Calcium oxide catalyzed pyrolysis of N-acyl lactams
by Brent Robert Larsen
A thesis submitted to the Graduate Faculty in partial fulfillment of the requirements for the degree of
MASTER OF SCIENCE in Chemistry
Montana State University
© Copyright by Brent Robert Larsen (1972)
Abstract:
A calcium oxide pyrolysis of several N-acyl lactams leads to a useful preparation of some pyrroline
and piperidine alkaloids. I
In p re s e n tin g t h i s th e s i s in p a r t i a l f u lf illm e n t o f th e r e q u ir e ­
m e n ts f o r a n a d v a n c e d d e g re e a t M ontana S t a t e U n i v e r s i t y , I a g r e e t h a t
t h e 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 i n s p e c t i o n .
I fu rth e r
■
a g r e e 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 in g o f t h i s t h e s i s f o r s c h o l a r ­
l y p u r p o s e s may b e g r a n t e d by my m a jo r p r o f e s s o r , o r , i n h i s a b s e n c e ,
by t h e D i r e c t o r o f L i b r a r i e s .
I t i s u n d e r s to o d t h a t a n y c o p y in g o r 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 n o t b e a llo w e d w i t h o u t
my w r i t t e n p e r m i s s i o n .
S ig n a tu r e
D a te
/h .
/
/6 ^ Z / / "
CALCIUM OXIDE CATALYZED
PYROLYSIS OF N-ACYL LACTAMS
by.
B r e n t.R o b e rt L a rse n
A t h e s i s s u b m itte d t o t h e G r a d u a te F a c u l t y i n p a r t i a l
f u l f i l l m e n t o f t h e r e q u i r e m e n ts f o r t h e d e g r e e
of
MASTER OF SCIENCE
.in
C h e m is try
A p p ro v e d :
H e a d 5 M a jo r D e p a rtm e n t
G r a d u a te f7Dean
MONTANA STATE UNIVERSITY
Bozem an5 M ontana
A u g u s t5 1972
iii
ACKNOWLEDGMENT
I w ould l i k e t o f i r s t a c k n o w le d g e t h e Endowment and R e s e a rc h F oun­
d a t i o n o f M ontana S t a t e U n i v e r s i t y f o r i t s . s u p p o r t o f D r . B . P . Mundy1s
re se a rc h e n d e av o rs.
I w ould a l s o l i k e t o t h a n k t h e D e p a rtm e n t o f Chem­
i s t r y a t M ontana S t a t e U n i v e r s i t y f o r t h e i r f i n a n c i a l s u p p o r t i n t h e
way o f t e a c h i n g a s s i s t a n t s h i p s and t u i t i o n w a i v e r s .
I w ould l i k e t o
a c k n o w le d g e P r o f e s s o r H en ry R a p o p o rt f o r h i s a n a l y t i c a l d a t a and h e l p ­
f u l d i s c u s s i o n w i t h D r. M undy.
I w ould l i k e t o t h a n k D r. Mundy f o r h i s
c o n tin u e d h e l p a n d i n t e r e s t n o t o n ly i n t h e a r e a o f my r e s e a r c h , b u t
a l s o t h e o v e r a l l v a lu e o f my e d u c a t i o n a t t h i s i n s t i t u t i o n .
W ith o u t
h i s c o n tin u e d s u p p o r t t h i s t h e s i s w o u ld n o t h a v e b e e n p o s s i b l e .
I
w ould a l s o l i k e t o a c k n o w le d g e t h e h e l p o f t h e s t a f f m em bers and g r a d ­
u a t e s t u d e n t s o f t h e d e p a r tm e n t f o r t h e i r d i s c u s s i o n and t e c h n i c a l a i d
t o my s p e c i a l p r o b le m s .
M ost i m p o r t a n t l y I w ould l i k e t o t h a n k my w i f e , N a n c y , f o r h e r
p a t i e n c e , u n d e r s t a n d i n g , and u n s e l f i s h s a c r i f i c e s w h ic h e n a b le d me t o
a c h ie v e t h e c o m p le tio n o f t h i s p h a s e o f my e d u c a t i o n .
TABLE OF CONTENTS
P age
LIST OF FIGURES . . .............................................. . .
ABSTRACT................................................
INTRODUCTION.................................. ,
..................................................... .....
. . ..................................................................................v i
. . .... ..........................................
I
CHAPTER
.I .
D is c u s s io n
H i s t o r i c a l s u rv e y o f p ro g re s s i n s y n th e s is o f to b a c c o
a l k a l o i d s ............................................................................................................................. .......
O ur p r e p a r a t i o n o f m yosm ine an d s i m i l a r ' p y r r o l i n e and
p i p e r i d i n e c o m p o u n d s ........................
............................. ............................ ....
. 13
The M u n d y -R ap o p o rt s y n t h e s i s f o r l a b e l e d n i c o t i n e
a lk a lo id s .
. . . . . . .
.................................................................... . . . .
21
P ro p o s e d a p p l i c a t i o n o f o u r s y n t h e t i c t e c h n i q u e s f o r
t h e p r e p a r a t i o n o f l a b e l e d n i c o t i n e a l k a l o i d s .......................................24
II.
Sum m ary. .................................. .... ................................. .... ............................................... . 2 6
III.
E x p e r im e n ta l ........................................... • .................................................................... . 2 7
REFERENCES.
42
LIST OF FIGURES
. P ag e
FIGURE
1.
The P i c t e t S y n t h e s i s o f N i c o t i n e
........................................................
2.
The S p a th and B r e s c h n e i d e r S y n t h e s i s o f N i c o t i n e . . . . . . . .
3.
The C r a ig S y n t h e s i s o f N o r n i c o t i n e an d N i c o t i n e ......................
4.
The
S p a th an d M am oli S y n t h e s i s o f M yosmine ................................................
5.
The
K o r te a n d S c h u l t z - S t e i n e n S y n t h e s i s o f M yosm ine............................. 9
6.
C o n v e rs io n o f M yosmine t o N i c o t i n e by D j e r a s s i ....................................... 10
7.
The
8.
S u s p e c te d I n t e r m e d i a t e o f t h e M u ra k o sh i S y n t h e s i s .
9.
The M cKenzie S y n t h e s i s o f 2 -p h e n y I p y r r o l i n e ................................................... 12
M u ra k o sh i S y n t h e s i s o f 2 -p h e n y I p y r r o l i n e
3
4
5
. . . . . . . . . .
. . . . . . . .
8
11
11
10.
S y n th e s is
o f M yosm ine........................................................................................................ 13
11.
G e n e r a l F o rm u la o f P y r r o l i n e a n d P i p e r i d i n e A l k a l o i d s .
12.
P y r o l y s i s P r e p a r a t i o n o f A n a b a se n e a n d A n a b a s in e
13.
S y n t h e s i s o f 2 - ( n - p r o p y l ) p y r r o l i n e . ..................................................... ....
14.
The
S y n t h e s i s o f C o n ic ie n e a n d C o n iin e . ........................................................ 18
15.
The
S y n th e s is o f C y c lo p ro p y lp y rro lin e and i t s d e r i v a t i v e s .
16.
S y n th e s is
o f L a b e le d N i c o t i n e b y Mundy and R a p o p o r t................................... 22
17.
S y n th e s is
o f L a b e le d 2 - p y r r o l i d one ' ...................................
. . . . .
15
............................. 16
. 17
. . . 19
24
vi
ABSTRACT
A c a lc iu m o x id e p y r o l y s i s o f s e v e r a l N - a c y l la c ta m s l e a d s t o a
u s e f u l p r e p a r a t i o n o f some p y r r o l i n e a n d p i p e r i d i n e a l k a l o i d s .
I
INTRODUCTION
I n 1893 w o rk e rs r e p o r t e d t h e i d e n t i f i c a t i o n o f a c l a s s o f a l k a l o i d
com pounds i s o l a t e d fro m t h e t o b a c c o p l a n t g e n u s , N i c o t i a n a T hese
n ic o tin e a lk a lo id s a re a s s o rte d d e riv a tiv e s o f 2 s u b s titu te d 3 ’-P y rid y l
p y rro le s .
T h e se a l k a l o i d s w ere l a t e r t o becom e t h e s u b j e c t o f many
s y n th e tic e n d e a v o rs.
M yosm ine
N ornicotine R=H
Nicotine
R=CH3
The f i r s t o f t h e s e e n d e a v o r s , c o m p le te d i n 1 8 9 5 ,
o f n i c o t i n e , t h e m o st a b u n d a n t o f t h e a l k a l o i d s .
9
w as a s y n t h e s i s
S in c e t h e n many new
a v e n u e s h a v e b e e n e x p lo r e d f o r p r e p a r a t i o n o f t h e s e s t r u c t u r a l l y s im p le
b u t s y n t h e t i c a l l y co m p lex com pounds.
E a r l y w o r k e rs fo u n d i t n e c e s s a r y t o s y n t h e s i z e t h e s e a l k a l o i d s a s
a m eans t o u n e q u i v o c a l l y p ro v e t h e h y p o t h e s i z e d s t r u c t u r e s stem m ing
fro m d e g r a d a t i v e i n v e s t i g a t i o n s .
A fte r th e s tr u c tu r e s o f th e s e a lk a ­
l o i d s h ad b e e n w e l l e s t a b l i s h e d , i n t e r e s t s h i f t e d t o s y n t h e s i s , n o t t o
s o lv e f u n d a m e n ta l p r o b le m s , b u t s im p ly t o d e r i v e new p r o c e d u r e s .
In
t h e l a s t d e c a d e , c h e m i s t s ’ i n t e r e s t s h a v e a g a in ch an g ed t o m ore v e r s a ­
tile
s y n t h e t i c p r o c e d u r e s i n a t t e m p t s t o l a b e l t h e s e a l k a l o i d s and p r o ­
v i d e t h e b i o c h e m is t w i t h t h e p r o p e r t o o l s f o r b i o g e n e t i c s t u d i e s .
2
U nder t h e d i r e c t i o n o f B . P . Mundy, a new a p p ro a c h t o t h e s y n th e ­
t i c p ro b le m was u n d e r t a k e n b y tw o u n d e r g r a d u a t e s , b e e F . M cKenzie a n d
G ary B r a d e n .
T h is new m e th o d o lo g y was n e i t h e r c o m p lic a te d n o r e l e g a n t .
The a p p r o a c h c o n s i s t e d o f a p y r o l y s i s o f a n N - a c y l la c t a m l e a d i n g t o
th e d e s ire d s u b s titu te d 2 - p y r r o lin e .
The m o d el s y s te m s t u d i e d t o b e g in
t h i s p r o b le m , a p y r o l y s i s l e a d i n g t o t h e p r e p a r a t i o n o f 2 - p h e n y l p y r r o l i d o n e , l a t e r b lo ss o m e d i n t o a p r e p a r a t i v e m ethod f a r b e y o n d o u r
m odest e x p e c t a t i o n s .
T h is t h e s i s w i l l show t h e e v o l u t i o n a r y r e f i n e m e n t o f s y n t h e t i c
t e c h n i q u e s e v e n t u a l l y l e a d i n g t o a r e l a t i v e l y s im p l e , h i g h y i e l d i n g ,
w id e ly a p p l i c a b l e s y n t h e s i s o f p y r r o l i d i n e an d p i p e r i d i n e a l k a l o i d s .
DISCUSSION
H i s t o r i c a l S u rv e y o f P r o g r e s s i n S y n t h e s i s o f T o b a c co A l k a lo i d s
A lth o u g h t h e 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 s o f t h e N i c o ti a n a s p e c i e s
had b e e n known f o r many y e a r s , a s t r u c t u r e p r o o f e lu d e d w o rk e rs u n t i l
P i n n e r ,1 i n 1893, r e p o r te d th e f i r s t d e ta i le d d e g ra d a tio n o f n i c o t i n e ,
t h e m o st a b u n d a n t member o f t h e f a m i l y .
T h is w ork p io n e e r e d t h e way
f o r f u r t h e r i n v e s tig a tio n s le a d in g to th e s tr u c tu r e p ro o f o f th e o th e r
u n r e s o l v e d mem bers o f t h e n i c o t i n e f a m i l y .
The f i r s t r e p o r t e d s y n t h e s i s
o f n i c o t i n e was a c c o m p lis h e d by A . P i c t e t and P . C r e p ie u x 2 i n 1 8 9 5 .
F ig u r e I .
The P i c t e t S y n t h e s is o f N ic o t in e
4
T h is m e th o d , a s o u t l i n e d i n F ig u r e I , b e g a n w i t h t h e d i s t i l l a t i o n o f
3 - a m in o p y r id in e m u ca te t o g iv e N -3- p y r i d y l p y r r o le ( I ) .
W ith t h e a i d o f
r e d h e a t , a n i t r o g e n t o c a rb o n r e a r r a n g e m e n t t o 3 * - p y r i d y l - 2 - p y r r o l e
(3.) was a c c o m p li s h e d .
M e th y la tio n w i t h MeI g a v e n i c o t r y n e m e th y lio d id e
(_3) w h ic h was t h e n d i s t i l l e d
fro m c a lc iu m o x id e y i e l d i n g n i c o t r y n e ( 4 ) .
R e d u c tio n o f t h e n i c o t r y n e was a c c o m p lis h e d i n t h r e e s t e p s w ith t h e
u s e o f i o d i n e and b r o m in e .
11
F ig u r e 2 .
Upon i s o l a t i o n o f t h e io d o compound ( 5 ) , a
7
S p ath & B r e t s c h n e id e r S y n t h e s is o f N ic o t in e
5
s im p le r e d u c t i o n y i e l d e d 4 ,5 - d i h y d r o n i c o t r y n e .
by h y d ro g e n r e d u c t i o n a f f o r d e d n i c o t i n e
^
r o is°3^
B r o m in a tio n f o llo w e d
(7 ).
s*.
KCN
cr
JVlgBif
18
F ig u r e 3 .
The C ra ig S y n t h e s is o f N o r n ic o tin e and N ic o t in e
6
B e c a u se o f P i c t e t ' s p o o r y i e l d an d e x tre m e c o n d i t i o n s , t h i s m ethod
o f s y n t h e s i s was n o t d e s i r a b l e .
I n 1 9 2 8 , S p a th and B r e t s c h n e i d e r 2 p r o ­
p o se d a s y n t h e s i s l e a d i n g t o n i c o t i n e shown i n F i g u r e 2 .
T h is s y n t h e s i s
in v o lv e d t h e c o m b in a tio n o f N -m e th y l p y r r o l i d one and e t h y l n i c o t i n a t e
i n so d iu m e t h o x i d e t o y i e l d t h e k e to n e ( 8 ) .
W ith fu m in g h y d r o c h l o r i c
a c i d t h e l a c ta m r i n g was o p e n e d , fo rm in g t h e k e to n e ( 9 ) .
R e d u c tio n
w i t h a n a l c o h o l i c z in c s o l u t i o n a f f o r d e d t h e a l c o h o l ( 1 0 ) .
D is p la c i n g
t h e a l c o h o l w i t h i o d i n e fo rm e d compound ( 1 1 ) w h ic h was t h e n c y c l i z e d
in s tro n g b a se to y ie ld d ,1 - n ic o tin e
(7_).
A r o u t e now e x i s t e d f o r t h e c o n v e n ie n t s y n t h e s i s l e a d i n g t o one
o f th e n a t u r a l p ro d u c ts i n th e a lk a l o id f a m ily .
The o t h e r members o f
t h e f a m i ly h a d , a s y e t , e lu d e d p r e p a r a t i o n by s im p le s y n t h e t i c t e c h n iq u e s .
I n 1 9 3 3 , L . C r a ig
4
r e p o r t e d a n o v e l s y n t h e s i s f o r a n o t h e r mem­
b e r o f th e f a m ily , n o r n ic o tin e , a s a p r e c u rs o r to n i c o t i n e .
To b e g i n h i s s y n t h e s i s , C r a ig d e v is e d a m ethod f o r s u l f o n a t i o n o f
p y r i d i n e w i t h fu m in g s u l f u r i c a c i d , y i e l d i n g
(1 2 ).
The a d d i t i o n o f
p o t a s s i u m c y a n id e t o d i s p l a c e t h e s u l f i n a t e g ro u p a f f o r d e d t h e cyano
compound ( 1 3 ) A y - e t h o x y - p r o p y l G r ig n a r d r e a g e n t was t h e n a d d e d ,^
y i e l d i n g a l - ( p - P y r i d y l ) - y - e t h o x y - p r o p y l k e to n e ( 1 4 ) .
A f t e r c o n v e r s io n
o f t h e k e to n e t o t h e oxim e ( 1 5 ) , r e d u c t i o n t o t h e p r im a ry a m in e , 1 ( 3 - P y r i d y l ) - l - a m i n o - 4 - e t h o x y b u ta n e ( 1 6 ) p ro c e e d e d s m o o t h l y .
The
e th o x y f u n c t i o n a l i t y was rem oved fro m ( 1 6 ) by a d d i t i o n o f h y d ro g e n
b r o m id e , r e s u l t i n g
in (1 7 ).
By d i s t i l l a t i o n
o f t h e e x c e s s h y d ro g e n
7
b ro m id e fro m t h e m i x t u r e , f o llo w e d b y a d d i t i o n o f s t r o n g b a s e , c y c l i z a t i o n was in d u c e d , g i v i n g n o r n i c o t i n e
n ic o tin e to n ic o tin e
(1 8 ).
The c o n v e r s i o n o f n o r -
(T ) was a c c o m p lis h e d b y t h e a d d i t i o n o f MeI t o a
m e th a n o lic s o l u t i o n o f n o r n i c o t i n e .
A f te r e q u i l i b r a t i o n , p u re n ic o tin e
was i s o l a t e d b y d i s t i l l a t i o n and com pared t o t h e n a t u r a l p r o d u c t .
A lth o u g h t h i s s y n t h e s i s p r o v id e d f o r p r e p a r a t i o n o f b o t h n o r n i c o tim e and n i c o t i n e , t h e o v e r a l l y i e l d o f .5% l e f t a n e e d f o r a more
e f f i c i e n t p a th w a y .
I n 1936 a n o t h e r o f t h e a l k a l o i d s o f t h e n i c o t i n e f a m i l y was s y n 7
t h e s i z e d . S p a th an d M am oli p r e s e n t e d t h e s y n t h e s i s o f m yosm ine a s
shown i n F i g u r e 4 .
As i n Sp a t h 's p r e v i o u s s y n t h e s i s , t h e c o n d e n s a tio n
o f b e n z o ic a n h y d r id e an d p y r r o l i d o n e f o rm in g t h e a c y l la c t a m
th is s y n th e s is .
(1 9 ) b e g a n
The e t h y l e s t e r o f n i c o t i n i c a c i d was t h e n ad d ed t o
t h e a c y l l a c ta m i n t h e p r e s e n c e o f so d iu m e t h o x id e t o p r o v id e ( 2 0 ) .
W ith o u t p u r i f i c a t i o n , a bomb was c h a rg e d w i t h fu m in g h y d r o c h l o r i c a c i d
and ( 2 0 ) .
I t was t h e n p o s t u l a t e d t h a t r i n g o p e n in g o c c u r r e d , fo rm in g
th e in te r m e d ia te
(2 1 ).
m ine was o b t a i n e d .
Upon d e c a r b o x y l a t i o n and r e c y c l i z a t i o n , m yos­
T h is s y n t h e t i c m ethod p ro d u c e d a p p r o x i m a t e ly 8%
o f t h e t h e o r e t i c a l a m o u n t o f m y o sm in e.
An im p ro v ed mode o f s y n t h e s i s '
u s in g t h e same g e n e r a l t e c h n i q u e s was d e m o n s tr a te d by K o r te and S c h u l z e S te in e r^ in 1962.
( F ig u r e 5)
N - N i c .o t i n y l - 2 - p y r r o l i d o n e
( 2 3 ) was fo rm e d by t h e a d d i t i o n o f 2 -
p y r r o l i d one t o a s o l u t i o n o f n i c o t i n o y l c h l o r i d e h y d r o c h l o r i d e su sp e n d e d
8
O T ^
22
F ig u r e 4 .
S y n t h e s is o f Myosmine by Spath & Mamoli
9
(O T i c ' + O "
0
0
o
22
F ig u r e 5 .
in p y r id in e .
S y n t h e s i s o f K o r te & S c h u l z e - S t e i n e r
The N - n i c o t i n y l - 2 - p y r r o l i d o n e was c o n d e n se d w i t h e t h y l
n i c o t i n a t e i n t h e p r e s e n c e o f so d iu m e t h o x i d e .
The r e s u l t i n g com pound,
d i n i c o t i n y l p y r r o l i d o n e ( 2 4 ) , was r e f l u x e d i n 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 u n t i l t h e e v o l u t i o n o f c a rb o n d i o x id e t e r m i n a t e d .
t h i s p ath w ay was a 28% y i e l d
o f m y o sm in e .
The r e s u l t o f
A lth o u g h a v a s t im p ro v em en t
was o b s e rv e d i n t h e o v e r a l l y i e l d o f t h i s com pound, t h e r e s t i l l r e ­
m ain ed room f o r im p ro v e m e n ts .
H ow ever, c o u p lin g t h e s y n t h e s i s o f K o r te
an d S c h u l z e - S t e i n e r w i t h tw o s t e p s p e rfo rm e d by D j e r a s s i 5 t h e t o t a l
s y n t h e s i s o f n o r n i c o t i n e and n i c o t i n e c o u ld be a c h ie v e d m ore e a s i l y
th a n b e f o r e .
As shown i n F i g u r e 6 , D j e r a s s i ^ p r e p a r e d n i c o t i n e by t h e
10
F ig u re 6 .
a b o v e m e th o d .
C o n v e r s io n o f M yosmine t o N i c o ti n e by D j e r a s s i
H y d r o g e n a tio n o f m yosm ine ( 2 2 ) w i t h t h e a i d o f P la tin u m
o x id e a f f o r d e d a q u a n t i t a t i v e y i e l d o f n o r n i c o t i n e ( 1 8 ) .
was t h e n a c c o m p lis h e d b y r e f l u x i n g
and f o r m ic a c i d y i e l d i n g n i c o t i n e
M e th y la tio n
( 1 8 ) i n a s o l u t i o n o f fo rm a ld e h y d e
(7 ) in e x c e lle n t q u a n titie s .
A h i g h y i e l d o f m yosm ine c o u p le d w i t h t h e e q u a l l y p r o d u c t i v e
D j e r a s s i s y n t h e s i s w ould le n d i t s e l f t o s a t i s f y i n g l y e f f i c i e n t p r e p a r ­
a t i o n o f n o r n i c o t i n e an d n i c o t i n e .
Mundy an d M cK enzie, r e a l i z i n g t h i s f a c t , em barked on a s y n t h e t i c
p r o c e d u r e b a s e d on t h e c a lc iu m o x id e p y r o l y s i s o f N - b e n z o y l- 4 - a m in o b u ty r ic a c id
( 2 5 ) p r e v i o u s l y r e p o r t e d by M u r a k o s h i.10
U sin g t h e p h e n y l-
s u b s t i t u t e d a c i d , (2 5 ,), f r e e f la m e , a n d c a lc iu m o x id e a s a c a t a l y s t ,
2 - p h e n y l p y r r o l i n e ( 2 6 ) was i s o l a t e d a c c o r d in g t o t h e m ethod o u t l i n e d
in F ig u re 7 .
Mundy p ro p o s e d t h e r e a c t i o n o f F ig u r e 7 t o be a c h ie v e d
11
O
25
26
F ig u r e 7 .
The M u ra k o sh i S y n t h e s i s o f P h e n y l p y r r o li n e
t h r o u g h t h e i n t e r m e d i a t e a c y l la c ta m ( 1 9 ) w h ic h t h e n d e c o m p o se d , l i b ­
e r a t i n g CO2 and y i e l d i n g t h e d e s i r e d p r o d u c t ( F ig u r e 8 ) .
O
19
F ig u re 8 .
26
S u s p e c te d I n t e r m e d i a t e o f t h e M u ra k o sh i S y n t h e s i s
Upon t h i s s u p p o s i t i o n , w ork was b eg u n t o s y n t h e t i c a l l y p ro d u c e th e
a c y l l a c ta m i n t e r m e d i a t e ( 1 9 ) .
A fte r is o la tio n o f 2 - ( 3 r-p h e n y l) -
p y r r o l i d o n e , ( 2 3 ) , a c a lc iu m o x id e p y r o l y s i s w ould y i e l d t h e d e s i r e d
p r o d u c t , i f t h e h y p o t h e s i s was c o r r e c t .
F ig u r e 9 d e p i c t s t h e s y n t h e s i s
u s e d by Mundy an d M cK enzie11 t o t e s t t h e i r m o d el s y s te m .
N - b e n z o y l- 2 -
p y r r o l i d one ( 1 9 ) was o b t a i n e d by r e a c t i n g b e n z o y l c h l o r i d e and p y r r o l i -
12
done i n t h e same m anner a s K o r te a n d S c h u l t z - S t e i n e r . 8
t i o n an d c h a r a c t e r i z a t i o n ,
A fte r p u r if ic a ­
( 1 9 ) was m ixed w i t h a n e q u a l w e ig h t o f c a l ­
cium o x id e and s u b j e c t e d t o a f r e e —fla m e p y r o l y s i s .
The p r o d u c t r e ­
c o v e re d was shown by b o i l i n g p o i n t and p i c r a t e d e r i v a t i v e t o b e 2 -
g
p h e n y lp y rro lin e .
( § r a+Q» —
O
F ig u r e 9 .
* (opo
0
The McKenzie S y n t h e s is o f P h en y l P y r r o lin e
13
O ur P r e p a r a t i o n o f M yosmine and
S i m i l a r P y r r o l i n e and P i p e r i d i n e Compounds
The s u c c e s s o f M cK en zie’s w ork i n s p i r e d o u r c o n ti n u e d i n v e s t i g a ­
t i o n o f a s i m i l a r p y r o l y t i c s y n t h e s i s l e a d i n g t o m yosm ine and o t h e r
a lk a lo id s .
F ig u r e 10 shows t h e s y n t h e t i c p r o c e s s t h a t e v e n t u a l l y
y i e l d e d m y o sm in e.
The r e a c t i o n s e q u e n c e fro m w h ich ( 2 £ ) was r e a l i z e d
i s p r e c i s e l y t h e same a s K o r te a n d S c h u l t z - S t e i n e r ( F ig u r e 5 ) , 8 a
p y r i d i n e c a t a l y z e d c o u p li n g o f n i c o t i n y l c h l o r i d e h y d r o c h l o r i d e and
2-p y rro lid o n e .
O
Il
O
F ig u r e 1 0 .
S y n t h e s is o f Myosmine
14
A fte r i s o la tio n ,
and
(23_) was m ixed w i t h a n e q u a l w e ig h t o f c a lc iu m o x id e
p y r o liz e d w ith a f r e e f la m e .
p ro d u ct is o la te d
P r o p e r t i e s an d d e r i v a t i v e s o f t h e
com pared e x a c t l y t o t h e d a ta g iv e n f o r m yosm ine i s o -
7
l a t e d by o t h e r w o r k e r s „
A lth o u g h t h e m echanism i s unknow n, t h e s e ­
q u e n c e p r o v id e d a n e a s y t w o - s t e p s y n t h e s i s o f m yosm ine.
The pathw ay
shown i n F i g u r e 10 i s a v a s t im p ro v e m e n t o v e r p r e v i o u s s y n t h e t i c a t ­
t e m p t s , p r o v id i n g a n o v e r a l l y i e l d o f 56.95% upon f i n a l d i s t i l l a t i o n .
To now c o m p le te t h e s y n t h e s i s o f n i c o t i n e , one m u st m e r e ly a p p ly t h e
re a c tio n s o f D je r a s s i.
9
By m ak in g u s e o f t h i s new s y n t h e t i c t e c h n i q u e
f o r m y o sm in e, c o u p le d w i t h t h e s i m p l i c i t y o f t h e D j e r a s s i p a th w a y , a
u n iq u e m ethod o f p r e p a r a t i o n f o r t h e n i c o t i n e a l k a l o i d s c a n be e n ­
v is io n e d .
T h is s im p le b u t e f f i c i e n t mode o f p r e p a r a t i o n w ould a p p e a r
t o h a v e a d v a n ta g e s o v e r t h e p r e v i o u s l y p r e s e n t e d t e c h n i q u e s .
T h e re a r e o t h e r a l k a l o i d com pounds, b o t h u n n a t u r a l a n d n a t u r a l
p r o d u c t s , e x h i b i t i n g a s i m i l a r s t r u c t u r e t o t h a t o f m yosm ine, n o r n i c o t i n e , and n i c o t i n e .
As shown i n F i g u r e 1 1 , t h e s e com pounds c o u ld
a l l le n d th e m s e lv e s t o s y n t h e s i s t h r o u g h p y r o l y s i s o f a n N - a c y l l a c t a m .
One compound o f t h i s n a t u r e i s a n a b e s e n e ( 2 4 a ) .
T h is compound i s v e r y
s i m i l a r t o m yosm ine an d i n f a c t was s y n t h e s i z e d by S p a th and M a m o l i,^
u s in g t h e i r same g e n e r a l p r o c e d u r e show n f o r m yosm ine ( F i g u r e 4 ) .
Our r e a c t i o n sequence"*"^ f o r a n a b e s i n e i s s i m i l a r t o t h a t p r o c e ­
d u r e p r e v i o u s l y d e m o n s tr a te d f o r m yosm ine ( F ig u r e 1 2 ) .
We p r e p a r e d t h e
N - a c y l la c t a m ( 2 4 a ) b y c o n d e n s in g n i c o t i n o y l c h l o r i d e h y d r o c h l o r id e
15
K
24a-25a
2
24b-25b
x /<
24c-25c
I
2
24d-25d
F ig u re 1 1 .
n
v '
I
G e n e r a l F o rm u la o f P y r r o l i n e and
P ip e r id in e A lk a lo id s
16
F ig u re 1 2 .
P y r o l y s i s P r o d u c ti o n o f A n a b a se n e a n d A n a b a s in e
w ith 6 - v a le r o la c ta m .
P y r o l y s i s o f ( 2 4 a ) u s in g c a lc iu m o x id e r e s u l t e d
i n t h e f o r m a ti o n o f a n a b a s e n e ( 2 5 a ) .
S im p le h y d r o g e n a t io n w ith p l a t ­
inum o x id e a s d e m o n s tr a te d b y D j e r a s s i , 9 w ould p ro d u c e t h e n a t u r a l
p r o d u c t, a n a b a s in e ( 2 6 ) .
c e d u re g e n e r a te d
As p r e v i o u s l y o b s e r v e d , o u r r e a c t i o n p r o ­
t h e d e s i r e d com pounds i n c o n s i d e r a b l y b e t t e r y i e l d s
th a n th e o th e r p r o c e s s e s .
The f u r t h e r u t i l i t y
s y n t h e s i s i s e x e m p l if ie d by i t s u t i l i t y
The l a t t e r ,
o f t h i s m e th o d o lo g y o f
i n p r e p a r i n g ( 2 5 b ) and ( 2 5 c ) .
(2 5 c) , is th e n a tu r a lly -o c c u r rin g a lk a lo id , c o n iin e , o f
t h e H em lock s p e c i e s .
T h is s y n t h e s i s was p re c e d e d by t h e s y n t h e s i s o f
( 2 5 b ) u s e d a s a m o d el s y s te m .
As i n t h e p r e v i o u s e x a m p le s , t h e p r o ­
d u c t s ( 2 5 b ) and ( 2 5 c ) h a v e b e e n s y n t h e s i z e d by o t h e r g ro u p s u s in g
te c h n iq u e s s im ila r t o p ro c u re th e d e s ir e d a lk a l o id .
B e c a u se o f t h e
17
b a s i c s t r u c t u r a l s i m i l a r i t i e s w i t h o t h e r a l k a l o i d s p r e p a r e d , th e
m e th o d o lo g y f o r t h e p r e p a r a t i o n o f ( 2 5 a ) and ( 2 5 b ) f o llo w e d t h e p r e ­
v i o u s l y e s t a b l i s h e d N- a c y l la c ta m p y r o l y s i s .
The s y n t h e s i s o f 2 - ( n -
p r o p y l ) - p y r r o l i n e , shown i n F i g u r e 1 3 , b e g in s w i t h t h e c o n d e n s a tio n o f
Il
0
25b
24b
F ig u re 1 3 .
S y n th e s is o f 2 - ( n - p r o p y l) p y r r o lin e
n - b u t y r y l c h l o r i d e w i t h 2 - p y r r o l i d o n e , t h i s tim e e x c lu d i n g t h e u s e o f
p y r i d i n e , t o form t h e N - a c y l la c ta m
(2 4 b ).
P y r o ly s is o f t h i s p ro d u c t
g a v e a c ru d e m ix tu r e w h ich upon d i s t i l l a t i o n p r o v id e d a n e x c e l l e n t
o v e ra ll y ie ld
o f 2 -(n -p ro p y l) p y r ro lin e .
The s y n t h e s i s o f C o n ic e in e 15 was a c c o m p lis h e d i n t h e same m a n n e r.
F ig u r e 14 show s t h e c o n d e n s a t io n o f n - b u t y r y l c h l o r i d e a n d g - v a l e r o l a c ta m t o y i e l d t h e d e s i r e d N - a c y l l a c ta m
compound l e d
(24c) .
P y ro ly s is o f t h is
t o t h e c ru d e m a t e r i a l w h ic h upon d i s t i l l a t i o n y i e l d e d
18
c o n ic e in e ( 2 5 c ) .
D j e r a s s i h a s shown t h a t t h e s a t u r a t e d c o n i i n e
(2 7 )
c a n be p r e p a r e d by t h e c a t a l y t i c h y d r o g e n a tio n o f c o n i c e i n e .
A
25c
F ig u re 1 4 .
27
The S y n t h e s i s o f C o n ic e in e and C o n iin e
T h ro u g h t h e s im p ly p y r o l y t i c r e a c t i o n d e s c r i b e d , one i s now a b le
t o o b t a i n n o t o n ly t h e n i c o t i n e a l k a l o i d s d e s c r i b e d , b u t many a l k a l o i d s
c o n t a i n i n g t h e p y r r o l i n e o r p i p e r i d i n e m o ie ty .
Y et w ith a l l th e ex ­
c e l l e n t r e s u l t s a l r e a d y p u b l i s h e d , t h i s s y n t h e t i c m ethod h a s m e re ly
s c ra tc h e d th e s u rfa c e o f i t s u t i l i t y .
i s y e t unknow n.
The m echanism o f t h e r e a c t i o n
T h e re h a s b e e n no e v id e n c e a s t o w h ic h s i d e o f th e
la c ta m i s bound t o t h e R -g ro u p ( F ig u r e 1 4 ) a f t e r c o m p le tio n o f t h e
p y ro ly s is .
T h e re i s a l s o no e v id e n c e d e f i n i n g t h e l o s s o f t h e tw o
ox y g en s an d one c a r b o n , o b s e rv e d by t h e p y r o l y s i s o f t h e N- a c y l l a c t a m .
I t h a s b e e n d e m o n s t r a t e d , h o w e v e r, t h a t t h e c o n d i t i o n s f o r t h e p y r o l y s i s
19
a r e g e n t l e eno u g h t h a t no r e a r r a n g e m e n t o f t h e a c y l g r o u p c a n be d e ­
te c te d .
A v e r y good e x am p le o f t h e s p e c i f i c i t y
p y r o l y s i s shown i n F i g u r e 1 5 .
o f th e r e a c tio n i s th e
C y c lo p r o p a n e c a r b o x c y lic a c i d c h l o r i d e
was c o n d e n se d w i t h 2 - p y r r o l i d o n e t o fo rm t h e N- a c y l la c ta m
(2 4 d ).
T h is
N - a c y l l a c ta m was p y r o l i z e d u n d e r t h e same c o n d i t i o n s a s p r e v i o u s l y
d e s c rib e d .
The d e s i r e d p r o d u c t , 2 - c y c l o p r o p y l p y r r o l i n e
( 2 5 d ) upon
nmr i n v e s t i g a t i o n e x h i b i t e d a n u n r e s o l v e d d o u b l e t a t 0 .8 ppm.
A lth o u g h
t h e d o u b l e t r e p r e s e n t e d 4 h y d r o g e n s ,t h e r e was d o u b t a s t o w h e th e r t h e
d o u b l e t r e p r e s e n t e d c y c lo p r o p a n e h y d r o g e n s .
O
M eI
Il
-------- ^
V 7 ' O
it
O
24d
25d
CH3 CH3
28
F ig u re 1 5 .
29
30
The S y n t h e s i s o f C y c l o p r o p y l p y r r o l in e an d I t s D e r i v a t i v e s
20
I n a n a t t e m p t t o r e s o l v e t h i s p r o b le m , a, m e th y l i o d i d e d e r i v a t i v e
was p r e p a r e d .
(2 8 )
The nmr s p e c tr u m o f t h e compound i s o l a t e d fro m th e
m e th y l i o d id e r e a c t i o n showed a s h i f t o f t h e d o u b l e t to 2.6 ppm and
a ch a n g e i n s h a p e t o a m u l t i p l e t .
A t f i r s t t h e p r o d u c t was t h o u g h t
t o be a r e a r r a n g e m e n t o f t h e f o r m e r p y r r o l i n e
(25d) , b u t in v e s tig a tio n
s u g g e s te d t h a t due t o t h e q u a t e r n a r y ammonium s a l t p r e p a r e d , t h e cy ­
c lo p r o p a n e h y d ro g e n s c o u ld b e moved t h e 1 .8 ppm d e p i c t e d by t h e m ul­
tip le t.
R e d u c tio n o f t h e u n s a t u r a t i o n o f ( 2 8 ) was u n d e r t a k e n by t h e
a d d i t i o n o f so d iu m b o r o h y d r i d e .
The nm r s p e c tru m o f ( 2 9 ) p r o v id e d
s u b s t a n t i a l p ro o f t h a t th e r e a c ti o n p ro ceed ed a s p r e d ic te d .
t r a d is p la y e d a m u lt ip l e t a t
g e n s , a t 2 . 4 ppm .
The s p e c ­
.3 ppm a n d a s i n g l e t , t h e N- m e th y l h y d r o ­
T h is w ould t h e n s u g g e s t t h a t t h e u n s a t u r a t e d p y r ­
r o l i n e h ad c a u s e d t h e f o r m a t i o n o f t h e d o u b l e t o b s e rv e d i n t h e nmr o f
(2 5 d ) .
To f i n a l i z e t h e r e s u l t s , t h e m e th y l i o d i d e d e r i v a t i v e
t h e t e r t i a r y am ine w as t h e n p r e p a r e d .
(3 0 ) o f
Upon nmr i n v e s t i g a t i o n o f t h i s
com pound, t h e c y c lo p r o p a n e h y d ro g e n s w e re a g a i n s h i f t e d d o w n f ie ld t o
a p o s i t i o n o f .8 ppm.
I t was t h e n p ro p o s e d t h a t t h e d a t a w ere c o n s i s ­
t e n t w i t h t h e s u g g e s te d s t r u c t u r e ,
( 2 5 d ) , 2 - c y c lo p r o p y l p y r r o l i n e .
21
The M u n d y -R ap o p p rt S y n t h e s i s f o r L a b e le d N i c o ti n e A l k a lo i d s
The p r e s e n t m o st i m p o r ta n t r e a s o n f o r a n a d e q u a te s y n t h e s i s o f
t h e s e a l k a l o i d s i s t o s tu d y t h e i r b i o g e n e s i s .
F o r th e s e ty p e s o f
s t u d i e s , one m u st s p e c i f i c a l l y l a b e l p o s i t i o n s i n t h e a l k a l o i d s d e ­
s ire d .
T h e r e f o r e , a s y n t h e s i s s h o u ld p r o c e e d w i t h a c c u r a c y ( e f f i c i e n t ­
l y ) o f l a b e l p la c e m e n t i n o r d e r t o p ro d u c e a s much l a b e l e d m a t e r i a l a s
p o s s ib le .
A s y n t h e s i s d e s ig n e d by Mundy and R a p o p o rt
( F ig u r e .16)
d e m o n s tr a te s how one c a n p l a c e a l a b e l s p e c i f i c a l l y i n t h e 4 - p o s i t i o n
o f th e p y r ro lin e r in g o f n o rn ic o tin e o r n ic o tin e .
A d d i t io n o f t h e
c a r b a n io n g e n e r a te d by b a s i c a c t i o n on maI o n i c a c i d l e a d s t o t h e v i n y l
d ia c id
(3 1 ).
H e a tin g t h e v i n y l d i a c i d c a u s e s d e c a r b o x y l a t i o n , fo rm in g
t h e v i n y l a c i d w h ic h , u p o n e s t e r i f i c a t i o n l e a d s t o t h e v i n y l e s t e r ( 3 2 ) .
A d d i t io n o f l a b e l e d N - c a r b o x y l g l y c i n e fo rm s compounds ( 3 3 ) and (3 6 )
in an e q u ilib riu m m ix tu r e .
c a l p ro d u c t.
P a th w a y s I and 2 l e a d t o t h e same e m p i r i ­
The d i f f e r e n c e b e tw e e n t h e p a th w a y s i s t h e p o s i t i o n o f
t h e l a b e l e d c a rb o n upon c y c l i z a t i o n .
I n compound ( 3 4 ) t h e l a b e l e d
c a rb o n i s i n t h e 4 - p o s i t i o n o f t h e p y r r o l i d i n e r i n g a s o p p o sed t o com­
pound ( 3 7 ) w h ere t h e l a b e l e d c a rb o n r e m a in s a s a n e s t e r f u n c t i o n b r a n c h ­
in g fro m t h e 5 - p o s i t i o n .
Upon re m o v a l o f t h e e x t e r n a l e s t e r f u n c t i o n s
o f ( 3 4 ) and ( 3 7 ) b y h y d r o l y s i s , a l l o f t h e l a b e l c a rb o n i s rem oved by
t h e f o r m a ti o n o f ( 3 8 ) , r e n d e r i n g i t u s e l e s s .
compound o f c o n c e r n h a v in g i t s
( 3 4 ) i s now t h e o n ly
l a b e l f ix e d in th e fo u r p o s itio n .
a d d i t i o n o f h y d ra z in e and r e d u c tio n y i e l d s n o r n ic o tin e
(IH ) w h ic h
The
22
upon m e t h y l a t i o n r e s u l t s i n s p e c i f i c a l l y l a b e l e d n i c o t i n e
__^COOH
COOH
COOH
"^C O O H
r
©N
©o.COOEt
i?
COOE+
Et-O-^jyj
rCOOEt.
^
(7).
O
©
to r © 8
^
Q ^O E t
xOEt
Hyd.
F ig u r e 1 6 .
S y n t h e s i s o f L a b e le d N i c o ti n e by Mundy a n d R a p o p o rt
( c o n t i n u e d on p a g e 2 3 )
23
COOE+
F ig u r e 1 6 .
COOE+
( c e n t.)
24
P ro p o s e d A p p l i c a t i o n o f O ur S y n t h e t i c T e c h n iq u e s
f o r t h e P r e p a r a t i o n o f L a b e le d N i c o ti n e A l k a l o i d s
D e s p ite t h e l o s s o f l a b e l e d m a t e r i a l , t h e e l e g a n t , b u t l e n g t h y ,
s y n t h e s i s p r o v id e s p la c e m e n t o f t h e c a rb o n f o u r t e e n f u n c t i o n w ith
s u r p r i s i n g l y h ig h y i e l d s .
As a n a l t e r n a t i v e m ethod f o r l a b e l e d a l k a l o i d p r e p a r a t i o n , r e a l ­
i z e d w i t h o u t t h e n e c e s s i t y o f a l e n g t h y c o m p lic a te d s e q u e n c e , an
a d a p t a t i o n t o o u r s y n t h e t i c p r o c e d u r e seem s p o s s i b l e .
By p r e p a r in g
s p e c i f i c a l l y l a b e l e d 2 - p y r r o l i d o n e , t h e d e s i r e d n a t u r a l p r o d u c t can
b e s y n t h e t i c a l l y g e n e r a te d a s i l l u s t r a t e d b y t h e f o rm e r s e q u e n c e s
( F ig u r e s 6 and 1 0 ) .
The e n v is i o n e d s y n t h e s i s , shown i n F i g u r e 1 7 ,
b e g in s w i t h b ro m o h y d rin , a r e a d i l y a v a i l a b l e s t a r t i n g m a t e r i a l , u n d e r -
HO
Ii
0
40
I. SOCI
PM
41
F ig u re 1 7 .
42
S y n t h e s i s o f L a b e le d 2 - p y r r o l i d o n e
25
g o in g d i s p l a c e m e n t o f t h e b ro m in e w i t h l a b e l e d so d iu m c y a n id e t o p r o ­
v i d e l a b e l e d c y a n o h y d rin ( 3 9 ) .
T h is compound c o u ld t h e n b e d e h y d r a te d
and h y d r o ly z e d t o p ro d u c e t h e a c i d
(40).
R e a c tio n o f t h e f r e e a c i d
w i t h r e f l u x i n g t h i o n y l c h l o r i d e , i s o l a t i o n o f t h e a c i d c h l o r i d e , and
r e a c t i o n w i t h ammonia w ould p ro d u c e t h e am id e ( 4 1 ) .
C y c l i z a t i o n c o u ld
t h e n b e a c c o m p lis h e d w i t h t h e m e th y l i o d i d e s a l t o f d i m e th y l s u l f o x i d e
i n t h e p r e s e n c e o f so d iu m h y d r i d e .
13
T h is c y c l i z a t i o n p r o d u c t (4 2 )
w ould t h e n b e s p e c i f i c a l l y l a b e l e d 2 - p y r r o l i d o n e w i t h t h e l a b e l r e ­
s i d i n g a t t h e 2 o r c a r b o n y l c a rb o n o f t h e l a c t a m .
T h is r e a c t i o n s e ­
q u e n c e c o u ld t h e n b e c o u p le d w i t h o u r p r e v i o u s l y p r e s e n t e d s y n t h e s i s
o f m yosm ine y i e l d i n g , we b e l i e v e , m yosm ine l a b e l e d i n t h e 2 p o s i t i o n .
Upon h y d r o g e n a t io n and m e t h y l a t i o n , n i c o t i n e , l a b e l e d i n t h e 2 p o s i ­
t i o n , w ould b e i s o l a t e d w i t h v e r y m in im a l l o s s o f l a b e l due t o t h e
s y n th e tic p ro c e d u re .
SUMMARY
W ith t h e w e a l th o f e v id e n c e p r e s e n t e d 5 we f e e l t h e p ro b le m
■ w a rra n ts f u r t h e r e x p l o r a t i o n .
The s y n t h e t i c re w a rd o f f e r e d b y t h i s
m ethod o f s y n t h e s i s i s , p e r h a p s , u n l i m i t e d .
The t o t a l p o t e n t i a l o f
t h e p o w e r f u l s y n t h e t i c t e c h n i q u e w i l l o n ly bb r e a l i z e d u p o n e x t e n s i v e
e x p e rim e n ta l i n v e s t i g a t i o n .
B u t,, f o r t h e p r e s e n t , t h i s m ethod p r e s e n t s
an e x c e l le n t h y p o th e tic a l e n tra n c e i n to s y n th e s is o f th e h a r d - to - o b ta in
l a b e l e d com pounds c o n c e rn e d w i t h b i o g e n e t i c s t u d i e s .
The a p p l i c a t i o n
o f t h i s s y n t h e s i s i n t h e b i o s y n t h e s i s o f t h e n i c o t i n e may w e l l ch an g e
t h e c l a s s i c a l b i o g e n e t i c p a th w a y s shown f o r p r o d u c t i o n o f t h e n i c o t i n e
a l k a l o i d s a s p r e l i m i n a r y i n v e s t i g a t i o n s b y B . P . Mundy h a v e s u g g e s t e d .
EXPERIMENTAL
N u c le a r m a g n e tic r e s o n a n c e s p e c t r a w ere r u n on a V a r ia n A -60
N u c le a r M a g n e tic R e so n a n c e S p e c tr o p h o to m e te r U sin g d e u t e r o c h l o r o f orm
a s a s o l v e n t a n d TMS a s a n i n t e r n a l s t a n d a r d .
G lc r e c o r d e r t r a c i n g s ' w e re o b t a i n e d fro m a V a r ia n A e ro g ra p h M odel
A -7 0 0 .
Work was p e rfo rm e d u s i n g a 7 ’ x ^ rr 3% OV-17 pn C hrom osorb W
(9 0 /1 2 0 m esh ) c o lu m n .
The g a s f lo w i n t h e s y s te m was k e p t a t a p p ro x ­
i m a t e l y 40 m l/m in .
Mass s p e c t r a o f b o t h s o l i d s and l i q u i d s w ere o b t a i n e d w i t h t h e
a i d o f a V a r ia n M odel CH5 m ass s p e c t r o p h o t o m e t e r .
The l i q u i d sa m p le s
w e re i n tr o d u c e d i n t o t h e m ac h in e t h r o u g h a 6 ' x 1 / 8” colum n p a c k ed
w i t h 10% A p e iz o n -L on C hrom psorb W ( 9 0 /1 2 0 m esh) i n t o a h e liu m s e p a r ­
a t o r w i t h t h e a i d o f a V a r ia n A e ro g ra p h S e r i e s 1 7 0 0 .
A l l m e l t i n g p o i n t s an d b o i l i n g p o i n t s a r e u n c o r r e c t e d .
P r e s s u r e s a r e r e p o r t e d i n mm o f m e rc u ry ( e , g . b p ^ 0 50°C i n d i c a t e s
t h e b o i l i n g p o i n t w as SO0C a t a p r e s s u r e o f 10 mm o f m e r c u r y ) .
G e n e r a l P r e p a r a t i o n o f t h e A c y b a te d L a c ta m s :
The s i m i l a r i t y o f t h e N - a c y l la c t a m s y s te m s !e n d e d th e m s e lv e s t o
a c o n s is te n t p r e p a ra tio n p ro c e d u re .
U n le s s o th e r w is e n o t e d , r e a c t i o n
t i m e s , c o n d i t i o n s , and w orkup p r o c e d u r e s re m a in e d s t a t i c f o r g e n e r a t i o n
o f a l l t h e s y s te m s p y r o l i z e d .
A s o l u t i o n p r e p a r e d by t h e s lo w a d d i t i o n o f n m o le s o f p y r i d i n e
t o x m o le s o f a n a c i d c h l o r i d e was s t i r r e d
f o r one h o u r .
A fte r th is
2 8
t i m e , y m o le s o f t h e d e s i r e d l a c t a m , d i s s o l v e d i n p y r i d i n e , w ere
a d d e d d ro p w is e t o t h e p r e v i o u s s o l u t i o n .
t h e n a llo w e d t o s t i r a t room t e m p e r a t u r e ..
The r e a c t i o n m ix tu r e was
A f t e r 8 h o u r s , t h e c ru d e
p r o d u c t was d i s s o l v e d i n m e th y le n e c h l o r i d e , and w ashed w i t h d i l u t e h y ­
d r o c h l o r i c a c i d u n t i l a pH o f 3 w as o b t a i n e d i n th e . a q u e o u s l a y e r „
A
s a t u r a t e d s o l u t i o n o f so d iu m b i c a r b o n a t e was t h e n u s e d t o r a i s e th e
pH t o 9 e l i m i n a t i n g a n y e x c e s s a c i d .
The m e th y le n e c h l o r i d e l a y e r
was t h e n d r i e d w i t h a n h y d ro u s so d iu m s u l f a t e and t h e s o l v e n t rem oved
a t red u ced p r e s s u r e .
The r e m a in in g r e s i d u e was p u r i f i e d by a v a r i e t y
o f p ro ce d u re s.
(N o te :
I f t h e a c y l la c ta m d e s i r e d c o n t a i n s a p y r i d i n e r i n g , one
s h o u ld n o t w ash t h e m e th y le n e c h l o r i d e m ix tu r e w i t h a c i d a s t h e com­
pound w i l l b e s a l t e d
o u t o f th e o rg a n ic l a y e r . )
G e n e r a l R e a rra n g e m e n t P r o c e d u r e o f t h e N r-acyl L a c ta m s :
As i n t h e N .-acyl a t i o n g e n e r a l p r o c e d u r e , t h e p y r o l y s i s c o n d i t i o n s
o f t h e s y s te m s i l l u s t r a t e d
re m a in e d c o n s t a n t fro m p r e p a r a t i o n o f t h e
r e a c t i o n m ix t u r e t o d i s t i l l a t i o n
o f t h e c ru d e p y r o l y s i s p r o d u c t .
The N- a c y l la c t a m was m ixed t h o r o u g h l y w i t h a n e q u a l w e ig h t o f
c a lc iu m o x id e and p la c e d i n a p y re x t u b e f i t t e d w i t h a s i d e a rm .
m ix tu r e was g e n t l y h e a te d w i t h t h e f la m e o f a m ic ro b u r n e r .
The
When a
m e l t w as o b s e r v e d , t h e h e a t was c o n tin u e d u n t i l t h e c ru d e p r o d u c t d i s ­
tille d .
T h is p r o d u c t w as t h e n s u b j e c t e d t o r e d u c e d p r e s s u r e d i s t i l l a -
29
CaO + L actam
C o lle c t
H eat
t i o n , p u r i t y b e in g c h e c k e d by g l c (3% OV-17 S t XX.2 5 " ) .
Id e n tific a tio n
was a c c o m p lis h e d by s p e c t r a l m eans an d b y p r e p a r a t i o n o f known d e r i v a ­
tiv e s .
P r e p a r a t i o n o f N - N ic o tin o y 1 - 2 - P y r r o l i d o n e , ( 2 3 ) :
U sin g t h e g e n e r a l p r o c e d u r e f o r a c y l a t i o n , a s o l u t i o n o f n i c o t i n o y l c h lo r id e h y d ro c h lo rid e
0 .1 2 6 m o le ) was p r e p a r e d .
(27 g , 0 .1 6 3 m o le ) and p y r i d i n e
(10 g ,
A f t e r a d d i t i o n o f 2 - p y r r o l i d o n e (4 0 g ,
m o le ) a c ru d e m ix tu r e c o n t a i n i n g ( 2 3 ) was i s o l a t e d .
.4 6 5
The c ru d e p r o d u c t
was s u c c e s s i v e l y r e c r y s t a l l i z e d fro m a m ix tu r e o f c h lo r o f o r m and h e x a n e
y i e l d i n g 2 2 .4 g (85% y i e l d ) o f ( 2 3 ) .
m p. I 040C
A n a l:
C a l c t d f o r C10H10N202 :
F ound":
C’ 6 3 i l 5 S
hj
5 .3 0 ; N, 1 4 .7 3
C, 6 3 .7 8 ; H, 5 .0 3 ; N, 1 4 .8 2
" A n a l y t i c a l d a ta f o r ( 2 3 ) was k i n d l y p r o v id e d by P r o f . H enry R a p o p o r t,
U n i v e r s i t y o f C a l i f o r n i a , B e r k e le y .
30
nmr Data
4
5
C h e m ic a l
S h ift (a)
Number o f
P r o to n s
N a tu re o f P e a k s
I.
2 .5 7
2
T rip le t
2.
2 .1 2
2
U n re s o lv e d Q u a r t e t
3.
3 .9 0
2
T rip le t
4.
7 .5 9
2
D o u b le t o f M u l t i p l e t s
5.
8 .7 0
2
M u l t i p l e t ( u n r e s o lv e d s i n g l e t )
P r e p a r a t i o n o f M yosm ine, ( 2 2 ) ;
U sin g t h e g e n e r a l p r o c e d u r e f o r r e a r r a n g e m e n t o f N- a c y l la c ta m s
N - n i c o t i n o y l - 2 - p y r r o l i d o n e ( 1 .5 g ,
.0 0 8 5 m o le ) and c a lc iu m o x id e
( I •5 § } 0 .0 2 0 9 m o le ) w e re g e n t l y h e a te d p r o v id i n g a c ru d e m ix tu r e w h ic h
upon vacuum d i s t i l l a t i o n y i e l d e d
.7 5 g (67% y i e l d ) o f m y o sm in e .
b p . 1() 8 2 -8 6 °
P i c r a t e d e r i v a t i v e mp. 1 8 4 - 1 8 5°C , L i t e r a t u r e 7 mp. 1 8 4 - 1 8 5°C
31
nmr Data
C h e m ic a l
S h i f t ( 6)
Number o f
P r o to n s
N a tu re o f P e a k s
I.
4 .0 5
2
T r ip le t of T rip le ts
2.
2 .0 8
2
Q u a rte t
3.
2 .9 1
2
U n re s o lv e d T r i p l e t
4.
7 .7 0
2
D o u b le t o f M u l t i p l e t
5.
8 .6 0
I
U n re s o lv e d S i n g l e t
6.
8 .9 3
I
U n re s o lv e d S i n g l e t
P re p a ra tio n o f N - n ic o tin o y l- 2 -P ip e rid o n e , ( 2 4 a ) :
U sin g t h e g e n e r a l p r o c e d u r e f o r a c y l a t i o n , a s o l u t i o n o f n i c o t i n y l
c h l o r i d e h y d r o c h l o r i d e (42 g ,
was p r e p a r e d .
.252 m o le ) and p y r i d i n e (2 0 g ,
.252 m o le )
To t h i s s o l u t i o n , a d d i t i o n o f p i p e r i d o n e (1 0 g ,
.0101
m o le ) l e d t o t h e i s o l a t i o n o f a c ru d e p r o d u c t m ix tu r e c o n t a i n i n g th e
d e s i r e d a c y l la c ta m
(2 4 a) .
P u r i f i c a t i o n o f t h e p r o d u c t by r e c r y s t a l ­
l i z a t i o n p ro v e d t o b e f r u i t l e s s .
The c ru d e m ix tu r e was t h e n e l u t e d
t h r o u g h a colum n c o n t a i n i n g B io - S il - A 1 0 0 -2 0 0 m esh .
E lu tio n began
w ith b e n z e n e , t h e s o l v e n t u s e d t o p a c k t h e c o lu m n , and t h e p r o d u c t was
i s o l a t e d a f t e r 500 m i s . o f 5 0 :5 0 b e n z e n e c h lo r o f o r m had p a s s e d th r o u g h
32
t h e c o lu m n .
A f te r e v a p o ra tio n o f th e s o lv e n ts , a s o lid r e s id u e r e ­
m ain ed w h ic h b y t i c
on s i l i c a g e l w i t h 10% m e th a n o l i n c h lo r o f o r m ,
show ed o n ly one s p o t w i t h a n r f v a l u e o f 4 . 4 .
The s o l i d m a t e r i a l was
s u b j e c t e d t o nmr sh o w in g t h e e x p e c te d p e a k p la c e m e n t f o r compound ( 2 4 a ) .
1 1 .2 g ram s o f ( 2 4 a ) was i s o l a t e d a c c o r d in g t o t h i s p r o c e d u r e a f f o r d i n g
a 54.5% y i e l d .
m p. 66- 68°C
nmr D ata
0
Il
5
5f f )
r
0
11
>
V
2
3
C h e m ic a l
S h ift (s)
Number o f
P r o to n s
N a tu re o f P e a k s
I.
2 .5
2
M u ltip le t
2.
1 .7 7
4
M u ltip le t
3.
1 .7 7
4
M u ltip le t
4.
3 .7 5
2
M u ltip le t
5.
7 .5
2
D o u b le t o f M u l t i p l e t
6.
8 .7
2
M u ltip le t
33
P re p a ra tio n o f A n abasene5 (2 5 a ) ;
The p y r o l y s i s o f t h e N- a c y l la c t a m ( 2 4 a ) p ro c e e d e d a c c o r d in g t o
th e g e n e r a l p ro c e d u re o u t l i n e d .
The la c ta m
( 2 4 a ) 5 ( I g 5 0 .0 0 4 9 m o le )
an d c a lc iu m o x id e ( I g 5 0 . 0156 m o le ) w h ic h upon g e n t l e h e a t i n g y i e l d e d
a c ru d e m ix tu r e shown b y nm r t o c o n t a i n t h e compound d e s i r e d
(2 5 a).
D i s t i l l a t i o n ' o f t h e c r u d e m a t e r i a l y i e l d e d 4 .3 gram s (62% y i e l d ) o f
■( 4 0 a ) .
b p .I Q 7 0 - 7 2 0C5 L i t e r a t u r e ^ b p . Q g 25°C
P i c r a t e d e r i v a t i v e m p. 1 7 1 -1 7 2 0C 5 L i t e r a t u r e ^ m p. 170-172°C
B e c a u s e o f t h e n a t u r e o f t h e compound 5 no nmr s p e c tr u m was t a k e n .
P r e p a r a tio n o f N -B u ty ry l-2 -p y rro lid o n e 5 ( 2 4 b ) ;
T h is p r e p a r a t i o n d e v i a t e s fro m t h e . g e n e r a l p r o c e d u r e i n t h a t t h e
b e s t y i e l d s o f t h e compound w e re p r e p a r e d w i t h o u t t h e u s e o f p y r i d i n e .
N - b u t y r y l c h l o r i d e (1 5 g 5 0 .1 2 4 m o le ) s u s p e n d e d i n b e n z e n e (1 0 m l) was
ad d ed d i r e c t l y t o a b e n z e n e (2 5 m l) s o l u t i o n o f 2 - p y r r o l i d o n e ( 2 4 .2 g 5
0 .2 8 5 m o le ) .
A f t e r one h o u r o f c o n s t a n t s t i r r i n g , t h e r e a c t i o n m ix tu r e
was t a k e n up i n m e th y le n e c h l o r i d e .
A f t e r t h e g e n e r a l a c i d and b a s e
w a s h in g s , t h e s o l v e n t w as rem oved a n d vacuum d i s t i l l a t i o n y i e l d e d 2 0 .8 g
(9 4 .5 % y i e l d ) o f t h e f i n a l p r o d u c t , ( 2 4 b ) .
34
b p . 1() IS S 0C
nmr D ata
I
C h e m ic a l
S h if t (g )
Number o f
P r o to n s
N a tu re o f P e a k s
I.
0 .9 2
3
T rip le t
3.
3 .7 2
2
T rip le t
2 , 5, & 4
U n re s o lv e d m u l t i p l e t r a n g i n g fro m 1 .2 5 - 2 .9 5
P re p a ra tio n o f 2 - ( n - p r o p y l) - p y r r o lin e , (2 5 b ):
U sin g t h e g e n e r a l p r o c e d u r e f o r p y r o l y s i s , p r e p a r a t i o n o f (2 5 b )
was a c c o m p li s h e d .
( 2 4 b ) , ( 1 . 5 g , 0 .0 9 7 m o le ) and c a lc iu m o x id e ( 1 .5 g ,
0 .0 2 9 m o le ) w e re r e a c t e d y i e l d i n g a c ru d e p r o d u c t m i x t u r e .
m ix tu r e was t h e n vacuum d i s t i l l e d a f f o r d i n g
T h is c ru d e
.8 1 g ( 75% y i e l d ) o f ( 4 0 b ) .
b p . 10 38°C
P i c r a t e d e r i v a t i v e m p. 1 0 5 - 1 0 5 .5 °C , L i t e r a t u r e 17 mp. 1 0 4 - 1 0 4 .5°C
35
nmr Data
a
C h e m ic a l
S h i f t (&)
N
5
Number o f
P r o to n s
N a tu re o f Peak:
I.
0 .9 5
3
T r i p l e t o f D o u b le t
5.
3 .7 5
2
M u ltip le !
2 , 3, & 4
U n re s o lv e d m u l t i p l e ! r a n g i n g fro m 1 .1 2 - 2 .6 7
P r e p a r a tio n o f N -B u ty ry l-p ip e rid o n e , ( 2 4 c ) ;
The p r e p a r a t i o n o f t h i s l a c ta m was a l s o fo u n d t o p r o c e e d w ith
maximum e f f i c i e n c y w i t h o u t t h e u s e o f p y r i d i n e .
N -b u ty ry l c h lo r id e
( 2 .3 g , 0 .0 2 2 5 m o le ) s u s p e n d e d i n b e n z e n e (1 0 m l) was a d d e d d i r e c t l y
t o a b e n z e n e s o l u t i o n (1 5 m l) o f 2 - p i p e r i d o n e (5 g , 0 .0 5 0 5 m o le ) .
A f t e r one h o u r o f c o n s t a n t s t i r r i n g , t h e r e a c t i o n m ix tu r e was ta k e n up
i n m e th y le n e c h l o r i d e .
A f t e r t h e s t a n d a r d a c i d and b a s e w a s h in g s , t h e
s o l v e n t was rem oved a n d vacuum d i s t i l l a t i o n y i e l d e d 2 .3 g (61% y i e l d )
of (24c) .
bp.155°C,
L i t e r a t u r e 16 b p . ^ ^ 820C
36
nmr Data
0 < - /X .5
C h e m ic a l
S h ift ( 5)
Number o f
P r o to n s
N a tu re o f P e a k s
I.
0 .9
3
T r i p l e t o f D o u b le ts
7.
3 .6 7
2
U n re s o lv e d T r i p l e t
2 , 3 , 4 , 5, & 6
u n r e s o l v e d r a n g i n g fro m 1 . 3 - 3 .0
P r e p a r a t i o n o f Y - C o n ic e in e , ( 2 5 c ) :
The p r e p a r a t i o n o f ( 2 5 c ) was a c c o m p lis h e d u s in g t h e g e n e r a l
p y r o ly s is p ro ce d u re a s o u tlin e d .
( 2 4 c ) , ( I g , 0 .0 0 5 9 m o le ) and
c a lc iu m o x id e ( I g , 0 .0 1 5 6 m o le ) g e n t l y h e a te d y i e l d e d
y i e l d ) o f ( 2 5 c ) a f t e r vacuum d i s t i l l a t i o n
bp.54°C,
.5 1 g (69%
o f t h e c ru d e m a t e r i a l .
L i t e r a t u r e ^ b p . ^ 54°C
P i c r a t e d e r i v a t i v e m p. 7 7 -7 8 ° C , L i t e r a t u r e 16 mp. 77-78°C
P r e p a r a t i o n o f N - c y c lo p r o p a n e c a r b o x o y l - 2 - p y r r o l i d o n e , ( 2 4 d ) :
U sin g t h e g e n e r a l p r o c e d u r e f o r a c y l a t i o n , a s o l u t i o n o f c y p r o p a n e c a rb o x y l a c id c h lo r id e
0 .0 1 2 6 m o le ) was p r e p a r e d .
( 5 g , 0 .0 4 8 4 m o le ) and p y r i d i n e
(1 0 g ,
A f t e r a d d i t i o n o f t h e 2 - p y r r o l i d o n e ( 8 .2 5
g , 0 .0 9 6 8 m o le ) a c ru d e m ix tu r e c o n t a i n i n g ( 2 4 d ) was i s o l a t e d .
The
37
c ru d e p r o d u c t was s u c c e s s f u l l y r e c r y s t a l l i z e d fro m a m ix tu r e o f c h l o r o ­
form an d h e x a n e y i e l d i n g 6 .9 6 5 g (90% y i e l d ) o f ( 2 4 d ) .
b p . 15 1 3 6 0C
m p. 62-63°C
A n a l:
C a l c ’d f o r CgH11NO2 :
Found:
C , 6 2 .7 ; H, 7 . 2 ; N, 9 .1
C , 6 2 .3 ; H, 7 . 1 ; N, 9 .3
nmr D ata
C h e m ic a l
S h if t (§ )
Number o f
P r o to n s
N a tu re o f P e a k s
1.
2 .6 1
2
T rip le t
2.
1 .9 5
2
Q u in te t
3.
3 .7 5
2
T rip le t
4.
3 .1 7
I
M u ltip le t
5.
0 .9 7
4
M u ltip le t
P re p a ra tio n o f 2-e y e lo p ro p y lp y rr o lin e ( 25 d ) :
U sin g t h e g e n e r a l p r o c e d u r e f o r p y r o l y s i s , t h e a c y l la c ta m (2 4 d )
( 1 . 5 g , 0 .0 0 9 8 m o le ) a n d c a lc iu m o x id e ( 1 . 5 g , 0 .0 2 9 m o le ) w e re r e a c ­
t e d y i e l d i n g a c ru d e m ix tu r e c o n t a i n i n g ( 2 5 d ) .
The m ix tu r e was th e n
d i s t i l l e d y i e l d i n g 7 .8 4 g (7 3 .5 % y i e l d ) o f ( 2 5 d ) .
38
bP - I 0 45°c
P i c r a t e d e r i v a t i v e m p. 150 -1 5 1 °C
A n a l y t i c a l D a ta ( a n a l y s i s p e rfo rm e d on p i c r a t e d e r i v a t i v e s ) :
C7HU N + C6H3N3 °7
C a l c ’d :
N , 1 6 .5 6
Found:
N , 1 6 .5 3
nmr D a ta
'NAV
5
C h e m ic a l
S h i f t ( s)
Number o f
P r o to n s
N a tu re o f P e a k s
I.
3 .7 5
2
T r i p l e t o f T r i p l e t s u n re
s o lv e d
5.
.8 1
4
D o u b le t
2 , 3, & 4
u n r e s o l v e d r a n g i n g fro m 1 . 5 - 2 .5 7
P r e p a r a t i o n o f t h e M e th y l I o d id e S a l t o f 2 - c y c l o p r o p y l - p y r r o l i n e , (28_):
A l a r g e e x c e s s o f m e th y l i o d i d e w as a d d e d t o a n e t h e r e a l s o l u t i o n
o f ( 2Sd) ,
( . 5 g , 0 .0 0 4 6 7 m o l e ) .
The s o l u t i o n was h e a te d t o r e f l u x f o r
f i f t e e n m in u te s and c o o le d t o room t e m p e r a t u r e .
The w h i t e c r y s t a l s o f
t h e s a l t ( 2 8 ) w ere c o l l e c t e d by vacuum f i l t r a t i o n .
m p. 34°C
Mass s p e c t r a p a r e n t p e a k 124
39
nmr Data
M
CH3
C h e m ic a l
S h i f t ( 6)
Number o f
P r o to n s
V 76
V
6
N a tu re
I.
3 .7 2
3
Sin g le t
2.
4 .3 5
2
T rip le t
6.
1 .6 9
4
M u ltip le t
3, 4, & 5
tw o p e a k s a t 2 .3 5 and 3 .0 6 u n r e s o lv e d
P r e p a r a tio n o f N -m e th y l-2 -c y lc o p ro p y l p y r r o l id i n e , ( 2 9 ):
To t h e s o l u t i o n o f ( 2 8 ) and a b s o l u t e m e th a n o l, a l a r g e e x c e s s o f
sodium b o r o h y d r id e was a d d e d .
one h o u r .
The r e a c t i o n was a llo w e d t o p ro c e e d f o r
A f t e r t h e a l l o t t e d tim e , w o rk -u p was e f f e c t e d b y t h e a d d i t i o n
o f a l a r g e e x c e s s o f w a t e r and e x t r a c t i o n w ith m e th y le n e c h l o r i d e , a
s o l u t i o n c o n t a i n i n g t h e d e s i r e d p r o d u c t w as o b t a i n e d .
D ry in g w ith
so d iu m s u l f a t e an d e v a p o r a t i o n o f t h e m e th y le n e c h l o r i d e y i e l d e d a
r e s i d u e sh o w in g o n ly one m a jo r co m p o n en t by g l c ( 7 T x
OV-17 c o lu m n ) .
40
nmr Data
C h e m ic a l
S h i f t (&)
Number o f
P r o to n s
N a tu re o f P e a k s
I.
2 .4 1
3
S in g le t
2.
3 .1 0
2
M u ltip le t
3.
.5
4
Wide M u l t i p l e t
P r e p a r a t i o n o f t h e M e th y l I o d id e S a l t o f N- m e th y 1 - 2 - c y c lo p r o p y l
p y r r o lid in e , (3 0 ):
A f t e r d i s s o l v i n g t h e p r e v i o u s l y p r e p a r e d n - m e th y l compound (2%
i n e t h e r and h e a t i n g t h e s o l u t i o n t o r e f l u x , a l a r g e e x c e s s o f m e th y l
i o d i d e was a d d e d .
A f t e r r e f l u x i n g f o r 15 m i n u t e s , t h e s o l u t i o n was
a llo w e d t o c o o l t o room t e m p e r a t u r e a t w h ic h tim e w h i t e c r y s t a l s b e g a n
to fo rm .
C o l l e c t i o n o f t h e c r y s t a l s w as a c c o m p lis h e d by vacuum f i l ­
tra tio n .
The nmr s p e c tr u m was t h e o n ly p h y s i c a l d a ta t a k e n on t h i s
com pound.
41
nmr Data
C h e m ic a l
S h ift ( 5)
I & 2
3.
3 .4 7 & 3 .2 2
.9
Number o f
P r o to n s
N a tu re o f P e a k s
6
Two S e p a r a t e S i n g l e t s
4
M u ltip le t
REFERENCES
1.
A . P i p n e r 5 B e r . , 2 6 , 2 9 2 , 765 ( 1 8 9 3 ) .
2.
A . P i c t e t and P . C r e i e u x ? i b i d . , 2 8 , 1904 ( 1 8 9 5 ) .
3.
E . S p a th
4.
L . C. C ra ig ,
5.
F i s h e r , B e r . , 1 5 , 62 ( 1 8 8 2 ) .
6.
N o y e s, J . A m er. Chem. S o c . , 1 9 , 766 ( 1 8 9 7 ) .
7.
E . S p a th
a n d L . M am oli, B e p .^ .6 9 , 757 ( 1 9 3 6 ) .
8.
F . K o r te
and H . S c h u l t z - S t e i n e r , i b i d . , 9 5 , 2444 ( 1 9 6 2 ) .
9'.
A . M. D u f f i e l d , H . B u d z ik ie w ic z , an d C . D j e r a s s i , J . A m er. Chem.
S o c . , 8 7 , 2926 ( 1 9 6 2 ) .
and H . B r e ts c h n e id e r , i b i d . ,
J . A g e r . Chem. S o c . ,
6 1 , 328 ( 1 9 2 8 ) .
5 5 , 2854 ( 1 9 3 3 ) .
10.
I . M u ra k o s h i, C . A . , 5 2 , 5376a ( 1 9 5 8 ) .
11.
B . P . Mundy, B . R . L a r s e n , L . F . M cK enzie, and G ary B ra d e n , J .
O r g . Chem. , 3 7 , 1635 ( 1 9 7 2 ) .
“
.
12.
B . P . Mundy a n d R. R a p o p o p t, u n p u b lis h e d s y n t h e s i s .
13.
H . K o n ig , H . M e tz g e r, an d K , S t e e l e r t , B e r . , 9 8 , 3 7 1 2 .
14.
E . S p a th and L . M am oli, i b i d . , 6 9 , 1082 ( 1 9 3 6 ) .
15.
B . P . Mundy a n d B . R . L a r s e n , S y n t h e t i c Comm. , i n p r e s s
16.
K . H. B u ch el and F . K o r te , B e r . ,
17.
S . G a b r i e l , i b i d . , 4 2 , 1259 ( 1 9 0 9 ) .
9 5 , 2460 ( 1 9 6 2 ) .
(1 9 7 2 ).
MttNTANA STATE UNIVERSITY LIBRARIES
*
3
762 10014457 3
i
N378
L328
cop. 2
L a rse n , B re n t R
C a lc iu m o x id e
c a ta ly z e d p y r o ly s is o f
TT-acyl la c ta m s
/
c'
C O U K S PUCI
KWDine
c au « puot, WA
3 -2 ^
-2.