  septum aceto-  -  64 -  acetate  ( 2 . 3 2 g , 0 . 0 2 m o l e ) was a d d e d  slurry,  and a f t e r  allowed  to stir  solution  the addition,  reaction  mixture  ten  minutes.  After  to the cooled  mixture  was a d d e d  dropwise t o  a n d i t was a l l o w e d t o s t i r  f o r another  addition  g, 0 . 0 2 m o l e ) ,  o f chloromethyl methyl  the temperature  was l o w e r e d  (ice  and a c e t o n e ) , and t h e r e a c t i o n  mixture  stir  f o r an a d d i t i o n a l  I t was t h e n  with  dilute  washed and  with  dried  by  sodium  b i c a r b o n a t e ( 2 x 50 m l ) , b r i n e  magnesium  150  o f crude  mg o f c o m p o u n d  (silica chloride were 91  methyl  and e t h y l  with  sulfate.  reduced  ether  5-methoxy-3-oxopentanoate  1 2 0 was p u r i f i e d  ether  ( 2 x 50 m l ) ,  The s o l v e n t s  pressure to give  g e l 2 0 0 m e s h ASTM) u s i n g  removed  mg  extracted  by column  a mixture  reduced  (50 ml)  were  removed  1.0586 g ( 1 2 0') . chromatography  o f carbon  ( 8 : 2 v/v) as e l u e n t .  by e v a p o r a t i o n under  t o -15°C  quenched  acid,  e v a p o r a t i o n under  (66%)  30 m i n u t e s .  ether  was a l l o w e d t o  acetic  over  was  n - B u t y l 1 i t h i u m , a s a 2.4 M  ( 9 . 0 m l , .02 m o l e )  the  (1.6102  the reaction  f o r ten minutes.  i n hexane  dropwise  The  tetra-  solvents  pressure to give  ( 4 0 % ) o f compound 1 2 0 ; ir  (CHC1 ) 3  1740 ( e s t e r  C = 0) , 1 7 1 5 (C = 0)  a n d 1 6 3 0 cm"  1  (enol); nmr  (CDCI3)  6 2.0-3.0  (m, 2 H ,  C H C H ) , 3.48 ( s , 2 H , C 0 C H C 0 ) , 3  3.75  2  ( s , 3H, C O O C H 3 )  2  a n d 5.2  ppm  0 C H C H C 0 ) , 3.35 2  3.35-3.80 (enol);  2  ( s , 3H,  (m, 2 H , C H 0 C H ) , 3  2  -  mass  spectrum  55(24),  59(9),  141(3),  142 ( 4 ) , a n d  analysis  Methyl  that  a  employed  57%  M  methyl  mineral  ether of  (12 3 ) . rohr)  85(13),  127(4),  129(6),  87(14),  160(2) ;  i n the  (120).  solution  (87%)  45(100),  for C y H i ^ :  C  52.49  H  7.55  found:  C  52.70  H  7.47  c o m p o u n d was  3-oxopentanoate 2.2  43(30),  (1_2_3)  5-methoxy-4-methy 1 - 3-oxopentanoate  oxopentanoate as  69(13),  -  (rel intensity)  calculated  This as  m/e  65  (0.5367  ir  give  reagents  o i l dispersion  g,  methyl  Purification to  The  (0.8667  g,  3  1740  the  same  methyl  used  g,  0.006 m o l e ) ,  sodium  hydride,  0.007 m o l e ) ,  methyl  n-butyllithium,  0.007 m o l e )  0.007 m o l e ) ;  procedure  5-methoxy-3-  were:  (0.3632  (3 m l ,  which  and gave  as  a  chloromethyl 1.0109  g  5-methoxy-4-methy1 - 3-oxopentanoate was  achieved  0.5324 g o f  (CHC1 )  by  preparation of  i n hexane  crude  prepared  1_2_3  (ester  by  distillation  ( 4 6 % ) , bp  C=0),  (Kugel  60°C,(11.0  1715  (C=0)  and  mm); 1630  cm  - 1  (enol) ; (CDC13)  nmr  6  1.16  0 C H C H ) , 3.1-3.5  (m,  2H,  (s,  and  3.75  2  C H 8  2H,  1 1 +  C0CH C0) 2  mass  spectrum:  0 :  1 74.0892  4  a) amu, b)  ( d , J=7.0 Hz, CH 0CH ), 3  ppm high  2  3H,  3.35  ( s , 3H,  CH ), 3  ( s , 3H,  2.0-3.0 0CH ), 3  (m,lH, 3.48  C00CH ); 3  resolution  found  174.0879  low  resolution  calculated  for  m/e; m/e  41(19),  43(15),  45(100),  57(19),  59(18),  85(10),  99(11),  101(48),  127(9),  142(20),  (rel intensity)  69(20), 143(10),  73(24), 156(6),  -  66  158(6)  and  Methyl  5-ethoxy-3-oxohexanoate  174 ( 2 ) .  This as  that  compound  employed  (12 0 ) .  were:  hydride,  sodium g,  mole), ml,  0.005  was  The  mole),  mole),  mole)  which  ir  =  5  (CDC1 ) 3  J  6.2  3H,  OCH3),  57%  methyl as  0.6846  1740  3  (d,  by  t h e same  o f methyl used  2.2  mineral  M  g(73%)  5-methoxy-3-  i n the  preparation  o i l dispersion  acetoacetate  a  procedure  ( 0 . 5 8 g,  solution ethyl  i n hexane  ether  of crude  0.005 (2.4  (0.54 g,  methyl  0.005  5-ethoxy-3-  ( 1 2 9) ;  (CHC 1 )  nmr  a  and a-ch1oroethy1  gave  oxohexanoate  prepared  reagents  as  n-buty11ithium,  0.005  (129)  i n the preparation  oxopentanoate  (0.27  -  Hz,  (ester  1.14  3H,  3.2-3.6  C = 0)  ( t ,J  =  and  1 720  cm  (C=0);  - 1  7.0  Hz,  3H,  OCH CH ),  CH CH) , 2.0-3.0  (m,  2H,  CH C0),  and  3.7-4.0  3  (m,  2H,  OCH CH ) 2  3  2  3  2  ppm  1.18  3.7 ( s , (m,  IH,  CHOEt) ; mass CgHigO^:  spectrum: 188.1049  a) amu, b)  41(24),  43(100),  73(33),  85(28),  127(32),  45(84), 99(33),  142(10),  high  resolution  calculated f o r  found  188.1052  m/e;  low  resolution  m/e  57(13), 101(16),  144(24),  59(13), 111(12),  157(11),  188(0.3).  .. p u r i f i e d by t i c f o r s p e c t r a l d a t a  ( r e l intensity)  69(55),  70(14),  115(31),  159(25),  170(7)  117(10), and  -  Methyl  5-niethoxy-3 -oxohexanoate  This as  that  compound  employed  in  ( 1 2 0) .  were:  hydride,  sodium  (1.0896  g,  mole),  gave  hexanoate  3.0882  2,-H,  g  as  a  57%  methyl a  6  3  1.1  0-CHCH C0),  (d,  3.30  2  mass  spectrum:  CsHntOi^:  1 74.0892  loses  hydrogen  M  preparation  dispersion (2.32  solution  C = 0) J  a) amu,  43(41),  59(100),  116(8),  117(8),  =  (s,  in  ether  g,  0.02  hexane  (1.88  methyl  and  6.0  3H,  5:76  high found  g,  (9.5  0.02  ml,  mole),  5 - methoxy-3-oxo-  1720  Hz,  3H,  0CH ),  ( s , 3H,  3  (s,  C00CH  resolution 1 73.0815  (C = 0 ) ;  - 1  CH -CH),  3.5  3  ppm  cm  3  2H,  2.0-3.0 C0CH C0 CH 2  69(29), 127(15),  );  c a 1 culat.ed. f o r  m/e;  (The  molecule  low  resolution  85(25),  m/e  ( r e l  intensity)  101(40),  110(8),  111(6),  143(8),  159(6),  168(3)  142(12),  173(1).  5-chloro-3-oxohexanoate  Chloroform hydrogen  chloride  solvent.  Methyl  2  readily.) b)  Methyl  o i l  procedure  5-methoxy-3-  the  acetoacetate  crude  (ester  -4:. 00'(m, III, OCHGH^:) , a n d  and  in  mineral  2.2  of  same  methyl  used  methyl  (89%)  1 740  (CDC1 )  one  the  (130)*;  nmr  3.20  reagent  a-ch1oroethy1  (CHC13)  ir  (m,  and  by  preparation of  The  mole),  (130)  prepared  n - b u t y 1 1 i t h i u r n , as  mole)  which  0.02  was  the  oxopentanoate  0.02  67  by  (50  ml)  direct  was  (154)  saturated  passage  of  with  the  5-ethoxy-3-oxohexanoate  gas  ( 1 2 9)  anhydrous through (0.55  g,  the  -  0.0029  mole)  the  reaction  two  hours.  ated  reduced  dissolved  mixture The  sodium  sulfate.  was  in  -  this  HCI/CHCI3  was  stirred  at  reaction  mixture  was  bicarbonate,  The  68  solvents  pressure  to  brine  were  give  and  room  0.5167  g  temperature  then  dried  removed  by  solution  washed over  of  for  with  satur-  magnesium  evaporation  (99%)  and  methyl  under 5-chloro-  * 3-oxohexanoate (CHCI3)  ir  (dd,  <5  1.5  J  7.0  J  =  =  2  Hz,  3  mass H  n  (ester  ( C D C 1 3)  2  7  1740  nmr  C0CH C0 CH ),  C  (154);  3.75  3.0  (s,  spectrum:  C10 :  43(98),  111(35),  amu,  Alkylation  Reaction  of  of  the  (1.0896 flask,  g, and  aluminium f i t t e d to  0°  0.02  was  hydride,  and  a  flushed  and  g-Keto  a  with  57%  (50  ml)  into  s t i r r e r ,  with  4.5  CH CHC1), 3  (s,  ppm  (m,  IH,  CH3CHCI);  for  m/e; m/e  ( r e l  intensity)  101(32),  110(37),  178(2).  esters  with  dianion  Dihaloalkanes  5_5_  mineral  o i l  into  oven-dried  was  3.0  2H,  calculated  69(100),  weighed  d i r e c t l y  magnetic  and  (C=0);  1  3.5  2  143(16)  as  3H,  resolution  of  cm"  178.0397  59(23),  tetrahydrofuran  with C  low  hydride,  Hz,  resolution  found  Dianion  1720  CH C=0),  3  142(52),  mole)  7.0  0CH )  1 ,4-dibromobutane  Sodium  and  2H,  high  44(51),  127(32),  =  Hz,  b) 41(81),  J  3H,  a)  178.0397  3  (d,  C=0)  an  dispersion  d i s t i l l e d  100  from  lithium  this  flask.  The  flask  septum  cap,  cooled  in  nitrogen.  Methyl  ml  was  i c e  acetoacetate  -  (2.32  g,  mixture  0.02 was  mole) s t i r r e d  69  was  added  for  ten  -  dropwise,  minutes  complete.  n-Butyllithium,  as  (9  mole)  dropwise  ml,  was  .02  allowed  addition  of  portion. an  The  nesium  with  sodium  evaporation  under  on  a  20  cm  mm,  ether  150 x  (7:3  20  cm  s i l i c a  v/v)  crude  mixture as  of  Two  these  ml),  give  (141a)  i n  dried were  8-bromo-3-oxooctanoate  (2 x  (CHC1 ) 3  1745  (ester  C=0)  and  3.2729  50  g  ml),  magby  of  was  achieved  chromatographed  g,  (0.0395  (141a)  ethyl  isolated  of  (0.0598  thickness  and  were  order  1720  x  removed  cm"  26%) g,  was  1  from  elution, and  15%).  character-  by : ir  for with  over  adsorbent  (62b)  one  s t i r  (2  tetrachloride  were,  in  ether  products was  the  quenched  ethyl  components  3,10-dioxododecanedioate  Methyl  (50  plate,  carbon  then  to  bicarbonate  to  which  mole)  allowed  was  hexane,  reaction  0.02  with  material  in  g,  these  coated  eluent. and  of  addition  before  solvents  pressure  8-bromo-5-oxooctanoate  dimethyl  The  P u r i f i c a t i o n  chromatography,  methyl  i s ed  reduced  the  a  solution  reaction  minutes  was  sodium  the  the  then  extracted  f i l t e r e d .  of  to  It  the  solution  ten  was  C.  saturated  mg  using  0°  chloride  and  products.  t i c :  this  at  acid,  M  (4.3186  one  hour  after  2.2  further  mixture  sulfate  by  a  reaction  washed  saturated  0.9  for  hydrochloric  ml),  crude  s t i r  added  1,4-dibromobutane  additional  dilute 50  to  was  a  and  (C=0);  70  nmr  ( C D C 13)  6  1.25-2.0  -  (m,  6H,  2.56  (t, J  =  7.0  Hz,  2H,  CH CO),  3.42  (t, J  =  6.2  Hz,  2H,  CH Br)  mass  spectrum  44(100),  55(9),  1 16 ( 2 0 ) ,  1 29 ( 2 ) ,  analysis Br  31.82  m/e  2  3.5  2  (s,  and  2  3.75  ( r e l intensity)  57(9),  59(6),  1 71 ( 1 1) ,  calculated  0  COCH CH CH CH CH Br),  69(16),  1 77 ( 5 ) , for  C  9  H  1  B r 0  :  31.98  ir  0  and  6  3  =  6.20  ppm  mass  1.1-1.8 Hz,  (s,  6H,  spectrum  59(33),  (ester  4H,  (m,  1720  8H,  2  101(8),  43(57), 113(11),  and  252 ( 1 ) ;  C  43.05  H  6.02  C  42.96  H  5.93  (62b)  was  charac-  m/e  69(22),  2  3.42  2  74(13),  181(13),  213(8),  calculated  83(17),  139(27), 255(8),  for  Ci  1,5-dibromopentane  procedure  employed  in  2  2  (s,  2  4H,  t +  H  the  used  2  2  C0CH C0) 2  2 2  0 : 5  reaction  this of  43(20),  97(45),  268(11)  with  in  41(20),  153(12),  found:  The  (C = 0 ) ;  1  C0CH CH CH CH CH CH C0),  ( r e l intensity)  172(10),  of  cm"  3  129(24),  that  3  0CH );  116(68),  analysis  C=0),  C0CH CH ),  111(22),  as  0CH );  41(16),  2 5 0 ( 1)  3,10-dioxododecanedi.oate  1 745  (CDC1 )  3.75  Reaction  3H,  19 . 1 3  (CHCI3)  (t, J  58(20),  (s,  by :  nmr 2.52  ppm  2  19 . 1 1  Dimethyl terized  2  C0CH C0),'  73(1),  3  2  2H,  1 79 ( 4 ) ,  5  2  40(44),  found: Br  2  C  101(37),  171(100),  and  C  286(1);  58.73 58.67  dianion  reaction  55(29),  H H  7.74 7.66  55  was  the  1,4-dibromobutane  same with  71  dianion 57%  5_5_.  The  mineral  (4.6  g,  in  (2.32  g,  0.02  hexane  (9  ml,  0.02  mole),  products. 150  mg  of  20  cm  x  20  using  a  mixture  cm  v/v)  as  crude  s i l i c a of  chromatography,  mole),  and  and  Two  g  of  products  was  plate,  were,  (141b)  as  mixture  was  and  were  order  (0.0459  (62c)  a  9-bromo-3-oxononaoate  2.2  M  crude by  a  thickness  from  elution,  25%)  0.9  mm,  ether  isolated  g,  of  on  ethyl  of  g,  (0.0344  a  achieved  adsorbent  in  a  methyl  chromatographed  components  these  mole),  as  1,5-dibromopentane  tetrachloride  3,11-dioxotridecanedioate  Methyl  4.1580  these  0.02  hydride,  n-butyllithium,  gave  coated  9-bromo-3-oxononaoate  g,  mole)  of  carbon  sodium  0.02  products  eluent.  were:  (1.0896  which  P u r i f i c a t i o n  t i c :  (7:3  used  o i l dispersion  acetoacetate solution  reagents  and  this  methyl  dimethyl  16%).  (141b)  was  characterised  by: ir  (CHC1 ) 3  nmr (t, 3.45  J  =  ( C D C 13) 7.0  (s,  Hz,  2H,  mass 58(40),  1745 6 2H,  (ester  1.2-2.0  2  2  59(21),  (m,  CH C0),  C0CH C0)  spectrum  and  m/e  69(12),  193(13),  264(0.1),  and  Br  29.90  0  calculated  cm"  (C=0);  1  C0CH (CH ) CH Br) , 2  (t, J ppm  74(17),  117(15),  30.14  8H,  1720  =  (s,  6.5  4  2.55  2  Hz,  2H,  CH Br), 2  0CH ); 3  43(72),  83(25),  127(9),  2  3H,  ( r e l intensity)  116(100),  Br  and  3.42  3.72  111(11),  analysis  C=0)  84(16),  129(8),  44(75),  55(56),  101(25),  185(25),  191(15),  266(0.1); for  C i  0  H i  :  C  45.30  H  6.46  found:  C  45.47  H  6.27  7  B r O  3  18.10;  72  Dimethyl characterised ir  2.5 3 . 75  ppm  =  7.0  (s ,  mass 69(28),  1 745  (CDC13)  ( t , J  6  4H,  OCH  spectrum  81(10),  3  m/e  1 720 COCH  3.45  2  (s,  ( r e l intensity)  84(22),  97(20),  267(16),  268(16)  cm"  (OO);  1  (CH )5CH CO) , 2  4H,  2  C0CH C0) ,  and  2  calculated  101(47),  167(76), and  for  43(35),  55(58),  111(43),  185(100),  59(48),  116(79),  195(20),  300(7); C  1  5  H  :  C  59.98  H  8.05  found:  C  59.87  H  8.05  1  1  +  0  6  31.96;  Reaction  of  1 , 1 0 - d i b r omo d e c a n e  The that  dianion  crude  used  in  5_5_.  reagents  The  g,  in  g,  0.02  hexane  0.02  tographed  150 on  mg a  in  (9  used  20  ml,  x  this  reaction  20  of  was  sodium  g,  mole)  gave of  0.02  and  7.0324 the of  s i l i c a  the  same  1,4-dibromobutane  were:  mixture cm  5JL  mole), as  a  as  methyl 2.2  a aceto-  M  1,10-dibromodecane g  of  a  products 6 2c  with  hydride,  n-butyllithium,  0.02  which  crude cm  dianion  (1.0896  P u r i f i c a t i o n of  with  reaction  mole),  mole),  products.  t i c :  the  o i l dispersion  (2.32  solution (5.996  procedure  employed  mineral  acetate  by  was  ) ;  227(18),  57%  and  10H,  2  153(25),  as  (m,  CH C0) ,  129(29),  analysis  C = 0)  1.2-1.8  Hz,  6H,  (ester  125(23),  0  (62c)  by:  (CHCI3)  nmr  3,11-dioxotridecanedioate  and  coated  mixture was  141c plate,  of  achieved was  chroma-  adsorbent  /s  -  thickness  0.9  and  ether  ethyl  isolated of  from  elution,  (0.0558 (62d) its  mm,  g,  (7:3  this  and  characterised ir  (CHC1  nmr (t,  J  =  J  6.5  C i  5  H  2  7  which  3  )  1 745 6  with  2H,  Hz,  2H,  CH Br)  2  and  2  spectrum  a)  334.1144  amu,  59(45),  85(33),  97(23),  101(26),  159(9), 195(8),  a  condenser  dropping to  the  236(5),  protected  funnel.  flask  oate  in  order  (141c)  comparison  authentic  50  of  compound.  (141c)  was  a of  2H,  (s,  resolution  ml  dry  sodium  (t,  OCH3);  calculated  for  m/e; ( r e l  intensity)  74(33),  129(41), 179(10),  and  3.42  2  m/e  2.5  2  C0CH C0) ,  3H,  71(40),  81(29),  130(16), 181(11),  83(31),  138(14), 183(11),  254(6).  (140a)  3-neck  calcium  (C=0);  1  2  334.1120  carboxylate  by  containing  2  resolution  252(3)  cm"  COCH (CH )9CH Br) ,  ppm  163(9),  100  ml  1720  (s,  116(100),  162(16),  oven-dried  3.42  69(45),  2-cyc1 oheptanone  An  were,  by  the  and  found  low  58(89),  Methyl  of  18H,  3.7  high  55(82),  193(6),  those  (m,  CH C0),  b)  149(11),  identified  C = 0)  1.0-1.6  Hz,  :  these  were  3,16-dioxooctadecanedioate  was  (ester  7.0  3  and  components  by:  3  B r 0  Two  tetrachloride  14-bromo-3-oxotetradecanoate  (CDC1 )  mass  carbon  eluent.  dimethyl  spectra  Methyl  as  of  14-bromo-3-oxotetradecan  and  nmr  mixture  chromatography,  methyl 39%)  a  v/v)  (0 . 0 3 4 1 g , 2 2 % )  i r  =  using  -  flask  chloride  methanol  was  (0.23  0.01  g,  was  f i t t e d  tube  and  added mole).  with a  10  ml  gradually When  -  sodium  has  and  methyl  8-bromo-3-oxooctanoate  to  of  the sodium  then It  mole  heated  was  then  (141a))  allowed  to cool  under  to  the solid,  ethyl with  ether water  nesium to  chloride tion  thickness  isolated  compound ir  3  1 735  ( C D C 1 3)  2  mass 4  this  carboxylate  CH C0),  3.5  6  110(37), 142 ( 4 3 )  was  55(73),  a) amu,  cm a  mg  (0.030  C = 0) (m,  high found  and 8H, and  low r e s o l u t i o n 74(31),  128(15),  pressure  plate,  o f carbon The  methyl  tetra-  top  frac-  2-cyclo-  on  bromo-  by: cm"  2  170.0944  mag-  product  1  (C = 0) ;  C0CH (CH )^CH), 3.7  washed  coated  73% base  1700  resolution  69(20),  was  added  with  over  of crude  eluent.  characterised  was  reduced  s i l i c a  g,  by  then  dried  was  hours.  removed  under  chromatography  mixture  was  mixture  (7:3 v / v ) as  113(27),  1 70 ( 6 0 ) .  layer  90  dropwise  extracted  litmus,  20  using  (ester  68(23),  111(6),  x  added  (25 ml)  was  removed  I H , COCHCO)  spectrum:  and  organic  cm  mm,  1.2-2.0  (m,  170.0943  5  (140a)  b) 41(33),  the product  to  was  62b  assuming  f o r 13  Water  product.  ether  from  (CHC1 )  a  was  reaction  and methanol  neutral  0.9  141a) which  nmr  C Hi 03:  on  ( 3 . 5 g,  and r e f l u x e d  The  o f crude  and e t h y l  heptanone  9  ml).  chromatographed  The  pressure.  and  i t was  g  (141a)  o f compound  o f methanol  and the solvent  1.9254  adsorbent  2H,  reduced  25  until  sulfate  give  was  (2 x  mixture  solution.  boiling  evaporation dissolve  crude  i n 2 ml  methoxide  to gentle  a  -  the  0.0052  dissolved,  74  2.5  2  ppm  ( s , 3H,  (m,  OCH3);  calculated f o r m/e; m/e  ( r e l  82(31),  138(100),  intensity) 87(25),  139(45),  75  Methyl  2-cyclooctanone  This as  that  (50  compound  employed  reagents ml)  used and  mg  (73%  of  crude  boxylate ir  (CDC13)  mass Ci4H  1  6  which 1 735  3  2  (4.2  compound  (CHC1 )  COCH ),  mixture  product  (140b)  nmr 2H,  on  3.38  (m,  IH, a)  43(32),  74 ( 1 0 0 ) ,  83 ( 2 3 ) ,  109(23),  124(27),  g,  assuming  0.005  of methyl  (m,  and  10H,  low  resolution  125(4),  59(19),  86 ( 1 8 ) ,  cm  mole  (141b)) .  give  0.050  g  car-  ( C = 0) ;  - 1  2  2.4  5  ppm  (s,  (m,  3H,.OCH ); 3  calculated  f o r  m/e; m/e  ( r e l intensity)  68(36),  87 ( 3 1 ) ,  152(63),  methanol 9-bromo-  of  (CH ) CH) ,  2  3.65  184.1098  55(92),  dry  methyl  to  The  by:  1700 C0CH  and  14 0 a .  2-cyclooctanone  resolution  found  84 ( 3 4 ) ,  and  chromatographed  C = 0)  procedure  mole),  6 2c  high  45(27),  0.01  compound  COCHCO)  amu,  same  compound  characterised  (ester  b) 41(52),  the  of  141b)  <5 1 . 0 - 2 . 0  184.1099  3  by  ( 0 . 2 3 g,  was  was  spectrum:  0 :  prepared  sodium  (141b)  crude  based  was  (140b)  i n the p r e p a r a t i o n of  were:  3-oxononaoate 150  carboxylate  68(36),  96 ( 2 7 ) ,  153(31),  69(44),  98 ( 2 3 ) ,  156(36),  and  184 ( 6 7 ) .  Methyl  2-oxa-cyc1ohepta-ethy1idene  Hexamethylphosphoramide oven-dried (as a  a  57%  magnetic  25  ml  mineral  flask  carboxy1 ate  (15  containing  0.027  o i ldispersion).  s t i r r e r ,  a  septum  cap  ml)  and  The  was g  of  flask  flushed  (142)  added  to  sodium was with  an  hydride  f i t t e d  with  nitrogen.  -  Methyl in  1  8-bromo-3-oxooctanoate  ml  of  reaction  was  then  mixture  diluted  over  magnesium  tion  under to  terised  cm"  (CHC1  OCH)  pentane, The  to  g,  dropwise s t i r  for  0.0005 to  1%  and  dried,  solvents  were  removed  g  compound  which  (59%)  It  water  was  of  14 2  solution.  hour.  with  P u r i f i c a t i o n  mole)  the  washed  pressure.  3  )  1 700  (unsaturated  ( t r i s u b s t i t u t e d  1  nmr 3.7  0.0502  added  allowed  sulfate.  (0.125  by  evapora-  achieved was  by  charac-  by:  ir 840  with  reduced  give  was  -  (141a)  t e t r a h y d r o f u r a n was  The  tic  76  (s,  ( C DC 13) 3H,  6  OCH ), 3  OC)  ester),  (OC)  and  ;  1.2-1.9  (m,  6H,  4.2  2H,  CH 0),  (m,  1630  ( C H  2  2  )  3  ) ,  and  3.2  5.25  (m, ppm  2H, (s,  CH C0), 2  IH,  ; mass  170.0943  spectrum: aim,  found  a)  high  170.0944 b)  low  resolution  resolution  43(36),  44(82),  56(100),  75(34),  83(32),  85(86),  87(51),  134(45),  139(77),  Reaction  of  Lithio  Sodio  for  C9H14O3:  m/e;  41(73),  129(30),  calcuated  60(28), 98(32),  140(61),  Methyl  m/e  ( r e l  intensity)  69(30), 102(28),  143(42),  Acetoacetate  and  70(86), 111(41), 170(66).  (55)  with  Dihaloalkene  Preparation  of  N-ch1 solved  in  400  c i s  1,4-dich1  orosuccinimide ml  of  anhydrous  oro-2-butene  (11.74  g,  methylene  0.088  mole)  chloride.  was  di s-  The  flask  77  was  f i t t e d  ice  and  with  a  flushed  with  0.088  mole)  white  precipitate  then and  was  cooled  to  solution The  white  utes,  (carbon  1,4-diol was  The  diluted  was  pentane  and  The  aqueous  (2  200  and  the  organic  cold  brine  then  washed  magnesium reduced  with  sulfate.  d i s t i l l e d  to  give  butene,  bp  cis  trans).  and  Alkylation cis  of  sodio  x  g  mm)  f o r an  were  crude  l i t h i o  400  of  minutes. colorless 70  min-  ml  o fi c e -  with  pentane  combined.  by  ml  resulting  clear  It  dried  was  over  evaporation  product  was  under  then  c i s 1,4-dich1oro-2 -  b p 7 2 - 7 5 ° C/4 0mm  methyl  i n 5 The  m l ) , and  removed  (72%) o f  ( l i t . ,  a  was  dry i c e )  additional  into  were  Intense  f o r 50  extracted  400  resulting  3.6104  128°C(760  acetoacetate  , mixtur e  (55)  of  with  1,4-dich1oro-2-butene  The that  The  s t i r r e d  layers (2  plus  i n g,  mixture  mole)  leaving  was  (5.456  minutes.  minutes.  poured  phase  Solvents  pressure.  few  0.040  and  cooled  sulfide  reaction  10  s t i r r e d  brine. ml)  over 0°C  cold x  g,  disappeared,  mixture with  The  (3.520  to  a  s t i r r e r ,  tetrachloride,  added  warmed  precipitate  solution.  over  observed.  -20°C  then  Methyl  dropwise  was  chloride was  cap, magnetic  nitrogen.  added  c i s 2-butene  methylene  septum  -  employed  dianion  5_5_.  procedure i n the The  used  i n this  reaction  reagents  of  i n this  reaction  was  the  1,4-dibromobutane p r e p a r a t i o n were:  same  as  with sodium  -  hydride, mole),  as  as  c i s  2.9913 was  57%  methyl  lithium, and  a  2.2  M  g  of  crude by  graphed  on  using  mixture  a  v/v)  a  t i c :  of  150  mg  carbon  and  Two  (CDC1 ) 3  C0CH C0),  3.75  2  and  5.5-5.8 mass  9  H  1  (9 0.02  crude  (146)  0.02  of  the  products  which  gave  products was  chromato-  thickness  and  with  mole)  ethyl  0.9  mm,  ether  i s o l a t e d  from  this  order  of  elution,  methyl  (0.0365  g,  18%)  dimethyl  (147)  (ester  n-butyl-  mole)  adsorbent  in  (146)  ml,  0.02  (0.0494 was  C=0),  g,  and  18%).  characterized  1720  (C = 0)  and  Methyl by:.  1660  cm"  1  CH = C H ) ; nmr  C  of  were,  3-oxo-8-chloro-6-octenoate  (cis  g,  components  these  1 745  (2.5  g,  mole),  tetrachloride  3,10-dioxo-6-dodecenedioate  (CHC13)  0.02  hexane  plate,  3-oxo-8-chloro-6-octenoate  ir  g,  (1.0896  P u r i f i c a t i o n  coated  eluent.  chromatography,  in  -butene  product.  s i l i c a  as  (2.32  s.olution  1,4-dich1oro-2  -  o i l dispersion  acetoacetate  a  achieved  (7:3  mineral  78  3  C10  3  5  (s,  3H,  (m,  2H,  spectrum:  a)  :  ppm  2.2-2.8  204.0553  0CH ), 3  55(16),  high  amu,  95 ( 1 3 ) ,  101 ( 7 9 ) ,  169(10)  and  59(20),  4.08  CH CH C0) , 2  (d,  2  J  resolution  found low  204.0540  resolution  67(42),  109 ( 1 3 ) ,  204 ( 1 ) .  4H,  =  6.5  3.45 Hz,  (s,  2H,  2H,  CH C1) 2  CH=CH);  b) 53(20),  (m,  69(100),  127 ( 1 3 ) ,  calculated  for  m/e; m/e  ( r e l  81(14),  136 ( 2 5 ) ,  intensity) 94(13),  137 ( 34) , 168 ( 37) ,  79  Dimethyl characterised ir (cis  (CHC1  was  by:  3  (CDC1  C0CH C0) , 2  )  1 740  (ester  OO),  1718  (OO)  and  1660  cm"  1  3)  3.75  6  2.18-2.8  (s,  3H,  (m,  0CH ),  8H,  and  3  CH CH C0), 2  5.4  ppm  (s,  3.45  2  ( t , J  =  4.0  4H, Hz,  CH=CH); mass  Cii H +  2  0  0 : 6  spectrum: 284.1259  a)  43(33),  57(10),  95(33),  101(61),  high  amu, b)  59(12),  low  109(13), 150(12),  179(11),  221(16),  252(11)  that  employed  reagents  used  methanol  (10  (146)  compound  (0.1383  methyl  in  were: ml) g,  and  the  was  0.0068  (0.1570  methyl  mole)  2-oxo-5-cycloheptene  91(16),  intensity) 94(29),  127(19),  159(12),  carboxylate  preparation  pure  ( r e l  129(13),  168(48),  169(100),  284(4).  prepared  sodium  m/e  116(20),  155(18),  for  m/e;  85(19),  113(12),  2-oxo-5 - eye 1 o h e p t e n e  This  resolution  and  calculated  284.1305  71(25),  137(45),  Methyl  resolution  found  136(12),  as  (14 7)  CH = C H ) ; nmr  2H,  3, 1 0 - d i o x o - 6 - d o d e c e n e d i o a t e  (148)  by  the  same  of  compound  g,  0.0068  procedure 14 0 a .  mole),  The dry  3-oxo-8-chloro-6-octenoate  which  gave  carboxylate  0.0460 ( 1 4 8)  g  (40%)  of  characterised  by: ir (cis  (CHCI3)  CH=CH);  1 735  (ester  0 0 ) ,  1700  ( 0 0 )  and  1660  cm"  1  80  nmr COCHCO),  (CDC1 )  6  3  -  2.0-2.8  3.72  (s,  3H,  0CH )  mass  spectrum:  (m,  and  3  4H,  5.78  CH )  ,  2  ppm  3.65  ( t , J  (m,  =  4.0  IH, Hz,  2H,  CH-CH);  C  9  H  1  2  0  3  :  168.0787  a)  amu,  high  found  168.0779  b) 32(100),  39(38),  66(22),  67(68),  101(21),  42(47),  low  79(24),  109(21),  calculated  53(22), 80(31),  110(21),  for  m/e;  resolution  44(28),  68(38),  108(23),  resolution  m/e  ( r e l  55(20),  59(23),  81(46),  136(95),  intensity)  84(34),  137(43)  and  168(60).  Dialkylation  at  the  y-carbon  of  the  Dianion  of  Methyl  Aceto-  acet ate.  Methyl  3 - o xo - 5 - c y c 1 o p e n t y 1  Sodium (1.0896 flask,  g,  0.02  and  aluminium  hydride,  with  to  and  0.02  a  was  for  10  Butyllithium mole) s t i r  was for  as  added a  was  weighed  10  o i l  into  oven-dried  ml)  into  after M  the  the  minutes  an  flask.  the  was  flask  was  in  ice (2.32  mixture  was  complete.  n-  (9.6  which  ml lithium  acetoacetate  hexane  the  100  from  cooled  reaction  reaction  before  The  cap,  addition in  dispersion,  d i s t i l l e d ,  Methyl  and  the  was  septum  solution to  (l_5_0_a_)  mineral  nitrogen.  dropwise  further  (50  dropwise,  minutes 2.2  57%  s t i r r e r ,  with  added  a  a  d i r e c t l y  magnetic  flushed  mole)  s t i r r e d  mole)  as  tetrahydrofuran  fitted 0°C  hydride,  propanoate  ml, was  addition  0.021 allowed  of  1,4-  to  g,  81  dibromobutane stirred  for  s t i r r i n g  It  one  3.08  lithium tion  (4.3186  at  ml  0°  mixture  was  with  were  to  give  by  t i c :  20  cm  mm,  150 20  using  (7:3  mg  cm a  v/v)  pound  15 0 a ir  CHCO),  mass 57(7),  added  for  an  crude crude  100%  product  under  0.0408  )  1 740  (CDC1 ) 3  (s,  6  2H,  spectrum  (ester  139(7)  and  acid,  extracted sodium Sol-  pressure was  achieved  thickness and  on  of  a 0.9  ethyl  based  ratio  on  ether  methyl  bromo-compound  propanoate  (15 0a) .  Com-  by: C = 0)  and  (m,  8H,  C0CH C0)  and  3.75  2  69(62),  (26%  the  1.05-2.0  m/e  minutes.  chromatographed  g  reac-  sulfate.  adsorbent  by  n-butylThe  P u r i f i c a t i o n  was  on  of  30  reduced  tetrachloride  characterised  ml  then  (made  saturated  magnesium  plate,  based  was  dropwise.  with  products.  coated  9.9  additional  washed  3-oxo-3-cyc1 openty1  was  reaction  hydrochloric  evaporation  give  3  was  over  to  analysis 0  dried  eluent  59(60),  129(86),  by  ml),  carbon  about  The  d i i s o p r o p y 1amide  dilute  of  (CHC1  3.5  50  and  of  methyl  nmr  with  s i l i c a  acetoacetate, of  stirred  x  of  hour)  mixture  as  141a)  g  lithium  1/2  (2  removed  mole).  diisopropylamine with  then  water  3.2887  x  of for  ether  0.02  and  quenched  bicarbonate, vents  C was  then  ethyl  hour  g,  1710  cm"  (CH ) ), 2  ppm  4  (s,  (C = 0 ) ;  1  3.0  (m,  3H,  0CH ) ;  ( r e l intensity)  41(64),  74(19),  97(100),  96(40),  IH,  3  43(50),  44(19),  101(73),  170(51);  calculated  for  C9H14O3:  C  63.51  H  8.29  found:  C  6 3.68  H  8.16  28.20  82  Methyl  3-oxo-3-cyclohexylpropanoate  This as  that  compound  employed  in  pentylpropanoate hydride, methyl (4.8  150 mg  0.01  mole  0°C  57%  of  (32%  the  preparation  of  methyl  The  mineral (1.16  reagents  on  used  were:  sodium  n- b u t y l 1 i t h i u m  0.01  mole),  (made  by  with  gave  product  (2.30  ml  1.7858  was  g  0.01  mole),  mole)  1.6678  of  crude  chromatographed  141b)  Compound  0.01  g,  of n-butyl1ithium  a c e t o a c e t a t e , about  (15 0 b ) .  g,  g,  s t i r r i n g  7.5  i n t e r m e d i a t e bromo-compound  cyclohexylpropanoate  3-oxo-3-cyclo-  g,  1,5-dibromopentane  methyl  procedure  (0.545  hour) , which crude  same  o i l dispersion  d i i s o p r o p y 1 amine  this  based  of  by  d i i s o p r o p y 1 amide  1/2  (15 0b)  prepared  (150a).  mole),  of  for  mg  ratio  a  was  the  acetoacetate  lithium  0.016 at  as  ml,  and  -  to  100% of  150b  products. give  based  methyl  was  50  on  the  3-oxo-3-  characterised  by: (CHC13)  ir nmr CHCO),  (CDC1 )  mass  106(20),  (s,  59(26),  (ester  1.8-2.0  2H,  spectrum  C = 0) (m,  C0CH C0), 2  m/e  and  10H, and  1710 ( C H  3.72  143(8)  calculated  74(22), and for  2  )  ppm  ( r e l intensity)  69(48),  129(33),  analysis 0  6  3  3.45  55(76),  1740  cm"  5  ) ,  (C = 0 ) ;  1  2.3-2.6  (s,  41(64),  83(100),  3H,  (m,  OCH ). 3  43(29),  100(25),  IH,  44(50),  101(35),  184(29); C[ QH\  ^0^:  C  65.19  H  8.75  C  65.19  H  8.70  26.05 found:  83  -  BIBLIOGRAPHY  1.  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RELATIVE INTENSITY  TkANSMITTANCE (%) 0.0  RELATIVE INTENSITY  25.0 1  50.0 1  :  "J5.Q 1  100.0 I  L  ID ON  m  - 97 -  n r  o  -  103  -  - 104  -  7  -  107  -  - 1 0 8 -  

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