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UBC Theses and Dissertations

Synthetic studies of indole alkaloids McKague, Allan Bruce 1967

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SYNTHETIC  STUDIES  OF I N D O L E  ALKALOIDS  by  ALLAN  BoScej  BRUCE MCKAGUE  M c M a s t e r U n i v e r s i t y , H a m i l t o n , O n t a r i o ^ , 1962  A. T H E S I S THE  SUBMITTED  IN PARTIAL  FULFILMENT  R E Q U I R E M E N T S FOR THE DEGREE DOCTOR  in  OF  OF  OF P H I LOS OPHY  the Department of Chemistry  We  accept t h i s  required  thesis  as c o n f o r m i n g  t o the  standard  THE U N I V E R S I T Y  OF B R I T I S H  January  s  196?  COLUMBIA  In p r e s e n t i n g  this thesis  i n p a r t i a l f u l f i l m e n t o f the r e q u i r e m e n t s  f o r an advanced degree a t t h e U n i v e r s i t y o f B r i t i s h Columbia, I agree that  che L i b r a r y s h a l l , make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e  study.  and  I f u r t h e r agree t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s  t h e s i s for* s c h o l a r l y purposes may be g r a n t e d by the Head o f my Department o r by h i s r e p r e s e n t a t i v e s .  I t i s understood t h a t  copying  or p u b l i c a t i o n o f t h i s t h e s i s f o r f i n a n c i a l g a i n s h a l l not be a l l o w e d w i t h o u t my w r i t t e n  permission,,  Department The U n i v e r s i t y o f B r i t i s h Vancouver 8, Canada Date  SP-e^r  22,  I  Columbia  ^  ii • Abstract  Two s y n t h e t i c a p p r o a c h e s t o t h e A s p i d o s p e r m a and I b o g a classes  of Indole  a l k a l o i d s are described,,  S e c t i o n A. d i s c u s s e s  a p o s s i b l e synthetic route  nine-membered r i n g a l k a l o i d acid  (75)  quebrachamine  (93a)°  t o y i e l d methyl nipecotate  p r e p a r a t i o n o f 3~carbomethoxy-3=°ethylpiperidine a l k y l a t i o n o f (77)  9  (77)= (67)  Attempted by  or o f i t s p -bromobenzamide d e r i v a t i v e  s u b s t i t u t e d p i p e r l d i n e (67)  another s y n t h e t i c sequence.  was t h e n p r e p a r e d  A l k y l a t i o n s of methyl  t o methyl 3~chloropropylethylcyanoacetate  reduction of the l a t t e r n i t r i l e allowed  (78)  by  cyanoacetate  (83)0  Catalytic  to the corresponding  amine  c y c l i z a t i o n t o 3-carbomethoxy=3-ethylpiperidine  Reaction (66)  (76)  unsuccessful„ The  led  Nicotinic  was r e d u c e d t o n i p e c o t i c a c i d h y d r o c h l o r i d e  w h i c h was e s t e r i f i e d  was  t o the  o f 67 w i t h  provided  2-carboethoxy-3-(^-chloroethyl)-indole  2~carboethoxy~3-(^-(3=carbomethoxy-3-ethyl-N-  piperidyl)-ethyl]-indole of the l a t t e r  (67)0  (68)„  Attempted a c y l o i n  condensation  t o a nine-membered r i n g compound (69)  was  u n s u c c e s s f u l and l e d o n l y t o h y d r o l y s i s products„ Section B describes  the f i r s t  total  synthesis of the nine-  membered r i n g compounds I4.00 and ljy3=> d i h y d r o c l e a v a m i n e and  (153)  5  i s o m e r i c w i t h quebrachamine„  Conversion  1^3-propanediol (106) t o t h e monobenzyl e t h e r treatment  with thionyl  c h l o r i d e provided  (107)  (152) of 2-ethyl followed  3-benzyloxy~2-ethyl-  iii p r o p y l c h l o r i d e (108)„  A l k y l a t i o n o f malonlc e s t e r w i t h the  latter  3»benzyloxy-2.-ethylpropylmalonate  afforded diethyl  (109 )°  A' s e c o n d a l k y l a t i o n o f 109 w i t h e t h y l b r o m o a c e t a t e y i e l d e d d i e t h y l 2~(2~benzyloxymethylbutyl)~2-carboethoxysuccinate Hydrolysis  decarboxylation  9  t r i e s t e r provided yield o yield  and r e - e s t e r i f i c a t i o n  of this (71a)  the s u b s t i t u t e d s u c c i n i c e s t e r  (113 )°  i n high  The s u c c i n i c es:ter (71a) was a l s o p r e p a r e d b u t i n l o w by h y d r o l y s i s , d e c a r b o x y l a t i o n (109)  the m a l o n l c e s t e r  and r e ~ e s t e r i f i c a t i o n o f  f o l l o w e d by a l k y l a t i o n w i t h e t h y l  iodoacetate,, Condensation of the s u c c i n i c e s t e r provided  (71a)  with  (130) w h i c h was r e d u c e d w i t h  the succinimide  to the t e r t i a r y  Mercuric  oxidation of the l a t t e r afforded a  of Isomeric benzyl  cyclized  ether  corresponding  72a „  compounds  Catalytic  aminoalcohol (73a)  quaternary  mesylate  chloride„  Reductive  9  amine  (131)  aluminum h y d r i d e acetate  i n high  debenzylation  with other  by t r e a t m e n t w i t h  mixture  t o the  methanesulfonyl  o f 73a w i t h s o d i u m i n l i q u i d  of the isomeric  s y n t h e t i c work provides  A s p i d o s p e r m a and I b o g a  yield„  y i e l d e d the  (llj-9) w h i c h was c o n v e r t e d  cleavage  lithium  one o f w h i c h was t h e d e s i r e d  ammonia y i e l d e d [LOW and l\./3- d i h y d r o c l e a v a m i n e The s y n t h e s i s  tryptamine  alkaloids,,  „  dihydrocleavamines a general  couplet!  e n t r y i n t o the  iv  Ta.ble o f C o n t e n t s Page T. i t l © Al'.t) S  t l  Table  Page S  O  O  O  O  C  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  c l C ' t o o o o o o o o o o o o o o o o o o o o o o o o o o t 5  o f Contents  List  O  Of FX^UPeS  o o o o o o o o o o o o o o o o o o o o  Acknowledgements Introductiono  o o o o o o o  O  <> o  0  o o o o o o o o o o o o o o o o o o  0  0 0  oo  0  o o o  o  0  0  0  0  o  0 0 0  e  I  s  i v V v i i  0  DlSCUSSlOnooooooooooooooooooooooooo  Exp  i i  o o 1  o „ <> <> o o  0 0  0  i  21  SeCt i o n  .Ai o  SeCtiOn  Booooooooooooooooooooo 2  ime  n  t  a  JL  Bibliography  O  O  o  O  O  o o o o o o o o o o o o o o o o o o o o  O  O  O  o o o o  O  0  O  0  O  0  O  O  O  o o o  O  0  O  O  O  O  O  o o o o o  O  0  O  O  O  O  o o o o  22  9*7  13 k-  V  Page  Figure O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  6  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  Lj- o o o  o  ^> o o0  6.  O  O  o  o  O  O  O  o  o  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  o  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O'  8 10  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  11  O  13  o a a o  O  O  O  O  O  O  O  O  O  O' O O O O  O O O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  Ik  8 0  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  16  9  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  17  O  10  o o o  11.  O"  18  0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  22  o o O O O O O O O O O O O O O O O O -  o e o o  OO'  12 • 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 13  oo  0000  O O O O O O  0 0 0 0 0 0 0 0 0 0  0 0 0 0 0 0 0 0 0 0 0 0 0  2LL  0 0 0 0 0 0 0 0  ILL.  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  15  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  o  o  o  o  o  o  O  16000 '  O  j  1  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  26  28 30  8  J - V - ' O O O O O O O O O O O O O O O O  o  o  o  o  o  o  1Q  20o  O O O O  O  21 „  O O O O  O O O O O O O O O O O O O O O O O O O O O O O '  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  O  k3 LL6  k7  - I - / O O O O O O O O O O O O O O O O O O O O O O O O O O O O  O  23  O  50  50  vi  List  of Figures  (Contldj  Figure 22  Page  o  o  o  o  o  o  o  o  o  o  o  o  o  o  23  o  o  o  ^  0  0  0  ^I  0  0  0  0  0  o  o  o  0  o  o  0  o  o  0  o  o  0  o  o  0  o  o  0  o  o  0  o  o  0  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  >  o  o  o  o  o  o  0  0  0  0  0  0  0  0  0  0  0  0  o  ^? 6  o- 6  0  0  2 . ^ 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  60  2 6 0 0 0 0 * 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  60  0 0 0 0 0 0 0 0 0  2  0 0 0 0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  CL 8  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  29  O  O  O  O  O  O  O  O  3 ^ o 0  31  o  0  o  0  o  0  o  0  o  0  o  0  O  o  0  O  o  0  O  o  0  O  O  O  O  O  63  ^  6  O  O  O  O  O  O  O  O  O  O  O  O  O  O  "  6  o  o  o  o  o  o  o  o  o  f  t  o  6 7  0  7"^-  o  o  o  o  o  o  o  o  o  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  3 2 . 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0  * Z 3  3 3  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  3 -|-  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  i L  6  3 3 *  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  ^  8  3^6  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  '7  9  3 ' 7 o  3  8  3 9  0  o  o  0  o  o o o o o o o o o o o o o o o o o o o o o o o o o o o > o »  0  o  0  o  0  o  0  o  0  o  0  o  0  o  0  o  0  o  0  8  2  ?  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  8  3  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  8  7  8  8  o  1-J- O  o  o  o  o  o  o  o  o  o  o  o  o  o  jL|_ X  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  0  o  o  0  0  o  0  o  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  0  t?  9  ^  vii  Acknowledgements  I w i s h t o e x p r e s s my s i n c e r e t h a n k s James P. K u t n e y f o r h i s c o n t i n u a l and h i s p r e v a i l i n g  to Dr.  encouragement  optimism during the course  o f my r e s e a r c h , I am a l s o v e r y g r a t e f u l constant assurance this  t o my w i f e f o r h e r  and f o r t h e p r e p a r a t i o n o f  manuscript. Financial  Council  a i d from the N a t i o n a l  o f Canada  i s greatly  Research  appreciated„  INTRODUCTION N a t u r e has p r o v i d e d  us w i t h a v a s t a r r a y o f o r g a n i c  compounds o f v a r y i n g  degrees of c o m p l e x i t y  l a r g e group of these  compounds, known as a l k a l o i d s , have b e e n  of c o n s i d e r a b l e science  i n t e r e s t , even s i n c e b e f o r e  i n t h e modern s e n s e o f t h e w o r d .  nitrogenous  bases t h a t occur  s y s t e m s , and t h i s  the stimulus  A l k a l o i d s are  C e r t a i n a l k a l o i d s have  l o n g b e e n known t o have c h a r a c t e r i s t i c  provided  the onset of  i n p l a n t s , u s u a l l y l o c a l i z e d In  the b a r k , r o o t s , seeds o r l e a v e s .  on b i o l o g i c a l  and i n t e r e s t „ A'  and p r o f o u n d e f f e c t s  observation  to t h e i r examination  u n d o u b t e d l y has i n ever  increasing  detail. The i n d o l e a l k a l o i d s c o n s t i t u t e a l a r g e c l a s s o f compounds ranging  i n complexity  psilocybine  from simple  ( 1 ) , the h a l l u c i n o g e n i c p r i n c i p l e  mushrooms, t o i n t r i c a t e strychnine  d e r i v a t i v e s s u c h as of Mexican  r i n g s y s t e m s such, as t h o s e  ( 2 ) , t h e w e l l known  found i n  poison.  I!  (2 ) ;  Approximately reported  isolated  s i x h u n d r e d i n d o l e a l k a l o i d s have b e e n t o date,  and s t r u c t u r a l  determinations  -2 carried of these  out on some t h r e e h u n d r e d o f them „ C h a r a c t e r i z a t i o n compounds, as w i t h most newer n a t u r a l p r o d u c t s  been i m m e n s e l y a i d e d by modern s c i e n t i f i c The  use  of such  analytical  tools  practice The has  as w i l l  be  illustrated  study of the  i n the  b i o s y n t h e s i s o f the  r e c e n t l y become a f i e l d  e x c l u s i v e l y by t h e use has The  s i m i l a r i t y t o the be  and  r e s e r p i n e ^ (8),,  vindolinine tryptophan  (11)  almost  precursors  (3)  has  a strong  now  structural  l o n g been f e l t molecule  (5),  ajmaline  (6),  i s decarboxylated  to tryptamine  0  O4),  serpentine (9)  as v i n d o l i n e - ^ A  c a t h a r a n t h i n e ^ (12 )„  to  b e e n shown by a  incorporated into, s e r o t o n i n  as w e l l  and  The  progress„  t r y p t o p h a n has  gramine  alkaloids  been d e t e r m i n e d  i n d o l e p o r t i o n of the  v a r i e t y o f w o r k e r s t o be  standard  interest,,  i n d o l e a l k a l o i d s , and has  Radioactively labelled  (1),  indole  of i n t e n s i f i e d  tryptophan  the p r e c u r s o r t o the  psilocybine  become  of r a d i o a c t i v e l y l a b e l l e d  l e d to remarkable amino a c i d  has  and  discussion section.  e l u c i d a t i o n o f b i o c h e m i c a l p a t h w a y s has  and  instrumentation,,  as mass s p e c t r o m e t r y  nuclear magnetic resonance spectroscopy  has  (7)  ibogaine^  s  (10)  It is felt  that  which then  undergoes  s  condensation r e a c t i o n s , In  c o n t r a s t to the  w i t h regard  g e n e r a l agreement of d i f f e r e n t  t o the " t r y p t o p h a n "  the b i o g e n e t i c o r i g i n  p o r t i o n o f the  of the "non-tryptophan"  ( t h i c k e n e d bonds I n s t r u c t u r e s - . , b e l o w ) , has  indole or  C O ^ X Q  been' t h e  workers alkaloids unit  subject  9  (14)  of c o n s i d e r a b l e  controversy.  proposed f o r t h i s the  last  year  A number o f t h e o r i e s have b e e n  p o r t i o n o f t h e alkaloids„  or two, however, provide  a m o n o t e r p e n e origin„  the  within  very strong evidence f o r  The m o n o t e r p e n e h y p o t h e s i s  was  originally  7  6  p r o p o s e d by Thomas  Results  and W e n k e r t ' a t a b o u t t h e same t i m e on  basis of s t r u c t u r a l  similarities  among many m o n o t e r p e n e s  and t h e Cc^io p o r t i o n o f t h e i n d o l e alkaloids„ Mevalonic a c i d ( 1 6 ) , an i n t e r m e d i a t e i n t e r p e n e b i o s y n t h e s i s , h a s been shown t o be i n c o r p o r a t e d i n t o t h e Cc;_io p o r t i o n o f vindoline ' * 8  9  1 0  (9),  reserpine  1 0  (8), serpentine * 8  1 2  (7),  8 catharanthine (12), 1,2-dehydroaspidospermidine (111) and ft -i-i ajmalicine ' (13)° G e r a n i o l (17), i t s e l f a monoterpene h a s b e e n shown t o be a. p r e c u r s o r o f a j m a l i c i n e , s e r p e n t i n e , TO 1 1 1 2 13 catharanthine and v i n d o l i n e ' . More r e c e n t l y , 9  9  Battersby  and c o - w o r k e r s ^ " h a v e i n c o r p o r a t e d  loganin ^  (15>)  1  1  into  t h e monoterpene  t h e a l k a l o i d s a j m a l i c i n e , v i n d o l i n e and  catharanthine. Degradation  of the l a b e l l e d  b i o g e n e t i c scheme shown i n F i g u r e 20 r e p r e s e n t  a l k a l o i d s has l e d t o t h e 1„  Structures 18,  19 and  t h e C]_Q u n i t s o f t h e C o r y n a n t h e , I b o g a and  =5-  Figure An a l t e r n a t e b i o g e n e t i c the  non-tryptophan p o r t i o n  1  scheme f o r t h e d e r i v a t i o n o f  o f t h e i n d o l e a l k a l o i d s was  pro-  p o s e d b y W e n k e r t ^ a t t h e same t i m e as h i s m o n o t e r p e n e  hypothesis  ( F i g u r e s 2$•  inter-  Rearrangement o f prephenic a c i d  mediate i n the b i o s y n t h e s i s of c o n f i g u r a t i o n hydration  discernible  of aromatic a c i d s , with  of the m i g r a t i n g  provides  (21),-an  pyruvate side chain,  I n t e r m e d i a t e 22 whose s t r u c t u r e  i n yohimbine  (23)°  retention then  is readily  Condensation of formaldehyde  -6-  Figure  2.  0  Incorporation  o f W e n k e r t s SPF 1  C o r y n a n t h e i n e and A j m a l i n e t y p e  unit  into  Alkaloids  with intermediate  22  f o l l o w e d by r i n g  r e t r o - a l d o l mechanism l e a d s (SPP)  (2l|),  unit  i n c o r p o r a t e d not (13)  alkaloids  important  a crucial  to a  intermediate which-could  also ajmaline  almost constant indole  W e n k e r t ' s SPF  unit  could  apply  oxidation  (2ii)  o f t h e SPF  unit with tryptamine  this  contains o f one  the  identical  c a r b o n atom, as  (18.),  The  carbon that  subsequent  at i t s appropriate  was  t o i n c l u d e the  ( F i g u r e 3)» envisaged  Aspidosperma  Condensation of the  as b e i n g  Michael  s t a t e s of o x i d a t i o n are and  and^Iboga-like The  f o l l o w e d by product  (31)  SPF  a  29°  f o r m e d whose  Mannich r e a c t i o n s l e a d t o the  bond m a k i n g and  If  piperiintra-  Aspidosperma  skeletons respectively. bond b r e a k i n g  the  d e r i v a t i o n o f t h e A s p i d o s p e r m a and  not  u n l i k e those  hypothesis  at  u n i t p r o p o s e d by W e n k e r t t h e r e f o r e  r e a c t i o n p r o v i d i n g the cleavage  of v a r i o u s  molecular (30)  that i t  undergoes o r d i n a r y o x i d a t i o n - r e d u c t i o n changes,  deines  An  0  Iboga groups of bases  retro-Michael  (26).  c o n f i g u r a t i o n observed  Wenkert extended h i s p r o p o s a l and  sarpagine  t o t h i s monoterpene i n t e r m e d i a t e  level  ajmalicine  a c i d p r o p o s a l was  i n the monoterpene h y p o t h e s i s  condensations  and  be  alkaloids.  s k e l e t o n , w i t h the e x c e p t i o n proposed  (25)  ( 6 ) ' and  f e a t u r e of the p r e p h e n i c  accounted f o r the  a  "seco-prephenate-formaldehyde"  only into corynantheine  but  carbon-15 i n t h e  o p e n i n g p o s s i b l y by  c u r r e n t l y proposed  described e a r l i e r  processes  Iboga a l k a l o i d s  i n the  (18-^19  depicted  and  are  monoterpene  20).  The  use  of  for  -8  Figure 3 «  _ 9 -  transannular cyclizationa  i n v o l v i n g iminium  salt  intermediates  i s p a r t i c u l a r l y i n t e r e s t i n g s i n c e K u t n e y and c o - w o r k e r s h a v e demonstrated  t h a t s u c h r e a c t i o n s a r e c h e m i c a l l y f e a s i b l e and  have l e d t o p a r t i a l type  skeletons.  syntheses  (See F i g u r e s i i and (32),  Dihydrocleavamine catharanthine ^ 1  o f t h e I b o g a and A s p i d o s p e r m a -  (33),  5°)  a v a i l a b l e from the a l k a l o i d  was c o n v e r t e d  o x i d a t i o n v i a the intermediate  by m e r c u r i c  iminium  (3H-)  salt  acetate to  s  1 Pi  7-ethyl-5~desethylaspidospermidine then  utilized  to convert (36)  quebrachamine  (35)»  This  r e a c t i o n was  the n a t u r a l l y o c c u r r i n g a l k a l o i d (-)-  t o t h e known a l k a l o i d  (+)~aspidospermidine  1 9  (37). A p p l i c a t i o n o f the t r a n s a n n u l a r  cyclization to  carbomethoxydihydrocleavamine.' provided  both  the Aspidosperma  20 and  Iboga-type skeletons  dihydrocleavamine transannular  (38)  .  O x i d a t i o n of carbomethoxy-  t o the iminium  c y c l i z a t i o n provided  salt  (39),  f o l l o w e d by (I4.O) -  pseudo-vincadifformine  a v a r i a t i o n o f the Aspidosperma skeleton,. A l t e r n a t e l y , oxidation  i n t h e same r e a c t i o n m i x t u r e ,  ( i l l ) f o l l o w e d by t r a n s a n n u l a r skeleton  c y c l i z a t i o n provided  salt  the Iboga  (IL2 ).  In the case of the iminium st  t o the Iminium  was e p i m e r i z e d  v i a t h e enamine  t h e known I b o g a a l k a l o i d dihydrocatharanthine  salt  (ii2)  (1+1), t h e e t h y l g r o u p (I4.3) w i t h t h e r e s u l t  c o r o n a r i d i n e and i t s were  obtained.  epimer  that  10  Figure it.  Transannular Cyclizations Providing the Aspidosperma  Skeleton  -11=  F i g , 5°  C o n v e r s i o n of Carbomethoxydihydrocleavamine the Aspidosperma  and  Iboga S k e l e t o n s  into  12The  transannular  biosynthetic  cyclization  and a v e r s a t i l e  synthetic entry  A s p i d o s p e r m a and I b o g a a l k a l o i d s . appropriate  nine-membered r i n g  dihydrocleavamine, exploit and  i n t o the  A synthesis  compounds l i k e  of the transannular  quebrachamine,  syntheses  cyclization  of large classes  a l k a l o i d s has appeared  would  t o the utmost  of a l k a l o i d s .  A- v a r i e t y o f a p p r o a c h e s t o t h e s y n t h e s i s  pertinent  of the  and c a r b o m e t h o x y d i h y d r o c l e a v a m i n e  the value  afford total  i s t h u s s e e n t o be a p o s s i b l e  of indole  I n t h e literature„. H o w e v e r , t h o s e  t o t h e work h e r e i n , t h a t  i s o f t h e A s p i d o s p e r m a and  Iboga groups, a r e r e l a t i v e l y few, A. r e c e n t route  synthesis  was r e p o r t e d  (Figure  6).  of desethylibogamine v i a a f a i r l y  by H u f f m a n  Epoxidation  mixture  s  followed  acid t o a mixture  (li7)»  reduced t o desethylibogamine t! Op  the N - i n d o l y l -  C y c l i z a t i o n of the t o s y l a t e t o the lactam  (LL8) w h i c h was  (IL9 ) i n h i g h  were t h e f i r s t  o f an I b o g a a l k a l o i d  gave a  C y c l i z a t i o n o f t h e amino a l c o h o l  i n d o l e r i n g gave d e s e t h y l i b o g a m i n e  et a l  (LLIJ.)  o f c i s and t r a n s  e p o x i d e , by h e a t i n g , p r o v i d e d  ethylisoquinuclidone  Buchi  a u s e f u l model  by r e a c t i o n w i t h t r y p t a m i n e  o f amino a l c o h o l s ,  (ii6) f r o m t h e t r a n s  and p r o v i d e s  of 3-cyclohexene-l-carboxylate  with metachloroperbenzoic epoxides  2 1  short  to date^»  to report  yield, the t o t a l  synthesis  The r e a c t i o n s e q u e n c e  ( a O The s y n t h e t i c w o r k c o n t a i n e d i n t h i s t h e s i s l e a d i n g t o d i h y d r o c l e a v a m i n e and s u b s e q u e n t l y t o t h e I b o g a a l k a l o i d s h a s now b e e n p u b l i s h e d i n J o u r n a l o f t h e A m e r i c a n C h e m i c a l S o c i e t y  88,  1+756  (1966).  -13-  involves via  the e l a b o r a t e  c o n s t r u c t i o n of the i s o q u i n u c l i d i n e  a c r u c i a l Hofmann r e a r r a n g e m e n t .  /3-indolylacetyl  Combination of 5 0 . w i t h '  c h l o r i d e gave t h e amide  ( 5 1 ) which  converted through the s e r i e s of r e a c t i o n s depicted to  (i)-ibogamine  ( 5 2 ) and  (-)-epiibogamine ( 5 3 ) •  (1+9)  H  Figure  6.  (50)  was i n F i g u r e ;7.  (b) D i c y c l o h e x y l c a r b o d i i m i d e  i n dimethyl  sulfoxide  -15Another recent entirely different ibogaine  i n v e s t i g a t i o n b y Due and F e t i z o n ^ u s i n g an a p p r o a c h l e d t o t h e s y n t h e s i s o f an  (51+)  analogue  S t o r k ^ reported 2  (57)  dl-aspidospermine F i g u r e 9-« prepared Ban  and i s shown i n F i g u r e 8 . the f i r s t  successful t o t a l synthesis of  and d l - q u e b r a c h a m l n e  Fischer indole cyclization phenylhydrazone  (36) as shown i n  of the a p p r o p r i a t e l y  (56) i s t h e k e y s t e p .  ^ and c o - w o r k e r s r e p o r t e d  More r e c e n t l y  a t o t a l synthesis of aspldospermine  again  u s i n g the F i s c h e r i n d o l e c y c l i z a t i o n of i n t e r m e d i a t e PA o f d i f f e r e n t stereochemistry„ Kuehne a l s o obtained the intermediate  5 5 which would l e a d  56 b u t  t o a s p l d o s p e r m i n e and  quebrachamine. A\n i n t e r e s t i n g r o u t e  t o t h e A s p i d o s p e r m a and  Hunteria 27  a l k a l o i d s has b e e n r e p o r t e d illustrated spermidine trifluoride  by B a r t o n  and H a r l e y - M a s o n  i n F i g u r e 10,. The f o r m a t i o n (60) f r o m t h e i n t e r m e d i a t e induced  o f ( X)-3  (5^)  -methylaspido-  i n v o l v e s a boron  rearrangement, while treatment  osmium t e t r o x i d e and s u b s e q u e n t c l e a v a g e  ' as  of,58 w i t h  of the d i o l  leads to  (-)-eburnamine (61). As d i s c u s s e d nine-membered r i n g  earlier,  intermediate  l a r g e number o f a l k a l o i d s , led  the t r a n s a n n u l a r provides  a synthetic route  Q u e b r a c h a m i n e and  t o the Aspidosperma s e r i e s w h i l e  c l e a v a m i n e l e d t o t h e I b o g a and V i n c a carbomethoxyquebrachamine  c y c l i z a t i o n of a  dihydrocleavamine  carbomethoxydibydroclasses*  (62) .could be e x p e c t e d  to a  Similarly to provide  -16-  F i g u r e Q,  -17COOCW  i) Pyrrol id in a. CH -CH CO=CHi 3  3) H a P ,  I  CH,0  OC\  3  ,) Pyrrolidine.  3  3) HO Ac,  HOflc  j-, Noc a  ) NHtf-OH  2  (55)  ( R = OCHi)  (57) F i g u r e ,9..  Total Synthesis Quebrachamine  o f d l - A . s p i d o s p e r m i n e and d l -  -18-  i) Pyrrol id in &  CtfO  COOCHs  -19(63)  vincadifformine  a naturally occurring alkaloid.  A s y n t h e s i s of quebrachamine, d i h y d r o c l e a v a m i n e corresponding desirable. cleavamine  carbomethoxy d e r i v a t i v e s  Furthermore,  and  t h e r e f o r e appeared  s i n c e q u e b r a c h a m i n e and  dihydro-  a r e e p i m e r i c , i t became o f I n t e r e s t t o e x a m i n e  w h e t h e r a s i m i l a r r o u t e t o these, compounds . t h e m s e l v e s a t t a i n a b l e , as s u c h synthesis In  their  of the  a route would c o n s t i t u t e a f a i r l y  aforementioned  a d d i t i o n to the  dihydrocleavamine  lies  intrinsic  was general  alkaloids. v a l u e o f the  i t s c o n s i d e r a t i o n as  means o f e n t r y t o d i m e r i c a l k a l o i d s ,  synthesis of  a possible eventual  some o f w h i c h a r e  well 29  known f o r t h e i r a n t i - l e u k e m i c p r o p e r t i e s . V i n b l a s t i n e and  vincristine^,  obtained  f r o m V i n c a r o s e a L i n n , have  r e c e n t l y b e e n shown by X - r a y a n a l y s i s ^ ! t o h a v e t h e s t r u c t u r e s 6I4. and  65 r e s p e c t i v e l y .  structural evidence  T h i s work c o n f i r m e d  a s s i g n m e n t b a s e d on c h e m i c a l  and  tion for this  most i m p o r t a n t l y p r o v i d e d molecule.  and  the  previous  spectroscopic  the a b s o l u t e c o n f i g u r a -  -20-  -21-  DISCUSSION Two  synthetic routes  were e x a m i n e d and  d i f f e r e n t modes o f g e n e r a t i o n membered r i n g . divided  For  i n t o two  appropriate The  of the  t h i s r e a s o n the  s e c t i o n s , A and  B,  i n i t i a l r o u t e w h i c h was  known a c y l o i n c o n d e n s a t i o n a c y l o i n condensation  available  ring closure.  become an This  i t i s appropriate  was  Involved*  and  the  f o r the  utilized  of the  few  12,  consisted  i n the- f i r s t  other workers  and  o f q u e b r a c h a m i n e by  to y i e l d  the  total  dihydrocleavamine,  T h i s method was synthesis out  of  the  be m e n t i o n e d  which  and o f the  nine-  five-  successful  and  dihydrocleavamine.  successful  d e s c r i b e d , as  of d i h y d r o c l e a v a m i n e  will  compounds  chemistry  c o n c u r r e n t l y i n our  second route  the  desired  i n the g e n e r a t i o n  which i n v o l v e d the  successful conversion  ring.  r i n g s , where non-bonded  o f a bond common t o a f u s e d  (73a )„  well  p r a c t i c a b l e methods  second r o u t e , a p p l i e d to dihydrocleavamine i n Figure  compound  the  nine-membered  t o m e n t i o n some o f the  A d d i t i o n a l work c a r r i e d by  been  Important c o n s i d e r a t i o n during  six-membered r i n g  resulted  designed  11  medium s i z e  membered r i n g b y c l e a v a g e and  nine-  each d e a l i n g w i t h  being  method f a i l e d  but  depicted  d i s c u s s i o n has  t o f o r m the i s one  for generating  interactions  The  a l l important  entirely  s y n t h e t i c approach.  quebrachamine i s o u t l i n e d In F i g u r e  The  involved  a t the  into end  laboratory  synthesis w e l l as  a  carbomethoxyof the d i s c u s s i o n .  -22 Section A The  synthesis  condensation  was  d i e s t e r (68)  o f the  accomplished  t h r o u g h the  2~carboethoxy-3(/2-chloroethyl)-indole 3-ethylpiperidine piperidine was  (67)  (67)°  The  itself  procedures of the (77)  dlsubstituted  1-4  (66)  w o u l d be  ^coo  /  at CU0OC  3-carbomethoxy-  Initially i t standard  3-carbometh.oxy p i p e r i d i n e  possible, alkylation  of  f a i r l y w e l l known  \  \ /  of  of the s u b s t i t u t e d  \  c 1  with  approaches.  obtainable  a c e t i c esters being  /  coupling  c a r b o n a l k y l a t i o n by  easily 13)  (see F i g u r e  (66)  synthesis  i n v o l v e d two  thought that a simple  desired for acyloin-  N  (68.)  (67)  Figure  11  32  33 3  -23=  (70)  (73a) (73b)  (71a) (71b)  R = OEt  (72a)  R = H  R = COOCH3  (72b)  R = COOCH  R = H  f< (7l+a ) R = (71+b) R =  R = COOCH3  Figure Nicotinic acid hydrochloride  12  (75>) was r e d u c e d  (76) b y t h e r e p o r t e d  (Adams c a t a l y s t ) i n h y d r o c h l o r i c  to nipecotic acid  method o f p l a t i n u m  aci  a f t e r d r y i n g , e x h i b i t e d no a b s o r p t i o n region  and was t h e r e f o r e  m e t h a n o l and h y d r o c h l o r i c  esterified acid-^.  n i p e c o t a t e - ^ (77) was t h u s p r e p a r e d nicotinic  acid.  H COOCH3  The c r u d e  oxide  product  i n the u l t r a v i o l e t  directly with The d e s i r e d  absolute  methyl  i n .35$ o v e r a l l y i e l d  from  ,coo  .CCOH  H |4 a / p f O j  V  (75)  (76)  (77)  COCCH?  coocl-ts Br  Et-  EH  y  (67)  (78)  Figure The  ) o  piperidine  ester  13  (77) e x h i b i t e d  a sharp  p r o t o n s i n g l e t i n t h e NMR s p e c t r u m at"/"" 6,30 methoxyl protons. supported  a t 1725  absorption  at  absorption  c m ~ l due t o t h e e s t e r  3250  cm"  (NH), E l e m e n t a l a n a l y s i s  1  (78) c o m p l e t e d  band i n t h e  g r o u p and a b r o a d  p a r e n t s u b s t a n c e and on i t s c r y s t a l l i n e derivative  due t o t h e  The s t r u c t u r a l a s s i g n m e n t was a l s o  by t h e p r e s e n c e o f a s t r o n g  infrared  three  on t h e  p-bromobenzamide  the c h a r a c t e r i z a t i o n of this  c ompound. I t was h o p e d t h a t the -X-carbon w i t h o u t  this ester  a l k y l a t i o n on n i t r o g e n  i r r e v e r s i b l y generating followed  (77) c o u l d  by t h e a d d i t i o n  the carbanion w i t h of e t h y l  iodide  0  be a l k y l a t e d a t by f i r s t  sodium Addition  hydride, of the  -25e s t e r t o sodium h y d r i d e and  i n toluene  c a u s e d t h e e v o l u t i o n o f gas  subsequent r e a c t i o n w i t h e t h y l  i o d i d e was e v i d e n t b y  t h e f o r m a t i o n o f a p a l e y e l l o w precipitate„ of the product which,  by d i s t i l l a t i o n  h o w e v e r , was i n d i c a t e d  N - e t h y l compound. by t h e p r e s e n c e and  of the methyl  by i t s NMR s p e c t r u m t o be t h e o f a n e t h y l g r o u p was shown  of a three proton  triplet  at; 7"8.'95 (-CHgCH-^)  (-CH^CR^). The l o w c h e m i c a l  and m e t h y l e n e p r o t o n s  N - a l k y l a t i o n had o c c u r r e d verified  gave a c l e a r c o l o r l e s s o i l  The p r e s e n c e  a q u a r t e t at7'7°6  Purification  and t h i s  s t r o n g l y suggested was  Since  that  subsequently  when t h e d e s i r e d compound was p r e p a r e d  route described  shift  by a n o t h e r  later.  i t was f e l t  t h a t t h e d e s i r e d e s t e r a n i o n had  been formed s u c c e s s f u l l y w i t h , sodium h y d r i d e , p r e v e n t i o n o f N - a l k y l a t i o n c o u l d be a c c o m p l i s h e d basic  by c o n v e r s i o n  amine t o a n e u t r a l amide d e r i v a t i v e .  hydrolysis  could then  of the  Subsequent  lead t o the desired piperidine  (67)  as shown i n F i g u r e II4.. The  p-bromobenzamide d e r i v a t i v e  techniques  (p-bromobenzoylchloride  beautifully crystalline latter  solid.  showed t h e p r e s e n c e  an amide band a t 1630  (3200 - 3500 cm'M  cm  - 1  region„  m e t h o x y l g r o u p as a s h a r p  (78) p r e p a r e d  by s t a n d a r d  I n p y r i d i n e ) was a  The i n f r a r e d  spectrum of the  o f an e s t e r c a r b o n y l a t 1730  cm"'-,  and no a b s o r p t i o n i n t h e NH The NMR s p e c t r u m showed t h e singlet  a t 7^6,3  and t h e a r o m a t i c  _26region  contained a pair  expected  of doublets  at7?'2.LL  f o r two n o n - e q u i v a l e n t p a i r s  a n d 7^2</7-. a s  o f protons,,  ,Cc?ocH_j fae.r,2.ayj c^h/on'cJe 14  (78)  (77)  E M  ,COOC.H-s J ^Ef -|\r (67) H-  Figure Iii  Refluxing (10%  excess)  the  slow  The  reaction  and e t h y l  evolution  compound  as  being  identified with  iodide  however  chromatography  comparison  o f t h e amide  o f gas and  product  chromatography Alumina  a mixture  (10%  was  initially  an a u t h e n t i c  excess)  sodium  indicated-  four  a.white  p-bromobenzoate sample  of a  by t h i n  of at least yielded  (mixed  hydride  i n toluene  the p r e c i p i t a t i o n  a mixture  as m e t h y l  (78),  caused solid  0  layer' compounds„  crystalline  (80)  melting  by point  -27and  superimposable  infrared  spectra).  c o n s i s t e n t l y f o r m e d i n ILO t o 50$  yield.  graphy a l s o e v e n t u a l l y l e d t o the a more p o l a r amorphous s o l i d . not the  d e s i r e d compound  the o l e f i n i c w.as ;  r e g i o n o f t h e NMR  difficult  f o r the  as e v i d e n c e d  integrating  aromatic  r e g i o n at/2.lL  infrared  s t a r t i n g amide 1630 due it  cm" o 1  minor o i l which  and 7^2'. 7 and  s p e c t r u m was (78)  and  I m p r a c t i c a b l e as  proton  The  identical  e v i d e n t as a s i n g l e t  and  low  y i e l d w h i c h a l s o made  obtained / as"mentioned  The  spectrum.  a t 7^6.3  and  Integral  being present  E s t e r and  as a  triplet,,  A methoxyl f u n c t i o n  two  aromatic  i n t h e 6.5  h o w e v e r i n d i c a t e d a number o f p r o t o n s desired product.  and  1  a synthetic Intermediate.  i n t h e NMR  were a g a i n p r e s e n t .  cm"  the  completely characterized  9  was  region  to that of  e x h i b i t e d a b s o r p t i o n a t 1725  amorphous s o l i d w h i c h was  a t 7^8.9  i n the  carbonyl  above :again" showed • an" e t h y l g r o u p . ' l i k e l y p r e s e n t appeared  Two  were p r e s e n t  low.  not  had  a methoxyl peak appeared  almost  T h i s compound was  spectral  Alkylation  of a three  f o r four protons  to separation d i f f i c u l t i e s  The  obviously  o f an e t h y l g r o u p .  a t 1^6i3-although i t s i n t e g r a l was of the  The  desired product,  by t h e p r e s e n c e  doublets  and  i t exhibited absorption in  spectrum.  a t 7/9'.2 5 f o r t h e m e t h y l  triplet  m a j o r o i l was  oils  t o p u r i f y appeared t o have the g e n e r a l  features expected occurred  as  was  C a r e f u l chromato-  s e p a r a t i o n o f two  The  (79)  T h i s compound  doublets  t o 7^8.5  f a r i n excess  region of  the  amide g r o u p s were i n d i c a t e d as  by a b s o r p t i o n i n t h e  infrared  a t 1725  cm~l  and  -28I63O c m " . 1  be a d i m e r i c  The p o l a r n a t u r e o f t h i s  m a t e r i a l suggested  or polymeric substance  and t h e f o r m a t i o n o f  i t may-  m e t h y l p - b r o m o b e n z o a t e i n t h e a b s e n c e o f any e x t e r n a l s o u r c e of methoxide are  indicates that intermolecular  not u n l i k e l y .  c a n be r a t i o n a l i z e d  The f o r m a t i o n o f m e t h y l  condensations p-bromobenzoate  by the t y p e o f mechanism i n d i c a t e d i n  Figure  15.  direct  n u c l e o p h i l i c d i s p l a c e m e n t by h y d r i d e ion„  A l t e r n a t e l y the methoxide  8r  Figure  15  could  arise  from  -29Because the  o f the d i f f i c u l t i e s  p r o d u c t s were n o t "examined  synthesis  o f the s u b s t i t u t e d  e n c o u n t e r e d i n t h e above  route,  f u r t h e r and a n o t h e r method o f  piperidine  (67) was e x a m i n e d .  a p p r o a c h p r o v e d t o be s u c c e s s f u l and w i l l be d i s c u s s e d  This  presently,  A p a r t i c u l a r l y convenient synthesis from cyanoacetic ester is  shown i n F i g u r e 16 and h a d p r e v i o u s l y been r e p o r t e d  p r e p a r a t i o n o f 3-carboethoxy-3-phenylpiperidine^7(86), piperidine ring of  i s generated i n the f i n a l  f o r the The  step through reduction  a n i t r i l e group f o l l o w e d by c y c l i z a t i o n  o f the  resulting  chloroamine, Alkylation  o f m e t h y l c y a n o a c e t a t e (8l) w i t h e t h y l  u s i n g sodium methoxide upon d i s t i l l a t i o n . chromatography indicated  a clear colorless o i l  T h i s r e a c t i o n p r o d u c t was shown b y gas  t o be a. m i x t u r e o f t h r e e components and NMR  the p r e s e n c e o f two d i f f e r e n t t r i p l e t  a r o u n d 7<90  Fractional distillation  (25 t o 30 t h e o r e t i c a l w h i c h had a c o m b i n e d of  as b a s e ^ y i e l d e d  iodide  on a s p i n n i n g band  plates) failed b o i l i n g range  methyl  resonances column  t o s e p a r a t e t h e components  of four degrees.  Separation  t h e m a j o r component w h i c h was e s t i m a t e d as 60% o f t h e m i x t u r e  was  p e r f o r m e d b y gas c h r o m a t o g r a p h y  was  easily  identified  i t s NMR s p e c t r u m .  at7^8;9-  (-CH2GH3)  as t h e d e s i r e d  on a n A p i e z o n J c o l u m n . alkylated  compound  T h i s s p e c t r u m showed a t h r e e p r o t o n a n d a one p r o t o n t r i p l e t  (82) b y triplet  at?'6.5'5 f o r t h e  hydrogen  a t o m on t h e c a r b o n a t e ithe c a r b o m e t h o x y - and. c y a n o  groups.  The m e t h o x y l p r o t o n s a p p e a r e d  as a s h a r p t h r e e  This  -30 proton  singlet  at?"6.25.  The p r e s e n c e o f t h e s e f u n c t i o n a l  g r o u p s was a l s o s u p p o r t e d b y n i t r i l e and  ester absorption  a t 171+0  at  2230 c i n " ^  cm~^ i n t h e i n f r a r e d s p e c t r u m . COOCH*,  C0QCH1  CH I  absorption  :  3  =»,.  .  —=*  cN  (81)  (82) 000c w  (83) COOCHj  3  Ha/pd  (814.)  (67)  11  (4 (86)  (85) Figure  It is  i s w e l l known t h a t  an i n t e r f e r i n g  with  The was  esters  smallest  separated  cyanoacetate  16  d i a l k y l a t i o n of cyanoacetic  s i d e r e a c t i o n and i s more s e r i o u s  m a l o n i c e s t e r s 33.  of c y a n o a c e t i c  \  This  i s due t o t h e g r e a t e r  as compared t o m a l o n i c  component o f t h e m i x t u r e ,  similarly  esters  here  than  acidity  esters, approximately  and shown t o be u n r e a c t e d  ( i n f r a r e d s p e c t r u m and t h i n l a y e r  10%,  methyl  chromatography)  -31c o m p o n e n t , r e p r e s e n t i n g a b o u t 30$ was  The r e m a i n i n g separated and  i n s m a l l q u a n t i t i e s and a g a i n  n i t r i l e absorption  spectrum of the i n i t i a l triplet  This  cyanoacetic  mixture  compound was  e s t e r as t h e NMR  h a d i n d i c a t e d two d i f f e r e n t .  methyl groups ,  The p r e s e n c e o f a m i x t u r e this  shown t o h a v e e s t e r  i n the i n f r a r e d .  undoubtedly the d i a l k y l a t e d  inseparable  by d i s t i l l a t i o n a t  p o i n t d i d n o t cause any p a r t i c u l a r d i f f i c u l t y  alkylated  again w i t h bromochloropropane,  l a r g e r g r o u p now a l l o w e d  dialkylated  presence of methyl d i e t h y l c y a n o a c e t a t e it  c o u l d n o t be a l k y l a t e d a g a i n  boiling  The i n t r o d u c t i o n o f  s e p a r a t i o n of the desired  (83) b y f r a c t i o n a l  compound  i n the  (82) was t o be  subsequent step s i n c e methyl e t h y l c y a n o a c e t a t e  this  also  distillation.  d i d not i n t e r f e r e  and h a d a s i g n i f i c a n t l y  since lower  point than the d e s i r e d methyl 3 - c h l o r o p r o p y l e t h y l -  cyanoacetate  (83),  The p r e s e n c e o f u n r e a c t e d  a c e t a t e however c o u l d  interfere  methyl  i f monoalkylated  f r o m t h e d e s i r e d one m e r e l y b y an e t h y l g r o u p , an e x c e s s o f a l k y l h a l i d e was u s e d a t t h i s dialkylation  of the methyl cyanoacetate  compound w o u l d c o n t a i n two l a r g e ' a l k y l boiling  technique  from methyl  Therefore,  point to effect  g r o u p s and be Indeed  cyanoacetate.  considerably  alkylation  w i t h bromochloropropane37 u s i n g  l e d t o the preparation  differ  since the r e s u l t i n g  t h a n t h e d e s i r e d compound.  o f t h e above m i x t u r e  cyano-  with  b r o m o c h l o r o p r o p a n e s i n c e t h e r e s u l t i n g compound w o u l d  higher  The  o f 83 i n 2>0% o v e r a l l  this yield  -32The  NMR  spectrum  good a g r e e m e n t w i t h t h e a s s i g n e d presence  revealed  the methyl  distorted  two  proton  methylene adjacent indicated at  2220  protons  as a t h r e e p r o t o n  triplet  contamination  by  sample p r e p a r e d  by  of the  t o 60%)  nitrile  and  (83)  peak  an  f r e e of analytical  Beilstein  separated  from  was  (8I4.)  salt  (67)  t h e n x^as c o n v e r t e d alkali.  hydrochloric acid  The  w h i c h was  as  followed  the d e s i r e d p i p e r i d i n e to  theoretical  t h e amine was  f o r a p e r i o d o f a few amine  t o t h e amine w i t h a l a r g e  initial  amount o f h y d r o g e n nitrile  (usually  accomplished  product  made b a s i c and  i t s hydrochloride salt.  by  of r e d u c t i o n then  allowed  days o r warmed t o p r o d u c e  t o t h e f r e e b a s e by  (67)°  completion,  Recovery of the unreacted  extraction.  with  spectrum  of t h i s m a t e r i a l  virtually  products  d i d n o t go  of the  preferential  cyclic  t o t h e •••  a nitrile  examination  with alkali-^? provided  b e i n g consumed.  stand  and  1  A  infrared  I n t h i s manner gave a p o s i t i v e  r e d u c t i o n of the n i t r i l e  the  cm"  The  t h a t i t was  other a l k y l a t i o n  u s u a l l y o n l y ILO t o $0%  50  atom.  chromatographic  of p a l l a d i u m i n methanolic  treatment  The  atY-8.95*  test.  Reduction excess  the  proton  a p p e a r e d a t 7^6.'.LL. due  t o the c h l o r i n e  Gas  1  (sharp three  centred  an e s t e r c a r b o n y l a t 1735  cm" .  I t showed  n  o f t h e e t h y l g r o u p were  triplet  (AYpiezon J c o l u m n ) i n d i c a t e d  halogen  structure.  at-/<6.:2  of a methoxyl group  s i n g l e t ) and  c(8.3;)cwia<s i&3 ) '\'-e  of the c h l o r i d e  The  a second  the  latter treatment  to  -33Purification  o f 3-carbomethoxy-3-ethylpiperidine  vacuum d i s t i l l a t i o n decomposition  was u s u a l l y a c c o m p a n i e d by c o n s i d e r a b l e  so t h a t s m a l l q u a n t i t i e s  s t r u c t u r a l and a n a l y t i c a l tography  The p u r e  a c o m p l e x p a t t e r n i n t h e NMR s p e c t r u m ,  (-C^CH^)0 band a t  The i n f r a r e d  3250  cm"  compound  exhibited  important features  at? 6.25 r  o f a sharp three proton s i n g l e t  and a t h r e e p r o t o n t r i p l e t  (-COOCH3)  necessary f o r  d a t a were o b t a i n e d b y g a s c h r o m a -  (Apiezon J column).  being the presence  spectrum  at'/'-''9»2  centered  possessed  a broad  (NH) and a s h a r p p e a k a t  1  by  A n a l y t i c a l and f u r t h e r s t r u c t u r a l  1725  evidence  absorption  c m " (-COOCH^), 1  f o r this  compound were p r o v i d e d f r o m t h e 3 , 5 - d i h i t r o b e n z a m i d e  deri-  v a t i v e . , (85)which was o b t a i n e d as a s h a r p m e l t i n g , e a s i l y crystallized  p a l e y e l l o w compound w h i c h p o s s e s s e d  spectral features.  Two v e r y p r o m i n e n t  bands  carbonyl region of the infrared  spectrum  ester  (1630 c m  (1725 c m  - 1  ) and t h e amide  characteristic  appeared'in.the  due t o t h e m e t h y l - 1  ) groups.  3030  a r o m a t i c p e a k was a l s o e a s i l y d i s c e r n i b l e  at  three proton t r i p l e t  atT9».2'5  evidence  i n t h e NMR s p e c t r u m  f o r the presence  group appeared  <  An  cm" . A 1  provided  o f an e t h y l g r o u p and t h e m e t h o x y l  as a s h a r p t h r e e p r o t o n s p i k e a t 7^6.. 3°  a r o m a t i c r e g i o n o f t h e NMR c o n s i s t e d o f a one p r o t o n at  ^0,9-and  shift  a two p r o t o n d o u b l e t a t T ^ l ' . i i .  o f these  presence  aromatic  protons  of electron withdrawing  the l o w e r t r i p l e t  The triplet  The l o w c h e m i c a l  i sattributable  t o the  s u b s t i t u e n t s on t h e r i n g ,  being r e a d i l y assigned t o the proton  between  t h e two n i t r o g r o u p s . this  derivative  Itself  The s p e c t r a l  as w e l l  as t h e s p e c t r a l  suffice to establish  The  final  the s t r u c t u r e  condensation  o f t h e compound„  (68).  the c o u p l i n g product  by c o l u m n c h r o m a t o g r a p h y on a l u m i n a sharp m e l t i n g c o l o r l e s s  /  V  2-carboethoxy-3-  The l a t t e r was p u r i f i e d and was o b t a i n e d as a  \  V  • COOEt  ,4  COOCH:  (66)  to the methyl  respectively, indole two  NH.  and c o n j u g a t e d  The NMR  -  spectrum groups,  a three proton s i n g l e t ester  (-C00CH  2  ethyl  appearing  ( 6 8 ) was  —1 cm" and 1675 ester  1  cm  c a r b o n y l groups  A band a t 3350 cm " - was a t t r i b u t a b l e  different ester  ethyl  of the coupling product  b y I n t e n s e b a n d s a t 1730  characterized due  spectrum  COoE"t-  x  (68)  (67)  infrared  a t 160~C  crystalline solid,  /  Cl  well.  (66) i n a s e a l e d t u b e  (/3-chloroethyl)-indole^  The  on t h e p i p e r i d i n e  proceeded  (67) w i t h  Reaction of the p i p e r i d i n e  provided  data  s t e p i n the sequence t o p r o v i d e the i n t e r -  (68) f o r a c y l o i n  mediate  and a n a l y t i c a l d a t a on  1  t o the  a g a i n showed t h e p r e s e n c e  of  t h e m e t h o x y g r o u p a p p e a r i n g as  at7"'6.35j,  and t h e e t h y l  as a t h r e e p r o t o n t r i p l e t  C H 3 ) and a two p r o t o n  group of the a t 7^-8.6,  q u a r t e t a t 7^5.57 ( - C 0 0 C H  ?  CH3)  -35A second  three proton t r i p l e t  the methyl  i n the r e g i o n f  readily'assigned  2 ."2-3iO  i n t h e NMR  and 297  Further structural analytical  d a t a was  spectrum  spectrum.  f o r compound 68  p r o v i d e d by e x a m i n a t i o n  The m o l e c u l a r i o n p e a k a t m/e  386  in addition  o f i t s mass  confirmed the  m o l e c u l a r f o r m u l a w h i l e an e x t r e m e l y i n t e n s e p e a k a t I8J4. was  dominant i n the spectrum.  available  appeared  and i t s t y p i c a l  m.u i n t h e u l t r a v i o l e t  evidence  m/e  From t h e e x t e n s i v e data  on t h e f r a g m e n t a t i o n o f i n d o l e a l k a l o i d s ^ ,  p e a k c a n be a t t r i b u t e d simple cleavage Fragmentation  t o the fragment  (87)  arising  this by  o f t h e bond f3 t o t h e p i p e r i d i n e n i t r o g e n .  of t h i s  compounds p r e p a r e d  t y p e was  i n this  to  The  shown by t h e a r o m a t i c a b s o r p t i o n w h i c h  a b s o r p t i o n a t 228  spectrum.  was  o f t h e e t h y l g r o u p on t h e p i p e r i d i n e r i n g .  I n d o l e r i n g was  to  atf9.2  a l s o encountered  i n other  w o r k t o be d i s c u s s e d l a t e r , ,  _ 63  Having obtained possible  to study  spectacular  rIngs^'''- ^" ^, ,  2,  product  (68) i t now became  the a c y l o i n condensation r e a c t i o n t o form the  nine-membered r i n g . with  the c o u p l i n g  The a c y l o i n c o n d e n s a t i o n h a s b e e n e m p l o y e d  success  i n the s y n t h e s i s  Y i e l d s obtained  o f medium s i z e d  by o t h e r methods  ( e . g . Dieckmann,  intermolecular a l k y l a t i o n , e t c , ) are s a t i s f a c t o r y f o r f i v e , six  and s e v e n membered r i n g s , h o w e v e r , a r e p o o r f o r e i g h t t o  f o u r t e e n membered  r i n g s and r e a c h  a minimum a t t e n , T h i s i s  explained  b y t h e f a c t t h a t non-bonded i n t e r a c t i o n s become  important  i n t h i s range  membered r i n g .  and r e a c h  Repulsive  a maximum i n t h e t e n -  f o r c e s , t h e r e f o r e , h i n d e r the  a p p r o a c h o f t h e two ends o f t h e m o l e c u l e w h i c h i n i t s e l f is  l e s s l i k e l y as t h e c h a i n l e n g t h i n c r e a s e s , r e s u l t i n g i n a  preponderance of p o l y m e r i z a t i o n of c y c l i z a t i o n  over c y c l i z a t i o n .  by t h e a c y l o i n method a l s o r e a c h  a t t h e ten-membered r i n g , b u t a r e s t i l l ( u s u a l l y a b o u t 50$).  The s u c c e s s  The y i e l d s  a minimum  i n a respectable  of the a c y l o i n condensation  I s a r e s u l t o f t h e r e a c t i o n o c c u r r i n g on t h e s u r f a c e sodium metal. and  since  in effect,  a r e a c t i o n at high  interaction The described  The e s t e r i s w e a k l y a d s o r b e d  the sodium i s d i s p e r s e d  and  range  as a f i n e  of the  on t h e s u r f a c e sand, t h i s  d i l u t i o n , reducing  becomes  intermolecular  polymerization.  method u s e d f o r t h e a c y l o i n c o n d e n s a t i o n was by L e o n a r d ^ - w h e r e b y a d i l u t e  was added t o a v i g o r o u s l y s t i r r e d sodium i n t o l u e n e ,  Initially  that  s o l u t i o n of the d i e s t e r  r e f l u x i n g suspension of  a r e l a t i v e l y low speed  stirrer  37was u s e d f o r t h e r e a c t i o n and t h e p r o d u c t was i n v e s t i g a t e d b y t h i n l a y e r chromatography, quantities could  and w i t h  R t values  was p o s s i b l e  Separation  i n small  t o be i d e n t i c a l comparison). spectra  i n addition t o a very  o f the three  s i m i l a r components  quantities.by preparative  c h r o m a t o g r a p h y on a l u m i n a .  thin layer  One o f t h e s e compounds was shown  t o the s t a r t i n g d i e s t e r  The o t h e r  equal  s i m i l a r t o the s t a r t i n g m a t e r i a l  be s e e n on t h e c h r o m a t o p l a t e  polar substance.  and  T h r e e compounds i n a b o u t  (TLC and i n f r a r e d  two compounds e x h i b i t e d i n f r a r e d  w h i c h w e r e r e m a r k a b l y s i m i l a r t o t h e s t a r t i n g compound  showed n o r m a l i n d o l e  absorption  i n the u l t r a v i o l e t  The NMR s p e c t r u m o f one o f t h e s e i n d i c a t e d t h a t ester o r i g i n a l l y attached a new t h r e e  compound.  The o t h e r  the e t h y l  t o t h e i n d o l e r i n g was a b s e n t b u t  p r o t o n ' s i g n a l was p r e s e n t a t  to the methoxyl spike  region.  7^6.05 i n  addition  a t ^6.35? o b s e r v e d i n t h e s t a r t i n g a c y l o i n p r o d u c t , however, l a c k e d the  m e t h o x y l s i g n a l at-7^6.35-but now p o s s e s s e d a new t r i p l e t and quartet  at s l i g h t l y higher  field  than that  observed f o r the  e t h y l e s t e r f u n c t i o n i n the s t a r t i n g d i e s t e r .  I t therefore  was a p p a r e n t t h a t t h e s t a r t i n g u n s y m m e t r i c a l m e t h y l e s t e r had s i m p l y and  undergone e s t e r exchange g i v i n g t h e d i m e t h y l  d i e t h y l esters  was l a t e r  ester39  ethyl  respectively.  shown t o be i d e n t i c a l  (thin layer  One o f t h e s e  compounds  to the authentic  dimethyl  chromatography).  The p o l a r m a t e r i a l was o n l y e x a m i n e d i n a p r e l i m i n a r y manner a t t h i s  point  as o n l y a s m a l l q u a n t i t y was. o b t a i n e d  0  -38Its  i n f r a r e d spectrum i n d i c a t e d that  containing  compound and  p r e s e n c e o f m e t h y l and observed  f o r the  were q u i t e  low  the  NMR  ethyl esters  a p e a k was  a  carbonyl  spectrum i n d i c a t e d i n the  starting diester.  and  i t was  Their  the  same r e g i o n  as  i n t e g r a l s , however,  present for approximately  one  p r o t o n a t 7"'=-l «7 • Subsequent a c y l o i n c o n d e n s a t i o n attempts u s i n g speed s t i r r i n g  a p p a r a t u s l e d t o the  polar material. preparative  The  l a t t e r was  material contained  infrared  region  present  occurring the  and  }  i n the  a t 225  starting  retained  obtained  t h i n l a y e r c h r o m a t o g r a p h y on  purified  was  formation  a slightly  ultraviolet  and  diester.  the  carbonyl  2 95 :  The  same g e n e r a l  the  i n pure form  by.  silica  This  absorption  s h i f t e d Indole  ill-defined.  as  that  for  predicted  with be  may  chromophoreo hydride,  so  d i e s t e r was  298 polar  entire  no  significant  be  the  not  312. treatment  reagent.  not  indole  l i t h i u m aluminum  crude a c y l o i n product c o n t a i n i n g this  the  present  m a t e r i a l , however, could  r e a d i l y r e d u c e d by  treated with  the  spectrum  t h i s method w i t h o u t d e s t r u c t i o n o f t h e I t was  material  in  p e a k s were  o x i d i z e d t o < X - d i k e t o n e s by This  for  mjut  observed  m o l e c u l a r i o n p e a k a t m/e  chromium t r i o x i d e ^ .  o x i d i z e d by  now  A. mass s p e c t r u m i n d i c a t e d t h i s was  a c y l o i n p r o d u c t as  Acyloins  the  absorption  spectrum of t h i s  features  desired the  in  and  c r u d e m a t e r i a l m e n t i o n e d above a l t h o u g h t h e was  gel.  r e g i o n , w i t h maxima  NMR  high  of o n l y  compared t o 227  m/>,  a  This  no  reduced  unreacted material  -39  was  p u r i f i e d by  gel  and  preparative  exhibited  no  layer  c h r o m a t o g r a p h y on  c a r b o n y l a b s o r p t i o n i n the  region.  The  singlets  a t ^ 5.? 3 5 ' and 7^ 6... 5 , b o t h i n t e g r a t i n g  two  NMR  thin  protons.  s p e c t r u m p o s s e s s e d two  A. t h i r d  concentration shifts oxide.  and  and  carried  acetylation  out.  shift  singlets  The  NMR  therefore  with acetic spectrum of  and  ofr0.57  r0-.'50  m e n t i o n e d above and  f u n c t i o n s were p r i m a r y . also  indicated  s p e c t r u m and  by  singlet  two  infrared  prominent for  atY-k»^was  approximately sensitive  r e a d i l y exchanged w i t h  T h i s compound was  a diol  field  broad  very  The  strongly  indicated  to  was  showed a downf o r the  t h a t the  two  alcoholic  presence of a c e t a t e groups  sharp spikes  atyS.Oin  c a r b o n y l a b s o r p t i o n at  1 7 2 5 cm"  be  in pyridine  latter  respectively  to  deuterium  suspected  anhydride the  silica  the  NMR  i n the  1  was  infrared  spectrum. The ester  by  diacetate  was  found to  f r o m the  c h r o m a t o g r a p h y on spectrometry). peak i n the attributable the  p r e p a r e d f r o m the  authentic  dimethyl  a s i m i l a r l i t h i u m aluminum h y d r i d e r e d u c t i o n  acetylation obtained  (88)  be  acyloin silica  I t i s of  i d e n t i c a l to the  condensations  ion  (thin  interest  (89)  type suggested e a r l i e r  to point a t m/e  which arises f o r compound  out 198 by (68).  diacetate  layer  g e l , alumina, infrared  mass s p e c t r u m o c c u r r e d to the  above  and  and  mass  t h a t the and  base  is  fragmentation  of  The p o l a r its  ability  hydride was  nature of the a c y l o i n condensation product  t o be r e d u c e d  indicated  confirmed  that  t o an a l c o h o l w i t h  of the a c y l o i n product  d i a z o m e t h a n e gave a m i x t u r e o f two e s t e r s . was  Identical  arising  One  This with  of these  (by t h i n l a y e r c h r o m a t o g r a p h y ) t o t h e d i e s t e r  used f o r the a c y l o i n c o n d e n s a t i o n identical  l i t h i u m aluminum  i t must h a v e been an a c i d .  as t r e a t m e n t  to the a u t h e n t i c  (68) w h i l e  dimethyl ester.  t h e o t h e r was The  products  from the a c y l o i n c o n d e n s a t i o n r e a c t i o n m i x t u r e  therefore  merely  (90)  and  t h e two a c i d - e s t e r s  (90) and ( 9 1 ) .  (91)  were  This and  explanation  s p e c t r a l data  also  give  the  diazomethane layer able  and  although  dimethyl  ester  i t would  be  ester  ester  signals  explicable  in  NMR  The  terms.  could  be  a t t r i b u t e d to  In  spite  of  great  we  hydrolysis  were' n o t  cause  of water the  only  our  was  being  now  like  synthesis  able of  attention  investigated to of  thesis.  discuss  The the  make  the  with  to  11+  the the  that the  for  the  taken  are  to  prevent  90  and  and  reaction  even  minute  sufficient  desired  to  a good  deal  diester  to  which  laboratory.I the  constitutes  first  of  we  d i f f e r e n t sequence  work which l e d  91,  cyclization.  acyloin  spend  i n our  the  mentioned  mono-acids  mg, ) w e r e  of  and  thin  proton.  desired  study  completely  dihydrocleavamine  on  a c y l o i n product  p e a k a t y'-l.7  to  could  i t indistinguish-  w h i c h were  concurrently  this  to  carboxyl  Rather  quantities to a  90  starting diester  ( u s u a l l y about  large  compound  of  diesters  above h y d r o l y s i s .  preparing  turned  this  were  d i a c i d of  i n t e g r a l s observed  in achieving  milligram quantities  traces  time  we  reactions  as  precautions  the  successful  Unfortunately with  of  observed  low  spectrum  these  the  esterification  such  earlier  simple  the  on  be  acids.  i n the  with  surprising i f its polarity  chromatography would from the  also  is consistent  would  total  section  B  of  -LL2-  Section  B  The  key  cleavage ring  as  in this  of a p a r t i c u l a r shown b e l o w .  intermediate  73a,  the  sequence c e n t r e s bond  provides  If this  cleavage  nine-membered  methoxy d e r i v a t i v e s (73b  and  methoxydihydrocleavamine  (7l+b) and  (vincadine)  (73a) (92a) (73b) (92b)  R R R R  = = = =  (93b)  the  92b)  reductive  and  six-membered  i s performed  ring  compound,  Similarly  (93a)°  quebrachamine  on  common t o a f i v e  (7l+a) i s g e n e r a t e d .  cleavamine 92a  step  The  the  on  dihydro-  intermediate  corresponding  would g i v e  the  rise  to  carbocarbo-  carbomethoxyquebrachamine  respectively.  R = H ,R = E t R"= H,R'= Et C O O C H _ , R'-= H,R" C O O C H ^ R' = E t ,  = Et' R"= H  The r e d u c t i v e c l e a v a g e q u a t e r n a r y ammonium s a l t s  (93a) (7k*) (93b)  R R  = = = R =  R  R = H,R = Et R"= H,R = Et COOCH R'= H,R"= Et C O O C H ^ , R ' = E t , R" = H  o f c a r b o n - n i t r o g e n bonds i n  i s a w e l l known r e a c t i o n and i s  e s p e c i a l l y u s e f u l i n the a l k a l o i d of i t s a p p l i c a t i o n t o a l k a l o i d s  field.  A number o f e x a m p l e s  of p a r t i c u l a r  interest  to this  s t u d y have a p p e a r e d r e c e n t l y i n t h e l i t e r a t u r e  deserve  comment.  The c l e a v a g e  i s normally  by t h e use o f s o d i u m o r l i t h i u m T n - l i q u i d  and  accomplished ammonia.  For example,  the r e d u c t i o n o f the q u a t e r n a r y i o d i d e 9 1 + t o the r i n g opened compound  (95)  has been r e p o r t e d i n 89% y i e l d  using  sodium i n l i q u i d  ammonia^.  No.  Ok)  Reduction  of  the  CHj  compound 96 b y e i t h e r  ammonia o r l i t h i u m a l u m i n u m h y d r i d e r i n g compound^  (97).  cleavages reported  This  by t h e  gives  reaction  sodium i n  a  8  liquid  ten-membered  and o t h e r  same a u t h o r s ^ -  (95)  are  similar  shown i n F i g u r e  Mcr/Nhj „ i  tr  +  C^  r — >  3  (96)  !•  (97)  6H  >  Figure A. r i n g c l e a v a g e a ten-membered carried  out  of  the  r i n g compound  i n our  17  quaternary (99) has  salt  98 t o  a l s o been  laboratory^ . 9  H (98)  (99)  provide, successfully  17.  -khIn a model s t u d y , d e s i g n e d W'enkert, e t a h ^  reported  the  means o f l i t h i u m i n l i q u i d  I t can  be  (73a  possible  and  s y s t e m s was  with  this  therefore  route  u n d e r s t u d y i n our with  73a  appropriately modified principle  isomeric  esters  t o the  b,  an  condensation with  The  since  analogous  and  and  work  (71b,  and  b was  desirable.  102b)  and  involved  The  synthesis  of  followed  by  to  are the underthe  interreactions  d i h y d r o c l e a v a m i n e , quebrachamine  c o r r e s p o n d i n g carbomethoxy d e r i v a t i v e s .  thesis  currently  t h e s e compounds  t h a t the  of  nine-membered  m e d i a t e s w h i c h t h r o u g h a common s e r i e s o f s u b s e q u e n t  their  b  sequence u t i l i z i n g was  of  A study  c e n t r a l p o r t i o n of t h i s  compounds 92a and  case  b).  t r y p t a m i n e would h o p e f u l l y l e a d  would e v e n t u a l l y y i e l d  by  considerable  compounds 73a  intermediates  102a)  t o 101  i n the  and  appropriate  i n v o l v e d h e r e was (71a,  (92a  warranted.  laboratory and  and  t o the  aspect c o n s t i t u t e s the  A promising  lying  b)  c l e a v a g e t o the  ring  synthesis,  ammonia.  a s y n t h e t i c sequence l e a d i n g  epimeric  o f 100  type of cleavage d e s i r e d  quaternary s a l t s  their  conversion  s e e n , t h e r e f o r e , t h a t t h e r e was  precedent f o r t h i s the  f o r quebrachamine  and  -k5~  C=0  ( 7 1 a ) R = OEt (71b)  An  considered  and  d i e s t e r s 102a  p r o p a n e d i o l - ^ (106)  i  b had  a l r e a d y been  by t h e scheme d e p i c t e d i n  1  n  (105)  was  91% yield  in tetrahydrofuran,  monobenzyl e t h e r  ^  H  71a  sequence i s summarized i n F i g u r e  D i e t h y l ethylmalonate  hydride  and  a n a l o g o u s s y n t h e s i s o f the d i e s t e r this  c  (102b) R = COOCH^  in> o u r l a b o r a t o r y ^  F i g u r e 18.  o  (102a) R = OEt  R = COOCH^  A'- s y n t h e s i s o f t h e achieved  C O O E t /  (107)  reduced  to  d i o l was  by t r e a t m e n t  19° s  converted  aluminum to  the  w i t h sodium i n hot  f o l l o w e d by r e a c t i o n w i t h b e n z y l c h l o r i d e ^ (77# preferential formation  xylene  yield) .  o f t h e m o n o b e n z y l e t h e r was diol  r e s u l t i n g mixture  d i o l and m o n o b e n z y l e t h e r  then separated spectrum of the  by f r a c t i o n a l  and  1  in  The  d e s i r e d b e n z y l ether possessed  band a t 3300 cm."-- (OH) of plane  t o the s o d i u m metal„  distillation.  characteristic  b e n d i n g modes a t 695  cm,"'- and 1  71+0  protons  and  a two  methylene protons. istic  proton  proton  s i n g l e t at Y2.7  an  The was  absorption  aromatic cm.-l  C-H  out  (also The  f o r the  s i n g l e t at7""5°5 f o r t h e  These two  by  infrared  a l l other benzyl ethers reported subsequently).  s p e c t r u m showed a f i v e  The  ensured  u s i n g a 3sl molar r a t i o of the of unreacted  now  2-ethyl-l 3=  by means o f l i t h i u m  The  was  present NMR  aromatic  benzyl  s i n g l e t s were a l s o v e r y  f o r a l l t h e s u b s e q u e n t compounds c o n t a i n i n g t h e  characterbenzyl  -1+6-  Na H0(GH )30H  0CH O(CH ) OH 2  2  2  3  0CH C1 2  S0C1COOEt  V  J#CH 0(CH )3C1  NaOEt  ^CHpO(CH )3CH  2  2  2  CH (C00Et) 2  COOEt  2  NaOEt Etl  V  COOEt  KOH  0CH2O(CH2) CCH CH3 3  COOH ^CH 0(CH )3CCH CH3 2  2  2  2  COOH  COOEt  (103)  -co CH2CH3 ^CH 0(CH )3CHC00Et 2  EtOH  2  H  (101+)  j^CNa Bf-CH C00Et 2  V  Y  2  CH CH3 2  jZfeHgOfCH^CHCOOH  2 [+ S0  4 °V. C  CH2CH3  ? 2 3 H  j^GH^CH^CCOOEt  G H  0CH O(CH i),C"COOEt y P  ?  CH C00Et  2  3  CH CC00Et  2  2  (102a)  (102b)  F i g u r e 18  0  COOEt  LiA'lH  CH'Et  THP  !  COOEt  CH-OH I CHEt I  CH OCH j2; 2  0CH G1  2  2  2  CHEt  Na  CH 0H 2  CH 0H 2  (105") CH 0CH J^ 2  socio  -9*  2  (107)  (106) CI1JCOOEt ) Mo o£j~  Et  2  CHEt  COOEt  0CH OCH CHCH CH 2  CH C1  2  2  ( 1 0 9 ) . COOEt  2  (108)  KOH H 0 2  Et  COOEt.  w  j?iCH 0CH CHCH CCH C00Et 2  2  2  COOH  jZfcH OCH„CHCH CH 2 2, 2 Et COOH (110  2  5  (  COOEt (113)  KOH H 0  -CO.  2  Et  COOH  $CH 0CH CHCH CCH C00H 2  2  2  0CH OCH CHCH CH COOH  2  2  2  COOH •CO.  V 2  2  2  El  EtOH H S0^  V 0CH OCH CHCH CH COOEt  0CH OCH CHCH CHCOOH"' 2  2  2  CHoCOOH EtOH H2 1+  V  ^CH 0CH CHCH CHGOOEt  $CH 0CH CHCH CHC00Et  2  t  2  0 -.0  S0  2  2  Et ' • (112)  (115)  2  2  Et  (111 )  (lilt)  2  2  CHoCOOEt  2  2  Et  (71a  (71b)  Figure  19  CH CC00Et 2  -1+8-  ether moiety. triplet  The C - m e t h y l  centered  a t 7 ' 9 * l while  at  7'^ 6 , i j . was a t t r i b u t e d  to  an o x y g e n  protons sharp  attached  one p r o t o n  hydroxyl  proton  deuterium It this  directly singlet  this  NMR  data  structure  a sharp  centered  adjacent  protons  identified  they  as t h e  upon  addition  of  again.  examined extremely  will  be  placed  (108),  no  spectrum  lacked  was c o n s i s t e n t w i t h t h e  at-/2,7 singlet  protons  at 7^5',5,  and c h l o r i n e  appeared  appeared  and t h e b e n z y l  Y  group  s  i n the s t a r t i n g ether-alcohol  a t - ? 6 , l ) . 5 was a s s i g n e d  t o the oxygen  i n N N-di-  ( 1 0 8 ) showed  T h e NMR  The a r o m a t i c  two p r o t o n  (108)  region but the aromatic  present.  singlet  to the c h l o r i d e  chloride  chloride  of the spectrum  of the ethyl  remaining  a l l possessed  thionyl  peak observed  proton  as a s h a r p  multiplet atoms  five  and two m e t h y l e n e  and t h e spectrum, t a k e n  i n the hydroxyl  above were  the remainder  assigned  with  The r e s u l t i n g  proton  adjacent  i n the region  f e a t u r e o f t h e compounds that  centered  the discussion.  by t r e a t m e n t  absorption  hydroxyl  protons  The  disappeared  proton  multiplet  s p e c t r a so c o n s i d e r a b l e emphasis  during  peaks mentioned  protons  a t 7 ^ 7 . 2 was  atom*  e t h e r - a l c o h o l ( 1 0 7 ) was c o n v e r t e d  66$ yield  and  t o the methine  t o a carbon  s y n t h e t i c sequence  infrared  as  proton m u l t i p l e t  to the solution  metbylaniline^.  the  three  was a d i s t i n c t i v e  The in  A  as a t h r e e  a four proton  as i t c o m p l e t e l y  oxide  informative on  atom,  appeared  t o the four methylene  t o 8 , 9 c o u l d be a s s i g n e d  yQiO  in  group  as•a  atoms. three  methylene  A four  t o the four The  proton  again  proton  hydrogen methyl triplet  -1+9centered methine  atT^.l,  and two m e t h y l e n e ) a p p e a r e d  Alkylation  of diethyl  sodium ethoxide  consistent  o f 50$  recoveries  was e a s i l y  alkylated  separable  malonic  ester  the r e a c t i o n .  product to  showed  strong  t h e NMR  establishing was  again  singlet proton  three  this  0  absorption  (Figure  20)  multiplet  since  was  proton  one a t t a c h e d  spectrum with  singlet  appeared  assignment  t h e NMR  1  due  aromatic  five  bands,  ether  proton  a t -r 5«5-  A  four  triplet;,  t o t h e m e t h y l e n e and respectively,  a t 7"6.55 c o u l d  of the methylene  at this  cm,"  The b e n z y l  of a sharp  assigned  t o the carbon This  was a t t a i n e d  a t 1735  compound.  group absorb  resonating  o f 89$  invaluable i n  e s t e r groups  which  observed,  boiling  and a s i x -proton  t h e two p r o t o n s  of the benzyloxy  groups.  a t 7 " 5*8  of the ethyl  3~benzyloxy-  h a l i d e were  as t h e two f a m i l i a r  were r e a d i l y  (108)  spectrum of the a l k y l a t i o n  by t h e presence  centered  at7"8 8  protons  remaining  ethoxy  and a y i e l d  the s t r u c t u r e of this  quartet  analyzed  the  (109)  carbonyl  spectrum  evident  proton  oxygen  i n the  s l u g g i s h and  t h e much h i g h e r  a t T'S,65 a n d a t w o p r o t o n  centered methyl  of unreacted  from  as w e l l  diethyl  T h e r e a c t i o n was  The i n f r a r e d  the e s t e r groups  Again  atoms (one  as a m u l t i p l e t  as b a s e - ^ p r o v i d e d  (109).  in  hydrogen  malonate w i t h the c h l o r i d e  2-ethylpropylmalonate  This  three  ofV7.9 - 8,%,  region  using  and t h e r e m a i n i n g  i n this  region.  frequency  atom b e a r i n g i s confirmed  next  A  be  easily  to the The  was e v i d e n t l y  t h e two  carbo-  by c o m p a r i s o n  spectrum of d i e t h y l  of  ethylmalonate  -50-  Et  COOEt  jZfcH20CH2CHCH2CH COOEt  J  Figure  20  Et j2fCH 0CH CHCH CH C00Et 2  2  2  Hi  Mi ~ t —  5"  Figure  21  2  11;  where t h e a n a l o g o u s p r o t o n a p p e a r s a t  -7*6.80  A somewhat  isolated  two  p r o t o n m u l t i p l e t was a p p a r e n t at7^8.05 and was a s s i g n e d t o  the  two p r o t o n s on t h e c a r b o n atom b e t w e e n t h e c a r b o n atoms  bearing  the e t h y l  g r o u p and t h e two c a r b o m e t h o x y g r o u p s .  a s s i g n m e n t was made on t h e b a s i s monoester  (112)  t o be d i s c u s s e d  substituted in  (113)  later.  group  Finally  the route from t h i s (71a)  a manner a n a l o g o u s t o t h a t  Figure the  18.  (103)  Indeed the synthes-is  e t h y l iodoacetate  this  (Figure  (Figure  was s u c c e s s f u l .  anticipated  i n better yield  and t h e n  by  first  alkylating  However t h e a l t e r n a t e  t o be d i s c u s s e d  l a t e r was  and t h i s  was  of the s u b s t i t u t e d malonic e s t e r  (109)  aqueous - p o t a s s i u m h y d r o x i d e - ^ , p r o v i d e d t h e c o r r e s p o n d i n g  malonlc acid  (110)  as a v i s c o u s  induced t o c r y s t a l l i z e  with  (71a)  verified.  Thus, h y d r o l y s i s  be  provide  19) I s o m e r i c w i t h t h e  e s t e r 112  (113)  with  sequence would  18).  route v i athe t r i e s t e r to proceed  investigated  ( 1 0 2 a ) shown i n  of the s u c c i n i c ester  i t t o the s u b s t i t u t e d  subsequently  19) was  tothe  f o r the conversion of the  (71b)  (102b)  at-7"9.l5°  malonlc ester  (Figure  I t was a l s o hoped t h a t  o< - k e t o g l u t a r i c e s t e r  with  centered  to the succinic ester  -ketoglutaric ester  converting  the methyl o f the e t h y l  proton t r i p l e t  succinic ester  malonlc ester  o f a NMR c o m p a r i s o n w i t h t h e  i n w h i c h i t i s a b s e n t and t h e t r i e s t e r  a p p e a r e d as a t h r e e Initially  This  o i l . T h i s compound c o u l d n o t  b u t t h e s p e c t r a l d a t a were i n a c c o r d  the assigned s t r u c t u r e .  The NMR s p e c t r u m i n d i c a t e d 'the  - 5 2 -  absence o f the e t h y l e s t e r protons appeared  integrating  at-7"1.0  chemical s h i f t  and a new a b s o r p t i o n p e a k  f o r two t o t h r e e p r o t o n s , ,  i s somewhat h i g h f o r t h e e x p e c t e d  t h e c a r b o x y l p r o t o n s ; ..however, t h e p r e s e n c e absorption i n the spectrum  confirmed  to  3 5 0 0  cm."  2LL00  the presence  1  substituted possessed spectrum  of carboxylic  f o r f i v e hours  w i t h e t h a n o l and s u l f u r i c  acid functions.  ( 1 1 1 ) was_'ef f e e t e d b y  at 1 2 0 ° C ^ .  a t ' / 2 . 6 5  and m e t h y l e n e p r o t o n s  indicated  methylene protons  at /5<>85 j  methylene protons  monoester  i n the i n f r a r e d  (109)  five proton f°  r  The NMR singlet  the benzyl  respectively.  A two  a l o n g with, a t r i p l e t  centered  on t h e c a r b o n  atom a d j a c e n t t h e b e n z y l  1  two p r o t o n d o u b l e t  atT 7.65/ :  on t h e c a r b o n  The " m a l o n i c "  two c a r b o e t h o x y  -r*8.05  This  o f one e t h y l e s t e r g r o u p .  a two p r o t o n . m u l t i p l e t  ester  t o provide the  the presence  ethe'r o x y g e n a p p e a r e d as a b r o a d  group.  a sharp  s i n g l e t atY5°5  and a two p r o t o n  proton quartet centered  and  1  purification  as w e l l as t h e two u s u a l a r o m a t i c b a n d s .  ether aromatic  a t ? ^ 8 , 7 5  acid  c a r b o n y l a b s o r p t i o n a t 1 7 3 0 cm."  The  6  ester 1 1 2i n 7 5 % overall yield.  spectrum . (Figure 2 1 ) possessed  broad  region of the i n f r a r e d  r e s u l t a n t v i s c o u s o i l was r e e s t e r i f l e d w i t h o u t by t r e a t m e n t  p o s i t i o n of  of very  Smooth d e c a r b o x y l a t i o n t o t h e m o n o a c i d heating the viscous diacid  The  had d i s a p p e a r e d  assigned earlier,,  at'T'6.6  c o u l d be a t t r i b u t e d  t o the  atom c*. t o t h e c a r b o m e t h o x y  p r o t o n on t h e c a r b o n  groups observed  The  atom b e t w e e n t h e  i n the spectrum  of the malonic  as h a d t h e two p r o t o n m u l t i p l e t a t  This data  i s c o n s i s t e n t with the  . .53chemical s h i f t s carboethoxy  one w o u l d  groups.  f o r the methyl  evident  on t h e  s t r o n g bases  o f one o f t h e  protons  centered  o f t h e e t h y l g r o u p was  of substituted  acetic  esters using very  such a t r i p h e n y l m e t b y l sodium are f a i r l y  well  s u c c e s s f u l l y , as m e n t i o n e d b e f o r e , t o  the s u b s t i t u t e d  (102b) e s t e r s .  also  spectrum,  known and w e r e used prepare  on r e m o v a l  The u s u a l t h r e e p r o t o n t r i p l e t  at-y^'l  Alkylations  expect  The  succinic  (102a) and < * - k e t o g l u t a r i c  -ketoglutaric  ester  (71b) was  of interest  ^0 s i n c e W e n k e r t and c o - w o r k e r s ^ c^-ketoglutarate  (117).  The a n a l o g o u s  o<-ketoglutarate convenient  •  (116)  route  (71b)  had condensed  w i t h tryptamine t o provide the lactam reaction  on t h e s u b s t i t u t e d  w o u l d have p o s s i b l y p r o v i d e d a v e r y  to'dihydrocleavamine,  (116.)  y, K J >  The  ethyl  e n o l a t e of the monoester  (117) (112)  '  was e a s i l y  w i t h t r i p h e n y l m e t h y l s o d i u m i n e t h e r as e v i d e n c e d almost  instantaneous  disappearance  generated by t h e  of the c h a r a c t e r i s t i c  deep r e d c o l o r o f t h e t r i p h e n y l m e t h y l a n i o n upon a d d i t i o n o f the e s t e r . addition  When t h i s  a d d i t i o n was i m m e d i a t e l y  f o l l o w e d by t h e  o f e t h y l <X - b r o m o p y r u v a t e , p r e c i p i t a t i o n  b r o m i d e was v i r t u a l l y  instantaneous.  m i x t u r e , h o w e v e r , l e d o n l y t o an 80  o f sodium  A n a l y s i s of the r e a c t i o n - 85$  recovery of unreacted  -5V monoester desired and  (112 ) , and no b r o m o p y r u v a t e c o u l d  a l k y l a t i o n product could  be r e c o v e r e d .  be i s o l a t e d and t h i n - l a y e r  gas c h r o m a t o g r a p h i c e x a m i n a t i o n o f t h e c r u d e  indicated material  no s i g n i f i c a n t  compounds o t h e r  and t r i p h e n y l m e t h a n e .  s o d i u m were s t i r r e d  f o r one h o u r b e f o r e  not  triphenylmethyl  the a d d i t i o n of the  b r o m o p y r u v a t e , a new compound was f o r m e d .  high  This  m a t e r i a l was  b y c o l u m n c h r o m a t o g r a p h y and p r o v e d t o be e x t r e m e l y  b o i l i n g . • The NMR s p e c t r u m i n d i c a t e d t h i s was the desired <x-ketoglutaric  ester  be s u r p r i s i n g s i n c e  esters  self-condensation  I s t h e w e l l known G l a i s e n  of monosubstituted  This  would  of substituted  acetic  e s t e r c o n d e n s a t i o n and t h i s i s  known t o c o n s t i t u t e t h e most s e r i o u s alkylations  obviously  (71b) and a p p e a r e d t o  be most p r o b a b l y t h e s e l f c o n d e n s a t i o n p r o d u c t . not  product  than s t a r t i n g  When t h e s o l u t i o n o f t h e e s t e r 112 and  purified  No  side r e a c t i o n i n the  acetic e s t e r s ^ ' ^ .  Attempted  ^8 a l k y l a t i o n using dimethyl  the anion o f dimethyl  s u l f o x i d e was a l s o  When e t h y l i o d o a c e t a t e ^ enolate  sulfoxide-^ i n  unsuccessful. 9  was added i m m e d i a t e l y t o t h e  o f t h e e s t e r 1 1 2 , t h e r e a c t i o n was a g a i n  virtually  i n s t a n t a n e o u s and s o d i u m i o d i d e p r e c i p i t a t e d .  Analysis  of the crude r e a c t i o n p r o d u c t under c o n d i t i o n s  similar to that  f o r the product o f t h e bromopyruvate and  gas c h r o m a t o g r a p h y ) c l e a r l y  reaction (thin-layer  i n d i c a t e d t h e p r e s e n c e o f a new  m i n o r compound b u t t h e m a j o r component was s t i l l ester.  The new p r o d u c t was s e p a r a t e d  the s t a r t i n g  and p u r i f i e d  by column  -55c h r o m a t o g r a p h y on a l u m i n a , a low y i e l d on a  20%  e s t e r (71a).  o f the s u c c i n i c  SE30  quantity  f o l l o w e d by d i s t i l l a t i o n  column- e f f e c t e d  Gas c h r o m a t o g r a p h y  further purification  diester  (71a)  possessed  carbonyl region of the i n f r a r e d two f a m i l i a r  aromatic  an a b s o r p t i o n band spectrum  bands,  The NMR  from  at-r2.7  proton  atr^5»5»  centered  e s t e r groups. the  indicated  7.6,  Again  ester  protons  u n s u c c e s s f u l attempt  the  (71a)  fact  by t h i s  (71b)  on t h e c a r b o n  b r o m o p y r u v a t e and e t h y l Since  atoms  o f t h e e t h y l g r o u p a p p e a r as a at7'9°l. a t p r e p a r i n g the s u b s t i t u t e d  technique  of the monoester  as a b a s e , r a t h e r t h a n  anion a b s t r a c t s a proton  t h e ester".112-0  adjacent  on t h e c a r b o n  and t h e l o w y i e l d  alkylation  t h a t the a n i o n  preferentially  o f two e t h y l  g r o u p s a p p e a r i n t h e r e g i o n o f 7*7 °0 t o  the methyl  c<-ketogIutaric ester  appeared  f u n c t i o n a p p e a r as a two p r o t o n  three proton - t r i p l e t centered The  apparent  and c o m b i n e d w i t h a  a t -T6.6, and t h e t h r e e p r o t o n s  t h e two c a r b o e t h o x y  and  (Figure 22)  quartets  the presence  The m e t h y l e n e p r o t o n s  oxygen o f t h e b e n z y l o x y  multiplet to  f o r four protons  atY8.75  1  and t h e two p r o t o n  Two'almost superimposable  a t r'5<.85 i n t e g r a t i n g triplet  singlet  i n the  spectrum  The b e n z y l e t h e r was  the f i v e  data.  a t 1730 cm."  was a g a i n v e r y i n f o r m a t i v e .  singlet  of a small  o f t h i s m a t e r i a l f o r a n a l y t i c a l and s p e c t r a l  The  the  to provide  from  of the s u c c i n i c  was p r o b a b l y ( 1 1 2 ) was  acting  a nucleophile.  thec<-carbon  due t o  I fthe  of e t h y l  i o d o a c e t a t e i t would  simply  regenerate  t h e p r e p a r a t i o n o f t h e °<»ketoglutaric e s t e r  -56  Et jZfcH 0CH CHCH CHC00Et 2  2  2  CH C00Et 2  I  J  l  i  -I-  4-  Figure 22  Et  COOEt  0CH2OCH CHCH CCH COOEt 2  2  2  COOEt  7  Figure 23  -57(71b)  was  not s u c c e s s f u l by  the p r e p a r a t i o n of the  the s i m p l e  succinic  e s t e r (71a)  t h e more d e s i r a b l e r o u t e u t i l i z i n g The  alkylation  alkylation  of the malonic  was  examined  the t r i e s t e r e s t e r (109)  discussed, by  113. with  ethyl  60 b r o m o a c e t a t e u s i n g s o d i u m e t h o x i d e as base yield  of the t r i e s t e r  starting material. sodium e t h o x i d e the t r i e s t e r The  }  be  The  use  of sodium i n e t h e r ^  h o w e v e r , p r o v i d e d an  very high b o i l i n g  separated  fractional  The  a l o n g w i t h a good r e c o v e r y 1  (195  spectrum  The  characteristic  mm.)  and  e s t e r by  cm.  and  -1  ( F i g u r e 23)  t h e two  a t y - 2 . 7 and  protons  respectively.  a t 7 ' 8 , 7 5 and  e s t e r w o u l d be  chemical expected  a two and  8.80  shift  at-f-5„Q5  o f the e t h y l e s t e r s and to the c o r r e s p o n d i n g  of the e s t e r protons  t o be s l i g h t l y  proton  methylene  A six. proton m u l t i p l e t centered  t o the methylene protons  The  The  shows a number o f i n t e r e s t i n g f e a t u r e s .  f i v e proton s i n g l e t  /  of  usual arosiatic bands.  at7-"5»55 a r e t h e f a m i l i a r b e n z y l a r o m a t i c  triplets  spectrum  of e s t e r c a r b o n y l  singlet  protons.  (30$).  - 200°C a t 0.25  f e a t u r e s i n the i n f r a r e d  were a g a i n t h e p r e s e n c e  NMR  two  of  ( 6 0 % ) of  ester  from the lower b o i l i n g malonic  characteristic  a b s o r p t i o n a t 1730  due  of  distillation.  the e s t e r (113)  is  fair  i n place  improved y i e l d  as w e l l as some r e c o v e r e d m a l o n i c  t r i e s t e r was  could  (113)  provided a  the  methyl  of the  malonic  d i f f e r e n t from, t h a t  of  t h e n e w l y i n t r o d u c e d e s t e r g r o u p b e c a u s e o f the d i f f e r e n c e o f an a d d i t i o n a l  i n t e r v e n i n g carbon  on the c a r b o n  next  atom.- The  t o the benzyloxy  methylene  g r o u p a p p e a r as a  protons two  - 5 8 -  proton doublet malonic  at"T 6o7 <  e s t e r compound  and t h e a d d i t i o n a l p e a k o b s e r v e d  ( 1 0 9 ) ( s e e F i g u r e 2 0 ) due t o t h e l o n e  h y d r o g e n a t o m on t h e c a r b o n disappeared.  i n the  between the c a r b o e t h o x y  groups has  I n a d d i t i o n , t h e two p r o t o n m u l t i p l e t  observed  i n the spectrum  slightly  down t o r ' ? , 9 -  of the malonic  at'r -8»05 /  e s t e r . ( 1 0 9 ) has  The c h e m i c a l s h i f t  shifted  o c c u r r i n g upon t h e  i n t r o d u c t i o n of the a d d i t i o n a l e s t e r f u n c t i o n i s t h e r e f o r e c o n s i s t e n t w i t h the e a r l i e r t h e two p r o t o n s  assignment of t h i s m u l t i p l e t t o  on t h e c a r b o n  atom b e t w e e n t h o s e b e a r i n g t h e  e t h y l and t h e two c a r b o e t h o x y that  this  multiplet  substituted  succinic  i s not present  introduced  carboethoxy  The t r i e s t e r  oil.  NMR  spectrum  group.  a t f 6 . 9 5  w  a  A new ^  s  u e  of the sharp  t o the  atom a d j a c e n t t o t h e n e w l y The m e t h y l  as a t h r e e p r o t o n  protons  triplet  of the e t h y l  at-7^9.15.  ( 1 1 3 ) was h y d r o l y z e d w i t h p o t a s s i u m  to the c o r r e s p o n d i n g viscous  appeared  on t h e c a r b o n  group again appeared  i n t h e NMR  ester ( 7 1 a ) (Figure 2 2 ) .  two p r o t o n s i n g l e t w h i c h methylene protons  I t i s all s o o f i n t e r e s t  groups.  triacid  (lllj.),  o b t a i n e d as a n o n - c r y s t a l l i n e  d a t a on t h e l a t t e r  indicated  o f t h e e t h y l e s t e r g r o u p s and a t h r e e p r o t o n appeared i n the expected  region  hydroxide-^  complete  broad  removal  singlet  (7-0,/j,) f o r the c a r b o x y l  hydrogen atoms. Decarboxylation derivative 1 6 5  -  170°C  ( 1 1 5 ) was  o f t h e above t r i a c i d  t o the s u c c i n i c  e f f e c t e d by h e a t i n g t h e t r i a c i d  f o r a period of  v i s c o u s a c i d was e s t e r i f i e d  3-|  hours.  The r e s u l t a n t  by t r e a t m e n t  at brown  w i t h e t h a n o l and  acid  -59sulfuric  acid  t o provide the desired  o f 78$ f r o m t h e t r i e s t e r .  overall yield pared  i n " t h i s • manner was  scopic comparison pared  succinic  identical  as w e l l  by t h e a l k y l a t i o n  (71a)  ester  The s u c c i n i c  by i n f r a r e d  ester  pre-  and NMR s p e c t r o -  as by gas c h r o m a t o g r a p h y  to that  e s t e r 112  of the s u b s t i t u t e d  i n an  pre-  with ethyl  iodoacetate ,  ;  When t h e s u c c i n i c e s t e r f r o m e i t h e r synthetic analysis pure  r o u t e s was s u b j e c t e d t o c a r e f u l gas an i n t e r e s t i n g  sample appeared  of a s l i g h t 260°C  of the d e s c r i b e d  phenomenon was o b s e r v e d .  almost  as one p e a k e x c e p t  s h o u l d e r when e x a m i n e d  (Figure  2I4.) .  chromatographic  on a  An  f o r the presence column a t  (20%)  SE30  analytically  a t 2[L5°C .  T h i s s h o u l d e r became more p r o n o u n c e d  E x a m i n a t i o n u s i n g a FFAP (20$) c o l u m n showed t h e p r e s e n c e peaks a t 2 6 5 °  more e f f e c t i v e l y  c  a t 2l+5°C  (Figure  produced  t h e same p e a k r a t i o s  being  altered  material  25).  and t h i s was much more  Collection  and r e i n j e c t i o n  indicating  b y t h e gas c h r o m a t o g r a p h i c  satisfied  o f two  pronounced  of t h i s  material  t h e compound was n o t procedure.  a l l the necessary c r i t e r i a  While  to support the  (71a)  and a p p e a r e d  as one compound by t h i n - l a y e r  chromatography,  the presence  o f two d i a s t e r e o i s o m e r s was  structure  since  t h e compound p o s s e s s e d  2'6),  S i n c e t h e s e as ynrmet>ric c e n t r e s w o u l d  t h e two a s y m m e t r i c indicated esters  centres  by t h e a s t e r i s k s ) ,  dihydropleavamines  their  expected  (see F i g u r e  u l t i m a t e l y appear  centres of dihydrocleavamine  s h o u l d be r e f l e c t e d  isomeric  two a s y m m e t r i c  this  demonstration  (7)4a, F i g , 2 6 i n the s u c c i n i c  by t h e s y n t h e s i s o f t h e two k n o w n (as w i l l  be shown  at  later).  D < c  -60-  SE 30  F i g u r e 21+  FFRP  Figure. 2 5  Et 0CH2OCH2CHCH2CHC OOEt CR^COOEt (74a  (71a)  F i g u r e 26  -61Because o f the h i g h of the s u c c i n i c e s t e r  degree o f success  (71a)  i n the synthesis  v i a the t r i e s t e r  a t t e m p t was made a t an a n a l o g o u s s y n t h e s i s ester  (120) v i a a l k y l a t i o n  of the aldehydo*-  of the malonic e s t e r  bromoacetaldehyde d i e t h y l a c e t a l (118). could  (113), a b r i e f  p o s s i b l y t h e n be d e c a r b o x y l a t e d  (109) w i t h  The p r o d u c t ( 1 1 9 ) and t h e a l d e h y d e  group  regenerated„ Et  COOEt  OEt  Et  +BrCH CH  jZfcHpOCHpCHCHpCH  ^>  2  A OOEt  COOEt.  j#CH 0CH CHCH CCH CH(0Et ) 2  2  2  OEt  2  COOEt  (118)  (109)  2  (119) Et  —  _^  jZ(CH 0CH CHCH CHC00Et 2  2  2  CH CH0 2  (120) The  condensation  of aldehyd'O^esters  a w e l l known and v a l u a b l e lies  i n the f a c t  before be  s y n t h e t i c route„  the e s t e r group w i t h the tryptamine  used t o d i r e c t  with tryptamine  the p o s i t i o n of the a l k y l  to y i e l d  preferentially  and c a n , t h e r e f o r e , side chain  the c y c l i z a t i o n product  and A s p i d o s p e r m a a l k a l o i d  (122) w h i c h  systems '''. 2  i n the  121 c o n d e n s e s  i n the synthesis ring  is  I t s importance  F o r example, the a l d e h y d o - e s t e r  been a s y n t h e t i c i n t e r m e d i a t e  Hunteria  tryptamine  t h a t the aldehyde group r e a c t s  r e s u l t a n t lactam.,  has  with  of c e r t a i n  -62  (122)  (121 ) S i m i l a r l y compound tryptamine  to provide  (70)  the  been c o n d e n s e d  cyclization  product  j  with  (12LL)<,  bromoacetaldehyde d i e t h y l a c e t a l f a i l e d  r e a c t w i t h the malonic s u c c e s s f u l f o r the acetal  We,  (109)  ester  under the  relatively  i n e r t ^ ' ^ 5 ^ and  an a l k y l a t i n g a g e n t i n t h i s  this  (71a)  condensation (125)  with  w i t h the had  as  isomeric ester  the  The  t o the results  of  the  (102a) t o p r o v i d e  i n d o l e nucleus of these  made i t  analogous  r e c e n t l y been s u c c e s s f u l i n o u r  its cyclization  inves ti-gated „  tryptamine  This  case,  t h e r e f o r e , proceeded t o the c o n d e n s a t i o n  succinic ester  to  conditions  a l k y l a t i o n w i t h e t h y l bromoacetate„  is apparently  u n s u i t a b l e as  and  has  CHpOC  Unfortunately  imide  (123)  was  particular  the  laboratory^ , 1  c u r r e n t l y being cyclization  66  studies  are  Thus t h e tryptamine  shown i n F i g u r e condensations  a t 190  -  27»  of the  200°C p r o v i d e d  succinic ester the  (71a)  d e s i r e d imide  with (130,  -63-  Figure  27  -6kF i g u r e 28) i n 77$ y i e l d .  The c r u d e  i m i d e was p u r i f i e d  c h r o m a t o g r a p h y on al umina and r e m a i n e d crystalline  gum.  quantities  of this  The analysis  as a l i g h t brown n o n -  I t was p o s s i b l e , h o w e v e r , t o d i s t i l l imide f o r a n a l y t i c a l  imide l e n t  itself  features.  small  data.  to a straightforward structural  due t o t h e p r e s e n c e  spectroscopic  by column  of c e r t a i n very  characteristic  The compound p o s s e s s e d  a typical indole  a b s o r p t i o n i n t h e u l t r a v i o l e t r e g i o n (>ma.x 222, 27l|- ( s h ) , 2 8 3 , 291 mu).  I n a d d i t i o n t o a b s o r p t i o n band a t 3320 c m  i n the i n f r a r e d  spectrum  t h e r e appeared  (medium i n t e n s i t y ) and 1685 c m " istic 29)  o f a five-membered r i n g  exhibited  - 1  (NH)  s h a r p bands a t 1755  imide^^.  TheNMR s p e c t r u m  (Figure  (NH) and a n i n e -  p r o t o n m u l t i p l e t c e n t e r e d at?''2-. 7 due t o t h e a r o m a t i c  protons  of t h e benzene r i n g s .  The o< - p r o t o n on t h e h e t e r o c y c l i c  ring  of the moiety  as a one p r o t o n d o u b l e t a t 7^3.0,  The  benzyl methylene protons singlet aty5•55•  appeared  as u s u a l as a two p r o t o n  A two p r o t o n t r i p l e t  to the methylene protons  1  (strong), which are c h a r a c t e r -  1  a one p r o t o n s i n g l e t a t - r ' 1 . 9  appeared  cm"  on t h e c a r b o n  a t 7 " 6 . 2 was a s s i g n e d atom a d j a c e n t t h e i m i d e  n i t r o g e n , and f o r m i n g p a r t o f t h e e t h y l e n e b r i d g e t o t h e i n d o l e ring.  The two p r o t o n s  on t h e c a r b o n  of t h e b e n z y l o x y group appeared three proton t r i p l e t the e t h y l The  appeared  atom a d j a c e n t t o t h e o x y g e n  as a m u l t i p l e t a t 7"6.65 and a  at7"9ol5 f o r the methyl  protons of  group* mass s p e c t r u m  of the succinimide (Figure 0)  further s t r u c t u r a l evidence.  3  The m o l e c u l a r  provided  i o n p e a k was  -65  CO>£t cOpFt  /OCH^  H  (130) (71a)  MeOH  (131)  'IT  (133)  H ft  (13li-)  8  Et I R = H 5 R" = C H C HCH OCH 0 2  and/or R  CHCrij  H  (136)  2  = H j R = CRgCHCRgOCHgjtf Et  F i g u r e 2'8  (135)  2  (137)  -  R E L A T I V E -INTE NS I T Y ~ -  418 OJ  O  -68i n d l c a t e d as b e i n g was  d o m i n a t e d by peaks a t m/e 11+3,  m/e 11+3 the  the desired value  and 130 (135)  type  I n many s i m p l e  130  are the c h a r a c t e r i s t i c  indole alkaloids^- . 0  subsequent p r o d u c t i o n  (125)  r e a c t i o n the benzyl  ether moiety could  of the benzyl  could  9  91 i s  g r o u p and  (137). time e s t a b l i s h e d  be c y c l i z e d  (126).  i n low y i e l d  but during the course  Although l o s s o f the  be a v o i d e d  by c y c l i z a t i o n  c h l o r i d e • (127 )j s u b s e q u e n t r e d u c t i o n l i t h i u m aluminum h y d r i d e  f ragmen tsu-of  g r o u p was l o s t and t h e p r o d u c t  i s o l a t e d was t h e e n o l l a c t a m benzyl  indole  o f t h e t r o p y l i u m ion°  imide  The p e a k s a t  The p e a k a t m/e  via Bischler - Napieralski reaction^ of t h i s  and 91.  i n o u r l a b o r a t o r y h a d by t h i s  that the isomeric  and t h e s p e c t r u m  commonly o b s e r v e d . 0  and ( 1 3 6 ^ r e s p e c t i v e l y  u n d o u b t e d l y due t o t h e c l e a v a g e  Studies  o f 1+18  of the lactam  of the (129)  with  r e s u l t e d also i n l o s s of the  c h l o r i n e group.  A l t h o u g h a l t e r n a t i v e s were p o s s i b l y a v a i l a b l e  to preclude  d i f f i c u l t y another approach t o the c y c l i z a t i o n  this  of the five-membered r i n g t o the i n d o l e nucleus  was now t h o u g h t 70  more a d v a n t a g e o u s .  Studies  b y W e n k e r t and W i c k b e r g '  had  shown t h a t N - f / 3 - ( 3 - i n d o l y l ) - e t h y l ] ] - p i p e r i d i n e s c o u l d be cyclized acetate the  onto the i n d o l e nucleus or other  amine  (138)  o x i d i z i n g agents. with mercuric  of the c y c l i z e d ' p r o d u c t led  t o a mixture  by t r e a t m e n t w i t h  F o r example o x i d a t i o n o f  acetate  (11+0).  of the isomeric  mercuric  provided  a good  Similar oxidation of products  ( l l + l a ,b) „ ,  yield  (139)  -69-  (li+O) R = R = H ( l l i l a ) R = H, R' = E t (ll|lb) R = E t , R = H The i m i d e  (130)  in tetrahydrofuran i n 95$  was  t o t h e t e r t i a r y amine ( 1 3 1 ,  hydride  see F i g u r e  28)  yield.  The c r u d e amine was on a l u m i n a a n d was quantities  colorless  obtained  by column chromatography  as a l i g h t  under reduced pressure  brown gum.  Small readily  and y i e l d e d a c l e a r  glass.  The i n f r a r e d absorption  purified  o f t h i s compound, as w i t h t h e i m i d e , were  distillable  had  reduced w i t h l i t h i u m aluminum  s p e c t r u m o f t h e amine e x h i b i t e d no  i n the c a r b o n y l  r e g i o n i n d i c a t i n g the imide  b e e n removed and t h e u l t r a v i o l e t  normal i n d o l e .  s p e c t r u m was  In a d d i t i o n t o the chemical  function  that of a  a n a l y s i s the  -70t h e m o l e c u l a r f o r m u l a was e s t a b l i s h e d by h i g h r e s o l u t i o n mass  71 s p e c t r o m e t r y as The  C26 3i| 2° (Found: H  mass s p e c t r u m  p e a k a t m/e 260  N  390. 267;  390. 267)  ( F i g u r e 31) was d o m i n a t e d b y a v e r y i n t e n s e  which  c o u l d be a t t r i b u t e d  fragmentation of the parent molecule f r a g m e n t a t i o n mode i s a n a l o g o u s coupling product  Calc.  t o the simple  t o t h e i o n li+2.  t o t h a t observed  (68) m e n t i o n e d e a r l i e r .  This  f o r the  The p r e s e n c e  ofthe  b e n z y l e t h e r was a g a i n i n d i c a t e d , as i n t h e i m i d e , b y a s t r o n g p e a k a t m/e  91.  lit-  (11+2) a c c u r a t e l y i n t h e NMR  I t now became i m p o r t a n t t o l o c a t e spectrum  the chemical s h i f t  o f t h e p r o t o n on t h e c a r b o n  .c£ t o t h e n i t r o g e n o f t h e i n d o l e r i n g . absence i n t h e r e a c t i o n products from  I t s presence or  the mercuric  o x i d a t i o n w o u l d be a measure o f "the s u c c e s s t o t h e amines  (134,  F i g u r e 2 8).  acetate  of the c y c l i z a t i o n  Fortunately, this  u s u a l l y located at s l i g h t l y higher f i e l d  proton i s  than the other  protons  o f t h e i n d o l e r i n g , a s shown by t h e a n a l y s i s  indoles  and tryptamines? «73. 2  atom  These s t a d i e s h a v e  that this  p r o t o n u s u a l l y appears  depending  on c o n c e n t r a t i o n ^ and i s c o u p l e d  aromatic  of simple  demonstrated  i n t h e r a n g e of7"'3.0 -  3-4  t o t h e p r o t o n on  • RELATIVE INTENSITY --  -72the  indole  n i t r o g e n atom.  Indeed, taken  examination  a t 100  this  of  the  the a r o m a t i c  centered  at  benzyl  methylene and  adjacent doublet due  the  to the It  was  oxidation  and  reaction  cyclized This  of  Wickberg^O  was  352  mu  then  was  (131+) t o  i n the easily  hydroxide  the  to study  the  of t h i s  as  singlet  atom  a two  proton  at7"9»l5  was  again  group. mercuric  amine.  acetate  Preliminary method  of  further  of the  already  the  oxidation  iminium was  of the  salt  also  133  138  and  of the  Wenkert  139,  addition oxidation  of  product  133  and  absorbed product  to the  dilute  28).  provided  oxidation  w i t h sodium borohydride The  by  chromophore which This  following  (see F i g u r e  observed  compounds  region.  the  The  that a convenient  (131+).  to a solution  multiplet  proton  triplet ethyl  32)  singlet.  carbon  appeared  of the  oxide  remainder  proton  a broad  on  proton  The  was  n i t r o g e n atom of  protons  ultraviolet  product  the  a two  characteristic  reduced  on  as  oxidation, which case  a nine  appeared  three  protons  above.  as  7^1.55 a s  function  through  i n the  cyclization  proton  at  indicated  a compound w i t h a at  the  possible  product  type  appeared  cyclization  investigations the  (Figure  benzyloxy  now  proton  to a singlet  methylene  A  amine  to collapse  protons  methyl  that this  c o u p l i n g mentioned  7^6,70,  at  showed  of t h i s  deuterium  appeared  the  spectrum  A d d i t i o n of  7^2.75 a n d  nucleus  NMR  a doublet,  protons  indole  a t 7^?. 55  as  doublet  demonstrating  the  ( F i g u r e 32)  atr3»H  located caused  Mc/s  of  desired  sodium caused  a  -73.-  = 74disappearance  o f the  a p p e a r a n c e o f two This as  a b s o r p t i o n maximum a t 352  new  spectral shift  maxima a t 310  is indicative  indicated in Figure Initially  in this and  34  and  considerable  observed  s t a r t i n g m a t e r i a l was scale.  In f a c t ,  of c y c l i z e d uncyclized  i t was  products  one  amine and  chromatography. c h l o r i d e as  very  could  spectrum  - 20$)  as  and  from u n c y c l i z e d a  practical  always d i f f e r e n t i a t e  mixture  the  amines by t h i n - l a y e r i n carbon  tetra-  reagent produced a c h a r a c t e r i s t i c compounds w h i l e  green  t h e u n c y c l i z e d amine  brown c o l o u r , of t h i s r e a c t i o n i n d i c a t e d  chromophoric system i n the  a b s o r p t i o n maximum a t 352  the  on  cyclization  f o r t u n a t e t h a t among t h e  A more c a r e f u l e x a m i n a t i o n t h a t the  impossible  the c y c l i z e d  c o l o u r w i t h the c y c l i z e d gave a l i g h t  (15  products  shift,  encountered  the u l t r a v i o l e t low  33)•  compounds^.  Oxidation,  Antimony p e n t a c h l o r i d e  a spray  the  (see F i g u r e  in similar  acetate.  of c y c l i z e d  virtually  and  imine-enamine  Y i e l d s were f a i r l y  the complete s e p a r a t i o n  mu  d i f f i c u l t i e s were  r e a c t i o n with mercuric  only p a r t i a l .  322  o f an  r e - o x i d a t i o n were i n d i c a t e d by  being  an  and  mu  filtration  and  mu  r e a c t i o n mixture  r a p i d l y degenerated  other manipulations  up.  Exposure of a f a i r l y concentrated  salt  (133)  to a i r during  c y c l i z a t i o n products  and  required  which during  d u r i n g the  s o l u t i o n of the  the work-up l e d t o v i r t u a l l y only recovered  work-  iminium no  starting material.  C o n s e q u e n t l y , t h e r e a c t i o n p r o c e d u r e s were p e r f o r m e d u n d e r atmosphere of p u r i f i e d  had  nitrogen using dilute  solutions with  an  -75  F i g u r e 3k  .-76the  r e s u l t t h a t an  was  37%  overall  yield  of c y c l i z e d p r o d u c t s  obtained. Thin-layer  mixture  chromatography i n d i c a t e d t h a t a complex  of c y c l i z a t i o n  p r o d u c t s was  c h r o m a t o g r a p h y on a l u m i n a f a i l e d quantities  at hand.  to  separate  alumina and/or s i l i c a  B,  c'  C and  on  the  basis  not  combination of t e c h n i q u e s .  The  compounds were e x a m i n e d and  i n the  C)  The  spectra  s i m i l a r and  uncyclized  patterns  are 0  the  (100  present e.g.  i o n ILLIL  this  of a l l f o u r  pure t o  products  allow  350  (Figure-  been  in  (13) i n the  and  spectra  of a l l .  alkaloids ajmalicine  169,  A. s e r i e s o f s i g n i f i c a n t 170  peaks  156,  the  a l k a l o i d s m e n t i o n e d , t o a r i s e f r o m the  of the  tetra-  and  d e m o n s t r a t e d as p a r t i a l l y a r i s i n g  ( F i g u r e 36).  and  the  yohimbine  a p p e a r e d a t m/e case  for  their  i n a l k a l o i d s of the  ajmalicine  i n the  very  Mc/s).  peak w h i c h appeared  f o u r compounds a l s o a p p e a r s y o h i m b i n e arid has  e v e n by  A- number o f peaks p r e s e n t  hydro-yfi-carboline type^- , A- s t r o n g m-l  A fifth  much d i f f e r e n t f r o m t h a t o b s e r v e d  (131).  amine  fragmentation  »•  obtained  of  designated  case of the major  mass- s p e c t r a o f a l l t h e s e compounds  were v e r y  (23.)  separated  mass s p e c t r a  s u f f i c i e n t m a t e r i a l was  e x a m i n a t i o n o f t h e i r NMR  separation  These were  be  column  t h i n - l a y e r chromatography  of t h e i r Rf v a l u e s .  m i n o r c y c l i z e d amine D c o u l d  (B and  significant  g e l l e d to the e v e n t u a l  s m a l l q u a n t i t i e s o f f o u r compounds. A,  any  column  o f p u r e compounds, h o w e v e r , a c o m b i n a t i o n o f  c h r o m a t o g r a p h y f o l l o w e d by p r e p a r a t i v e on  Careful  from then  I8I4. w h i c h h a v e b e e n shown i n indole  -77p o r t i o n of the molecule.  D e u t e r a t i o n s t u d i e s have e s t a b l i s h e d  t h a t t h e l i k e l y f r a g m e n t s c o n t r i b u t i n g t o t h e s e peaks a r e those shown i n F i g u r e 36. was  indicated  and  m/e 91  The p r e s e n c e  by t h e p r e s e n c e  of the benzyl ether  The i n d o l i c n a t u r e  compounds was f u r t h e r shown by t h e i r in the ultraviolet..region  297 (m-91) and  o f p e a k s a t m/e  (tropylium ion).  (Mnax 22$,  typical  moiety  of a l l four  indole absorption  27k ( a h ) , 283,  291  mu) •.  (13) CHpOOOH  High of these C  r e s o l u t i o n mass s p e c t r o m e t r y benzyl ethers possessed  26 32 2° ( H  N  388*251). its  Found  -  R  9  mass s p e c t r u m as h a v i n g  Isomeric'products,  Calc:  (C«) I s o l a t e d was a l s o i n d i c a t e d b y a molecular weight  occurred  of  388.  t o produce a m i x t u r e o f  s i d e c h a i n on t h e f i v e - m e m b e r e d  i n d i c a t e d b y s t r u c t u r e 132  ( F i g u r e 28),  s a l t s w h i c h c o u l d be c o n s i d e r e d  to the indole nucleus. formed  388°252;  C,  there remained the q u e s t i o n of the l o c a t i o n  of the b e n z y l o x y p r o p y l  iminium  formula  t h e s e mass s p e c t r o m e t r i c r e s u l t s e s t a b l i s h e d t h a t  the c y c l i z a t i o n had i n f a c t  As  the molecular  388*251; B, 388*252;  The f o u r t h e t h e r  While  e s t a b l i s h e d t h a t three'  A third  i n the r e a c t i o n mixture  iminium  ring.  t h e r e w e r e two  as p o s s i b l y c y c l i z i n g salt  c o u l d a l s o be  i n vh i c h t h e d o u b l e  bond was  -79-  F i g u r e 3'6  -80 exocyclic  t o the  five-membered r i n g .  formation  o f t h e l a t t e r was  to a h i g h l y unfavorable two  observed llLla  and  products  o n l y one  dihydrocleavamine. the  realized  (139),  of b o t h - p o s s i b l e c y c l i z a t i o n  to had products  3  increased  e f f e c t s c r e a t e d -by t h e p r o x i m i t y of t h e s i d e c h a i n t o  the f o r m a t i o n  The  two  of isomer  were i m m e d i a t e l y  benzyl ethers  spectroscopy  a r e shown i n F i g u r e 37  would minimize  and  apparent  38  (100  this  obtained  the  preclude  (B and  Mc/s:) and  respectively.  i n the  t h e most o u t s t a n d i n g o f w h i c h was C w h i c h was  or  steric  li|5«  major c y c l i z e d  e x a m i n e d by NMR  the  o f A/-L/ - O - i n d o l y l ) - e t h y l J -  i t h a d been hoped t h a t the  i n d o l e p o r t i o n of the molecule  of  d e r i v a b l e from t h i s r e a c t i o n  A l t h o u g h W e n k e r t and W i c k b e r g ^  formation  would l e a d  Therefore,  (72a) w o u l d u l t i m a t e l y l e a d  b i n the c y c l i z a t i o n  piperidines  i t s cyclization  four-membered r i n g .  possible cyclization  ( 7 2 a and  However, even i f the  C)  the s p e c t r a  obtained  Radical differences  spectra of these the  were  aromatic  two  compounds,  region.  Ether  i n s l i g h t l y g r e a t e r amount t h a n e t h e r  reaction, e x h i b i t e d a nine proton m u l t i p l e t  r2»5 t o 3«1 ( s e e F i g u r e 38).  The  characteristic  i n the one  B.in  region  proton  -81doublet at7^3»H the  i n t h e u n c y c l i z e d amine due t o t h e  i n d o l e n u c l e u s was now a b s e n t .  a r o m a t i c p e a k s i n t h e NMR s p e c t r u m located  at h i g h e r f i e l d ,  By c o n t r a s t , some o f t h e o f e t h e r B ( F i g u r e 37)  i n t h e r e g i o n 7^3.0  t o 3*5.  t h e mass s p e c t r a l e v i d e n c e h a d a l r e a d y e s t a b l i s h e d B was i n f a c t  a cyclized  were  Although that ether  compound, t h e a b s e n c e o f t h e <* - p r o t o n  on t h e i n d o l e n u c l e u s was a l s o c o m p l e t e l y c o n f i r m e d deuteration experiment.  - p r o t o n on  by a  E x c h a n g e o f t h e p r o t o n on t h e i n d o l e  n i t r o g e n atom w i t h d e u t e r i u m c a u s e d  no change i n t h e a r o m a t i c  r e g i o n o f the spectrum,  for this  shift  i n the aromatic  became a p p a r e n t spectra. was  The r e a s o n  r e g i o n o f t h e NMR s p e c t r u m  upon e x a m i n a t i o n  The p r o t o n  at-rl.80.  of ether B while i n ether  The m e t h y l e n e p r o t o n s  of the benzyloxy methylene protons  t o e t h e r C r e v e a l e d t h e most  feature  spectra.  of ether B which  one  The s p e c t r u m  integrated  at-r5°60 i n  for approximately  o f ether C possessed  f o r approximately  T h i s was p a r t i a l l y  important  A. d o u b l e t was p r e s e n t  the s p e c t r u m  integrating  The d o w n f i e l d  i n the spectrum of  ether B r e l a t i v e  proton.  of the benzyloxy  at7"5>«>30 and 5°60 I n  t h e s p e c t r a o f e t h e r s B and C r e s p e c t i v e l y .  of these  of ether B  on t h e n i t r o g e n a t o m o f t h e i n d o l e n u c l e u s  g r o u p were l o c a t e d a s t w o p r o t o n s i n g l e t s  shift  upfield  o f o t h e r f e a t u r e s o f t h e two  l o c a t e d a t yO.^O i n t h e s p e c t r u m  C i t appeared  dramatic  a broad  multiplet  one p r o t o n I n t h e r e g i o n 7^5*7.  o b s c u r e d , however, by t h e m e t h y l e n e  singlet  of  t h e benzyloxy group.  NMR s t u d i e s ^ ° * ^ o f i n d o l e a l k a l o i d s  of  t h e t e t r a h y d r o - / ? - c a r b o l i n e t y p e h a v e shown t h a t t h e C-3  -82-  -81+p r o t o n may tion  be  l o c a t e d as l o w  of the molecule o  p r o t o n appears  as 7 ^ 5 « 5 d e p e n d i n g on t h e  I n the case  as a m u l t i p l e t  conforma-  o f t h e compound ll+6  this  i n t h e r e g i o n T " ? * 8 t o 6.0^°„  if  (11+6) While expected  the d e s i r e d c y c l i z e d b e n z y l e t h e r C  to e x h i b i t  a one  proton multiplet  C-3j, t h e u n d e s l r e d c y c l i z a t i o n p r o d u c t show a d o u b l e t j one  of the protons  undesirable  c y c l i z a t i o n product  although i n s l i g h t l y  (II4.5) was  a t C-11+  now  The  upfield  observed  shift  than  of the a r o m a t i c  i n the spectrum  appeared,  protons  obtained,  of the  72a.  indole nucleus  be a t t r i b u t e d  to  M o l e c u l a r models of  be e a s i l y l o c a t e d d i r e c t l y b e n e a t h  the  the d e s i r e d product  compound 11+5 show t h a t the b e n z e n e r i n g may  to  been  i n fact being  o f e t h e r B may  p r o x i m i t y o f the b e n z y l o x y group.  having  It  at  expected  spectral data, that  11+5 was  lower y i e l d  was  f o r the proton  r e p l a c e d by t h e b e n z y l o x y p r o p y l s i d e c h a i n . t h e r e f o r e , on t h e b a s i s o f t h i s NMR  (72a)  the  the  of the benzyloxy" group the i n d o l e n u c l e u s .  S u c h an a r r a n g e m e n t c o u l d c a u s e a. s h i e l d i n g o f t h e i n d o l e aromatic  protons  chemical s h i f t s protons  observed  and  a l s o l e a d to the d i f f e r e n c e s i n the  of the  i n d o l e (NH)  i n these  two  and  the b e n z y l o x y  compounds.  A similar  methylene orientation  -85of the benzyloxy  group w i t h r e s p e c t t o the i n d o l e nucleus i n  t h e c a s e o f e t h e r C i s shown b y m o l e c u l a r m o d e l s t o be v e r y unlikely. I t now became e v i d e n t t h a t a s e p a r a t i o n o f t h e d e s i r e d c y c l i z a t i o n products as e p i m e r i c  H o w e v e r , s e p a r a t i o n o f compounds  and a t t h e p o s i t i o n  r e a c t i o n i n the f i n a l  stages  is lost  Since  during the  of the s y n t h e s i s while  the s y n t h e s i s o f b o t h d i h y d r o c l e a v a m i n e s position  epimeric  o f t h e e t h y l g r o u p i n 72a w o u l d be  u n n e c e s s a r y s i n c e t h e a s y m m e t r y a t C-3 cleavage  compounds was r e q u i r e d  compounds w i t h t h e s t r u c t u r e U4.5 w o u l d n o t y i e l d  dihydrocleavamine„ a t C-3  from the undesired  epimeric a t the  o f t h e e t h y l g r o u p , w o u l d be a d e s i r a b l e f e a t u r e .  s e p a r a t i o n o f t h e v a r i o u s b e n z y l e t h e r s was n o t f e a s i b l e  on a s c a l e s u i t a b l e of the c y c l i z e d  f o r continued  s y n t h e t i c work, the m i x t u r e  and u n c y c l i z e d e t h e r s was c o n v e r t e d  t o the  corresponding a l c o h o l s . Removal o f t h e b e n z y l e t h e r g r o u p i n a m i x t u r e above compounds was hydrogenolysis  accomplished  acid??*? .  mixture  indicated  8  catalytic  T h i n - l a y e r chromatography of the r e a c t i o n the presence of f i v e  a g a i n by t h e i r c h a r a c t e r i s t i c p e n t a c h l o r i d e , as w e l l  cyclized  compounds  color reaction with  antimony  as t h e u n c y c l i z e d amino a l c o h o l .  a l c o h o l s had a g r e a t e r v a r i a t i o n  .G, was  by  u s i n g p a l l a d i u m on c h a r c o a l i n g l a c i a l  acetic  corresponding  i n 85$ y i e l d  o f the  benzyl ethers  r e a d i l y separated  i n Rf values  The  than the  and t h e m a j o r a l c o h o l d e s i g n a t e d  by c o l u m n c h r o m a t o g r a p h y on  alumina  D  - 8 6 -  T h i s a l c o h o l was o b t a i n e d as an amorphous s o l i d as b e i n g t h e d e s i r e d compound by i t s s p e c t r a l High  r e s o l u t i o n mass s p e c t r o m e t r y  m o l e c u l a r f o r m u l a was C  1 9  H  N 0 2  2 6  The mass s p e c t r u m  2 9 8 ° 2 0 5 ) »  significant  peaks a t M - l  a l s o observed  (Found?  m/e l 8 1 i  possessed  3 9 )  1 7 0 ,  1 6 9  and  1 5 6 ,  i n t h e mass s p e c t r a o f t h e b e n z y l e t h e r s .  H o w e v e r , t h e s t r o n g p e a k a t m/e  9 1 observed  t h e b e n z y l e t h e r s was l a c k i n g .  The u l t r a v i o l e t  was  that the  Calc:  2 9 8 ° 2 0 3 ;  s  indicated  characteri.stics.  established  (see F i g u r e  ( 2 9 7 ) ,  and was  i n the spectra of  t h a t o f a n o r m a l i n d o l e and t h e i n f r a r e d  chloroform possessed  absorption  spectrum i n  a b s o r p t i o n i n the h y d r o x y l r e g i o n  i ( 3 1 0 0  -  (NH),  3 6 0 0  cm,  - 1  ) i n addition  t o the sharp s p i k e a t  The 1 0 0 Mc/s NMR s p e c t r u m  3 3 5 0  (Figure 1+0) indicated  cm."  that the  b e n z y l g r o u p h a d been r e m o v e d as t h e a r o m a t i c r e g i o n now consisted the  of a four proton m u l t i p l e t  two p r o t o n s i n g l e t  originally The  removal  observed of this  at7^2,85  of the benzyloxy methylene  i n the region latter  c l e a r l y r e v e a l e d a broad ascribed  centered  signal  T ' 5 ° 3  to  5 » 7  to the C - 3 proton.  group  had d i s a p p e a r e d .  i n t h e NMR s p e c t r u m  one p r o t o n m u l t i p l e t That t h i s  s i g n a l was n o t s i m p l y deuterium  which  The m e t h y l e n e  of t h e p r i m a r y a t r 6 , 6 l  no e f f e c t alcohol  and t h e m e t h y l  as a d i s t o r t e d  triplet  on t h i s  peak.  exchange,  g r o u p were p r e s e n t as a b r o a d protons centered  now  atY^>„7o  t h e h y d r o x y l i c p r o t o n was shown t h r o u g h produced  and  o f the e t h y l group a t 7 ^ 9 o l 8  0  protons singlet  appeared  -88-  -89The a l c o h o l C was e s t a b l i s h e d as b e i n g d e r i v e d f r o m t h e ether C i n a separate was p u r i f i e d  experiment.  A. s m a l l q u a n t i t y o f e t h e r C  by t h e chromatographic  e a r l i e r and h y d r o g e n o l y z e d  procedures  described  under the i d e n t i c a l c o n d i t i o n s .  The r e s u l t a n t a l c o h o l o b t a i n e d  was shown by t h i n  layer  c h r o m a t o g r a p h y t o be i d e n t i c a l  t o a l c o h o l C obtained  hydrogenolysis  o f t h e e t h e r m i x t u r e , and d i f f e r e n t  other Isomeric  alcohols  Small  quantities  from a l l  obtained.  of three a d d i t i o n a l  a l c o h o l s were o b t a i n e d  from the  by a c o m b i n a t i o n  isomeric cyclized  amino  o f column- c h r o m a t o g r a p h y  f o l l o w e d b y p r e p a r a t i v e t h i n - l a y e r c h r o m a t o g r a p h y on s i l i c a gel.  The a l c o h o l d e s i g n a t e d  B was f o r m e d  q u a n t i t y t h a n a l c o h o l C and was s u s p e c t e d d e r i v e d f r o m e t h e r B,  High  provided  formula •  Gale.  298°205)»  spectrum and  the molecular  as h a v i n g  r e s o l u t i o n mass C ^ O ^ A ^ O  The f r a g m e n t a t i o n  spectrometry  t h a t o f a normal i n d o l e .  consisted of a four  multiplet  t o 3.15  two p r o t o n  The r e m o v a l  singlet  shift  of the benzyloxy  o f the protons  7^3.1'5'to 3.5 i n t h e b e n z y l e t h e r . i n accord w i t h the e a r l i e r indole nucleus  proton  and no l o n g e r  o f t h e b e n z y l g r o u p was t h u s  by a d o w n f i e l d  298*205;  (Pound:  The NMR s p e c t r u m ( F i g u r e  the  been  to t h a t of a l c o h o l C  s p e c t r u m was a g a i n  i n t h e r e g i o n r2.5  less  p a t t e r n i n t h e mass  ( s e e F i g u r e 39) was s i m i l a r  the u l t r a v i o l e t  inslightly  possessed  m e t h y l e n e g r o u p at7'5°3» s e e n t o be a c c o m p a n i e d  w h i c h were l o c a t e d a t This s h i f t  suggestion  i s , therefore,  that the protons  of the  were s h i e l d e d t o some e x t e n t b y t h e b e n z y l o x y  Figure  i|l  -91group.  An I s o l a t e d one p r o t o n  w h i c h was a s c r i b e d amino a l c o h o l .  t o t h e C-3 p r o t o n  Again t h i s  with deuterium oxide. as NMR  d o u b l e t .was p r e s e n t a t T'5.72  usual appeared  o f the undesired  cyclized  s i g n a l was n o t a f f e c t e d b y e x c h a n g e  The m e t h y l p r o t o n s o f t h e e t h y l g r o u p  as a t h r e e  proton  triplet  atT"9.l5»  The  spectrum of this.compound, t h e r e f o r e , supported the e a r l i e r  proposal  t h a t c y c l i z a t i o n was o c c u r r i n g  acetate  r e a c t i o n t o provide  product  (72a;) and t h e u n d e s i r e d  The  formula  both the desired  r e m a i n i n g two I s o m e r i c  obtained  during  the mercuric  cyclization  p r o d u c t (11+5)« amino a l c o h o l s w h i c h were  p u r e w e r e a l s o i n d i c a t e d as p o s s e s s i n g C  H A 2° n  1 9  b  v  t  n  e  f  o  u  n  d  2  ( C a l c . 298*205).  quantities  (see F i g u r e  of the alcohols  normal i n d o l e u l t r a v i o l e t  molecular  298°205 and 29&°20l+  T h e i r mass s p e c t r a  e s s e n t i a l l y t h e same as t h a t exhibited  values  the  B and C and b o t h  absorption.  o f t h e s e i s o m e r s were o b t a i n e d  39) were  Insufficient  i n a pure  state f o r  NMR a n a l y s i s . The (73a)  conversion  desired  intramolecular  of the a l c o h o l  II4.9  to the quaternary  f o r r i n g c l e a v a g e was now e x a m i n e d .  salt  Spontaneous  q u a t e r n i z a t i o n h a d been o b s e r v e d d u r i n g t h e  e l u c i d a t i o n o f the s t r u c t u r e of r e s e r p i n e ? 9 r e a c t i o n had been r e c e n t l y r e p o r t e d  and a s i m i l a r  i n the l i t e r a t u r e .  N.  fin Y o n e d a and c o - w o r k e r s containing final  i n the synthesis  the sarpagine  r i n g formation  o f compounds  r i n g s y s t e m (11+8) h a d a c h i e v e d  the  t h r o u g h t o s y l a t i o n o f t h e a l c o h o l s 11+7 „  (147)  (148)  A\n a n a l o g o u s c o n v e r s i o n quaternary  s a l t was  of the  c a r r i e d out  a l c o h o l 149  v i a the  with methansulfonyl  pyridine  an  p o s s i b l y the the  provided  s a l t 15>0,  presence of the  e x a m i n a t i o n of the  w h i c h was  f r e e base  new  green s p o t s ,  than the  starting  one  normal i n d o l e a b s o r p t i o n standing  for a period  g r a d u a l l y faded w i t h base l i n e  of the  quaternary  salt.  t r e a t e d w i t h ammonia t o e n s u r e  (l^l).  Thin-layer  at the base l i n e This  i n the  o f a few the  chloride in  chromatographic  time i n d i c a t e d  s t a r t i n g a l c o h o l and  alcohol.  mesylates.  Insoluble material,  r e a c t i o n product at this  complete absence of the two  ether  the  intermediate  T r e a t m e n t o f compound 149 a t 0°C.  to  and  the  presence  one  less  p r o d u c t p o s s e s s e d an ultraviolet region.  days the l e s s p o l a r  appearance of a s t r o n g e r  be  compound so t h i s  m a t e r i a l was  sodium i n l i q u i d  ammonia^7  0  e x p e c t e d t o be subjected  essentially  spot spot at  a very  to-reduction  E x a m i n a t i o n o f the  polar  Upon  t h i n - l a y e r chromatographic p l a t e .  (73a). w o u l d  authentic  o f w h i c h were i d e n t i c a l  polar with  crude  samples of the  two  isomeric  i n c o l o u r and  the  The  product  by t h i n - l a y e r c h r o m a t o g r a p h y i n d i c a t e d t h e p r e s e n c e o f compounds, two  of  Rf  three to  dihydrocleavamines.  the  -93-  (152:) U n f o r t u n a t e l y the t h i r d  (153)  component o f t h e m i x t u r e h a d a' v e r y  s i m i l a r R f v a l u e t o t h e two d i h y d r o c l e a v a m i n e s  although i t  was r e a d i l y d i s t i n g u i s h a b l e  by i t s c o l o u r .  chromatography of t h e t o t a l  product p r o v i d e d a pure  w h i c h was  identical  Careful  alumina compound  t o a u t h e n t i c [(.oodihydrocleavamine  by t h i n - l a y e r c h r o m a t o g r a p h y on b o t h a l u m i n a  (153)  and s i l i c a g e l  w i t h r e s p e c t t o R f and c o l o u r r e a c t i o n s o b t a i n e d w i t h a v a r i e t y of spray r e a g e n t s . was s u p e r i m p o s a b l e  A mass s p e c t r u m  of t h i s  w i t h t h e mass s p e c t r u m  sample o b t a i n e d f r o m n a t u r a l  sources.  synthetic  compound  o f an a u t h e n t i c  -94Preparative mixture  t h i n - l a y e r chromatography of the  o f compounds  afforded  i d e n t i c a l t o an a u t h e n t i c by  remaining  a n o t h e r p u r e compound w h i c h was  s a m p l e o f [(./^-dihydrocleavamine  t h i n - l a y e r c h r o m a t o g r a p h y on a l u m i n a and s i l i c a  variety  of spray  was i d e n t i c a l  reagents,  to that  dihydrocleavamines  (93a)  The mass s p e c t r u m o f t h i s  compound  described  here f o r the s y n t h e s i s of  has a l s o been a p p l i e d t o quebrachamine  by o t h e r w o r k e r s  51 recently published,. „  i n o u r l a b o r a t o r y and h a s b e e n The c o n d e n s a t i o n  e s t e r d e r i v a t i v e (102a) w i t h conversions  gel with a  of a u t h e n t i c 4/3-dihydrocleavamine „  The s u c c e s s f u l r o u t e the  (152)  of the i s o m e r i c s u c c i n i c  tryptamine  t o the q u a t e r n a r y  mesylate  and s u b s e q u e n t (92a) f o l l o w e d  reduction  t o quebrachamine has d e m o n s t r a t e d  a general  route  that  this  analogous by i s i n fact  t o t h e q u e b r a c h a m i n e and d i h y d r o c l e a v a m i n e  The s u c c e s s f u l c o n v e r s i o n  series.  of 4y8-dihydrocleavamine t o  fti  carbomethoxydihydrocleavamine  has a l s o been a c c o m p l i s h e d i n  o u r l a b o r a t o r y and w i l l  now be m e n t i o n e d b r i e f l y .  o f [(./^-dihydrocleavamine  (152)  provided  the chloroindolenine  potassium c y a n i d e  8 2  to provide  with t-butyl hypochlorite (154)  w h i c h was r e a c t e d  in  provided  carbomethoxy^^-dihydrocleavamine  a l l respects  conversion studyo  with  an a u t h e n t i c  sample.  of quebrachamine t o v i n c a d i n e  An  8 2  with  a cyanodihydrocleavamine  The l a t t e r compound, on t r e a t m e n t w i t h m e t h a n o l i c acid  Oxidation  (155 )•  hydrochloric (156)  identical  analogous  i s c u r r e n t l y under  -95-  It  c a n be  seen, t h e r e f o r e , t h a t the  i n S.ection B i s not and  only a general route  quebrachamine but  m e t h o x y g r o u p as w e l l studies and  as  The  (157)  Shortly after this  had  entry into  use  the  and  to  transannular the  Iboga,  a route  (158)  carbo-  cyclization Aspidosperma  of v a r i o u s methoxylated  pyrifolidin  described  dihydrocleavamine  i n t r o d u c t i o n of a  s y n t h e t i c sequence would p r o v i d e  s u c h as voa.cangin  mine and  w i t h the  the p r e v i o u s  completes a general  V i n c a al k a l o i d s .  in this  coupled  s y n t h e t i c route  to  tryptamines alkaloids  „  s y n t h e s i s o f [jc(- and l L / 3 - d i h y d - r o c l e a v a -  corresponding  ij.y8~carbomethoxydihydrocleavam.ine  been p u b l i s h e d , a second s y n t h e s i s of the  two  isomeric  dihydrocleavamines  appeared  ~97~ Experimental  ° Fart A  M e l t i n g p o i n t s were d e t e r m i n e d uncorrected.  The u l t r a v i o l e t  95% e t h a n o l infrared  spectrometers=  second  (unless  scale with reference  shifts  on an A t l a s CH-Ij. mass s p e c t r o m e t e r weight determinations  performed  on a W i l k i n s recorded  and h i g h r e s o l u t i o n m o l e c u l a r  A n a l y s i s were c a r r i e d  Silica  i n t h e T i e r s T*  Mass s p e c t r a w e r e  were d e t e r m i n e d  M u l h e i m ( R u h r ) , Germany, M i s s  Columbia.  are given  A60  t o t e t r a m e t h y l s i l a n e as t h e I n t e r n a l  A e r o g r a p h A u t o p r e p , Model A-700.  the rnicroa n a l y t i e a l  (NMR)  a t 60 m e g a c y c l e s  i n d i c a t e d ) on a V a r l a n  Gas c h r o m a t o g r a p h y was  spectrometer..  magnetic resonance  i n deuteriochloroform  otherwise  M o d e l 2 1 and  on P e r k i n - E l m e r  Nuclear  i n s t r u m e n t - and t h e c h e m i c a l  'standard.  In  on a C a r y 11 r e c o r d i n g s p e c t r o p h o t o m e t e r , and t h e  s p e c t r a were r e c o r d e d per  (UV) s p e c t r a were r e c o r d e d  ( I R ) s p e c t r a were t a k e n  M o d e l 137  on a K o f l e r b l o c k and a r e  on an A E I MS'-9 o u t by D r . A..  C. J e n k i n s  mass Bernhardt,  1  and Mr. P. B o r d a o f  l a b o r a t o r y , the U n i v e r s i t y of B r i t i s h  G e l G a n d Wbelm a l u m i n a c o n t a i n i n g e l e c t r o n i c  p h o s p h o r were u s e d f o r t h i n - l a y e r c h r o m a t o g r a p h y and Shawinigan alumina d e a c t i v a t e d w i t h 3 ml. of 10% a c e t i c acid per  100 g . ( u n l e s s  otherwise  i n d i c a t e d ) was u s e d f o r c o l u m n  chromatography, Nipecotic  acid hydrochloride  Nicotinic hydrqchloric oxide  (U46  acid  (76)  (2.0.0 g . , 0.163 m o l e ) was  a c i d and h y d r o g e n a t e d g.) a t 1 . 5  d i s s o l v e d i n IN  i n the presence of  atmospheres pressure  until  platinum  the uptake  „ 89  of hydrogen had ceased  (approximately  was removed b y f i l t r a t i o n , and  3 hours)  0  (73 g») was a d d e d ,  barium hydroxide  a n y r e s u l t i n g p i p e r i d i n e was s t e a m distilled„  of the steam d i s t i l l a t i o n sulfuric  87$) mp. 2l+2-2l|l|.  ( L i t o ^ 239°) as a w h i t e  0  3  absorption  for  nipecotate,,  the preparation  of methyl  Crude n i p e c o t i c a c i d h y d r o c h l o r i d e reduction of n i c o t i n i c  solid.  m l . ) and t h e m i x t u r e  cooled and  This  and was u s e d  s  crude  directly  (20 g.) p r e p a r e d b y  a c i d , was c o v e r e d  w i t h a %%> b y  weight s o l u t i o n o f hydrogen c h l o r i d e i n absolute  methanol  r e f l u x e d f o r 10-12 h o u r s .  s o l u t i o n was c o n c e n t r a t e d  60 ml„, c o o l e d  (23.1+ g .  (77)  nipecotate  resulting  Evaporation  nipecotic acid hydrochloride  a c i d p o s s e s s e d no u l t r a v i o l e t  (160  amount o f  a c i d t o n e u t r a l i z e t h e e x c e s s b a s e and t h e  of the f i l t r a t e p r o v i d e d  Methyl  The r e s i d u e  was t r e a t e d w i t h a n e x a c t  r e s u l t a n t b a r i u m s u l f a t e removed b y f i l t r a t i o n .  the  The c a t a l y s t  The  i n vacuo t o approximately  I n an i c e - b a t h and d i l u t e d w i t h e t h e r .  This  s o l u t i o n was q u i c k l y t r a n s f e r r e d t o a s e p a r a t o r y  s h a k e n w i t h a 30% s o d i u m h y d r o x i d e  solution.  funnel  The- aqueous  a l k a l i n e l a y e r was e x t r a c t e d w i t h t w o a d d i t i o n a l p o r t i o n s o f ether, the e x t r a c t s being and  combined w i t h t h e o r i g i n a l  d r i e d over anhydrous sodium s u l f a t e .  of t h e r e m a i n i n g yellow  colorless  layer  The e t h e r and most  a l c o h o l was e v a p o r a t e d and t h e r e s i d u a l  o i l distilled  nipecotate  ether  under reduced pressure  (6.7 g , 3% 0  yield  from n i c o t i n i c  o i l , b . p . 53-54°/0«7 mm. ( L i t . .  3 6  t o provide  methyl  a c i d ) as a c l e a r  82.-81+°/6 mm.).  -99-  Infrared  (film):  signals:  6 . 3  ( s i n g l e t , 3H  -OCH3).  S  (-NH) c m , ' .  NMR  1  3 2 5 0  9,9$. G a l e , f o r C y H ^ O g N r  N,  9 c 2 5 ;  (-COOCH^),  1 7 2 5  Pound: C  C, 5 8 . 6 1 ; H,  5 8 . 7 2 ;  5  H, N,  9 . 1 5 ;  9 . 7 8 »  n i p e c o t a t e p-bromobenzamide ( 7 8 )  Methyl  A mixture  of methyl  nipecotate  to  ml „ ) b r o u g h t i n t o stand  then  poured rapid  into  by f i l t r a t i o n ,  by s l i g h t w a r m i n g and a l l o w e d  f o r 21). h o u r s .  The s o l u t i o n  ( 3 0 ml.) w i t h  d i l u t e ammonium h y d r o x i d e  The r e s u l t a n t  white  was  5 m l . , then  I n vacuo t o a p p r o x i m a t e l y  ice-cold  stirring.  zation  solution  a t room t e m p e r a t u r e  concentrated  mols),  ( 2 . 2 g», 0 . 0 1 0 mols )'•' and p y r i d i n e  p-bromobenzoyl c h l o r i d e (15  ( 1 . 0 go, 7 ° 0 1 .  p r e c i p i t a t e was removed  washed w i t h w a t e r and a i r d r i e d ,  Recrystalli-  of t h i s m a t e r i a l from methanol-water provided the  p u r e amide as c o l o r l e s s  p l a t e l e t s , mp.  1 0 9 . 5 - 1 1 0 „ 0 ° C „ Pi  Infrared  (loge)t  >max„  1 7 3 0 (-COOCH^), 1 6 3 0 (-CN-Jem." .  (KBr):  Ultraviolet,  1  2 2 8  iru*.  (IL.11)  NMR s i g n a l s :  2»1+  (doublet,  2H, a r o m a t i c ) , 2 . 7 ( d o u b l e t , 2H, a r o m a t i c ) , 6 . 3 ( s i n g l e t , Pounds  -OCH3K  1  lij..71;  Methyl  Br,  H,  5 ° 1 0 ;  l 6  3  C,  N,  0, 1 1 + , 6 6 ; B r ,  1+.23;  H,  5 1 . 5 5 ;  N,  1+.95;  1 + . 3 0 ;  21+.80.  ethyleyanoacetate ( 8 2 )  To a s o l u t i o n methanol (30  5 1 . 7 0 ; -  Calc. f o r C j^H 0 NBr:-  21L.70. 0 ,  C,  3H,  o f sodium  ( 7 « 1  go,  0 . 3 0 8  ( 1 2 5 ml.)"was added a s o l u t i o n  of methyl  g . , 0.301+ m o l s ) i n a b s o l u t e m e t h a n o l  reaction  mixture  was c o o l e d  mols) i n absolute  with s t i r r i n g  cyanoacetate  ( 1 2 5 ml.).  The  i n an i c e - b a t h  -100d u r i n g the a d d i t i o n , ,  The  resultant  warm t o room t e m p e r a t u r e , iodide was  stirred  was  evolved.  temperature  f o r 10 m i n u t e s ,  then  The  during this  m i x t u r e was  by d i s t i l l a t i o n and  ethyl  a d d i t i o n , as c o n s i d e r a b l e  then s t i r r e d  a t room i t was  M o s t o f t h e m e t h a n o l was  the r e s i d u a l d a r k r e d m i x t u r e  removed  of  liquid  sodium i o d i d e t r a n s f e r r e d to a s e p a r a t o r y funnel,,  water,  c o n t a i n i n g a few m l .  a c i d was ether.  a d d e d , and The  of c o n c e n t r a t e d h y d r o c h l o r i c  the m i x t u r e  with  e t h e r e x t r a c t s were c o m b i n e d , washed w i t h  cold  and  dried  over anhydrous sodium  sulfate.  E v a p o r a t i o n o f t h e e t h e r p r o v i d e d an o r a n g e o i l w h i c h under reduced  (31 go) b p , triplets,  Ice  e x t r a c t e d three times  water to n e u t r a l i t y  distilled  to  The r e a c t i o n . f l a s k  f o r a f u r t h e r !•§- h o u r s , a f t e r w h i c h t i m e  n e a r l y n e u t r a l t o litmus».  and  allowed  ( 5 l „ 0 g „, 0,327 m o l s ) added d r o p w i s e .  cooled i n t e r m i t t e n t l y  heat  s o l u t i o n was  pressure  110-ll8°/ 8 mm.  to give a clear colorless o i l  NMR  3  was  signals:  8„9  and  9*0  (two  -CH2CH3),  T h i s p r o d u c t was  shown by gas  chromatography  (detailed  c o n d i t i o n s b e l o w ) as b e i n g a m i x t u r e  of t h r e e components, the  major  ethylcyanoacetate.  (60$) b e i n g t h e d e s i r e d m e t h y l Small quantities  separated J column  by gas  of the methyl  c h r o m a t o g r a p h y on an  (I4.5/6O Chrom W  5' x -^", !  9  h e l i u m f l o w r a t e 90 m l / m i n ) o 0  2230 (-C=N) c m o " , NMR 1  8„9  (triplet,  3  e t h y l c y a n o a c e t a t e were  signalsr  H , .-CH2CH3), 6.55  analytical  20$  column temperature  Infrared (film):  110°C  17I4.O (-COOCH3),  6„25 ( s i n g l e t , 3H, (triplet,  Apiezon  -OCH3),  I H , NC-CHCOOCH3).  -101Pound:  C,  56.22:; H,  6.93,  N,  11.55-  Calc. for C H N0 r 6  9  C,  2  56.68° H, 7.13; N, 11.02. Similar isolation (10$)  o f t h e s m a l l e s t component o f t h e  a l l o w e d i t s i d e n t i f i c a t i o n as u n r e a c t e d m e t h y l  (superimposable properties The  infrared  - silica  third  s p e c t r a and  thin-layer  mixture  cyanoacetate  chromatographic  g e l , benzene).  component o f t h e m i x t u r e  in small quantity.  Infrared  (30$)  1740  (film):  was  also  isolated  2230  (-COOCH3),  (-car) cm." . 1  Methyl 3-chloropropylethyIcyanoacetate To a s o l u t i o n methanol  (350  ml.)  a c e t a t e , methyl  of sodium was  (l5«6 and  chloropropane  r e s u l t a n t m i x t u r e was heat  o f r e a c t i o n had  which  1.18  m o l e s ) was  t i m e t h e s o l u t i o n was  neutral  and  orange o i l t r a n s f e r r e d  alkylated)  l-bromo-3-  added d r o p w i s e .  subsided', then r e f l u x e d  l a r g e l y removed I n v a c u o and  was  minutes,  warmed o n l y s l i g h t l y u n t i l  was  water  ethylcyano-  m o l e s o f m a t e r i a l w h i c h c a n be  g„,  i n absolute  (101 g„, c o n t a i n i n g  A f t e r a p p r o x i m a t e l y 15 (186  0.680 m o l e s )  methyl d i e t h y l c y a n o a c e t a t e  as o b t a i n e d i n t h e a b o v e e x p e r i m e n t  with s t i r r i n g .  s  added a m i x t u r e o f m e t h y l  cyanoacetate  a p p r o x i m a t e l y 0.58  g.  (83)  the  The initial  f o r 2 hours  to litmus.  The  methanol  the r e s i d u a l mixture  to a separatory funnel.  after  of  solid  Cold  c o n t a i n i n g a. few m l . o f c o n c e n t r a t e d h y d r o c h l o r i c a c i d  added and  the o i l which  aqueous l a y e r was  s e p a r a t e d t a k e n up  in ether.  e x t r a c t e d t w i c e more w i t h e t h e r , t h e  c o m b i n e d , washed w i t h w a t e r  t o n e u t r a l i t y and  dried  The  extracts  over  102 anhydrous sodium s u l f a t e . gave an  o r a n g e o i l w h i c h was  t h r o u g h a 15 35=1+0°C was mixture  C o n c e n t r a t i o n of the e t h e r  cm.  distilled  V i g r e u x column.  The  a t 5 mm. first  acetate with ethyl ethylcyanoacetate  82-95°)' obtained  cyanoacetate)  d i e t h y l c y a n o a c e t a t e ( I d e n t i c a l by  i o d i d e a b o v e ) and (50  g.)  0  1735  o v e r a l l y i e l d from  210°,  (-COOCH3),  30$  (distorted, t r i p l e t ,  o b t a i n e d by  gas  (1+5/60 Chrom.  h e l i u m p r e s s u r e 50] p s i . ) 2220 (-G=N) cm." . 1  2H,  (triplet,  -CH C1) . 2  3H,  Pound:  C a l c . f o r C H i ^ N 0 2 C i : C, 9  W,  5' x \"\  Infrared  NMR  signals:  -CH CH ), 2  C,  3  52.61+j H,  53-13; H,  6.93;  6.88.  3-Carbomethoxy°3°ethylpiperidine Methyl m o l e s ) was (8.0  methyl  o i l bp 11+0-11;8° ( m o s t l y  J column  - O G H 3 ) , 8.95  '6.1+  N,  3-chloropropyl-  (60 g„,  ( s i n g l e t , 3H,  6.56.  cyano-  3-chloropropylethylcyanoacetate  6.2  N,  of methyl  Pure methyl  as a c l e a r c o l o r l e s s  column temperature  gas  b o i l i n g i n t h e r a n g e 82-11+0°  c h r o m a t o g r a p h y on an A p i e z o n  7.10;  methyl  -An a n a l y t i c a l s a m p l e was  • II4.I4.—II4.7 )»  (film)?  b.p.  r e c o v e r e d b r o m o c h l o r o p r o p a n e f o l l o w e d by a  of methyl  t h e n was  pressure  fraction,  c h r o m a t o g r a p h y t o t h a t o b t a i n e d by a l k y l a t i o n  (mostly  solution  go,  w h i c h SN  21; h o u r s  3-chloropropylethylcyanoacetate  (8.0 g., 0.0393  added o v e r 1 h o u r . t o a s t i r r e d s u s p e n s i o n  10$  o f Pd  on c h a r c o a l ) i n a b s o l u t e me t h a i o l (100 ml.)  hydrochloric acid  been added.  (67)  i n a b s o l u t e methanol  S t i r r i n g a t room t e m p e r a t u r e  at which  t i m e a p p r o x i m a t e l y 1100  was  (20 ml.)  to had  continued f o r  ml, of hydrogen  -103(55-60%  o f t h e t h e o r e t i c a l amount) had  t a k e had  essentially  filtration  and  the  ceased.  The  filtrate  been consumed and  c a t a l y s t was  evaporated  removed  transferred to a  f u n n e l and  The  extracted and  aqueous l a y e r .  anhydrous sodium s u l f a t e  separatory  aqueous a c i d i c  the w a t e r wash b e i n g  layer  evaporated  added t o  The  e t h e r l a y e r was  and  l a t e r combined w i t h t h a t  from the r e d u c t i o n of another  56%  Ether  was  once more w i t h e t h e r , t h e e t h e r e x t r a c t s c o m b i n e d  washed once w i t h w a t e r ,  original  by  to a s m a l l volume.  and w a t e r were a d d e d , t h e m i x t u r e the l a y e r s s e p a r a t e d .  up-  8 g-„  (83)0  dried  the  over obtained  These w e r e  t o g i v e e s s e n t i a l l y pure recovered  nitrile  (9.0  g.,  recovery). The  aqueous a c i d i c  l a y e r was  the a d d i t i o n of i c e - c o l d extracted  three  times  were c o m b i n e d , d r i e d evaporated w h i c h was  to y i e l d allowed  30%  sodium hydroxide  with ether. rapidly  over  The  solution  This  h e a t i n g the  o i l briefly  This  a f t e r 2 days was  amount o f w a t e r was  g«)  ether  a small  added t o t h e m a t e r i a l s o b t a i n e d  in this  (8.0  g,  of n i t r i l e  u s e d i n e a c h e x p e r i m e n t ) f o l l o w e d by c o l d The  r e s u l t a n t mixtures  and  the layers separated.  Ether  by  and  reductions  a steam b a t h .  30%  having sodium  were,combined i n a s e p a r a t o r y The  and  o i l upon s t a n d i n g  c o n v e r s i o n c o u l d a l s o be a c c o m p l i s h e d on  and  anhydrous sodium s u l f a t e  t o stand f o r 2 days.  insoluble.  by  basic ether extracts  a pale yellow o i l (approximately 3  became i n c r e a s i n g l y v i s c o u s and  manner f r o m two  t h e n made s t r o n g l y b a s i c  aqueous l a y e r was  been hydroxide. funnel  then e x t r a c t e d  with  two  additional  were d r i e d the  over  solvent  yield)  as  gave  mg.) mm.  of t h i s provided  on  distilled an  temperature (film)r 6.25  a t 1.50° f o r the  analysis  f o r carbon  (five and  reagent  Further  0.66 m.  m o l s ) and  until  the  complete  9 0 ml/min.).  325'0  (NH)  cm." .  determinations)  petroleum  ether  NMR  column Infrared signals:  3H,-CH 0H3).  Repeated  2  gave u n s a t i s f a c t o r y  5-dTnltrobenzamide ( 8 5 )  3 , 5-dinitrobenzoic  was  chloride.  acid  freshly  (l)j.O mg .,  pentachloride  (llj.5 mg.,  on  a small  a flame  Initiated.  resultant liquid  (30-60°)  3,5-dinitrobenzoyl  of  hydrogen.  phosphorus  the  3,5-  chromatography  5 ' x ij:"',  1  at  purification  rate  r e a c t i o n was  and  of t h e  flow  m o l e s ) were warmed g e n t l y  tube was  m.  gas  (triplet,  amount  temperature)  3 , 5 - d i n i t r o b e n z o y l c h l o r i d e was  a s follows :  prepared  further  of a small  preparation  3-Carbomethoxy-3-ethylplperidlne-3. The  characteristic  (bath  e f f e c t e d by  -OCH3), 9 . 2  of  8 2 % crude  used w i t h o u t  (I4.5/6O Chrom W.  helium  3'H,  a  extracts  2-carboethoxy-3-(/?-cbloro-  derivative (85).  (-COOCH3),  (singlet,  results  compound  150°,  combined  Evaporation  Vaccuum d i s t i l l a t i o n  J column  1725  elemental  r e a c t i o n with  m a t e r i a l was  Apiezon  the  sulfate.  m a t e r i a l was  a sample  dinitrobenzamide the  sodium  and  o i l possessing  This  (66).  of e t h e r  d e s i r e d p i p e r i d i n e ( J i . 8 g.,  yellow  f o r the  ethyl)-lndole  0,1  the  odour.  purification  (200  anhydrous  a pale  piperidine  portions  added The  In  0.70 test-  A f t e r the r e a c t i o n cooled,  in order petroleum  to  a f e w ml.  of  precipitate  e t h e r w a s removed  - 1 0 5 -  w i t h a p i p e t and twiice more w i t h oxychloride m.  the  3 5 - d i n i t r o b e n z o y l c h l o r i d e washed 9  petroleum ether  to  remove t r a c e s  3™Carbomethoxy-3-ethylpiperidine  0  m o l s ) was  added, and  the  mixture  was  The  p r o d u c t was  a f t e r the  initial  warmed g e n t l y i n t h e  of  ( 9 0 mg.,  0 . 5 3  r e a c t i o n had  subsided  for 5  minutes.  steam b a t h  d i s s o l v e d i n ether.and  phosphorus  washed  successively  w i t h 5 $ h y d r o c h l o r i c a c i d , w a t e r , 5 $ sodium h y d r o x i d e , finally  water.  e t h e r , the residue the  solvent  w h i c h was  cm." . 1  (KBr):  the  was  product  pale yellow 1 7 2 5  3  directly  needles, 1 6 3 0  (loge):  mp.  (l+o30)  2 3 0  3  3  IH, aromatic),  G,  5 2 . 6 5 ?  H,  5 . 1 * 4 ;  N,  ll.lj.8y  0 ,  C,  52.60;  H,  5 o 2 l + ;  N,  1 1 . 5 0 ;  0,  crystalline provide  3 0  (aromatic)  0  3  NMR  m/4,  signals:  -CH CH ), 0 . 9  H,  1 . 1 ) . ( d o u b l e t , 2H,  (triplet,  a  1 2 2 . 0 - 1 2 2 . 5 ° °  (-CN-),  -0CH_ ), 9 . 2 5 ( t r i p l e t ,  H,  to y i e l d  from  once from, m e t h a n o l t o  (-COOCH^),  U l t r a v i o l e t , > max  (singlet,  tended t o c r y s t a l l i z e  evaporated  recrystallized  p u r e amide as  Infrared  6.3  Since  and  2  3  aromatic).  Found:  Calc. f o r C^H-^OyN^  3 0 . 7 4 °  3 0 . 6 6 .  2-Carboe'"thoxy-3-r^ - ( 3 - c a r b o m e t h o x y - 3 - e t h y l - N - p i p e r i d y l ) ethylj-indole ( 6 8 ) " ~ ~ ~ 2-Carboethoxy-3-(/S-chloroethyl )-indole m m o l s ) and  3 - c a r b o m e t h o x y - 3 ' e t h y l p i p e r i d ine =  mols) i n dioxane tube i n a pressure been s a t u r a t e d to  were h e a t e d  t u b e was  sealing.  opened, the  i n the  0 g . ,  ( 2 . 8 g.,  8 . 0  16.1+  m  t u b e was  tube  having  After cooling  dioxane s o l u t i o n  f r o m t h e gummy, i n s o l u b l e m a t e r i a l and remaining  o  i n a thick-walled sealed  w i t h dry n i t r o g e n before  gummy r e s i d u e  ( 2  bomb f o r 2 0 h o u r s a t 1 6 0 ° , t h e  room t e m p e r a t u r e t h e  decanted The  ( 2 5 ml.)  ( 6 6 )  evaporated.  conblned w i t h  this  -106r e a c t i o n p r o d u c t by and  water.  The  of c o n c e n t r a t e d funnel. dried  The  thoroughly  washing the  r e s u l t a n t mixture  acidified  h y d r o c h l o r i c a c i d and  l a y e r s were s e p a r a t e d  and  the  ether  starting  a b o v e a q u e o u s l a y e r was  of s o l i d  addition  separatory layer  was  concentrated  to  indolic  (1.2  ester  potassium carbonate,  extracted  three  the  g.,  s a t u r a t e d w i t h sodium c h l o r i d e ,  times w i t h e t h e r .  anhydrous magnesium s u l f a t e . a basic fraction (alumina, mainly  The  spot.  (120  desired  g.)  ether  e x t r a c t s were  be  r e m o v e d by  chromatographed  e l u t i o n w i t h benzene-ether  compound  (1.0  g.).  The  later  rechromatography.  an a n a l y t i c a l  s a m p l e as  signals:  0,92  (3*1)  yielded  f r a c t i o n s of  ( 6 0 - 8 0 ° ) gave v e r y  10IL-106°, r e c r y s t a l l i z a t i o n  U l t r a v i o l e t ; ^max  on  Crystallization  c r y s t a l s , mp.  ( K B r ) : 1730  gave  this  a s l i g h t l y more p o l a r compound w h i c h  pure product from p e t , e t h e r  Infrared  ether  over  t h i n - l a y e r chromatography  m a t e r i a l was  chromatography contained could  of the  dried  p o t a s s i u m p e r m a n g a n a t e s p r a y ) showed  This and  Evaporation  g . ) w h i c h by  chloroform,  one  alumina  (1„6  of  careful addition  c o m b i n e d , washed w i t h a s m a l l amount o f w a t e r and  NMR  the  w a s h e d w i t h a s m a l l amount  e t h e r , ( d i s c a r d e d ) , t h e n made b a s i c by  the  ether  recovery). The  and  by  shaken i n a  o v e r a n h y d r o u s m a g n e s i u m s u l f a t e and  g i v e e s s e n t i a l l y pure unreacted 60%  was  tube w i t h  of w h i c h  (loge)r (broad  229  1675  orange provided  (-COOEt), 3350 (NH)  ( i i . 3 5 ) , 298  s i n g l e t , 1H,  NH),  the  105".5-106.5°«  c o l o r l e s s p r i s m s mp.  (-COOCH3),  pale  of  cm."" . 1  (1+. 2ii ) wyx.  2.2-3.0 ( m u l t i p l e t s ,  -107l\E  a r o m a t i c ) , 5.57  9  T  0CH3),  ( q u a r t e t , 2H, - O C H C H ) , 6.35 2  8.6 ( t r i p l e t ,  Mass s p e c t r u m M.W!.  9.2 ( t r i p l e t ,  -OCH2CH3),  386, b a s e p e a k m/e I8I4.  7.77;  N, 7 . i | 0 ; 0 , 1 6 . 6 3 .  7.82;  N, 7.25? 0 , 1 6 . 5 6 .  Toluene w h i c h h a d been f r e s h l y d i s t i l l e d  reaction  3  C, 6 8 . 3 8 ; H,  f r o m s o d i u m was a g a i n  v e s s e l e q u i p p e d w i t h a h i g h speed s t i r r e r  68 (300 mg., O.78 m m o l s ) added  i n the  through the d i l u -  (90 mg.) was added  F r e s h l y c u t sodium  and a d i l u t i o n  The t o l u e n e c o l l e c t e d  f l a s k was t h e n c o n t i n u o u s l y d i s t i l l e d  flask containing the refluxing  (continued f o r t o the r e a c t i o n  t o l u e n e (30-I|.0 m l . ) and t h e d i e s t e r through the d i l u t i o n  chamber  c o n t a i n i n g t o l u e n e ( a p p r o x i m a t e l y 50 m l . ) o v e r a p e r i o d h o u r s w h i l e t h e s o d i u m s u s p e n s i o n was b e i n g s t i r r e d rpm„ was  H,  (68)  t i o n chamber t o remove waiter f r o m t h e a p p a r a t u s § hour).  2  from sodium under d r y n i t r o g e n i n t o a t h r e e - n e c k e d  chamber a t t a c h e d t o a c o n d e n s e r . reaction  -CH CH_ ).  C, 6 8 . 3 7 ;  2  Attempted A c y l o i n Condensation o f the D i e s t e r  distilled  3H,  Calc. f o r C H N 0^:' 3 0  3  Found:  0  2 2  (singlet, H),  3  o f I4.  a t lj.000-5000  A f t e r t h e a d d i t i o n o f t h e d i e s t e r was c o m p l e t e t h e m i x t u r e refluxed with stirring  r e a c t i o n m i x t u r e was c o o l e d added  until  f o r an a d d i t i o n a l 2% h o u r s .  The  i n a n i c e - b a t h and g l a c i a l  acetic  t h e m i x t u r e was n e u t r a l t o l i t m u s . ,  acid  The p r e c i p i t a t e d  m a t e r i a l was removed b y f i l t r a t i o n , washed w i t h e t h e r and t h e combined sulfate. the  f i l t r a t e and w a s h i n g s  then dried  over anhydrous  sodium  The r e s i d u e was t h e n washed w e l l w i t h c h l o r o f o r m and  c h l o r o f o r m s o l u t i o n was d r i e d  o v e r anhydrous  sodium  sulfate.  E v a p o r a t i o n o f t h e t o l u e n e - e t h e r and c h l o r o f o r m f r a c t i o n s  pro-  v i d e d b r o w n gums (85 mg. a n d 205 mg. r e s p e c t i v e l y ) w h i c h were  -108i n d l c a t e d by t h i n - l a y e r chromatography acetate lly  ( 5 : 1 ) , and s i l i c a  ( a l u m i n a , benzene  g e l , m e t h a n o l ) as c o n t a i n i n g  t h e same m a t e r i a l and no s t a r t i n g d i e s t e r .  t h i n - l a y e r chromatography  on s i l i c a  g e l ( 0 , 5 mm., m e t h a n o l ) on  (60$ r e c o v e r y ) as an amorphous s o l i d , Infrared  U l t r a v i o l e t , 7-max 2  (CHCI3):  2 2 5 , 295 m//.  essentia-  Preparative  a p o r t i o n o f t h e combined p r o d u c t s a f f o r d e d a p o l a r  chromatography.  ethyl  product  one s p o t b y t h i n - l a y e r  1720 c m .  - 1  NMR s i g n a l s :  (carbonyl). 6 . 0 (broad  m u l t i p l e t , 1 - 1 . 5 H ) 6.1+0 ( b r o a d s i n g l e t , 1.5H)„s  L i t h i u m Aluminum H y d r i d e R e d u c t i o n o f the A c y l o i n The  crude  acyloin  (175 mg.) was d i s s o l v e d  product  i n dry  (10 m l . ) and added t o a s u s p e n s i o n o f l i t h i u m  tetrahydrofuran aluminum h y d r i d e  (175 mg.) i n d r y t e t r a h y d r o f u r a n (18 m l . ) .  r e s u l t i n g m i x t u r e was r e f l u x e d ice-salt  Product  f o r 2,-g- h o u r s , t h e n c o o l e d i n an  b a t h and t h e e x c e s s l i t h i u m a l u m i n u m h y d r i d e d e s t r o y e d  by the c a r e f u l  addition of ice-water.  the m i x t u r e f i l t e r e d  C h l o r o f o r m was added and  through C e l i t e which  well with chloroform.  i n t u r n was washed  The c o m b i n e d f i l t r a t e  and w a s h i n g s  were  dried  over anhydrous p o t a s s i u m c a r b o n a t e , then evaporated t o  yield  a brown o i l (155 mg.).  to  plates  by t h e same p r o c e s s  2.92 m/*,  on s i l i c a  (20 x 20 cm., 0„5 mm,,, e t h y l a c e t a t e - m e t h a n o l ,  provide a p u r i f i e d  (CHCI3):  (108 mg.)  A portion of this material  was p u r i f i e d b y p r e p a r a t i v e t h i n l a y e r c h r o m a t o g r a p h y gel  The  product  toyield  no c a r b o n y l . NMR s i g n a l s :  (50 mg.).  T h i s was a g a i n  a pure product  Ultraviole t;  max:  (1+0 mg.).  purified Infrared  2 2 5 , 272. ( s h ) , 281+.,  0 . 9 0 ( s i n g l e t , I H , -NH), 2.1+-3.1  p l e t , 1+H, a r o m a t i c ) , 1+.1+0 ( b r o a d s i n g l e t  2:1)  (multi-  subject to concentration  -109s h i f t s and exchanged 2H)  6.1+5  9  5*35 ( s i n g l e t ,  b y d e u t e r i u m o x i d e , -OH),  ( b r o a d s i n g l e t , 2 H ) , 9 = 25  3H, - C H 2 C H 3 ) .  (triplet,  A c e t y l a t i o n of the A l c o h o l Obtained from Reduction o f the A c y l o i n Product The  a l c o h o l o b t a i n e d as d e s c r i b e d above  t r e a t e d w i t h anhydrous (0.05  pyridine  (0.5  ml.)  (13 mg.) was  and a c e t i c  anhydride  f o r 1 hour.  m l . ) and t h e m i x t u r e warmed t o n e a r r e f l u x  The  p y r i d i n e was e v a p o r a t e d u n d e r a s t r e a m o f n i t r o g e n ,  the  residue dissolved  potassium carbonate. a d a r k brown gum. (singlet), 9.2:0  i n c h l o r o f o r m and d r i e d  2.1L-3°0 ( a r o m a t i c ) , li.78  NMR s i g n a l s :  3H, - C H 2 C H 3 ) .  This material  p r e p a r a t i v e t h i n - l a y e r chromatography  cm." . 1  Mass s p e c t r u m r  (9 mg.).  Infrared  (film)r  U l t r a v i o l e t , >max: b a s e p e a k m/e  -OOCH3),  was p u r i f i e d b y  on s i l i c a  20 cm., 0.5 mm., b e n z e n e r e t h y 1 a c e t a t e , 1:1) l i g h t b r o w n gum  anhydrous  E v a p o r a t i o n of the solvent provided  5*95 ( s i n g l e t ) , 8„0 (two s i n g l e t s ,  (triplet,  (-OCOCH3)  over  g e l (20 x  t o provide a  3300 (-NH), 1725  221;, 273 281+, 292.5 m//.  198.  2-HydrOxymethyi-3C^-(3-ethyl-3-hydroxymethyl-N-plperidyl)e t h y l j - i n d o l e d i a c e t a t e (boJ T h i s compound was p r e p a r e d  from a u t h e n t i c  2-carbomethoxy-  3~[^~(3-carbomethoxy-3~ethyl-N-piperidyl)-ethyl] - i n d o l e by reduction  and a c e t y l a t i o n I n t h e i d e n t i c a l manner t o t h a t  d e s c r i b e d above f o r t h e a c y l o i n c o n d e n s a t i o n p r o d u c t . diacetate  o b t a i n e d was i d e n t i c a l  t o t h a t d e s c r i b e d above  ( i n f r a r e d , mass s p e c t r a , t h i n - l a y e r c h r o m a t o g r a p h y gel,  b e n z e n e - e t h y l a c e t a t e , 1:1,  The  - silica  a l u m i n a , benzene - e t h y l  -110-  5*1).  acetate,  Eateriflcation Ihe  crude  dissolved (2 m l . ,  of the A c y l o i n Condensation acyloin condensation  i n c h l o r o f o r m (0.5  a p p r o x i m a t e l y 0.1+  ml.)  M) was  Product  product  and  (20 mg.)  diazomethane i n e t h e r  added ( e f f e r v e s c e n c e ) .  A f t e r s t a n d i n g f o r one  hour w i t h o c c a s s i o n a l shaking  s o l v e n t was  under a stream  evaporated  o f n i t r o g e n and  f u r t h e r s o l u t i o n of diazomethane i n e t h e r d i r e c t l y t o the was  oily residue.  A f t e r one  (2 m l . ) hour the  i n v e s t i g a t e d by t h i n - l a y e r chromatography  benzene - e t h y l a c e t a t e , 5:1) 2-carboethoxy-3-r/ -indole  and  authentic  3 -  was  the a added,  product  (aluminum,  shown t o c o n t a i n b o t h  ( 3 - c a r b o m e t h o x y - 3 - e t h y l - N - p i p e r i d y l )- e t h y l / /  the c o r r e s p o n d i n g samples.  and  was  d i m e t h y l e s t e r by c o m p a r i s o n  with  -IllExperimental  - Fart B  2 -Ethyl-l 3-propanediol  (106)-  :  0  To 0,79 was  a stirred  suspension  moles) i n d r y t e t r a h y d r o f u r a n  (750 m l ) u n d e r d r y n i t r o g e n ,  added o v e r a p e r i o d o f 1+5 m i n u t e s a s o l u t i o n o f d i e t h y l (91+ g » , 0.50  ethylmalonate ml).  cooled fully  t o 0-5°  The r e a c t i o n m i x t u r e  i n an i c e - s a l t b a t h  inorganic material.  was f i l t e r e d  through  viscous  by v a c u u m d i s t i l l a t i o n .  o i l was t a k e n  2-ethyl-l ,3-propanediol  (film):  '3300  cm,  3-Benzyloxy-2-ethylpropanol F r e s h l y c u t sodium small pieces  to a hot  1,3-propanediol the  t o remove  The r e s u l t a n t  - 1  and d r i e d  The o i l o b t a i n e d  by e v a p o r a -  under reduced  pressure  (1+7.5 g o , 91$ y i e l d ) as a  c l e a r c o l o r l e s s o i l , b p , 92-9l+°/0.7 mm. Infrared  f o r 10-  and w a s h i n g s  up i n f r e s h t e t r a h y d r o f u r a n  o f t h e t e t r a h y d r o f u r a n was d i s t i l l e d  provide  having  The p r e c i p i t a t e was washed w e l l w i t h  over anhydrous magnesium s u l f a t e . tion  care-  After  Celite  t e t r a h y d r o f u r a n and t h e c o m b i n e d f i l t r a t e  were c o n c e n t r a t e d  under  and c o l d w a t e r added  t o come t o room t e m p e r a t u r e and t o s t a n d  15 m i n u t e s t h e m i x t u r e  (250  was t h e n  t o d e s t r o y excess l i t h i u m aluminum h y d r i d e .  been a l l o w e d  hot  moles) i n d r y t e t r a h y d r o f uran  The r e s u l t i n g m i x t u r e , was r e f l u x e d w i t h s t i r r i n g  dry n i t r o g e n f o r 6 hours.  to  (30 g , ,  o f l i t h i u m aluminum h y d r i d e  (Lit,^  3  (-0H), no c a r b o n y l  87°/0.5  mm,).  absorption,  (107)  (1,06 g . , 0,01+6 m o l e s )  (115-120°)  stirred  (11+.1+ g , , 0,138 m o l e s )  temperature being maintained  was added i n  s o l u t i o n of 2-ethyl-  i n dry xylene  (6  ml),  by r e m o v i n g o r a p p l y i n g t h e  -112heat  source  min.)  as r e q u i r e d .  benzyl chloride  wise, the temperature mixture to  was s t i r r e d  room t e m p e r a t u r e  (2.69  g»)o  When a l l t h e sodium, had r e a c t e d (ii5  (6.5 g . , 0.051 m o l e s ) was added again maintained  a t 120° f o r 1 h o u r , and f i l t e r e d  through  a spiral  column  (5 mm. x 33 c m . ) , e q u i p p e d  removal  of the x y l e n e , unreacted  (9.1  g . ) , b p . 102-108°/2 mm.  3<=-benzyloxy-2-ethylpropanol colorless  o b t a i n e d , f o l l o w e d by as a c l e a r  Infrared (film): NMR  signals:  ILH,  C6H5CH2OCH2-,  8.9  ( m u l t i p l e t s , 3H, - C H C H 2 C H 3 ) , 9.1  G, 71+.19, H, 9.3l+  s  (multiplet,  (triplet,  3H, -CH2CH3).  Calc. f o r C  1 7  H  l 8  0 : 2  0, I6.IJ.7  3-Benzyloxy-2-ethylpropyl Thionyl chloride  chloride  (108)  (18.5 g«. 0.155 m o l e s ) was added  mixture  of  the temperature  i n an i c e - b a t h .  drop-  3-benzyloxy-2-ethylpropanol  ( 2 9 . 0 g o , 0.150 m o l e s ) and N , N - d i m e t h y l a n i l l n e  cooling  (singlet,  and H O C H 2 - ) , 7.2 ( s i n g l e t , 1 H , -OH), 8.0-  7I+.01; H, 9.58; 0, 16.60.  0.165 m o l e s ) ,  3300  2.70  ( s i n g l e t , 2 H , C ^ C H g O - ) , 6J4  a r o m a t i c ) , 5.50  (107)  After  2-ethyl-1,3-propanediol  o i l , b p . 130-133° / 2 mm.  to a stirred  distillation  with heating jacket.  5H,  wise  chloride  i n v a c u o and t h e  (6.88 g . , 77% y i e l d ) ,  1  C,  to cool  u n d e r n i t r o g e n and a t  tantalum  was f i r s t  (OH),. 7I1O, 695 ( a r o m a t i c ) c m . " .  Pound:  then allowed  The f i l t r a t e was c o n c e n t r a t e d  pressure  The r e s u l t i n g  t o remove t h e s o d i u m  resultant viscous yellow o i l d i s t i l l e d reduced  as a b o v e .  drop-  being maintained  (20.0 g „ ,  b e l o w IL5° b y  The r e s u l t a n t m i x t u r e was s t i r r e d f o r  |- h o u r a t LL5° t h e n p o u r e d i n t o d i l u t e h y d r o c h l o r i c a c i d  -113contained  i na separatory funnel.  The h e a v y o i l w h i c h  separated  was r e m o v e d w i t h c h l o r o f o r m , w a s h e d once w i t h d i l u t e  hydro-  chloric  washed  acid  t o remove a n y N , N - d i m e t h y l a n i l i n e , t h e n  w i t h s e v e r a l p o r t i o n s o f water u n t i l  neutral to litmus  The  c h l o r o f o r m s o l u t i o n was d r i e d  over anhydrous sodium  and  the pale yellow o i l r e s u l t i n g  on e v a p o r a t i o n  f o r m was d i s t i l l e d  under reduced  pressure  to yield  3-benzyloxy-  c h l o r i d e (21.0 g . , 6 6 $ y i e l d ) as a c l e a r  less  88-90 /0 3mm. o  ( a r o m a t i c ) cm." . 1  5.50  (singlet,  CAH5CH2OCH29.10  NMR s i g n a l s :  2  3  67.75;  (multiplet,  Found: H,  C,  3  H , -CHCH2CH3), H, 8.10.  67.39?  8.06.  3-benzyloxy-2-ethylpropylmalonate ( 1 0 9 )  F r e s h l y cut sodium small pieces t o absolute solution  ( 3 . 6 8 g . , 0 . 1 6 m o l e s ) was added i n ethanol  ( 7 5ml) w i t h s t i r r i n g .  o f s o d i u m e t h o x i d e was a l l o w e d  then d i e t h y l malonate 10 m i n u t e p e r i o d . and  735, 695  2 . 7 0 ( s i n g l e t , 5H, a r o m a t i c ) ,  7.9-8.8  H , -CH2CH.3).  Calc. f o rCi2Hi70Cl:C, Diethyl  color-  2H, C^H^CH^O-), 6.1+5 ( m u l t i p l e t , 1+H, and C1CH -),  (triplet,  Infrared (film):  o  sulfate  of thechloro-  2-ethylpropyl o i l , bp.  paper.  t o c o o l t o about 5 0 °  ( 3 7 g . , 0 . 2 3 m o l e s ) was added  The r e s u l t i n g  The  s o l u t i o n was h e a t e d  over a to reflux  3 - h e n z y l o x y - 2 - e t h y l p r o p y l c h l o r i d e ( 3 2 . 5 g«, 0 . 1 5 3 m o l e s )  added d r o p w i s e mixture  over a 3 hour p e r i o d , a f t e r which time t h e  was r e f l u x e d f o r a f u r t h e r 2 0 h o u r s .  e t h a n o l was r e m o v e d b y d i s t i l l a t i o n , o f s o d i u m c h l o r i d e and o i l p o u r e d acetic  acid  (10 m l ) .  then  Most o f the  the cooled  mixture  i n t o cold water c o n t a i n i n g  The l a y e r s w e r e s e p a r a t e d  and t h e  - l l l i -  aqueous l a y e r e x t r a c t e d t h r e e separated  o i l and e t h e r  times  with ether.  The  e x t r a c t s were combined and washed  once w i t h w a t e r , t w i c e w i t h , a 1 0 % s o d i u m b i c a r b o n a t e and  finally  once w i t h a s a t u r a t e d  sodium c h l o r i d e s o l u t i o n .  A f t e r d r y i n g o v e r a n h y d r o u s s o d i u m s u l f a t e and of the s o l v e n t , a viscous product  was d i s t i l l e d  initial  fractions,  unreacted  diethyl  89% y i e l d . b a s e d yellow  evaporation  o i l was o b t a i n e d .  a t reduced pressure  benzyloxy-2-ethylpropyl finally  yellow  solution  This  to yield,  i n the  d i e t h y l m a l o n a t e , t h e n 3-  c h l o r i d e (16.8 g . , 52% r e c o v e r y ) and  3-t>enzyloxy-2=ethylpropyl on r e c o v e r e d  malonate  (22 g»,  s t a r t i n g m a t e r i a l ) as a p a l e  o i l b p . l 5 5 - l 6 0 A > . 3 mm. o  (-COOEt), 6 9 0 , 735 ( a r o m a t i c )  Infrared  cm." .  (film):  1735  NMR s i g n a l s :  1  2.65  ( s i n g l e t , 5 H , a r o m a t i c ) , 5»50 ( s i n g l e t , 2H, C H ^ C H 0 - ) , 5.8O 6  ( q u a r t e t , i i H , -OCH2CH3), 6.55 - C H ( C 0 0 E T ) 2 ) , 8.05 (triplet,  3H, C ^ C H ^ O C H ^ - and  ( m u l t i p l e t , 2H, - C I ^ C H ( C O O E t ) ) , 2  -OCH2CH3), 9.15  C, 68.17y"H, 8.5.  (multiplet,  2  (triplet,  8.8  3H, -CHCH2CH3).  Found:  C a l c . f o r C H 2 8 0 5 ; C, 67.83? H, 8.39. 19  3°Benzyloxy-2-ethylpropylmalonic a c i d ( 1 1 0 ) To  a cold stirred  In w a t e r  s o l u t i o n of p o t a s s i u m h y d r o x i d e  (9 m l ) and e t h a n o l  (1 m l ) was added d i e t h y l  benzyloxy-2-ethylpropylmalonate o v e r 1^ h o u r s . ice ture  bath,  The m i x t u r e  twice with ether,  3-  (109) (9.0 g . , 0.02.68 m o l e s )  was t h e n s t i r r e d w i t h c o o l i n g i n an  f o r f o u r h o u r s , then allowed  overnight.  (5.9 g.)  The r e s u l t a n t y e l l o w then c o o l e d  t o stand  a t room t e m p e r a -  s o l u t i o n was e x t r a c t e d  i n an i c e - b a t h , d i l u t e d w i t h  water  -115( 2 0 m l ) a n d made s t r o n g l y a c i d i c  (10 m l ) and e t h e r red  paper) by the c a r e f u l  chloric acidic  acid.  a d d i t i o n of concentrated  The l a y e r s were s e p a r a t e d  l a y e r extracted twice w i t h ether.  hydro-  and t h e aqueous The c o m b i n e d  e x t r a c t s w e r e w a s h e d t w i c e w i t h w a t e r , once w i t h  viscous  Evaporation  of the solvent provided  o i l which d i d not c r y s t a l l i z e  t r i t u r a t i o n with various 2 1 + 0 0 , 1710 2H,  solvents.  (-C00H) cm.- .  -C00H), 2.61  C6H5CH2O-),  9.11  heated light was  acid  2H,  CAH5CH2OCH2-),  (111)  (110)  (approximately  7-5 g•) was  o i l w h i c h c o u l d n o t be i n d u c e d  -0.6 ( b r o a d  a r o m a t i c ) , 5.50  Infrared  (film):  1710  singlet, IH, - C 0 0 H ) ,  to crystallize (-C00H)  2.65  7.6  1  (singlet,  ( m u l t i p l e t , 2H, - C H C 0 0 H ) , 2  9.11  3H, - C H 2 C H 3 ) .  crude a c i d  i n anhydrous e t h a n o l  (111)  (112)  (approximately  5 S«) was d i s s o l v e d  ( 2 0 ml) containing concentrated  (1 m l ) and t h e s o l u t i o n r e f l u x e d f o r 1-| h o u r s .  resulting  cm." .  ( s i n g l e t , 2H, C^H^CH^O-), 6.60 ( d o u b l e t ,  E t h y l l+-benzyloxymethylhexanoate  acid  singlet,  a t 120° f o r 5 h o u r s and t h e r e s u l t i n g .  further.  5H,  The  1.0 ( b r o a d  3500-  3H, -CH2CH3).  brown v i s c o u s  (triplet,  (film):  (triplet,  i n an o i l b a t h  NMR s i g n a l s :  Infrared  o r upon  5H, a r o m a t i c ) , 5.J4.9 ( s i n g l e t , 2H,  crude malonic  notp u r i f i e d  an e x t r e m e l y  (singlet,  1+-Benzyloxymethylhexanolc a c i d The  sodium  upon s t a n d i n g  NMR s i g n a l s :  1  ether  saturated  sodium c h l o r i d e s o l u t i o n and d r i e d over anhydrous sulfate.  ( t o Congo  s o l u t i o n was a l l o w e d  t o c o o l then  poured  sulfuric The into  cold  -116w a t e r and e x t r a c t e d t w i c e w i t h e t h e r .  The c o m b i n e d e x t r a c t s  were w a s h e d s u c c e s s i v e l y w i t h w a t e r , 5 % s o d i u m and  saturated  bicarbonate  sodium c h l o r i d e s o l u t i o n s , then d r i e d  anhydrous sodium s u l f a t e .  over  The e t h e r was e v a p o r a t e d and t h e  r e s i d u a l yellow, o i l d i s t i l l e d  under reduced pressure  e t h y l ii=benzyloxymethylhexanoate  ( 5 ° 3 g . , 75% y i e l d  t o provide from  t h e m a l o n i c e s t e r 109) as a c l e a r c o l o r l e s s o i l , b p . 122-128° /b.6  mm.  cm." . 1  Infrared  (film):.  NMR s i g n a l s :  doublet,  5 * 8 5 ( q u a r t e t , 2H,  p  -CHCH2CH3). c  16 2!L°3 h  s  C  Preparation  7  2  o  6  9  -OCH2CH3),  9.10 ( t r i p l e t , 3H,  w i t h a flame u n t i l  i t melted.  n i t r o g e n and m e r c u r y  sodium (10 m l ) was warmed c a r e f u l l y  The f l a s k was f l u s h e d w i t h d r y  (200 g„) added v e r y  The r e s u l t a n t m i x t u r e  c a u t i o u s l y to the  was a l l o w e d  room t e m p e r a t u r e u n d e r n i t r o g e n and t h e s u p e r n a t a n t A\nhydrous e t h e r  The r e s u l t a n t d a r k r e d  well sealed.  dry n i t r o g e n t o a buret  xylene chloride  t h e n shaken f o r  solution of triphenylmethyl  s o d i u m was t h e n d i l u t e d w i t h a n h y d r o u s e t h e r maintained  to cool t o  (50 m l ) and t r i p h e n y l m e t h y l  (11 g.) was a d d e d , t h e f l a s k w e l l s t o p p e r e d , 6 hours.  Calc. f o r  h  S o d i u m (3 g») i n d r y x y l e n e  decanted.  5°50  5 > 9 . 1 5 , 0, 1 8 . 1 6 .  of Triphenylmethyl  melted sodium.  (aromatic)  -OCH2CH3),  C, 7 2 . 3 ^ ; H, 9 . 2 7 ; 0, l 8 . 5 1 i .  Found: »  695  2H, G^H^C^OCH^-), 7.65 ( m u l t i p l e t , 2H,  -CH C00Et) . 8.75 ( t r i p l e t , 2  s  2 . 6 5 ( s i n g l e t , 5H, a r o m a t i c ) ,  ( s i n g l e t , 2H, CfcH^CH^O-), 6.60 ( b r o a d  1730 (-COOEt), 7 3 5  (80 m l ) and  The s o l u t i o n was t r a n s f e r r e d u n d e r f o r a measured a d d i t i o n t o t h e r e a c t i o n  -117f l a s k and f o r s t a n d a r d i z a t i o n b y t i t r a t i o n w i t h ac i d + .  The  8 1  c o n c e n t r a t i o n as d e t e r m i n e d  by t h i s method on v a r i o u s  o c c a s i o n s was 0.18-0.22 No Diethyl 2-(2-benzyloxymethylbutyl)-succinate  (71a)  A\n e t h e r s o l u t i o n o f 0„22 N t r i p h e n y l m e t h y l s o d i u m  (86.5  !  ml  9  0 019 m o l e s ) was q u i c k l y r u n i n t o a r o u n d b o t t o m e d o  t h a t had been f l u s h e d w i t h d r y n i t r o g e n . (5»0 g ° stirred  flask  (112)  The e s t e r  0.019 m o l e s ) was I m m e d i a t e l y added and t h e s o l u t i o n  9  f o r 2 minutes.  Ethyl  i o d o a c e t a t e (l|.»05 g . , 0.019  m o l e s ) was t h e n added d r o p w i s e and t h e r e s u l t a n t m i x t u r e stirred  f o r j% h o u r a t room t e m p e r a t u r e .  Glacial acetic  acid  (2.5 m l ) was added t o remove a n y e x c e s s b a s e s , t h e m i x t u r e filtered  t o remove s o d i u m i o d i d e  anhydrous  sodium  sulfate.  and t h e f i l t r a t e  Triphenylmethane  ether=benzene  (Ipl).  over  The e t h e r was e v a p o r a t e d and  t h e r e s i d u a l l i g h t brown o i l c h r o m a t o g r a p h e d 750 g o ) °  dried  on a l u m i n a  was I n i t i a l l y e l u t e d w i t h p e t r o l e u m  The u n r e a c t e d s t a r t i n g  was removed w i t h p e t r o l e u m e t h e r - b e n z e n e  ester  (2:1)  (2.5 g . )  and (1:1)  but  was c o n t a m i n a t e d w i t h s m a l l amounts o f t r i p h e r i y l c a r b i n o l . mixture  of unreacted  starting material  and p r o d u c t  (1.6  Ad-  g„) was  then e l u t e d w i t h benzene, again contaminated w i t h a small amount o f t r i p h e n y l c a r b i n o l w h i c h c r y s t a l l i z e d  from the m i x t u r e  T h i s e s t e r m i x t u r e was s e p a r a t e d f r o m t h e t r i p h e n y l c a r b i n o l b y means o f a p i p e t and r e c h r o r a a t o g r a p h e d on a l u m i n a C a r e f u l e l u t i o n w i t h petroleum ether-benzene starting material  i n the i n i t i a l  the d e s i r e d p r o d u c t .  (3:1)  (96 g . ) . provided  f r a c t i o n s , f o l l o w e d by  F u r t h e r p u r i f i c a t i o n b y vacuum  0  - 1 1 8 -  dlatillation desired Gas  b a t h t e m p e r a t u r e / 0 . 1 mm) y i e l d e d t h e  ( 1 3 0 - 1 8 0 ° ,  succinic  ester  ( 38.0  c h r o m a t o g r a p h y on a  2 0 %  mg») as a c l e a r c o l o r l e s s SE  Chrom W., 1 0 ' x f " c o l u m n temp. provided 735,  an a n a l y t i c a l  2 3 0 ° ,  sample.  6 9 0 ( a r o m a t i c ) cm." .  aromatic),  5 » 5 0  -OCH2CH3),  6.60 (multiplet,  column  (60/80  helium flow rate  ml/rain.) (-COOEt),  2 . 7 0 ( s i n g l e t , 5H,  2H, C ^ C I ^ O - )  5 « 8 5  (two q u a r t e t s , l i H ,  2H, C H ^ C H 0 C H - ) , 6  9 0  (film): . 1 7 3 0  Infrared  NMR s i g n a l s :  1  (singlet,  analytical  3 0  oil.  2  (multiplet,  7 . 0 5  2  1H, -CHCOOEt), 7ok ( m u l t i p l e t , 2H, - C H C 0 0 E t ) , 8 . 7 5 ( t r i p l e t , 2  9.1 (triplet,  -OCH2CH3),  H,  C a l c . f o r C20H30O5:  8 . 7 9 c  gas c h r o m a t o g r a p h i c SE  2 0 %  rate on  3 0  1 0 0  column  C,  Chrom W.) ,  Chrom W.),  8 . 6 3 o  ,  Detailed  on an a n a l y t i c a l  and 260°C., a l s o  c  helium flow rate  and  21L5°  68„IL2°  2 6 5 ° °  2°(2-benzyloxymethylbutyl)-2-carboethoxysuccinate ( 1 1 3 )  F r e s h l y cut sodium xylene  2 l i 5 ° m  C,  x J ' " , helium flow  1 0 *  10' x i  TOO m l / m i n . , c o l u m n t e m p e r a t u r e Diethyl  H,  examination was performed  (60/80  (60/80  Found:  6 8 . 5 1 ; ;  ml/min„, c o l u m n t e m p e r a t u r e  FFAP  2 0 %  3H, -CHCH2CH3).  i n a round  external s t i r r i n g sodium melted  ( 1 . 7 1  g»,  0 . 0 7 5  bottomed 3-necked motor.  m o l e s ) was added t o d r y  flask  equipped  The x y l e n e was h e a t e d  and t h e s t i r r e r  w i t h an  u n t i l the  t u r n e d on and o f f a f e w t i m e s  to  d i s p e r s e t h e s o d i u m as a f i n e  to  c o o l t o room t e m p e r a t u r e  sand.  The x y l e n e was a l l o w e d  and a l a r g e p o r t i o n was d e c a n t e d .  A n h y d r o u s e t h e r was a d d e d and d e c a n t e d  from t h e sodium a few  times  The s o d i u m sand was  t o remove t h e r e m a i n i n g x y l e n e .  finally  covered w i t h anhydrous e t h e r  ( 1 0 0 ml).  The m a l o n i c  -119ester  ( 1 0 9 )  ceased  dropwise  ( 1 2 , 7  poured acid,  a t which  g.  0 „ 0 7 6  s  t o the pale green  the r e s u l t i n g  •§ h o u r ,  m o l e s ) was added and t h e m i x t u r e  solution  i n t o c o l d water and t h e l a y e r s  Ethyl  m o l e s ) was c a r e f u l l y  added  s o l u t i o n o f the malonate stirred  salt  a t room t e m p e r a t u r e f o r  f o r 1 hour.  then r e f l u x e d  extracted  time e v o l u t i o n of hydrogen  and a l l t h e s o d i u m h a d d i s a p p e a r e d .  bromoacetate  and  0 . 0 7 5  f o r 3 hours  refluxed had  go,  ( 2 5  The r e a c t i o n m i x t u r e was  c o n t a i n i n g a s m a l l amount o f a c e t i c  separated.  The aqueous l a y e r the combined  extracts  washed once w i t h w a t e r , t h e n d r i e d  over anhydrous  sodium  sulfate.  and t h e r e m a i n i n g y e l l o w  viscous  twice f u r t h e r w i t h e t h e r  was  p  The e t h e r was e v a p o r a t e d o i l distilled  under reduced  head w e l l wrapped w i t h g l a s s w o o l . unreacted distilling  s t a r t i n g malonic i n the range  e s t i m a t e b y NMR  pressure using a Claisen Initially  e s t e r and t h e t r i e s t e r  l 4 0 ° - 1 9 0 ° / 0 . 2  mm.  of 2 : 1 .  distillation  c o n t a i n e d pure  1 9 0 - 2 0 0 ° / 0 . 2  mm.  g°)  was o b t a i n e d .  An  The s u b s e q u e n t  desired triester  Redistillation  The o v e r a l l y i e l d was 7 8 $ b a s e d  starting material.  Infrared  ( a r o m a t i c ) cm." . 1  f r a c t i o n of the ( 1 0 . 9 go) b p .  o f the l o w e r b o i l i n g  when c o m b i n e d w i t h o t h e r r e a c t i o n p r o d u c t s  730  (lI|.o5  s p e c t r o s c o p y r e v e a l e d t h e t r i e s t e r and m a l o n i c  e s t e r were i n a r a t i o  triester.  a mixture of  (film):  NMR s i g n a l s :  provided  fraction  additional  on r e c o v e r e d  1 7 3 0 (-COOEt), 6 9 5 , . 2 . 7 0 ( s i n g l e t , 5H,  a r o m a t i c ) , 5 . 5 5 ( s i n g l e t , 2H, C A H ^ C R ^ O - ) , 5 . 8 5 ( m u l t i p l e t , 6H,  -OCH2CH3),  6 . 7 (doublet,  2H,  C6H5CH2OCH2-)  6 . 9 5 (singlet,  -120-  7.9  2H, - C H C 0 0 E t ) , 2  2  8.80 (two t r i p l e t s , -0CH CH_3), 9.15 2  Pound:: H,  65.06; H, 7.95.  C,  2  ( t r i p l e t , 3H, CH CH_3). 2  Calc. for C^R^Oy:  C,  65.38.,  8.11.  2— ( 2 - B e n z y l o x y m e t h y l b u t y l ) - 2 - c a r b o x y s u c . c i n i e A\ m i x t u r e  25$  .(113) (11.5  of the t r i e s t e r  and  a  95$  e t h a n o l was r e f l u x e d f o r 5 h o u r s .  and  the residue  ether. bath  s o l u t i o n of potassium  taken  g.,  0.0273  Evaporation  dried  over  brown o i l w h i c h d i d n o t c r y s t a l l i z e  (film):  1715  (-C00H) cm." . 1  solvents.  -0.1).  NMR s i g n a l s :  ( s i n g l e t , 5H, a r o m a t i c ) ,  ( s i n g l e t , 2H,- CAH5CH 0-),  6.7  2  (broad  s i n g l e t , 2H, -CH2C00H),  - C H C H C ( C 0 0 H ) ) , 9.2 j  ( t r i p l e t , 3H,  2-(2-Benzyloxymethylbutyl)°succlnic The c r u d e t r l a c i d was h e a t e d a t product  165-170°  Infrared  5.55  d o u b l e t , 2H, C A H ^ C H ^ O C H ^ 8.0  ),  ( m u l t i p l e t , 2H,  -CH CH_3). 2  acid  (111).) o b t a i n e d  (115)  above  f o r a period of  was r e f l u x e d i n a 20$  upon  (broad  s i n g l e t , 3H, - C 0 0 H ) , 2.69  2  The .  o f t h e e t h e r gave a  o r upon t r i t u r a t i o n w i t h v a r i o u s  2  with  i n an i c e -  hydrochloric acid.  standing  (broad  distilled  was e x t r a c t e d t w i c e w i t h e t h e r , t h e e x t r a c t s  anhydrous sodium s u l f a t e . light  moles) i n  ( t o Congo r e d p a p e r ) b y t h e  and washed t w i c e w i t h w a t e r , t h e n  very viscous  moles)  The a l c o h o l was  The aqueous a l k a l i n e s o l u t i o n was. c o o l e d  r e s u l t a n t mixture  (III)-)  up i n w a t e r and e x t r a c t e d t w i c e  and made s t r o n g l y a c i d i c  combined  acid  (0.0905  hydroxide  c a r e f u l a d d i t i o n of concentrated  6.85  8.75*  ( m u l t i p l e t , 2H - C H C H C ( C O O E t ) ) ,  (approximately  3 hours.  The c r u d e  aqueous s o l u t i o n o f  potassium  9 g,'). #  -121(2.5 m o l e s ) ,  hydroxide until  a c l e a r s o l u t i o n was obtained)„  was t h e n c o o l e d  (2-3 hours o r  t o remove a n y a n h y d r i d e ,  The aqueous  solution  i n an i c e b a t h , made s t r o n g l y a c i d i c ( t o  Congo r e d p a p e r ) b y t h e c a r e f u l a d d i t i o n o f c o n c e n t r a t e d hydrochloric  a c i d , and e x t r a c t e d t h r e e t i m e s w i t h e t h e r .  c o m b i n e d e x t r a c t s were washed t w i c e w i t h w a t e r , a n h y d r o u s s o d i u m s u l f a t e , and e v a p o r a t e d succinic  acid  Infrared  (film):  NMR  as a m i x t u r e 1700  of c r y s t a l s  dried  to provide  (-C00H), 71L0, 695 ( a r o m a t i c )  o  C6H5CH2OCH2-)  -CHC00H)  P  9.15  7.3' ( v e r y b r o a d  p  dissolved  crude  succinic  (115)  acid  i n absolute ethanol  solution  was c o o l e d  twice with ether.  (71a)  (approximately  7 g») was  (20 m l ) c o n t a i n i n g c o n c e n t r a t e d  and p o u r e d  The r e s u l t a n t  i n t o c o l d w a t e r and e x t r a c t e d  The c o m b i n e d e x t r a c t s were washed -twice  with water,  once w i t h 5% s o d i u m b i c a r b o n a t e  with water,  then  dried  over  of the ether provided under reduced  t h e t r i e s t e r 113) chromatographic  s o l u t i o n , and once  anhydrous sodium s u l f a t e .  Evapora-  a l i g h t y e l l o w o i l w h i c h was  pressure  to p r o v i d e the pure s u c c i n i c  gas  (multiplet, 2  (1 m l ) and r e f l u x e d f o r 1-|- h o u r s .  acid  distilled  1  ( t r i p l e t , 3H, - C H ^ H ^ ) .  sulfuric  tion  cm." .  m u l t i p l e t , 3H, -CH C00H,  Diethyl 2-(2-benzyloxymethylbutyl)-succinate The  the crude  (singlet,  5H, a r o m a t i c ) , 5»50 ( s i n g l e t , 2H, C ^ C H ^ O - ) , 6 6 0 2H,  over  and v i s c o u s o i l .  1.0£ {.broad s i n g l e t , -COOH), 2.70  signals:  The  ( b a t h temp. 1 3 5 - l 6 5 ° / 0 ° 5  e s t e r (7.1il| g . , 78% y i e l d  as a c l e a r c o l o r l e s s p r o p e r t i e s of t h i s  oil.  from  S p e c t r a l and  succinic  ester  mm)  122d e r i v a t l v e were i d e n t i c a l  t o t h o s e f o r t h e compound o b t a i n e d  by t h e a l t e r n a t e r o u t e as d e s c r i b e d e a r l i e r , N-Q?- ( 3 - I n d o I y l ) - e t h y l l - 3 - ( 2 - b e n z y l o x y m e t h y l b u t y l )succinimide (130) Tryptamine  h y d r o c h l o r i d e (5" g . ) was s u s p e n d e d  sodium h y d r o x i d e s o l u t i o n  i n a s e p a r a t o r y f u n n e l and s h a k e n  three times w i t h e t h e r t o e x t r a c t the f r e e base. e x t r a c t s were washed t h r e e t i m e s w i t h w a t e r anhydrous  magnesium s u l f a t e .  provided the c r y s t a l l i n e  i n 5"%  and d r i e d  116-117° ( L i t . 1 1 6 ° ) .  (3»1 g». 0.0191). m o l e s ) ,  t r y p t a m i n e h y d r o c h l o r i d e (lf>0 mg. ) a n d t h e s u c c i n i c  (71a) (2.2  g.,  0.0063  2;-(2-EthoxyethoxyJ hours  under  allowed  moles ) was r e f l u x e d  -ethanol  dry•nitrogen„  (30  ml, bp.  ester  i nfreshly  distilled  190-200°C) f o r 50  The r e s u l t a n t m i x t u r e was t h e n  t o c o o l t o room t e m p e r a t u r e , t a k e n up i n e t h e r and  washed t h r e e t i m e s w i t h w a t e r , f i v e acid  over  Evaporation of the solvent  t r y p t a m i n e mp.  A\ m i x t u r e o f t r y p t a m i n e  The c o m b i n e d  t i m e s w i t h 10%  acetic  t o r e m o v e t r y p t a m i n e and t h r e e t i m e s w i t h w a t e r .  g r e e n e t h e r e a l s o l u t i o n was d r i e d  over anhydrous  The  sodium  sulfate  and e v a p o r a t e d t o g i v e a d a r k b r o w n gum ( a p p r o x i m a t e l y 3«1 g . ) . T h i s m a t e r i a l was c h r b m a t o g r a p h e d the  desired  Imide  under  (175" g») a n d  e l u t e d w i t h b e n z e n e and b e n z e n e - e t h e r  as a l i g h t brown gum 77% y i e l d ) .  on a l u m i n a  (2.02.  g. - d r i e d  (li:l)  to constant weight,  A. s m a l l q u a n t i t y o f t h i s m a t e r i a l was d i s t i l l e d  • vacuum t o p r o v i d e an a n a l y t i c a l s a m p l e as an a l m o s t  colorless  l i g h t brown g l a s s b p .  260-270°/0.005  mm (-bath  temp,).  -123 Infrared  ( i m i d e ) 71+0 (log  3320  (Nujol):  and 695  1755  (NH),  ( a r o m a t i c ) cm." .  ( b r o a d s i n g l e t , I H , N H ) , 2.7  NMR  6.20  2  (triplet,  CAH5CH 0CH -), 1+18;  M.W. Hp  7..1+0;  N  6.69.  s  9.15  2  2  N,  6.52.  2H, - C H N ) 2  (triplet,  m a i n peaks?,  3.00  ( s i n g l e t , 2H, 6.65  S  (multiplet,  3H, - C H C H ) . 2  Mass  3  11+1+, 11+3, 130,91.  m/e  1.9  signals:  ( m u l t i p l e t , 9H, a r o m a t i c ) ,  ( d o u b l e t ^ l H , c < - p r o t o n o f i n d o l e ) , 5.55 CAH£CH 0-),  (strong)  U l t r a v i o l e t , >- max  1  222. (1+.57), 283 (3.79) ryu.  & ):  1685  (medium),  "Calc. for C ^ H ^ N ^ :  C  g  2H,  spectrum:  Found:  C, 71+.81;  7.23;  71+.61; H,  N - f _ / 8 - ( 3 - I n d o l y l ) - e t h y l J - 3 - ( 2 - b e n z y l o x y m e t h y l b u t y l )pyrrolidine (13U The furan  imide  (25  (130)  ml) was  aluminum hydride (25  ml), and  (925  mg.,  2.21  added to a s t i r r e d suspension (250  mg.,  6.60  hydride  and  i n c o l d water and  destroyed  hydrof uran.  The mixture was  allowed  of c o l d wet  tetra-  to warm to room temperature  f o r a few minutes i t was  washed w e l l w i t h hot t e t r a h y d r o f u r a n and  The  filtered  G e l l t e was  the combined  the crude amine (925  mg)  then  filtrate  over anhydrous sodium s u l f a t e .  t i o n of the s o l v e n t y i e l d e d  was  the excess l i t h i u m aluminum  through G e l i t e to remove InoEganic s a l t s .  and washings were d r i e d  stirring  r e d u c t i o n product  by the c a r e f u l a d d i t i o n  a f t e r a l l o w i n g to stand  pale yellow  tetrahydrofuran  the r e s u l t i n g mixture r e f l u x e d with The  tetrahydro-  of l i t h i u m  m moles) In dry  under dry n i t r o g e n f o r 8-§- hours. then cooled  m moles) i n dry  Evapora-  as a  o i l . Chromatography of t h i s m a t e r i a l on alumina  -124g o ) and e l u t i o n w i t h b e n z e n e and b e n z e n e - e t h e r  (50  provided 95$  ( 8 l 5 mg. - d r i e d t o c o n s t a n t  t h e p u r e amine  yield)  quantity provided mm.  (loge):  3 5  2 2 2  ".Vacuum d i s t i l l a t i o n  an a n a l y t i c a l  as a c l e a r  (NH), 7  3 3 5 0  and  colorless  6 9 5  ( 4 . 5 6 ) ,  2 8 3  ( d o u b l e t , I H , c* - p r o t o n 2  ( d o u b l e t ^ , 2H,  C A H 5 C H  Mass s p e c t r u m : H, N,  (bath  temp.)/  U l t r a v i o l e t >max a  NMR s i g n a l s  ( 1 0 0  Mc/s):  N,  8 . 8 2 ?  5 - 5 5 ( s i n g l e t , 2H, C^CH^O-•) 6 . 7 0 9  0 C H  2  - )  9  (triplet,  9 . 1 5  Gale,  7 . 3 5 .  3H, -CHgCH-j) „  2 6 0 , s t r o n g m/e  Molecular wt.  7 ° 1 7 .  Mercuric  2  of indole = collapses to singlet  b a s e p e a k m/e  9 1 .  Found:  for C26H34N2O:  3 9 0 . 2 6 7  (Calc.  C,  7 9 . 9 5 ;  3 9 0 . 2 6 7 ) .  O x i d a t i o n o f t h e Amine ( 1 3 1 )  Mercuric Acetate  131  21+0-250°,  s i n g l e t , I H , N H ) , 2 . 7 5 ( m u l t i p l e t , 9H, a r o m a t i c ) ,  upon a d d i t i o n o f D 0 ) ,  8 . 7 8 ;  of a small  Infrared (neat):  mMo  ( 3 » 8 0 )  3.11  H,  glass. 1  (broad  8 0 . 0 2 ;  sample bp.  ( a r o m a t i c K'cm." .  1.55  C,  weight,  as a v e r y p a l e y e l l o w gum w h i c h g r a d u a l l y  d a r k e n e d upon s t a n d i n g .  0 o 0 0 5  (I4. t X )  acetate  ( 3 . 4 0  g . ,  0 . 0 1 0 7  m o l e s ) and t h e amine  ( 5 0 0 mg., 1 " 2 8 m m o l e s ) were r e f l u x e d i n a n h y d r o u s 0  methanol  ( 2 6 0 ml) containing g l a c i a l  4i- hours under h i g h l y p u r i f i e d Liquid  A i r Ltd.)  treating  acetic  nitrogen  acid  ( 7 . 5 ml) f o r  ("L" g r a d e , C a n a d i a n  The r e a c t i o n was f o l l o w e d b y p e r i o d i c a l l y  an a l i q u o t  of the mixture  w i t h hydrogen  sulfide  gas  and o b s e r v i n g t h e d e v e l o p m e n t o f t h e a b s o r p t i o n p e a k o f  the  supernatant,  mixture glass  1  a t 3 5 3 m/*.  was a l l o w e d  disc  The r e s u l t a n t g r e e n i s h - y e l l o w  t o c o o l and f i l t e r e d  (medium p o r o s i t y ) ,  through  i n t o a 3-necked  a sintered  round  bottomed  -125flask, The  t o remove t h e m e r c u r o u s  f i l t r a t e was  purified  resultant  sintered was  bubbled  a filter  of mercury s u l f i d e s  a i d and  one  obtained  was  a high  by  another  that  Celite  vacuum ( o i l pump) w;as  o n l y i f the e n t i r e  operation  i n e r t atmosphere.  by b e n t a d a p t e r s , w h i c h a l r e a d y  g l a s s d i s c s , was filtration,  used.  of  three-necked contained  In t h i s manner,  e t c . , c o u l d be  this  this  flasks  interconnected  of a s e r i e s  For  In  described  consisting  of reagents,  The  removed  p u r p o s e ^ an a p p a r a t u s  sintered  the  t o emphasize t h a t optimum y i e l d s  above i s c o n d u c t e d u n d e r an  the  neck  filtration.  Is important are  of  into  under a n i t r o g e n atmosphere through  employed t o a i d  reaction  moles).  a flow  g]a ss d i s c '-as d e s c r i b e d above e x c e p t  u s e d as  It  50°,  1.8  minutes to d e s t r o y mercury complexes.  precipitate  filtration,  g»,  e  c o n t i n u o u s l y passed through  t h e n h y d r o g e n s u l f i d e gas  f o r 15  solution  (l l8  warmed t o a p p r o x i m a t e l y  nitrogen being  of the f l a s k p  acetate  conveniently  addition carried  o u t u n d e r an a t m o s p h e r e o f d r y n i t r o g e n . Sodium borohydride filtrate  and  the s o l u t i o n  a f t e r w h i c h time  the  disappeared.  The  approximately  20 ml  water.  The  (2.2  g.)  stirred  immediately  solution and  was  m/zhad  then concentrated  partitioned  the  completely  to  between c h l o r o f o r m  and  e x t r a c t e d t w i c e more w i t h c h l o r o -  f o r m , t h e e x t r a c t s c o m b i n e d and sodium hydroxide  added t o  u n d e r n i t r o g e n f o r [|. h o u r s  a b s o r p t i o n p e a k a t 353  aqueous l a y e r was  t w i c e w i t h 5$  was  washed t w i c e w i t h w a t e r , solution  and  t w i c e more w i t h  -126water.  A f t e r d r y i n g over anhydrous  sodium  c h l o r o f o r m was e v a p o r a t e d  to yield  w h i c h was c h r o m a t o g r a p h e d  on a l u m i n a  benzene:ether  (li:l  and 1:1)  s u l f a t e , the  a brown gum (20 g o ) .  (J+30 mg) Elutlon  with  removed a m i x t u r e o f t h e c y c l i z e d  b e n z y l e t h e r s o f i n c r e a s i n g p o l a r i t y and t h e s e w e r e d e s i g n a t e d A, B,  C,  c'  (C and C* were i n d i s t i n g u i s h a b l e b y t h i n  chromatography•on material  alumina)  ( t o t a l 175  mg).  and D as w e l l as u n c y c l i z e d Initially  B w;as o b t a i n e d , f o l l o w e d by m i x t u r e s o f i s o m e r s  and  a s m a l l amount o f u n c y c l i z e d m a t e r i a l , yielded  The  to give additional  t o t a l weight  based  Elutlon with  of the c y c l i z e d  C, c' and D  p r o d u c t was 210  on an e s t i m a t e by t h i n - l a y e r  mg  chromatography  of pure  (35  (yield  37%  T h i s t o t a l m i x t u r e was Small  b e n z y l e t h e r s were o b t a i n e d by p r e p a r a t i v e  t h i n - l a y e r chromatography  (as d e s c r i b e d b e l o w ) o f t h e  p a r t i a l l y s e p a r a t e d m i x t u r e s o b t a i n e d above b y c o l u m n chromatography. A m i x t u r e o f one o f t h e m i n o r major  i s o m e r s A and one o f t h e  i s o m e r s B (16 mg) were s p o t t e d on a t h i n - l a y e r  chromatoplate developed  mg„)o  o f 20%  f o r the p r e p a r a t i o n of the corresponding a l c o h o l s .  quantities  and D  mg) w h i c h was r e -  isomers  uncyclized material being present). used  B, C, C~  an a d d i t i o n a l m i x t u r e o f i s o m e r s C, C'  a l o n g w i t h some p o l a r m a t e r i a l , ( t o t a l 160 chromatographed  starting  a mixture of isomers A  and  methanol  layer  ( a l u m i n a , 20 x 20 cm.,. 0„3  i n benzene:ethyl acetate  mm t h i c k n e s s ) and  (2.5:1).  p l a t e was e x a m i n e d u n d e r u l t r a v i o l e t  The  developed  light while s t i l l  wet  s  -127and  t h e bainds c o r r e s p o n d i n g t o i s o m e r s A" and  B scraped  and  e x t r a c t e d s e p a r a t e l y w i t h methanol.  extracts  filtered  through  m e t h a n o l and  a sintered  the  filtrates  glass disc, evaporated  r e s u l t a n t r e s i d u e s were t a k e n up removed f r o m any  alumina  the e t h e r s o l u t i o n s o f c r y s t a l s and  283, 291  m,Uo  388,251  and  Infrared  (film):  Mc/s)::  isomer  32I4.O  aromatic),  0.50  5°30  (9  B  mg),  226,  275  The  -CH2CH3),  fractions  g r a p h y and found  by  which  ( s h ) , 283,  2H,  as  methanol).  mg)  The  H 26  32 2°N  glass.  2,5-3°5  NMR  signals  (multiplet,  5„60' ( b r o a d  doublet  t o be a pure  now  was  9,10  chromato-  e t h e r C were  gel  (methanol)  d e s i g n a t e d (1 .  A  mixture  s e p a r a t e d by p r e p a r a t i v e gel  (20  x 20 cm,,  0,3  bands w e r e s e p a r a t e d as d e s c r i b e d a b o v e  provide  the pure  major isomer  glass.  Infrared  (film):  cm," .  U l t r a v i o l e t , > max:  1  HVM,  above c o l u m n  t h i n - l a y e r c h r o m a t o g r a p h y on s i l i c a mm,  291  obtained In the  (30  G  1  388,252.  minor isomer  isomers  (sh),  (quartet, CAH5CH2OCH2-),  Initially  of  ( a r o m a t i c ) cm," .  t h i n l a y e r c h r o m a t o g r a p h y on . s i l i c a  two  274  Calc. for  C^H^CHgO-),  and  as a m i x t u r e  Molecular weight:  appeared  to c o n t a i n another of these  (3 mg)  695  and  ( s i n g l e t , I H , -NH), (singlet,  with  The  0  as a p a l e g r e e n  740  (-NH),  were  Evaporation  226,  388,251°  a p p r o x i m a t e l y I H , CC-3H), 6,32 (triplet,  isomer A  U l t r a v i o l e t , . > max:  U l t r a v i o l e t , > max t  (100  to dryness  by means o f a p i p e t .  M o l e c u l a r weight pure  washing w e l l  i n anhydrous e t h e r  p r o v i d e d pure  gum,  The  off  C  3300  (13  mg)  (-NH),  225,  273  as a c l e a r p a l e  740  and  695  ( s h ) , 282,  green  (aromatic) 290  m/x.  to  - 1 2 8  NMR s i g n a l s  Mc/s):  ( 1 0 0  l  o  ( s i n g l e t , I H , -NH),  8 0  ( m u l t i p l e t , 9 H , a r o m a t i c ) , no d o u b l e t 2H,  CAH5GH2O-),  U l t r a v i o l e t , Mnax  3 H , - C H 2 C H 3 ).  (triplet,  and p u r e i s o m e r  22.5,. 2  3 ° 1 1 ,  C  ( 3  ? 5  (sh),  5 ° 6 0  IH, C-3H),  (broad m u l t i p l e t ,  5 ° 7 5  C6H5-GH2OCH2-),.. 9.25 3 8 8 o . 2 ' 5 2  at  2 , 5 ~ 3 ° 1  mg) a s a c l e a r  (doublet,  6 , 8  Molecular weight r pale green  290.5 m/*:.  2 8 2 , 5 ,  (singlet,  glass.  Molecular  weight 3 8 8 . Hydrogenolysls  of the Mixture  A mixture  of the benzyl ethers  ( 2 3 5 mg) and p a l l a d i u m acetic  ( 2 5 ml)  acid  of Cyclized  was s t i r r e d  The  (approximately  catalyst  evaporated  obtained  as d e s c r i b e d  t h e uptake had e s s e n t i a l l y  8 0 $ of the t h e o r e t i c a l  The r e s i d u a l  amount c o n s u m e d ) .  and t h e a c e t i c  gum was t a k e n  f o r m , t h e l a t t e r washed w i t h 5 $ sodium h y d r o x i d e t w i c e w i t h w a t e r and f i n a l l y Evaporation  dried  chromatography  antimony p e n t a c h l o r i d e i n carbon reagent)  showed t h e p r e s e n c e  as a m i x t u r e The  over  of the chloroform yielded  which by t h i n - l a y e r  of unreacted  ( 1 : 1 ) removed t h e u n r e a c t e d  recovery).  Ether: methanol  sulfate.  acetate,  benzyl  e t h e r s as w e l l  and one p o l a r brown  acid),  then  1 : 1 as s p r a y  was chromat'ographed on a l u m i n a  ethyl 28$  solution,  o r a n g e gum ( 1 6 5 mg,)  tetrachloride,  w i t h 0 , 5 ml, 1 0 $ a c e t i c  ether  up i n c h l o r o -  (alumina, e t h y l  deactivated  acid  anhydrous sodium  a pale  o f more p o l a r g r e e n s p o t s  crude product  above  u n d e r an a t m o s p h e r e o f h y d r o g e n  was removed b y f i l t r a t i o n  i n vacuo.  Ethers  ( 2 3 5 mg, 1 0 $ on c h a r c o a l ) i n g l a c i a l  f o r 3 i f hours a f t e r which time ceased  Benzyl  ( 1 0 g,,  Elutlon with  benzyl  spot.  ethers  benzene:  ( 6 5 mg,.  ( 9 9 ? 1 ) removed a m i x t u r e  of the  -129-  alcohols  designated  removed a m i x t u r e  A. and  B  (21 mg)  of a l c o h o l s  e l u t l o n with ether:methanol further mixture alcohol  ( l i 9 mg).  The  B and  ( 9 8 , 2  of a l c o h o l s  and  B,  B  uncyclized  ether: methanol (5  B  mg).  and  9 5 ° 5 )  and  the  Continued  removed a  uncyclized  amino a l c o h o l was  by t h i n - l a y e r c h r o m a t o g r a p h y t o t h a t p r e p a r e d by o f a s m a l l amount o f u n c y c l i z e d b e n z y l e t h e r rme t h a n o l ( 9 5 " : 5" t o 9 : 1 ) ( 2 6 mg)  cyclized alcohol C elutlon with ( 6 mg).  Although a very  observed i n  more p o l a r  f r o m the  column.  (10? mg)  represented  The  t o t a l weight an  C.  cm.' . signals  aromatic),  Mc/s ) r  ( 1 0 0  9 o l 8  weight:  2 9 8 . 2 0 3 .  B  amino  product  recovered alcohols  the  uncyclized  the  amino  of these c y c l i z e d a l c o h o l s  3 5 0 0 ,  2 2 5 ,  2 7 3  Oj+O (-NH),  Calc. for C  1 9  H  3H,2 6  3 3 5 0 ,  3 1 5 0  (sh),  2 8 2 ,  2 . 5 - 3 . 0  G-3H), 6 . 6 1  (distorted t r i p l e t ,  Preparative a l c o h o l s A and  and  (CHCT^):  ( m u l t i p l e t , 1H,  5 * 7 8  was  crude not  C  alcohols.  Infrared  -CH 0H), 2  B  U l t r a v i o l e t , > max:  1  NMR  B,  D  Rechromatography of  complete s e p a r a t i o n  uncyclized  • Alcohol ~0H)  designated  of t h e  8 3 %y i e l d .  m i x t u r e of c y c l i z e d a l c o h o l s alcohol allowed  while  ( l i : l ) removed r e s i d u a l a l c o h o l  t h i s m a t e r i a l was  5  hydrogenolysis  an amorphous w h i t e s o l i d  minor a l c o h o l  than C  identical,  Elution with  t h i n - l a y e r chromatography of the  as b e i n g  from the  ether.  amino  t h e n removed t h e m a j o r p u r e  as  ether;methanol  (98„2)  2  2 9 0  (broad  on  silica  gel  rajj.  singlet, Molecular  2 9 8 . 2 0 5 .  t h i n - l a y e r chromatography of a m i x t u r e ( 3 0 mg)  and  ( m u l t i p l e t , LLH,  -CHjCH^) „  N 0?  (-NH  ( 2 0 x 2 0 cm.,  0.3  of mm,  -130-  m e t h a n o l ) was p e r f o r m e d .  The bands removed f r o m t h e p l a t e  were e x t r a c t e d w i t h m e t h a n o l and f i l t e r e d . filtrate to  provided  Evaporation  of the  r e s i d u e s w h i c h were t a k e n up i n c h l o r o f o r m  remove a n y s i l i c a  g e l and t h e s o l v e n t e v a p o r a t e d  again t o  yield  p u r e a l c o h o l A (9 mg) and p u r e a l c o h o l B (16 mg) b o t h as  white  amorphous s o l i d s .  on a m i x t u r e  o f a l c o h o l s B and B  tions provided and  A l c o h o l A.-  (11 mg) u s i n g t h e same c o n d i -  (2 mg) as amorphous  U l t r a v i o l e t , > max:  (100 M c / s ) :  I+H, a r o m a t i c ) , 5.72 -CH CH )„ 2  3  22:6,  2„50-3»l5  274  m/^o  ( d o u b l e t , 0.7H, C - 3 H ) , 9.15  Molecular weight:  The  mixture.  m/A  approximately (triplet,.  226,  27k ( s h ) ,  282.5,  298„20IL  C  of C y c l i z e d Benzyl Ether C  e t h e r C (8 mg) o b t a i n e d  pure by p r e p a r a t i v e  c h r o m a t o g r a p h y as d e s c r i b e d e a r l i e r was t r e a t e d w i t h catalyst  291  298.205.  M o l e c u l a r weight:.  Hydrogenolysls  ( s h ) , 283,  (multiplet,  A l c o h o l fi'. U l t r a v i o l e t , > max:  290.5  282,5,  3^4-00, 3330, 3200 (-NH and  3  NMR s i g n a l s  (sh),  298.205.  A l c o h o l B. ' I n f r a r e d ( C H C 1 ) : 1  solids.  226, 273  U l t r a v i o l e t , ^ max:  Molecular weight?  -OH) cm," .  chromatography  an a d d i t i o n a l q u a n t i t y o f p u r e a l c o h o l B (5 mg)  pure a l c o h o l B  290.5.m/(,  Preparative thin-layer  according  t o the procedure  The p r o d u c t  l a y e r chromatography  obtained (alumina,  thin-layer palladium  u s e d above f o r t h e i s o m e r i c  (5 mg) was i d e n t i c a l b y t h i n ethyl  acetate, s i l i c a  gel,  methanol) t o a l c o h o l C i s o l a t e d  from the hydrogenolysls  mixture  from the i s o m e r i c a l c o h o l s A,  o f e t h e r s and d i f f e r e n t  o f the  -131-  B and B»„ Mesylation of Alcohol G A. s o l u t i o n o f t h e a l c o h o l C (1+3 mg) i n d r y p y r i d i n e ( 0 . 3 ml  9  distilled  from potassium  was c o o l e d  i n an i c e  and added t o i c e - c o l d me t h a n e s u l f o n y l c h l o r i d e (120  bath  in a small test-tube. allowed time was  hydroxide)  The r e s u l t a n t l i g h t o r a n g e s o l u t i o n was  i n a r e f r i g e r a t o r f o r 16 h o u r s a f t e r w h i c h  t o stand  t h e s o l u t i o n was d a r k r e d . evaporated  The m a j o r i t y o f t h e p y r i d i n e  under a stream o f n i t r o g e n w i t h t h e a i d o f  s l i g h t w a r m i n g , and t h e l a s t pump.  t r a c e s f i n a l l y r e m o v e d on an o i l  The gummy r e d r e s i d u e was washed t w i c e w i t h  ether, treated with water dissolve  the product,  (0.5  anhydrous  ml) which appeared t o p a r t i a l l y  and washed t w i c e  further with  benzene.  (1 m l , 6N) was added and t h e aqueous  Ammonium h y d r o x i d e extracted  mg)  thoroughly  with chloroform  e x t r a c t was o n l y p a l e y e l l o w ) .  (until  mixture  the c o l o r o f the  The r e s u l t a n t d a r k r e d c h l o r o -  f o r m was d r i e d q u i c k l y o v e r a n h y d r o u s s o d i u m s u l f a t e and evaporated  to provide  chromatography spray)  a d a r k r e d gum (60 mg).  Thin-layer  (alumina, e t h y l a c e t a t e , antimony  pentachloride  showed t h e c o m p l e t e a b s e n c e o f t h e s t a r t i n g a l c o h o l  (Rj. 0.25-0.30) and t h e p r e s e n c e o f a l e s s p o l a r g r e e n (Rj:0„70) as w e l l as a g r e e n s p o t >maxr due  226,  282,  289  ( s h o u l d e r a t 273 d i s t o r t e d ,  t o presence of p y r i d i n e ) .  stand  on t h e base l i n e .  This  product  spot Ultraviolet,  probably  was a l l o w e d t o  i n a vacuum d e s s i c a t o r f o r \\ days a f t e r w h i c h t i m e  very hygroscopic considerable  I t was  and t h i n - l a y e r c h r o m a t o g r a p h y i n d i c a t e d a  Increase  i n . i n t e n s i t y o f t h e base l i n e  spot  relative  -132-  t o t h e s p o t w h i c h was l e s s R e f l u x i n g the m a t e r i a l not n o t i c e a b l y a l t e r  The  the r e l a t i v e  i n a round  quantities  o f t h e s e two s p o t s  f o r the following reduction.  of the Quaternary mesylate  Mesylate  (73s ) 1  o b t a i n e d as d e s c r i b e d above  bottom three-necked  t r a p and an ammonia i n l e t ,  f l a s k equipped  (30 mg) was p l a c e d with a dry i c e  ( T h i s o p e r a t i o n was c a r r i e d o u t  as r a p i d l y as p o s s i b l e b u t t h e amorphous m e s y l a t e very q u i c k l y ) , (50  The  A'mmonia  f o r 20 m i n u t e s  The r e s u l t i n g b l u e  b e t w e e n c h l o r o f o r m and w a t e r .  and t h e r e s i d u e p a r t i t i o n e d  The l a y e r s were s e p a r a t e d and  t h e c h l o r o f o r m l a y e r washed t h r e e t i m e s w i t h w a t e r over anhydrous sodium s u l f a t e . p r o v i d e d a brown r e s i d u e  product gel  (1.0  Evaporation of the chloroform  (20 mg) ,  Chromatography of t h i s  antimony pentachl'oride)  c o n t a i n e d b o t h !|<x - and 1+/3 - d i h y d r o c l e a v a m i n e  mg).  as w e l l as a t h i r d  had an Rj: v a l u e i n t e r m e d i a t e b e t w e e n t h e two  derivatives.  •The above p r o c e d u r e was r e p e a t e d mesylate  material  by t h i n - l a y e r c h r o m a t o g r a p h y on s i l i c a  ( c h l o r o f o r m ? e t h y l a c e t a t e , 1:1,  cleavamine  and d r i e d  g ) and e l u t i o n w i t h b e n z e n e removed t h e m a j o r  (8 mg) w h i c h  component w h i c h  solution  t h e n q u e n c h e d w i t h ammonium c h l o r i d e .  ammonia was a l l o w e d t o e v a p o r a t e  on a l u m i n a  t u r n e d gummy  (5 m l ) was r u n i n t o t h e f l a s k and s o d i u m  mg) added t o t h e s u s p e n s i o n .  was s t i r r e d  alcohol,  i n c h l o r o f o r m , f o r a few m i n u t e s d i d  so t h i s m a t e r i a l was u s e d Reduction  p o l a r than the s t a r t i n g  (28 mg) t o y i e l d  an a d d i t i o n a l  The c o m b i n e d p r o d u c t s  (15  on t h e r e m a i n i n g i d e n t i c a l mixture  (7  mg) were c h r o m a t o g r a p h e d on  133 alumina  (10  g„, W b e l m ) ,  dihydrocleavamine sample  (1 mg)  w h i c h was  p u r e [LD(-  i d e n t i c a l t o an a u t h e n t i c  (mass s p e c t r o m e t r y , t h i n - l a y e r c h r o m a t o g r a p h y on  systems - s i l i c a pentachloride acid  Elutlon with ether yielded  g e l , c h l o r o f o r m : e t h y l a c e t a t e 1:1,  and  1% e e r i e ammonium s u l f a t e  as s p r a y r e a g e n t s ; a l u m i n a , p e t r o l e u m  same s p r a y r e a g e n t s ) . mixture  Continued  several  antimony  i n Q$%> p h o s p h o r i c e t h e r :benzene  1L:1,  e l u t l o n w i t h e t h e r removed a  o f the t h r e e compounds  (8 mg)  w h i c h was  then  further  purified„ P r e p a r a t i v e t h i n - l a y e r c h r o m a t o g r a p h y on s i l i c a (20  x 20  cm,  performed  0„3  9  mm,  on t h i s m i x t u r e .  Ily^-dihydrocleavamine t h e two  c h l o r o f o r m : e t h y l a c e t a t e 1:1)  and  with methanol. methanol,  t h e bands c o r r e s p o n d i n g  to  overlapped e x t e n s i v e l y , o n l y the  o f t h e d e s i r e d band was  removed and e x t r a c t e d  E x t r a c t i o n of the r e s i d u e uponremoval of the  w i t h c h l o r o f o r m and  pure i i y g - d i h y d r o c l e a v a m i n e a u t h e n t i c sample several  was  t h e unknown compound o c c u r r i n g b e t w e e n  dihydrocleavamines  very top p o r t i o n  In  As  gel  e v a p o r a t i o n of the  (1 mg)  which  was  identical  (mass s p e c t r o m e t r y , t h i n - l a y e r  systems - s i l i c a  and a l u m i n a , p e t r o l e u m  solvent provided to  an  chromatography  g e l , chloroform:ethyl acetate.  ether:benzene  IL:1, u s i n g s p r a y s  1:1,  mentioned  above). 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