New synthetic methodologies for natural products
by William Gerard Bornmann
A thesis submitted in partial fulfillment of the requirements for the degree of MASTER OF SCIENCE
in Chemistry
Montana State University
© Copyright by William Gerard Bornmann (1978)
Abstract:
The orbital symmetry allowed [3.3] sigmatropic rearrangement of enamines derived from
2-acetyl-6-methyl-3,4-dihydro-2H-pyran has allowed for facile entry into highly functionalized
cyclohexanone derivatives. This new synthetic methodology offers promise for entry into sesquiterpene
natural products. A by-product of this research has led to a symple synthesis of brevicomin, the
aggregating sex pheromone of the pine bark beetle, Dendroctonus brevicomis. /
t' '
STATEMENT OF PERMISSION TO COPY
In p r e s e n tin g t h i s t h e s is in p a r t i a l
f u l f i l l m e n t o f th e require m en ts
■for an advanced degree a t Montana S ta te U n i v e r s i t y ,
L i b r a r y s h a ll make i t
I agree t h a t th e
f r e e l y a v a i l a b l e f o r in s p e c t io n .
I f u r t h e r agree
t h a t p e rm is s io n f o r e x te n s iv e copying o f t h i s t h e s is f o r s c h o l a r l y purposes
may be g ra n te d by my m a jo r p r o f e s s o r , o r , in h is absence, by th e D i r e c t o r
o f L ib ra rie s .
I t i s understood t h a t any copying 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 in s h a l l n o t be a llo w e d w i t h o u t my w r i t t e n
p e rm is s io n .
S ig n a tu re
Date
/ <77F
To my w i f e .
D aria
NEW SYNTHETIC METHODOLOGIES
FOR NATURAL PRODUCTS
by .
WILLIAM GERARD BORNMANN
A t h e s is s u b m itte d in p a r t i a l f u l f i l l m e n t
o f the re q u ire m e n ts f o r the degree
•
of
MASTER OF SCIENCE
in
Chem istry
Approved:
XVvvi
on, Graduate Committee
Chairperson
Head, M ajor Department
Graduate Dean
MONTANA STATE UNIVERSITY
Bozeman, Montana
December, 1978
-V •
iv
ACKNOWLEDGMENTS
Several people have had a m a jo r r o l e in. making t h i s research
stu d y p o s s ib le and I would l i k e t o ta ke t h i s o p p o r t u n it y to thank them.
I would e s p e c i a l l y l i k e to thank my pare n ts w i t h o u t whose help
the c o m p le tio n o f t h i s t h e s is would n o t have been made p o s s ib le . I
would l i k e t o thank Mr. C h ris Evans f o r the e x p e r t g la ss b lo w in g , and
M rs. K je s t in e Carey o f th e L i b r a r y f o r always g e t t i n g a much needed
book.
S p ecial thanks a re a ls o extended to Mr. Gordon W illia m s o n o f
Mechanical E n g in e e rin g f o r le n d in g me p re c io u s equipment and g iv in g
h e l p f u l a d v ic e .
I would a ls o l i k e t o thank my f e l l o w re s e a r c h e r s .
My s p e c ia l
thanks t o Dr. B ra d fo rd P. Mundy f o r h is guidance and unending p a tie n c e
w i t h my many ta n g e n ts .
And, most im p o r t a n t l y , I would l i k e thank my
w i f e , D a r i a , f o r her p a t ie n c e , u n d e rs ta n d in g and u n s e l f i s h s a c r i f i c e s
which have enable me to a c h ie ve .
TABLE OF CONTENTS.
Page
DEDICATION...................... ...............................................................................................
VITA................................... ..................... '............................................................ ■ . . .
i
iii
ACKNOWLEDGMENTS..................................
iv
TABLE OF CONTENTS................................... ................................................... :
•
v
LIST OF TABLES..................................................................■.........................................
vi
LIST OF FIGURES .........................................................................................................
V ii
ABSTRACT.
. ........................
x
PART I
A NEW SYNTHETIC APPROACH TO SESQUITERPENE INTERMEDIATES
Chapter
1.
HISTORICAL.................................................................................. .....................
2.
RESULTS AND DISCUSSION. . . ......................................................... ....
3.
APPLICATION OF THE ENAMINE COPE REARRANGEMENT ..........................
33
■ 4.
FUTURE RESEARCH ......................................................................
36
5.
EXPERIMENTAL. . ...........................■ ....................................38
REFERENCES. ,
.......................... ..............................
.
I
. . . . . . . . . . . .
H
64
PART I I
A NEW SYNTHESIS OF BREVICOMIN
1.
HISTORICAL...........................................
70
2.
RESULTS AND DISCUSSION...................... ..............................' .......................
84
3.
EXPERIMENTAL........................................... ....
.......................................
90
REFERENCES. . ..............................................................................................................
102
.
vi
LIST OF TABLES
Table
1.
2.
3.
4.
Page
P r i n c i p l e S p e c tro s c o p ic C h a r a c t e r i s t i c s o f
Reactant and Products ..........................................................................
13
Temperature Study o f th e P y r o ly s is C o n d itio n s o f The
Methyl Imine o f 2 - A c e t y l- 6 - M e t h y l- 3 ,4 -D ih y d ro -2 H -P y ra n . .
14
P r i n c i p l e S p e c tro s c o p ic C h a r a c t e r i s t i c s o f
Reactants and P r o d u c ts ..........................................................................
244
Temperature Study o f . t h e P y r o ly s is C o n d itio n s o f the
P y r r o l i d i n e Enamine o f 2 - A c e t y l- 6 - M e t h y l3 ,4 -D i h yd ro -2 H -P yra n ..............................................................................
26
vi i
LIST OF FIGURES
Fi gure
1.
'
Page
[ 3 , 3 ] S ig m a tro p ic Rearrangement o f 2 - f o r m y l- 2 , 5 d i h y d r o - 4 H - p y r a n . . ...................................................................................
2
2.
Biichi S y n th e sis o f S u b s t it u t e d 4 - A c e ty l cyclohexenes . . . .
3
3.
L ip k o w it z S y n th e sis o f 2 - A c e t y l- 6 - M e t h y l- 3 , 4 - D ih y d r o 2H -Thipyran .......................................
4
Proposed S yn th e sis o f 1 , 2 - D im e t h y l- 6 A c e t y l - P i p e r i d i n e ....................................... .
4
4.
. . ...........................
5.
[ 3 , 3 ] S ig m a tro p ic Rearrangement o f O - a lT y lh e xa n o la c tim .
5.
Amino [ 3 , 3 ] S ig m a tro p ic Rearrangement o f H i l l
7.
Thermal S ig m a tro p ic Rearrangement o f
4 - A l l y l IsopyrazoTe t o a P y r a z o I . . ..........................................
7
8.
Eschenmoser1s S y n th e s is o f y ,s -U n s a tu ra te d Amides ..................
3
9.
H i l l and Gilman S y n th e sis o f
N -M e th y l- 2 ,2 -D im e th y l P e n t - 4 - E n a m in e . .......................................
9
10.
11.
12.
.
.
5
and Newkom.
.
6
[ 3 , 3 ] S ig m a tro p ic Rearrangement o f the P y r r o T id in o
Enamine o f A c e ty l Furan t o O-Amino Phenol . . . . . . . .
10
P r e p a ra tio n o f 4 - A c e ty l Cyclohexene and 3 - A c e ty l
Cyclohexanone By th e Enamine Cope Rearrangement . . . . .
12
Thermal I s o m e r iz a tio n o f the Imine
t o the Corresponding Enamin e . ................................... ....
.
16
13.
Proposed [ 1 , 3 ] S ig m a tro p ic Hydrogen S h i f t ............................... .
16
14.
Klopman's Proposed Keto-Enol T a u to m e r iz a tio n ...............................
17
15.
Proposed [ 3 , 3 ] S ig m a tro p ic M i g r a t i o n ...............................' . . . .
18
16.
Boat T r a n s i t i o n S ta te Geometry.......................................
19
17.
Geometry o f S - A c e t y l - I - ( I - M e t h y l ) Amino Cyclohexene . . . .
20
18.
Proposed Hydrogen Bonding . . . . '.............................
21
. . .
v iii
F ig u re
Page
19.
Proposed S upraannular E f f e c t ......................................................................
20.
P r e p a ra tio n o f 5 - A c e t y l - I - ( I - P y r r o l i d i n y l ) Cyclohexene
by the Enamine Cope Rearrangement Proceeded
by E th e r A l k y l a t i o n o r A cid H y d r o l y s i s .......................... ....
21
. .
25
Proposed [ 3 , 3 ] S ig m a tro p ic Rearrangement o f th e P y r r o l i d i n o
Enamine o f 2 - A c e t y l- 6 - M e th y l- 3 ,4 - D ih y d r o - 2 H - P y r a n . . . .
28
22.
Geometry o f 5 - A c e t y l - I - ( I - P y r r o l i d i n y l ) C y c l o h e x e n e .................
29
23.
Proposed S y n th e sis o f 3 -A c e ty l cyclohexanone by D i e l s - A ld e r
Reaction and th e Form ation o f
th e Corresponding P y r r o l i d i n o Enamines.......................................
31
21.
24.
Proposed Cope Rearrangement o f the A c e ty l Enol o f
2 -A c e ty l -6 -M e th y l - 3 ,4 -D i h y d ro -2 H -P y ra n ............................................
32
25.
Proposed
S y n th e s is o f a -C yperone.........................................................
34
26.
Proposed
S y n th e sis o f 7g,10g S e lin a - 4 , 1 1 - D ie n e ...........................
35
27.
General S u b s t i t u t i o n P a tte r n o f Reactants and
Products in th e Enamine Cope Rearrangement...................................
37
28.
Vacuum P y r o ly s is A p p a ra tu s ......................................................................
40
29.
S i l v e r s t e i n ' s B revicom in S y n th e s is ....................................................
73
30.
S i l v e r s t e i n 1s A l t e r n a t e Scheme.................................................... ....
.
74
31.
Wasserman S y n th e sis o f B revicom in ....................................................
75
32.
Improved S i l v e r s t e i n S yn th e sis o f B re v ic o m in ...............................
76
33.
K o cienski S y n th e sis o f B revicom in ....................................................
77
34.
Coke S y n th e sis o f B re v ic o m in ..............................
78
35.
Mundy S y n th e sis o f B revicom in .............................................................
80
36.
Kassanye
S y n th e s is o f B r e v ic o m in ..........................................................
81
37.
S harpless S y n th e s is o f C y c lic E t h e r s ................................................
82
IX
F i gure
-
Page
38.
N ic o la o u S y n th e sis o f B i c y c l i c Ethers ...................................
39.
S y n th e sis o f 2 - P r o p io n y l- 5 - M e th y l- 3 , 4 - D ih y d r o - 2 H - P y r a n .
. .
85
40.
Novel S y n th e tic Approach to B r e v i c o m i n . - .......................................
87
41.
Reaction Mechanism f o r the Form ation o f 5 - M e th y l- 7 E t h y l - 6 , 8 - D io x a b ic y c l o [ 3 . 2 . 1 ] o c t - 3 - e n e .......................................
88
R e action Mechanism f o r th e Formation o f 5 - M e th y l- 7 E th yl - 6 ,8 -D i oxabi c y c l o [ 3 .2.1 ] o c t - 4 - o n e .......................................
89
42.
83
X
ABSTRACT
The o r b i t a l symmetry a llo w e d [ 3 . 3 ] s ig m a tr o p ic rearrangem ent
o f enamines d e r iv e d from 2 - a c e 't y l- 6 - m e t h y l- 3 ,4 -d ih y d ro -2 H -p y ra n has
a llo w e d f o r f a c i l e e n t r y i n t o h i g h l y f u n c t i o n a l i z e d cyclohexanone
d e riv a tiv e s .
This new s y n t h e t i c methodology o f f e r s promise, f o r e n t r y
i n t o s e s q u ite rp e n e n a t u r a l p r o d u c ts .
A b y - p r o d u c t o f t h i s research
has le d t o a symple s y n th e s is o f b r e v ic o m in , the a g g re g a tin g sex
pheromone o f the p in e bark b e e t l e , Dendrootonus brevioomis.
xi
E xperim ental ideas are o f t e n born by chance, w i t h the help
o f some casual o b s e r v a tio n .
N othing i s more common; and t h i s
i s r e a l l y the s im p le s t way o f b e g in n in g a piece o f s c i e n t i f i c
work. We take a w a lk , so t o speak, i n the realm o f s c ie n c e ,
and we pursue what happens to p re s e n t i t s e l f to o u r eyes.
" S e r e n d ip it y "
Claude Bernard
1865
P a rt I :
A NEW SYNTHETIC APPROACH TO SESQUITERPENE • INTERMEDIATES
CHAPTER I
HISTORICAL
In r e c e n t y e a r s , two concepts have emerged in s y n t h e t i c method­
o lo g y ;
t h a t o f l a t e n t f u n c t i o n a l i t y and th e use o f h e t e r o c y c l ic conI
pounds in o r g a n ic s y n t h e s i s . D. L e d n ic e r in 1972 q u i t e a p t l y v e r b a l i z ­
ed the concept o f l a t e n t f u n c t i o n a l i t y as:
"One c a r r i e s some necessary
f u n c t io n th ro u g h one o r more steps o f a s y n th e s is in a p re c u r s o r fo rm ;
and a t the p ro p e r stage th e p r e c u r s o r i s conve rted to th e needed g r o u p ."
One c o u ld say t h a t t h i s concept i s a more s o p h is t ic a t e d use o f p r o t e c t ­
in g g ro u p s .
The second and th e most im p o r ta n t concept was discussed by
A. I . Meyers,
s y n t h e s is .
and in v o lv e s th e use o f h e t e r o c y c l ic compounds in o r g a n ic
By d i r e c t l y a p p ly in g t h e . p r i n c i p l e o f l a t e n t f u n c t i o n a l i t y
in a h e t e r o c y c l i c s y n t h e s i s , one c o u ld , i n e f f e c t , design a h e te r o c y c le
which c o u ld a llo w f o r the i n t r o d u c t i o n o f a v a r i e t y o f f u n c t io n a l groups
o r carbon s k e le to n s .
Thus in s h o r t , Meyers' concept was t h a t o f using
a h e te r o c y c le as a p r e c u r s o r o r v e h i c le f o r the s y n th e s is o f a more
complex m o le c u le .
These concepts were r e f l e c t e d in the s y n t h e t ic approach t o sub­
s t i t u t e d cyclohexenes taken by B u c h i3 ' 4 which was based on the p re v io u s
work by J. D. R o berts5 and L u tz t h a t d e u te r iu m - la b e le d 2 - f o r m y l- 2 , 5 - d i ­
methyl - 2 , 3 - d ih y d ro -4 H -p y ra n [ 1 ] c o u ld t h e r m a lly is o m e riz e by means o f a
[ 3 , 3 ] s ig m a tr o p ic rearrangem ent.
A s e r ie s o f w e ll- p la n n e d NMR s tu d ie s
c o n c l u s i v e ly demonstrated t h a t th e a ld e h y d ic d e u te riu m CDO la b e l e x-
2
changed w i t h H-6.
I t was a ls o noted t h a t the o p t i c a l a c t i v i t y due to
the asymmetric c e n te r ( * ) was n o t l o s t .
H
3
2
F igure I .
d i hydro-4H-Pyran
[ 3 , 3 ] S ig m a tro p ic Rearrangement o f 2 - f o r m y l - 2 , 5 -
By d i m e r iz in g a ,B -u n s a tu r a te d compounds [ 4 ] , Biichi was a b le to
o b t a in acyl d ih y d ro p y ra n s [ 5 ] w h ic h , when fo llo w e d by a W i t t i g condensa­
t i o n , gave 3 , 4 - d ih y d r o - 2 H - p y r a n e t h y lenes [ 5 ] ,
essence, a l l y !
These compounds were, in
v i n y l e th e rs whose thermal oxy-Cope rearrangem ent had
been p r e v io u s ly w e ll documented in the l i t e r a t u r e .
J u s t as had been
e xpe cted , these s u b s t it u t e d 3 ,4 -d ih y d ro - 2 H -p y r a n e t h y l enes underwent
oxy-Cope rearrangem ents to y i e l d s u b s t it u t e d cyclohexene [ 7 ] compounds.
Such s u b s t i t u t e d acyl cyclohexenes are n o t r e a d i l y o b t a in a b le from mixed
D i e l s - A ld e r r e a c t io n s and, in f a c t , are o n ly m inor p ro d u cts from these
r e a c tio n s .
3
R
Il
4
0
5
0
6
R
0
7
F ig u re 2.
Biichi S yn th e sis o f S u b s titu te d 4 - A c e ty l cyclohexenes
Now, in a c o n t in u in g e f f o r t in t h i s la b o r a t o r y to r e a l i z e the
fu ll
i m p l i c a t i o n s o f t h i s w o rk, i t was conceived t o s u b s t i t u t e d i f f e r e n t
heteroatoms f o r the carbon yl oxygen and re a rra n g e them i n t o the r i n g .
Thus K. L i p k o w it z 7 ' 8 f i r s t made th e th io c a r b o n y l by r e f l u x i n g 2 - a c e t y l 6 - m e th y l- 3 , 4 -d ih y d ro -2 H -p y ra n in p y r id i n e and phosphorous p e n t a s u lf id e .
Sealed tube p y r o l y s i s o f the t h i o a c e t y l
ra n y l system [ 1 0 ] .
pyran [ 9 ] y ie ld e d the t h ia p y -
4
F ig u re 3.
L ip k o w it z S y n th e sis o f 2- A c e t y l- 6 - M e t h y l- 3 , 4 D ihydro-Z H -T hiapyran
Thus, my o b j e c t i v e was to a tte m p t the n e xt heteroatom , n itr o g e n
The methyl im ine o f 2 - a c e t y l - 6 - m e t h y l - 3 , 4 -d ih y d ro -2 H -p y ra n [ 1 1 ] was pre
pared and was s u b je c te d to c o n d it io n s o f the Cope rearran gem ent.
The
expected p ro d u c t from the p y r o l y s i s was the s u b s t i t u t e d I , 2 -d im e th y -6 a c e ty l-p ip e rid in e [1 2 ].
O
N
Il
F ig u re 4.
O
^
12
Proposed S y n th e sis o f 1 , 2 - D im e t h y l- 6 - A c e t y l- P i p e r ­
i d in e
However, t h i s was n o t observed, and c a r e f u l a n a ly s is o f the s p e c tr a l
data from the p ro d u c t le d to our assignment f o r the s t r u c t u r e o f the
5
observed compound as 5 - a c e t y l - I - ( I - m e t h y l) amino cyclohexene [ 1 3 ] .
A f t e r c o n s id e r a t io n o f a mechanism f o r the r e a c t i o n , i t became
app arent t h a t an im ine-enam ine t a u t o m e r iz a t io n had f i r s t taken p la c e ,
fo llo w e d by a [ 3 , 3 ] s ig m a tr o p ic s h i f t o r Cope rearrangem ent.
This would
account f o r the carbon s k e le to n o f the r i n g .
Thermal is o m e r iz a t io n o f im ine to enamines have been th o ro u g h ly
discussed i n the l i t e r a t u r e 9 f o r many y e a r s .
However, the a p p l i c a t i o n
o f such is o m e r iz a t io n p r i o r to a [ 3 , 3 ] s ig m a tr o p ic s h i f t has re c e iv e d
ve ry l i t t l e
however.
a tte n tio n .
Some i n t e r e s t i n g examples can be p o in te d t o ,
P y r o ly s is o f 0 - a l I y l h exa nola c t im 10 [ 1 4 ] gave the 3 - a l l y l -
hexanolactam [ 1 6 ] in b e t t e r than 60% y i e l d .
F ig u re 5.
[ 3 , 3 ] S ig m a tro p ic Rearrangement o f 0 - a ll y lh e x a n o la c t im
6
R a t i o n a l i z a t i o n o f t h i s r e a c t io n sequence was t h a t th e im ine [ 1 4 ] had
r e a d i l y iso m e rize d to the enamine [ 1 5 ] .
T h is in te r m e d ia te was then s e t
up f o r a t h e r m a lly - a llo w e d [ 3 , 3 ] s ig m a tr o p ic s h i f t .
H ill
and Newkom11 demonstrated t h a t when q u a te rn a ry ammonium
s a l t s o f i mines w i t h an a l k y l group in the 2 p o s i t i o n were conve rted to
the anhydro base ( e n a m in e )[T 8 ],th e y co u ld be then t h e r m a lly rearranged
to [ 1 9 ] , presumably by a [ 3 , 3 ] s ig m a tr o p ic s h i f t .
F ig u re 6.
Amino [ 3 , 3 ] S ig m a tro p ic Rearrangement o f H i l l and
Newkom
Based on t h i s w o r k , 12 Bramley and G rigg demonstrated t h a t 4 , 4 - d i a l I y l 3 , 5 - d im e t h y lp y r a z o le f i r s t is o m e rize d to the enamine [ 2 1 ] and then r e ­
arranged by way o f a [ 3 , 3 ] s ig m a tr o p ic s h i f t to [ 2 2 ] .
7
N -N
20
F ig u re 7.
z o le t o a Pyrazol
N -N H
21
N -N H
22
Thermal S ig m a tro p ic Rearrangement o f 4 - A l l y l
Isopyra-
Another system in v e s t i g a t e d by the same a u th o rs was t h a t o f 3 - a l l y l i n doIe m ime ketemine [ 2 3 ] which f i r s t t h e r m a lly iso m e rize d to the enamine
[ 2 4 ] and then rearran ged to [ 2 5 ] by means o f a [ 3 , 3 ] s ig m a tr o p ic s h i f t .
To s u b s t a n t ia t e t h i s c o n c lu s io n , th e enamine [ 2 6 ] was prepared (CH3I /
NaOH), and therm al rearrangem ent gave the expected p ro d u c t [ 2 7 ] .
8
27
Eschenmoser has employed the method o f t r a n s v i n y l e t h e r i f i c a t i o n o f 1d im e th yla m in o -1 -m e th o xy-e th e n e and the d im e th yl a c e ta l o f N ,I V d im e t h y lacetamide as a v i n y l a t i n g a ge nt.
Again note the enamine in te r m e d ia te
[ 3 1 ] which then p a r t i c i p a t e s in the a c tu a l
[ 3 , 3 ] s ig m a tr o p ic s h i f t .
(OCH3)2
OCH3
+
\
28
N(CH3)2
31
F ig u re 8.
CH3- C
CH2— ( /
/
\
N(CH3 )2
N(CH3)2
N(CH3)2
32
Eschenmoser' s S y n th e sis o f Y ,6 -U n s a tu ra te d Amides
9
H i l l and Gilman have demonstrated t h a t the enamine [ 3 3 ] prepared from
N-methyl a l ly l a m i n e and a - d i s u b s t i t u t e d aldehydes p y ro ly z e d q u a n t i t a ­
t i v e l y to [ 3 4 ] v ia a [ 3 , 3 ] s ig m a tr o p ic s h i f t a t 250° C.
M ild h y d r o ly s is
o f [ 3 4 ] gave the aldehyde [ 3 5 ] .
F ig u re 9.
Pent-4-Enamine
H ill
and Gilman S y n th e sis o f N -M e th y l- 2 ,2 Dimethyl
We now c o u ld view o u r enamine s ig m a tr o p ic rearrangem ent in terms
o f E. J . C o re y 's 15 r e t r o - s y n t h e t i c a n a ly s is as:
From such a n a ly s is o f th e s y n t h e t ic t r e e , i t
amine tr a n s fo r m i s the key in te r m e d ia t e .
seems obvious t h a t the en­
Thus, th e d i r e c t p r e p a ra tio n
and rearrangem ent o f th e enamine was u nd ertake n.
The p y r r o l i d i n e en-
10
amine o f 2 - a c e t y l - 6 - m e t h y l - 3 , 4 - d ih y d r o pyran rearranged q u i t e e a s i l y
under the p y r o l y s i s c o n d it io n s as b e fo r e .
R e tr o s y n t h e t ic a n a ly s is
y i e l d s th e obvious c o n c lu s io n t h a t the new enamine [ 4 1 ] i s a ls o q u i t e a
u s e fu l s y n t h e t ic in t e r m e d ia t e :
40
41
The o n ly l i t e r a t u r e analogy to our system was re p o r te d by B i r k o f f e r 16 and Daum in 1962.
Here the p y r r o l i d i n e enamine o f a c e ty l fu ra n
[ 4 3 ] was prepared and Cope rearran ged to the co rre s p o n d in g o-amino
phenol [ 4 4 ] .
F ig u re 10.
[ 3 , 3 ] S ig m a tro p ic Rearrangement o f the P y r r o l i d i n e
Enamine o f A c e ty l Furan to o -Amino Phenol
CHAPTER 2
RESULTS AND DISCUSSION
The N-methyl im ine o f 2 - a c e t y l- 6 - m e t h y l- 3 , 4 - d ih y d r o - 2 H - p y r a n was
prepared by passing methyl amine i n t o a c o ld s o l u t i o n o f e t h e r c o n t a i n ­
in g 2 - a c e t y l - 6 - m e t h y l - 3 , 4 -d ih y d ro -2 H -p y ra n and m o le c u la r s ie v e s .
F o l­
lo w in g i s o l a t i o n and p u r i f i c a t i o n , th e methyl im ine [ 1 1 ] was vacuum
p y ro ly z e d a t 250° C to y i e l d [ 1 5 ] in 66% y i e l d a f t e r d i s t i l l a t i o n .
The
p ro d u c t o f th e p y r o l y s i s was assigned th e s t r u c t u r e [ 1 3 ] based on the
f o l l o w i n g s p e c tr o s c o p ic evidence (T able 1 ) :
-I
the im ine C=N s t r e t c h 1667 cm
fo r [1 1 ];
The i n f r a r e d s p e c tra shows
-I
and th e e t h e r C-O-C s t r e t c h 105.3 cm
however, th e p ro d u c t does n o t e x h i b i t a C-O-C s t r e t c h nor a
C=N s t r e t c h ;
“I
however an N-H s t r e t c h 3413 cm
was observed as w e ll as a
C=C s t r e t c h 1645 cm~^ which i s a ls o c h a r a c t e r i s t i c o f a c a r b o n y l.
ondary enamines C=C s t r e t c h a t 1695 cm~^ was observed.
a b s o r p tio n s p e c tra shows the d i s t i n c t n
[1 1 ];
tt *
Sec­
The u l t r a v i o l e t
band 231 nm f o r the im in e
however, th e p y r o l y s i s p ro d u c t has an a b s o rp tio n a t 220 nm as
w e l l . a s 284 nm.
T h is i s i n d i c a t i v e o f both a secondary enamine and a
carbon yl group p re s e n t as w e l l .
NMR sp ectroscopy c o n firm e d the s t r u c ­
t u r e as t h a t o f [ 1 3 ] by th e o b s e rv a tio n o f the v i n y l
hydrogen as a
t r i p l e t a t 4.486 which i s in e x c e l l e n t agreement w i t h th e observed
chemical s h i f t o f the v i n y l h y d r o l y s is o f 1 - N - p ip e r id in o c y c lo h e x - l- e n e
a t 4 .5 6 s , which i s a ls o observed as a t r i p l e t .
a d ja c e n t to the carbon yl was observed a t 2.166.
A lso th e methyl group
F u r th e r s t r u c t u r a l
12
a n a ly s is was done by chemical d e g ra d a tio n as f o l l o w s .
Simple c a t a l y t i c
h yd ro g e n a tio n o f [ 1 3 ] w it h Pd/C produces the s a tu r a te d amine [ 4 5 ] in 82%
y ie ld .
The q u a te rn a ry ammonium s a l t o f [ 4 5 ] was prepared in e th e r and
excess methyl i o d id e , and t h i s , when f o llo w e d by a Hoffman e l i m i n a t i o n
w it h potassium t e r t - b u t o x i d e 17 gave 4 - a c e t y l cyclohexene [ 4 7 ] in 62%
y ie ld .
A cid h y d r o l y s is o f [ 1 3 ] gave 3 - a c e t y l cyclohexanone [ 3 6 ] in 72%
y ie ld .
A tem p era ture versus p ro d u c t stu d y (Table 2) was then c a r r i e d
o u t w i t h the r e s u l t s t h a t 250° C was the optimum p y r o l y s i s te m p e ra tu re .
Temperatures any h ig h e r u s u a ll y gave e x te n s iv e p o ly m e r iz a t io n and a
marked decrease in p ro d u c t y i e l d .
F ig u re 11.
P r e p a ra tio n o f 4 - A c e ty l Cyclohexene and 3 -A c e ty l
Cyclohexanone By th e Enamine Cope Rearrangement
P r i n c i p l e S p e c tro s c o p ic C h a r a c t e r i s t i c s o f R eactant and Products
NMR Spectroscopy
I n f r a r e d S pectroscopy
1053 cm ^
C-O-C
s tre tc h o f
th e e t h e r
rn
3.076
\
C=N s t r e t c h
o f im ine
13
O
Il
1667 cm"^
11
N-H s t r e t c h
o f secondary
enamine
3413 cm '1
C=C s t r e t c h
o f secondary
enamine
1645 cm 1
C=O s t r e t c h
1695 cm 1
E
oJ
13
11
Z
Table I .
CH- C
xN
4.486
CH3-NH
2.686
CH3 i "
0
2.166
14
Table 2. Temperature Study o f The P y r o ly s is C o n d itio n s o f The
Methyl !mine o f 2 - A c e t y l- 6 - M e t h y l- 3 , 4-D ihyd ro -2 H -P yra n
11
T ( 0C)
% 11*
% 13*
5 .0 grams
150° C
100%
------
5 .0 grams
175° C
100%
5 .0 grams
200° C
81 .6%
,18.4%
5 .0 grams
225° C
29.0%
71.0%
5 .0 grams
250° C
5 .0 grams
275° C
—
73.0%**
5 .0 grams
300° C
------
48.2%**
100%
* R e l a t iv e g lc peak areas o f m a te r ia l i s o l a t e d , a n a ly s is was done
on 10% SE-30 Chromosorb W a t 160° C and peak areas were measured by t r i a n g u la t io n .
* * E x t e n s iv e p o ly m e r iz a t io n was observed in th e p y r o l y s i s tu b e .
15
In c o n s id e r in g the r e a c t io n mechanism f o r o u r plan i t was o f i n ­
t e r e s t to e s t a b l i s h the c o n f i g u r a t i o n o f the N-methyl im in e as syn o r
a n ti.
C a re fu l e v a lu a t io n o f the NMR18 data e s t a b lis h e d the C-methyl
group was observed a t a h ig h e r f i e l d
syn.
f o r the a n t i isomer than f o r the
T his i s a ls o observed f o r the N-methyl group f o r the a n t i as w e l l ;
however, th e C-H p ro to n i s observed a t a lo w e r f i e l d f o r th e a n t i isomer
than f o r th e s y n .
The c o u p lin g c o n s ta n t f o r the C-methyl group and the
N-methyl group i s s m a lle r (J = 8 .9 H e rtz ) f o r the a n t i
isomer than f o r
the S^m isomer (J = 1.5 H e r t z ) .
The c o u p lin g c o n s ta n t between CH and
N-methyl i s l a r g e r f o r the a n t i
(J = 8 .9 H e rtz ) than f o r the Sjm (J =
0 .5 H e r t z ) .
We can conclude t h a t our N-methyl im ine i s 92% a n t i and
8% s y n .
The f i r s t c r i t i c a l
step in th e rearrangem ent i s the thermal i s o ­
m e r i z a t io n 19 o f the N-methyl k e tim in e [ 1 1 ] to the N-methyl enamine [ I I A ] .
16
F ig u re 12.
ponding Enamine
Thermal
I s o m e r iz a tio n o f the Imine to the C o rre s ­
The mechanism f o r t h i s is o m e r iz a t io n can be p o s tu la te d to be a
[1 ,3 ]
s ig m a tr o p ic hydrogen s h i f t .
For such a s h i f t to be th e r m a lI y
a llo w e d an a n t a r a f a c i a l m i g r a t i o n 203-0 o f the hydrogen on C-j, would have
to be accom plished ( F ig u re 13).
F ig u re 13.
Proposed [ 1 , 3 ] S ig m a tro p ic Hydrogen S h i f t
From the o r b i t a l
to p o lo g y diagram , we can see t h a t as the n i -
tro g e n atom r e h y b r id iz e s from sp
p
to sp
O
th e re i s a sim ultaneous re h y -
17
b r i d i z a t i o n o f C-I from an sp
o
2
c o n f i g u r a t i o n to sp .
Thus as the h y d ro ­
gen i s being t r a n s f e r r e d from carbon to the n itr o g e n th e re i s a syn­
chronous is o m e r iz a tio n o f th e double bond from C^=N to
Thus th e
non-bonding p a i r o f e le c t r o n s on the n i tr o g e n now becomes a v a i l a b l e f o r
o v e r la p w i t h the n-system o f the double bond, and c o u ld be the d r i v i n g
f o r c e f o r the r e a c t i o n .
Klopman20f has suggested t h a t k e to -e n o l tautom -
erism co u ld p o s s ib ly be a [ 1 , 3 ] s ig m a tr o p ic s h i f t system in v o lv i n g a
heteroatom (oxygen) possessing an occupied p - o r b i t a l
p e r p e n d ic u la r to
the p -ir -p la n e .
F ig u re 14.
Klopman's Proposed Keto-Enol T a u to m e riz a tio n
18
One can note t h a t i n the geometry o f IA severe s t e r i c i n t e r a c ­
t io n s between the enamine and the methyl group are a t a minimum and t h a t
c o p l a n a r i t y has been m a in ta in e d between the n itr o g e n and the carbon o f
the double bond.
The second ste p o f the rearrangem ent i s a co n c e rte d [ 3 , 3 ] sigmat r o p i c m i g r a t i o n . 2 0 ' 22
For t h i s rearrangem ent to be t h e r m a lly a llo w e d ,
th e r e must be a s u p r a f a c i a l - s u p r a f a c i a l o v e r la p o f the p - o r b i t a l lobes
( F ig u re 1 5 ).
c lic
An o r b i t a l
to p o lo g y diagram c l e a r l y shows t h i s in the c y ­
six-membered t r a n s i t i o n s t a t e [ I I B ] .
Il-A
F ig u re 15.
We w i l l
Il-B
Proposed [ 3 , 3 ] S ig m a tro p ic M ig r a t io n
a ls o note t h a t in both [ I I A ] and [ I I B ] t h a t the o v e r la p
between the u n p a ire d e le c t r o n s on the n itr o g e n and th e ir-system o f the
double bond are a t a maximum due to the c o p l a n a r i t y o f the N and carbon
atoms.
Thus in a co n c e rte d f a s h io n , as the carbons 3 and 3' are re h y -
19
b r i d i z i n g t o form the a-bond, carbon I '
from sp
o
to sp
O
which w i l l
i n t e r a c t i o n o f the c e n t r a l
and
are a ls o r e h y b r i d i z i n g
form th e ir-system between I '
and 2 1.
The
p -lo b e s o f C -2 1 and oxygen s l i g h t l y d e s t a b i-
I i z e the system and c o n t r i b u t e to the extreme p y r o l y s i s c o n d it io n s .
F ig u re 16.
22
Boat T r a n s i t i o n S ta te Geometry
Even though the c h a i r - l i k e t r a n s i t i o n s t a t e geometry i s lo w er in
energy due to the q u a s i- p la n a r arrangement o f the s i x p - lo b e s , i t
a ls o s t e r i c a l I y im p o s s ib le to be a t t a i n e d . 22,3
is
Thus th e o n ly a c c e s s i­
b le t r a n s i t i o n s t a t e geometry i s t h a t o f the boa t.
20
F ig u re 17.
Geometry o f 5 - A c e t y l - I - ( I - M e t h y l) Amino Cyclohexene
Again in the p r o d u c t, 5 - a c e t y l - I - ( I - m e t h y l) amino cyclohexene c o p l a n a r i ­
t y has been m a in ta in e d between the n it r o g e n atom and the carbon s, hence,
the o v e r la p between the u np aired e le c tr o n s o f the n i tr o g e n and the
system o f the double atom i s a t a maximum.
tt-
23
One would e xpe ct t h a t the p ro d u c t [ 1 3 ] would is o m e riz e again
from th e enamine to the im ine [ 4 8 ] .
However, NMR data does not show
[ 4 8 ] to be p re s e n t in a p p re c ia b le amounts ( le s s than 1%).
One may be a b le to r a t i o n a l i z e t h i s by the f a c t t h a t in c e r t a i n systems
hydrogen bonding may s t a b i l i z e the enamine ta u to m e r24 thro ugh i n t e r -
21
m o le c u la r c h e la t e fo r m a tio n between the carbon yl oxygen and the NH p r o ­
ton ( F ig u re 1 8 ).
T his co u ld a ls o account f o r the high b o i l i n g p o i n t o f
the rearran ged p ro d u c t [ 4 8 ] .
F ig u re 18.
Proposed Hydrogen Bonding
An a l t e r n a t i v e e x p la n a tio n c o u ld be a t t r i b u t e d to the supraannuI a r e f f e c t . 25
In o u r system, the w - e le c tr o n s o f the enamine double bond
co u ld i n t e r a c t w it h th e carbon yl group.
Thus we would n o t see the r e ­
v e r s io n back to the methyl im ine b u t r a t h e r the s t a b i l i z e d enamine form .
3
F ig u re 19.
Proposed S upraannular E f f e c t
22
To t e s t the v a l i d i t y o f t h i s rearran gem ent, o t h e r examples were
examined.
The e t h y l
[5 1 A ] , pro p yl
[5 1 B ] , and b u ty l
[51C] i mines were
prepared in the manner p r e v io u s ly d e s c rib e d and p y ro ly z e d under the same
c o n d it io n s to y i e l d the c o rre s p o n d in g a l k y l amin o - 5 - a c e t y lcyclohexene in
every case.
A cid h y d r o l y s is a ls o y ie ld e d the 5 - a c e t y I cyclohexanone.
The severe disadvan tag e o f s y n t h e t i c a l l y u sin g these compounds would be
th a t a ll
the a l k y l amin o - 5 - a c e t y lcyclohexenes are e x tre m e ly a i r s e n s i t i v e
and have to be s to re d under n i t r o g e n .
Based on the data a lre a d y d is c u s s e d , the s p e c i f i c i t y o f p y r o l y ­
s is co u ld be f u r t h e r e d by the d i r e c t p r e p a r a tio n o f th e enamine, thus
e l i m i n a t i n g the i n i t i a l
im ine-enam ine t a u t o m e r iz a t io n .
A ls o , i t would
unambiguously e s t a b l i s h t h a t the fo r m a tio n o f the enamine i s the key
step in th e thermal rearran gem ent.
The p y r r o l i d i n e enamine o f 2 - a c e t y l -
6 - m e t h y l- 3 , 4 -deh ydro -2H -p yra n [ 5 3 ] was formed by g e n t ly warming a m ix ­
t u r e o f the pyran and p y r r o l i d i n e o ver m o le c u la r s ie v e s .
The vacuum
p y r r o l y s i s o f the r e s u l t i n g enamines [ 5 3 ] under the same c o n d it io n s p r e ­
v i o u s l y d e s c rib e d p ro v id e d an e x c e l l e n t y i e l d o f the d e s ire d p ro d u ct
23
[4 1 ].
In s tru m e n ta l a n a ly s is aga in v e r i f i e d the s t r u c t u r e (Table 3 ) .
The i n f r a r e d s p e c tra o f th e i n i t i a l
enamine [ 8 ] e x h i b i t e d a C=C
s t r e t c h o f enamine a t 1672 cnf^ and an e t h e r C-O-C s t r e t c h a t 1070 cm \
The re a rra n g e d p ro d u c t [ 4 1 ] d id n o t e x h i b i t the e t h e r C-O-C s t r e t c h ,
however th e C=C s t r e t c h o f enamine was observed a t 1639 cm" 1 as w e ll as
the C=O s t r e t c h o f carbon yl a t 1698 cm"1 .
The u l t r a v i o l e t a b s o rp tio n
s p e c tra showed an a b s o r p tio n a t 228 nm f o r [ 8] , however th e rearranged
p ro d u c t [ 4 1 ] g ive s tw o:
227 nm ( c h a r a c t e r i s t i c o f enamine) and 281 nm
( c h a r a c t e r i s t i c o f th e t r a n s i t i o n o f a c a r b o n y l) .
The n u c le a r magnetic
resonance spectrum co n firm e d th e s t r e t c h as [ 4 1 ] by th e o b s e rv a tio n o f
th e methyl group a d ja c e n t t o th e carbon yl a t 2.146 and a ls o the v in y l
hydrogen as a t r i p l e t a t 4 .2 8 6 .
Simple a c id h y d r o l y s is o f [ 4 1 ] gave
a c e t y l c y c l ohexanene [ 3 6 ] i n 73% y i e l d .
A l k y l a t i o n o f [ 4 1 ] w it h methyl -
io d id e f o llo w e d by a c id h y d r o l y s is y i e l d 2 - m e th y l-5 -a c e ty lc y c lo h e x a n o n e
[ 4 0 ] i n 76% y i e l d .
Note:
*B oth isomers were observed.
Table 3.
P r i n c i p l e S p e c tro s c o p ic C h a r a c t e r i s t i c s o f Reactants and Products
NMR Spectroscopy
I n f r a r e d Spectroscopy
41
53
1070 cm' 1
C-O-C s t r e t c h
o f the
e th e r
1672 cm" 1
C=C s t r e t c h
o f the
enamine
C=O s t r e t c h
o f the
carbon yl
53
3.645
41
CH2— CXN_
1639 cm" 1
XcH=cvI
4.285
1598 cm' 1
CHo— C—
2.145
3 Ii
25
F ig u re 20.
P r e p a ra tio n o f 5 - A c e t y l - I - ( I - P y r r o l i d i n y l )Cyc1ohexene by the Enamine Cope Rearrangement Proceeded by E th e r A l k y l a t i o n
o r A cid H y d ro ly s is
A g a in , a tem p era ture versus p ro d u c t study (Table 4) was u nd er­
taken w it h the r e s u l t s t h a t 250° C was the optimum p y r o l y s i s tem p era ture
which concurs w it h t h a t o f the im ine rearrangem ent.
Temperatures any
h ig h e r gave e x te n s iv e p o ly m e r iz a t io n and a marked decrease in p rodu ct
j u s t as we observed in the p re v io u s imine p y r o l y s i s
The i n i t i a l
(Table I ,
f o rm a tio n o f the p y r r o d id in o enamine c o u ld , in
t h e o r y , y i e l d two isomers [53A] and [ 5 3 B ] ;
however, o n ly [53A] was
observed.
,N
*
8
O
p. 13).
53-A
5 3 -B
26
Table 4. Temperature Study o f th e P y r o ly s is C o n d itio n s o f the
P y r r o l i d i n e Enamine o f 2 - A c e t y l - 6- M e th y l-3 ,4 -D ih y d ro -2 H -P y ra n
53
T ( 0C)
% 53*
% 41*
5 .0 grams
150° C
100% ' '
----
5 .0 grams
175° C
100%
—
5 .0 grams
200° C
79.0%
21. 0%
5 .0 grams
225° C
31.0%
69.0%
5 .0 grams
250° C
—
5 .0 grams
275° C
—
70.0%**
5 .0 grams
300° C
—
55.0%**
. 100%
* R e l a t iv e g l c peak areas o f m a te r ia l i s o l a t e d ; a n a ly s is was
done on 10% SE-30 Chromosorb W a t 160° C peak areas were measured by
tria n g u la tio n .
* * E x t e n s iv e p o ly m e r iz a t io n was observed in th e p y r o l y s i s tu b e .
27
T his c o u ld be r a t i o n a l i z e d by the severe s t e r i c
i n t e r a c t i o n s between the
methylene groups ( * ) a d ja c e n t to the n i tr o g e n atom and the c o p la n a r
pyran r i n g in [ 5 3 B ] .
Such i n t e r a c t i o n s are m inim ized in [53A ] w h ile
o v e r la p o f the e l e c t r o n p a i r on the n it r o g e n and the m -e le c tro n s o f the
double bond are maximized by the r e q u ire d c o p l a n a r i t y o f the n itr o g e n o f
the n i tr o g e n and carbon atom s. 23,28
Thus, severe d e s t a b i l i z i n g non-
bonded r e p u ls io n a r is e s from the more s u b s t it u t e d iso m er.
T h is can be
f u r t h e r s u b s t a n t ia te d by the re p o rte d p r e p a r a tio n o f the p y r r o l i d i n e
enamine o f a c e t y l cyclo p e n ta n e [ 5 3 ] [ 5 4 ] e x c l u s i v e l y in the le s s s u b s t i ­
tu te d isomer [55A] . 29
The mechanism f o r the thermal rearrangem ent o f th e p y r r o l i d i n e
enamine o f 2 - a c e t y l - 6- m e t h y l- 3 , 4- d ih y d ro -2 H -p y ra n to 5 - a c e t y l - I - ( I p y r r o l i d i n y l ) cyclohexene was aga in e n v is io n e d as a co n c e rte d [ 3 , 3 ] s i g m a tro p ic s h i f t o f oxy-Cope re a rra n g e m e n t. 20' 22
For such a rearrangement
to be t h e r m a lly a llo w e d , th e r e must be a s u p r a f a c i a l - s u p r e f a c i a l o v e rla p
o f the i n t e r a c t i n g p - o r b i t a l
to p o lo g y o f [ 5 3 C ] .
lobes which can be seen from the o r b i t a l
28
F ig u re 21.
Proposed [ 3 , 3 ] S ig m a tro p ic Rearrangement o f the
P y r r o l i d i n o Enamine o f 2 - A c e t y l - 6- M e t h y l- 3 ,4-D ih yd ro -2 H -P yra n
A g a in , even though the c h a i r - l i k e t r a n s i t i o n s t a t e geomet r y 2 2 ' 3 a ' b i s c l e a r l y fa v o re d o ver th e b o a t, i t
i s a ls o c l e a r once again
t h a t the c h a i r t r a n s i t i o n s t a t e i s s t e r i c a l l y im p o s s ib le to be a t t a in e d
in [ 5 3 C ] , hence the boat t r a n s i t i o n s t a t e re p re s e n ts th e o n ly a c c e s s ib le
pathway.
One must note t h a t in the rearran ged p ro d u c t [ 4 1 ] , the o v e r la p
between the e l e c t r o n p a i r on the n it r o g e n and the e le c t r o n s o f the irsystem are a t a maximum due to the c o p l a n a r i t y o f th e n itr o g e n and the
2 3 , 28Cyclohexene carbon s.
S t e r ic h indrance between the methylene h y d ro -
29
gens a d ja c e n t to the n itr o g e n ( * ) and the 4 a c e ty l cyclohexene r i n g are
a t a minimum, which s i g n i f i c a n t l y c o n t r ib u t e s to the s t a b i l i t y o f the
m olecu le.
41
F ig u re 22.
Geometry o f S - A c e t y l - I - ( I - P y r r o l i d i n y l ) C y c l o h e x e n e
In c o n c lu s io n , o f the two systems in v e s t i g a t e d , the im ine and
enamine;
the 5- a c e t y l - I - ( I - p y r r o l i d i n y l jcyclohe xene i s e a s ie r to work
w i t h , a i r s t a b le f o r s h o r t p e rio d s o f tim e and the y i e l d s are much
b e tte r.
In s y n t h e t ic s t r a t e g i e s t h i s would be the in te r m e d ia te compound
o f c h o ic e .
Another p l a u s i b l e s y n t h e t ic s t r a t e g y would be the D i e l s - A ld e r
r e a c t io n between 2-methoxy b u ta d ie n e -5 ,6 and m e th y l-3 -b u te n e -2 -o n e [ 5 7 ] ;
however, th e r e would be two pro d u cts from t h i s r e a c t io n [58A] and [58B]
and w hether o r n o t one co u ld se pa ra te these i s unknown.
However, i f one
could sepa ra te these two components, m ild a c id h y d r o l y s is o f [58A] would
g iv e the 5 - a c e t y l cyclohexanone [ 5 9 ] .
Now the p r e p a r a t io n o f the p y r r o l -
id in o enamine o f 5- a c e t y l cyclohexanone w i l l y i e l d f i v e compounds
30
[OOA9B ] , o f which o n ly one w i l l
be the t a r g e t compound [6 0 A ].
T h e re fo re
one can conclude t h a t th e enamine-Cope rearrangem ent would be the
method o f ch o ic e f o r p re p a rin g compounds o f the n a tu re because o f the
f a c t t h a t th e enamine f u n c t i o n a l i t y w i l l
f o r a d d i t i o n a l work".
be in th e c o r r e c t c o n f i g u r a t i o n
I t has been a ls o suggested t h a t th e a c e ty l enol
[ 6 1 ] d e r i v a t i v e co u ld a ls o p o s s ib ly be Cope rearran ged t o g iv e [ 6 2 ] ,
which then co u ld be a l k y l a t e d in th e 2 p o s i t i o n .
The shortcom ings to
t h i s co u ld be th e f a c t t h a t upon a c id h y d r o ly s is to th e ketone [ 6 3 ] ,
enamine fo r m a tio n w i l l
be i n d i s c r i m i n a t e and y i e l d 6 compounds [6 4 A -F ].
31
F ig u re 23.
Proposed S y n th e sis o f 3 -A c e ty l cyclohexanone By
D i e l s - A ld e r R eaction And the Formation o f the Corresponding P y r r o l i d i n e
Enamines
32
F ig u re 24.
Proposed Cope Rearrangement o f the A c e ty l Enol o f
2 - A c e t y l - 6- M e th y l-3 ,4 -D ih y d ro -2 H -P y ra n
CHAPTER 3
APPLICATION OF THE ENAMINE COPE REARRANGEMENT
R e tr o s y n t h e t ic a n a l y s i s 15 o f the b i c y c l i c s e s q u ite rp e n e s s k e le t o n s 30a,b o f the eudesmanes [ 6 5 ] , erem ophilanes [ 66] , and valera nes [ 6 7 ]
re ve a l one key in te r m e d ia te [ 68] which m ig h t serve as a common p r e c u r s o r .
For eudesmanes (R = CH3 ) , and f o r erem ophilane (R = H ), Robinson
a n n e la tio n o f [ 68] w i t h e th y l v i n y l
ketone w i l l a llo w f o r the c o n s t r u c ­
t i o n o f the b a sic o c t a l ene s k e le to n e s s e n t ia l f o r th e t o t a l s y n t h e s is 31
o f compounds r e la t e d to the abovementioned carbon s k e le to n s .
Thus,
a p p l i c a t i o n o f the enamine Cope rearrangem ent can b e s t be demonstrated
34
by the proposed s y n th e s is o f a-cyperone [ 7 4 ] .
Robinson a n n e la t i o n 32a,b
o f the r e s u l t i n g enamine [ 7 1 ] would g iv e [ 7 2 ] .
S e le c t iv e k e t a l i z a t i o n
o f oc,0-u n s a tu r a te d ketones such as [ 7 2 ] w it h o t h e r ketones p re s e n t i s
w e ll-k n o w n .
Thus the p ro d u c t [ 7 3 ] fo llo w e d by a W i t t i g condensation
would c o n v e rt the a c e t y l carbon yl to a methylene group.
H y d ro ly s is o f
the k e ta l would once again re g e n e ra te our a ,B - u n s a tu r a te d ketone and
thus complete the t o t a l
s y n th e s is o f a-cyperone [ 7 4 ] .
Note t h a t the
s y n th e s is i s accom plished in f i v e h i g h - y i e l d steps as compared to the
s y n th e s is developed by P ie rs
which was accomplished in e i g h t s te p s .
Another s y n th e s is o f a-cyperone by J. K. Roy34 c o n s is te d o f the Robinson
a n n exation o f dehydrocarvone which gave a r e p o rte d 3% y i e l d .
74
F ig u re 25.
Proposed S y n th e sis o f a-Cyperone
35
Another d e m o n s tra tio n o f the enamine Cope rearrangem ent as a
u s e fu l s y n t h e t i c t o o l co u ld be in the proposed s y n th e s is o f 7 b , 106
s e l i n a - 4 , 1 1- d ie n e .
Again Robinson a n n e la t i o n 32 o f [ 7 1 ] w i t h e th y l v i n y l
ketone would g iv e [ 7 2 ] .
P re fe re n tia l
k e t a l i z a t i o n w i t h e t h a n e d i t h i o l 33
o f the a ,B -u n s a tu r a te d ketone in [ 7 2 ] , fo llo w e d by Raney n ic k e l d e s u l­
f u r i z a t i o n , would y i e l d th e u n s a tu ra te d compound [ 7 5 ] .
Subsequent
W i t t i g cond ensatio n o f [ 7 6 ] would g iv e [ 7 7 ] .
F ig u re 26.
Proposed S y n th e sis o f 7 b , IO b S e li n a - 4 , 1 1-Diene
CHAPTER 4
FUTURE RESEARCH
F uture research in the area o f the enamine-oxy-Cope r e a rra n g e ­
ment w i l l
have to depend on the s y n th e s is o f v a rio u s s u b s t it u t e d 2-
a c e t y l - 3 , 4 - d ih y d r o - 2 H - p y r a n s . 36-39
We can e a s i l y see t h a t a s p e c i f i ­
c a l l y s u b s t it u t e d pyran p r e c u r s o r w i l l
g iv e a s p e c i f i c a l l y s u b s t it u t e d
5 - a c e t y l - I - ( I - p y r r o l i d i n y l )cyclo h e xe n e .
Thus we co u ld g e n e r a liz e the s u b s t i t u t i o n p a t t e r n in both s t a r t i n g pyran
[ 8 1 ] and rearran ged enamine [ 8 3 ] as:
37
Ra
81
F igure 27. General S u b s t i t u t i o n P a tte rn o f Reactants and
Products in the Enamine Cope Rearrangement
T h e re fo r e , one co u ld s y n th e s iz e a s p e c i f i c a l l y s u b s t it u t e d pyran which
would in t u r n g iv e a s p e c i f i c enamine [ 8 5 ] .
Several e x c e l l e n t re v ie w s 36,37 have been p u b lis h e d which deal
w it h the D i e l s - A ld e r r e a c t io n s o f a , g - u n s a tu r a te d carbon yl compound g i v ­
in g 3 , 4 - d i h y d r o - 2H-pyrans and v a r io u s o t h e r f u n c t io n a l groups in the 2p o s i t i o n as a c e t y l o r carbom ethoxy.
One must keep in mind t h a t an
a c e ty l group (methyl ketone) in the 2- p o s i t i o n i s a p r e r e q u i s i t e f o r
p y r r o l i d i n o enamine fo r m a tio n and subsequent rearran ged p ro d u c t.
we can see, the f u l l
As
p o t e n t i a l o f t h i s s y n t h e t ic te c h n iq u e can o n ly be
r e a li z e d by the pro p e r development o f the i n i t i a l
pyran r i n g p r e c u r s o r .
CHAPTER 5
EXPERIMENTAL
Proton n u c le a r m agnetic resonance s p e c tra were recorded on
V a rian A-60 o r V a rian T-60 n u c le a r magnetic resonance S pectrom eters.
Peak p o s i t i o n s are g ive n in p a r t s per m i l l i o n d o w n fie ld from t e t r a m e th y ls il a n e as an i n t e r n a l s ta n d a rd .
Mass s p e c tra f o r both l i q u i d
and s o l i d compounds were o b ta in e d from a V a rian Model CH-5 mass spec­
t r o m e te r .
Glc analyses were c a r r i e d o u t u sin g a V a rian Aerograph s e r ie s
2700 in s tr u m e n t and a l l work was done u s in g a 10' x 3 / 8 ' copper column
packed w i t h 1.5% 0V-101 on Chromosorb G.
m l/s e c .
Gas f lo w was m a in ta in e d a t 18
I n f r a r e d s p e c tra were o b ta in e d w it h Beckman IR 5A o r IR20 i n ­
f r a r e d sp e c tro p h o to m e te rs .
UV s p e c tra were recorded on a Cary 14 r e ­
c o r d in g sp e c tro p h o to m e te r o r on a V a ria n s e r ie s 634 U V - v i s ib le s p e c t r o ­
photom eter.
M e lt in g p o in t s were performed on a Fishe r-Jo h n s h o t stage m e lt ­
in g p o i n t apparatus and are u n c o rr e c te d .
and re p o rte d in mm o f mercury ( b . p .
p o i n t was 75° C a t 10 mm o f m e rc u ry ).
B o i l i n g p o in t s are u n c o rre c te d
75° C in d ic a t e s th e b o i l i n g
S o lve n ts were g e n e r a lly removed
under reduced p re ssu re v ia Buchi r o t a t o r y e v a p o ra to r.
General Procedure f o r th e P y r o ly s is o f !mines and Enamines
The vacuum p y r o l y s i s c o n d it io n s f o r e i t h e r th e im ines o r enamines were th e same.
A 15 ml round bottom f l a s k was charged w it h the
39
i mine o r examine to be pyr o ly z e d and was placed on the Pyrex p y r o l y s i s
: 1 '■
*- 1
tube ( Pyrex h e l ic e s ) and th e e n t i r e system was evacuated ( 0 .3 mm o f
m e rc u ry ).
The h e a tin g element (18 f e e t o f r e s i s t a n t mi chrome w ir e ) f o r
I
the p y r o l y s i s tube was c o n t r o l l e d by a V a r ia b le P ow erstat T ra n s fo rm e r.
The i n t e r n a l te m p e ra tu re o f th e column was m onitored w i t h an ir o n - c o n s ta n ta n therm ocouple fused i n t o th e w a ll o f th e column and the tempera­
t u r e was recorded w i t h an Omega Type 2809 D i g i t a l Thermometer.
When
th e i n t e r n a l tem p era ture reached 250° C the h e a tin g m antle was a c t iv a t e d
and th e im ine o r enamine was a llo w e d to r e f l u x .
The crude p y ro ly z e d p ro d u c t was c o l l e c t e d in a pyrex U-tube
f i l l e d w i t h pyrex h e lic e s and e x t e r n a l l y cooled in a Dewar f l a s k con­
t a i n i n g e i t h e r is o p ro p y l a l c o h o l / d r y ic e o r i c e / s a l t m ix t u r e s .
When
e i t h e r the im in e o r enamine was no lo n g e r p re s e n t in th e 15 ml round
bottom f l a s k , both tra n s fo r m e rs were s h u t o f f and th e system was a llo w e d
to cool down to room te m p e ra tu re .
A t t h i s p o i n t the vacuum was broken ,
and the c o n te n ts o f th e U-tube were removed by f l u s h i n g w i t h d ry hexane.
Removal o f t h i s s o lv e n t under reduced p ressure y i e l d s th e p ro d u c t.
(Re­
f e r to diagram on f o l l o w i n g p a g e .)
Pr e p a r a t io n o f 2 - A c e t y l - 6- M e t h y l- 3 , 4-D ihyd ro -2 H -P yra n [ 8 ]
As d e s c rib e d in th e l i t e r a t u r e , 40 m e th y l-3 -b u te n e -2 -o n e 100
grams (1 .4 2 moles) was placed in a s t e e l pressure vessel and d im e rize d
a t 185° C f o r f o u r h ou rs.
vacuum d i s t i l l e d
A f t e r c o o l i n g , the c o n te n ts were removed and
(w a te r a s p i r a t o r ) t o g iv e a c o l o r l e s s l i q u i d , b .p .
40
HOSE TO V A C C U U M
G LASS WOOL W ITH A LU M IN U M
b
F O IL
W R A P P IN G
IUND G L A S S JO IN T
TO V A R IA B L E POWER
TRANSFORM ER
2 c m D IA M E T E R
P Y R E X T U B IN G
TEM PERTURE
BATH
N IC RO M E W IRE
PYREX
H E L IC E S
A S B E S T O S TA P E
W R A P P IN G '
DEW AR
2 cm . X 3 0 cm . P YR EX
T U B IN G
FLASK
PYREX
H E LIC E S
TO D IG IT A L
THERM OM ETER
TO V A R IA B LE POWER
TR A N S FO R M E R
P O IN T E D
STO PPER
G R O U N D G LA S S JO IN T
'
TO V A R IA B L E PO W ER
TRANSFORM ER
F ig u re 28.
Vacuum P y r o l y s is Apparatus
15 m l. ROUND
B O TTO M F L A S K
H E A TIN G
M AN TLE
41
74° C, 4 2.5 grams (85% y i e l d ) .
nmr data
8
'
Il
O
Chemical
S h i f t ( 6)
4.17
I
broad t r i p l e t
2 .0 3 -1 .5 6
4
m u ltip le t
2
3,4
Nature
o f Peaks
Number
o f Protons
5
4.48
1(7 c p s )
m u lt i pi e t
7
1 .73
3
s in g le t
8
2.17
3
s in g le t
I . R. ( f i l m ) cm
2874 (C-H s t r e t c h ) ;
1712 (C=O s t r e t c h ) ;
1385;
1232 (C-O-C s t r e t c h ) ;
1351;
s tre tc h );
1279;
9 1 7 .4 ;
8 9 4 .5 ;
U. V. (hexane)
208 nm (e3.32)
281 ( e l .59)
1675 (C=C s t r e t c h ) ;
1163;
758.7 (CH==CH s t r e t c h ) .
1103;
1429;
1070 ( C-O-C
42
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y
140 (37%);
97 (100%);
43 (2 .5 % );
41 (15.1% ).
■
79 (5.3% ); 69 (9.0 % );
General P re p a ra tio n o f N -A lk y l
55 (7 .5 % );
53 (4.5% );
!mines o f 2 - A c e t y l - 6- M e t h y l- 3 , 4-D ih yd ro
Pyrans
For th e sake o f b r e v i t y we w i l l
o n ly c o n s id e r in d e t a i l the
p r e p a r a t io n o f th e N-methyl im ine o f 2 - a c e t y l - 6- m e t h y l- 3 ,4-dehydro
pyran [ 1 1 ] .
A l l o t h e r i mines were prepared in the same manner w i t h the
id e n tic a l r e s u lts .
Only t h e i r s p e c t r a l c h a r a c t e r i s t i c s w i l l
be g iv e n .
A s o l u t i o n o f 2 - a c e t y l - 6- m e t h y l- 3 , 4 - d ih y d r o pyran (19 grams,
0.071 mole) and 100 ml o f d i e t h y l e t h e r c o n t a in in g 15 grams o f Linde 4
A m o le c u la r 41 sie ve s was cooled t o O0 C in an i c e / s a l t b a th .
I n to t h i s
s o l u t i o n was bubbled 2.48 grams (8.0 85 moles) o f m ethyl amine (a 20%
e x c e s s ).
The r e s u l t i n g s o l u t i o n was a llo w e d to come to room tem p era ture
and s t i r o v e r n i g h t , a t th e end o f which tim e the m o le c u la r sie ves were
f i l t e r e d from th e r e a c t io n m ix tu re and washed tw ic e w i t h 25 ml p o r t io n s
o f anhydrous d i e t h y l e t h e r .
The s o lv e n t was then removed from the com­
bined e t h e r f r a c t i o n s under reduced p re s s u re and the rem a ining re s id u e
was vacuum d i s t i l l e d
97% b .p .
component.
(w a te r a s p i r a t e d ) t o g iv e 9.72 grams (0.068 mole)
25) 37° C, a 97% y i e l d ,
A n a ly s is by g lc in d ic a t e d o n ly one
43
4
Nature
o f Peaks
Number
o f Protons
Chemical
S h ift ( 6)
2
4 .18
I
m u lt i p i e t
3,4
1 .4 4 -2 .2 3
4
muI t i p l e t
5
4.42
I
muI t i p l e t
7
I .74
3
s in g le t
8
1 .87
3
s in g le t
9
3.07
3
s in g le t
( f i l m ) cm" 1
1667 (C=N s t r e t c h ) ;
s tre tc h );
1163;
1429;
1379;
1053 ( C-O-C s t r e t c h ) ;
1299;
1282;
917.4;
873.4;
1235 ( C-O-C
754.7
U.V. (hexane)
231 nm ( e3.70) Amax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
153 (28.2%);
124 (13.6%);
97 (100%);
70 (16.1%);
56 (32.1%);
29
44
(12.4%)
N -E thyl
!mine o f 5 - M e t h y l - 2 - A c e t y l- 3 , 4 -D ihydro-2H -P yran [51 A]
9
Chemical
S h ift ( 6)
2
3,4
4.16
I .2 9 -2 .2 6
Number
o f Protons
Nature
o f Peaks
I
m u ltip le t
4
m u lt i p i e t
5
4.37
I
m u ltip le t
7
1 .70
3
s in g le t
8
2.15
3
s in g le t
9
3.09
2
q u a rte t
10
0.91
3
trip le t
I . R. ( f i l m ) cm
2902;
1678 (C=N s t r e t c h ) ;
1660 (C=C s t r e t c h ) ;
1440;
1386;
1238
45
1170 ( C-O-C s t r e t c h ) ;
1072 ( C-O-C s t r e t c h ) ;
923;
754
U.V. (hexane)
230 nm (e 3 .4 7 ) Xmas.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
167 (29.3% );
N-Propyl
124 (16.1% );
97 (100%);
70 (56.1% );
43 (16.2%)
!mine o f 5 - M e t h . y l - 2 - A c e t y l - 3 , 4-D ihyd ro -2 H -P yra n [5 1 B]
4
IO
9
46
. Chemical
S h ift ( 6)
Number
o f Protons
Nature
o f Peaks
4.14
I
m u l t i pi e t
I .3 2 -2 .2 4
6
m u l t i pi e t
5
4.39
I
m u lt i p i e t
7
1 .71
3
s in g le t
8
2.14
3
s in g le t
9
2.15
3
broad t r i p l e t
11
0.93
3
trip le t
2
3 ,4 ,1 0
I.R .
( f i l m ) cm
2899;
1675 (C=N s t r e t c h ) ;
1168 ( C-O-C s t r e t c h ) ;
U.V.
1664 (C=C s t r e t c h ) ;
1070 ( C-O-C s t r e t c h ) ;
1440;
9 2 0 .8 ;
1383;
753.0
(hexane)
232 nm (e 3 .4 4 ) Xmax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
181 (31.1% );
N -Butyl
124 (14.6% );
97 (100%);
84 (40.1% );
57 (18.8%)
!mine o f 2- A c e t y l - 6- M e t h y l- 3 , 4-Dih.ydro-2H-P,yran [51C]
b - p * (0 .2 5 )
67° C
1236;
47
4
7
11
9
12
Chemical
S h ift ( 6)
4.12
2
3 ,4 ,1 0 ,1 1
I .3 0 -2 .2 5
Nature
o f Peaks
Number
o f Protons
I
m u lt i p i e t
8
muI t i p l e t
5
4.36
I
m u lt i p i e t
7
1 .76
3
s in g le t
8
2.18
3
s i n g le t
9
3.19
2
trip le t
12
0.96
3
trip le t
( f i l m ) cm ^
2892;
1674 (C-N s t r e t c h ) ;
1167 ( C-O-C s t r e t c h ) ;
U.V. (hexane)
236 ntn (e 3 .4 0 ) Xmax.
1665 (C=C s t r e t c h ) ;
1070 ( C-O-C s t r e t c h ) ;
1446;
921;
756
1380;
1236
48
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
195 (28.6% );
98 (51.2% );
97 (100%);
71 (26.1%)
General P re p a ra tio n o f S - A c e t y I - I - ( I - A l k y I ) A m i n o Cyclohexene
Again we w i l l o n ly d e s c r ib e in d e t a i l the p r e p a r a t io n o f 5a c e t y l - I - ( I -m ethyl Jamino cyclohexene [ 1 3 ] .
a ls o in v e s t i g a t e d ( e t h y l
[ 5 2 8 ] , pro p yl
The o t h e r im ines which were
[5 2 8 ] and b u ty l
[5 2 C ]) were a c ­
com plished in e x a c t ly the same manner, o n ly the s p e c t r a l data w i l l
be
g ive n f o r these compounds.
Using the general p y r o l y s i s p ro ce d u re , 5.0 grams (0.035 mole)
o f [ 11] were placed i n th e 15 ml round bottom f l a s k and f o l l o w i n g the
c o n d it io n s p r e v io u s ly d e s c r ib e d , p y r o l y s i s was i n i t i a t e d .
A f t e r th re e
h o u rs, th e apparatus was cooled and the crude p y r o l y s i s p ro d u c t was
removed, y i e l d i n g 4.7 grams o f an a i r - s e n s i t i v e compound which had to
be s to re d under n i t r o g e n .
p r e s e n t.
A n a ly s is by g lc suggested o n ly one compound
D i s t i l l a t i o n under high vacuum gave 3.3 grams (9.023 mole)
o f [ 1 3 ], b .p .
(Q g) 125° C, 66% y i e l d .
re s id u e remained in the d i s t i l l a t i o n
9
(N ote:
fla s k .)
O
1.4 grams o f polym e rized
49
0.84-2.41
3 , 4 , 5 ,6
Nature
o f Peaks
Number
o f Protons
Chemical
S h ift ( 6)
7
u n reso lved m u lt i p i e t
2
4.48
I
trip le t
7
2.16
3
s in g le t
8
3.40
I
broad m u l t i pi e t
9
2.68
3
d o u b le t
I . R. ( f i l m ) cm
3413 (NH s t r e t c h ) ;
(C=C-H s t r e t c h ) ;
2857;
3268;
1645 (C=C s t r e t c h ) ;
1695 (C=O s t r e t c h ) ;
1429;
1342;
1563;
8 4 0 .3 ;
3086
751.9 (C=C)
U.V. (hexane)
220 nm (e3.79)
284 nm (el .77)
Xmax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
153 (28.6%);
(11.8%);
123 (16.3%);
110 (100%);
83 (12.6%);
43 (26.8%)
5- A c e t y l - I - ( I - E t h y l ) Amino Cyclohexene [52A]
b -p- ( 0 . 8)
132° C
80 (98.2%);
70
50
3
=If
T
B
^
8 NH
6
O
, o >
Chemical
S h i f t ( 6)
3 , 4 , 5 ,6
Nature
o f Peaks
Number
o f Protons
I .0 2 -2 .5 0
7
mu I t i p l e t
2
4.44
I
trip le t
7
2.14
3
s in g le t
8
3.44
I
mult i p l e t
9
2.74
2
m u lt i pi e t
10
0.87
3
trip le t
I . R. ( f i l m ) cm
3421 (N-H s t r e t c h ) ;
s t r e t c h o f ena m ine);
3254;
1558;
2850;
1428;
U.V. (hexane)
222 nm (c3.80) 283 nm ( e l . 71) Xmax.
1697 (C=0 s t r e t c h ) ;
134;
8 4 4 .6 ;
750.1
1637 (C=C
51
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
167 (41.6% );
123 (27%);
80 (100%);
70 (21.7% );
44 (33.4%)
5 - A c e t y l - I - ( I - P r o p y l ) Ami no Cyclohexene [52B]
b‘ p* (0.8) 140° C
3
I4
2 If
8
^
8 NH
6
Il
O
IO
Chemical
S h ift ( 6)
3 ,4 ,5 ,6 ,1 0
I .R .
I .0 8 -2 .5 6
Nature
o f Peaks
Number
o f Protons
9
m u lt i p i e t
9
2.70
2
m u ltip le t
2
4.45
I
mu I t i p l e t
7
2.16
3
s in g le t
8
3.38
I
mult i p l e t
11
0.91
3
tr ip le t
( f i l m ) cm
3405 (N-H s t r e t c h ) ;
3259;
3094 (=Cx ^ s t r e t c h ) ;
2890;
1704 (C=0
52
s tre tc h );
U.V.
1643 (enamine C=C);
1408;
1351;
986;
892;
740.9
(hexene)
223 nm ( e 3 . 7 7 ) ; 2.81 nm ( e l . 6 8 ) , Xmax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
181 (30.6% );
(21.2% );
138 (172%);
123 (22%);
80 (100%);
43 (39.1%)
5- A c e t y l - I - ( I - B u t y l ) Ami no Cyclohexene [52C]
b-p -( 0. 8) 146° C
12
IO
70 (15%);
58
53
Chemical
S h i f t (S)
3 ,4 , 5 ,6 ,1 0 ,1 1
I.R .
Number
o f Protons
Nature
o f Peaks
11
mul t i pi e t
1 .1-2 .51
2
4.42
I
m u ltip le t
7
2.15
3
s in g le t
8
3.31
I
m u ltip le t
9
2.67
2
m u ltip le t
12
0.92
3
trip le t
( f i l m ) cm
3400 (NH s t r e t c h ) ;
enam ine);
1562;
3261;
1423;
3089 (=Cs ^ s t r e t c h ) ;
1353;
852;
1649 (C=C s t r e t c h o f
746.1
U.V. (hexane)
229 nm ( e3 .7 6 ) ;
282 nm ( e l . 8 8 ) , Xmax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
195 (36.4% );
(14.2% );
152 (16.9% );
123 (21.3% );
80 (100%);
72 (20.6% );
70
43 (33.2%)
H y d ro q e n o lysls o f S - A c e t y l - I - ( I - M e t h y l) A m in o Cyclohexene [ 4 5 ]
3 .0 grams (0.021 mole) o f 5 - a c e t y l - I - ( I -m eth yl)a m in o cyclohexene
were d is s o lv e d in a 50 ml o f d r y e t h a n o l , to which was added '1 .5 grams
o f 10% Pd/C.
T h is e n t i r e m ix tu r e was placed in a P a rr C a t a l y t i c Hydro­
g e n a tio n apparatus under a hydrogen atmosphere o f 25 I b s . w i t h shaking
a t room te m p e ra tu re .
A t th e end o f 24 h o u rs , the c o n te n ts were removed.
54
and the Pd/C was f i l t e r e d and washed tw ic e w it h 25 ml p o r t io n s o f d ry
e t h a n o l.
The ethanol f r a c t i o n s were combined and the s o lv e n t removed
under reduced p re s s u re .
The rem a ining re s id u e was vacuum d i s t i l l e d
(w a te r a s p i r a t o r ) to g iv e 2.46 grams (0.017 m o le ), b . p .
(82% y i e l d ) ;
^ 23
C
g lc a n a ly s is on 10% SE-30 150° C in d ic a t e d o n ly one
component.
3
Chemical
S h i f t (6)
7
1 , 2 ,3 ,4 ,5 ,6
9
LR.
2.16
3
0 .8 4 -2 .1 4
10
2.42
3
s in g le t
u n re so lve d m u l t i p l e t
s in g le t
( f i l m ) cm™1
3333 (NB s t r e t c h ) ;
U.V.
Nature
o f Peaks
Number
o f Protons
2857;
1701 (C=0 s t r e t c h ) ;
(hexane)
284 nm ( e l . 9 2 ) ;
201 nm ( e 3 . 8 ) , xmax.
1445;
1346
55
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
155 (22.4% );
(13.3% );
140 (12.3% );
125 (9 .6 % );
112 (100%);
97 (14%);
82
43 (26.1%)
P re p a ra tio n o f 4 - A c e ty l cyclohexene [ 4 7 ]
2 .0 grams (0.0 13 mole) o f [ 4 5 ] was added to a s o l u t i o n o f 50 ml
o f anhydrous d i e t h y l e t h e r and 2 .3 grams (0.016 mole) o f 25% excess
methyl io d id e .
The s o l u t i o n was a llo w e d to s t i r under N2 atmosphere f o r
f o u r hours a t room te m p e ra tu re , a t the end o f which tim e the q u a te rn a ry
ammonia s a l t was c o l l e c t e d by vacuum f i l t r a t i o n
w it h 25 ml p o r t io n s o f anhydrous e t h e r .
and washed th re e tim es
The s a l t s were then added to a
s o l u t i o n o f 1.45 grams (0.013 mole) o f potassium t e r t - b u t o x i d e in 50 ml
o f t e r t - b u t y l a lc o h o l a t 80° C w i t h s t i r r i n g .
A f t e r f i v e h ou rs, the
s o l u t i o n was cooled and e x t r a c te d w i t h 50 ml p o r t io n s o f anhydrous
e t h e r , d r ie d o ver anhydrous magnesium s u l f a t e , and the s o lv e n t removed
under reduced p r e s s u re .
The rem a ining re s id u e was vacuum d i s t i l l e d
(w a te r a s p i r a t o r ) to g iv e a c l e a r l i q u i d
a y i e l d o f 62%.
1.0 grams, b .p .
75° C,
A n a ly s is by g lc in d ic a t e d o n ly one compound p re s e n t.
3
O
56
Number
o f Protons
Chemical
S h ift
(6)
Nature
o f Peaks
I .1 2 -2 .8 4
7
u n re so lve d m u lt i p i e t
L2
5.64
2
broadened s i n g l e t
8
2.14
3
s in g le t
3 , 4 , 5 ;6
s tro n g peaks a t 2.19 and 2 .0 6 .
I.R .
2857;
U.V.
( f i l m ) cm~^
1724;
1429;
1351;
1220;
7 1 6 .3 ;
651.6
(hexane)
180 nm ( e4 . 0 3 ) ;
284 nm ( e3.380) , Xmax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
124 (22.6% );
81 (59.3% );
70 (33.8% );
54 (29.2% );
43 (100%)
General P re p a ra tio n o f 3 - A c e ty l cyclohexanone [ 3 6 ]
Since a l l
o f th e 5- a c e t y l - I - ( I - a l k y l ) ami no cyclohexenes were
a c id h yd ro ly z e d to th e same p r o d u c t, 3 - a c e t y l cyclohexanone [ 3 6 ] , o n ly
the a c id h y d r o l y s is o f 5 - a c e t y l - I - ( I - m e t h y l) ami no cyclohexene w i l l
d e s c rib e d in f u l l
be
d e ta il.
The p r e p a r a t io n o f 3 - a c e t y l cyclohexanone was achieved in the
f o l l o w i n g manner.
3 .0 grams (0.0 19 mole) o f f r e s h l y d i s t i l l e d
were d is s o lv e d in 50 ml o f a 5% aqueous s u l f u r i c a c i d .
[1 3 ]
This e n t i r e
s o l u t i o n was r e f l u x e d under a n it r o g e n atmosphere f o r 24 hours and th e
r e s u l t i n g o ra n g e -c o lo re d s o l u t i o n was cooled and th e benzene la y e r
57
se p a ra te d .
o f benzene.
The aqueous la y e r was e x t r a c te d tw ic e w it h 25 ml p o r t io n s
The combined benzene p o r t io n s were washed th re e times w i t h
50 ml p o r t io n s o f s a tu r a te d sodium b ic a rb o n a te and d r ie d o ver anhydrous
magnesium s u l f a t e .
Removal o f the s o lv e n t under reduced pressure l e f t
a re s id u e which was vacuum d i s t i l l e d
(w a te r a s p i r a t o r ) , b .p . 124° C, to
y i e l d 1.97 grams o f a c o l o r l e s s l i q u i d , a y i e l d o f 72%.
A n a ly s is by
g lc showed o n ly one compound p r e s e n t.
5
6
4
6
O
O
Chemical
S h i f t (6)
2.16
3
s in g le t
1 .16-2.48
9
m u lt i p i e t
8
2 ,3 ,4 ,5 ,6
Nature
o f Peaks
Number
o f Protons
I . R. ( f i l m ) cm
2857;
1701 (CK) s t r e t c h ) ;
LI. V. (hexane)
288 nm (e3.70)
1721;
1429;
1351;
1255;
1220;
1163
58
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
140 (10%); 97 (61.25% );
(71.25% );
69 (37.5% );
55 (40%);
43 (100%);
41
39 (33.5%)
General P re p a ra tio n o f P y r r o l i d i n o Enamine o f 2 - A c e t y l- 6 - M e t h y l- 3 , 4 D ihydro-^H -P yran [ 5 3 ]
10 grams (0.071 mole) o f 2 - a c e t y l - 6 - m e t h y l - 3 ,4 -d ih y d ro - 2 H pyran were added to 5.5 grams (0.077 mole) o f p y r r o l i d i n e and 15 grams
o f Linde 4A m o le c u la r s ie v e s .
This m ix tu r e was then warmed to 35° C
and m a in ta in e d a t t h i s te m p e ra tu re , w h ile s t i r r i n g under a n itr o g e n
atmosphere f o r 24 h ou rs.
A f t e r t h i s tim e the r e a c t io n m ix tu re was
c o o le d , the m o le c u la r sie ve s were f i l t e r e d from th e m ix t u r e and were
washed tw ic e w it h 25 ml p o r t io n s o f anhydrous e t h e r .
combined w i t h th e f i l t r a t e
The e th e r was
and removed under reduced p re s s u re .
re s id u e was vacuum d i s t i l l e d
The
to g iv e a c o l o r l e s s l i q u i d , b .p .
83° C, 12.45 grams, a y i e l d o f 91%.
Glc a n a ly s is suggested t h a t o n ly
one compound was p r e s e n t.
nmr data
8
59
Chemical
S h i f t (<5)
6
Number
o f Protons
1 .82
Nature
o f Peaks
3
s in g le t
I .4 2 -2 .2 6
8
u n reso lved m u lt i p i e t
4
4.49
I
mu I t i p l e t
I
4.24
I
m u lt i pi e t
8
2.64
2
d o u b le t
9,12
2.94
4
u n re so lve d mult i p l e t
2 ,3 ,1 0 ,1 1
I.R .
( f i l m ) cm~^
3078 ((X ^ s t r e t c h ) ;
2857;
1250;
1070 ( C-O-C s t r e t c h ) ;
U.V.
1235;
1166;
1672 (C=C s t r e t c h o f enam ine);
9 5 0 .6 ;
1613;
1287;
754.7 (C=C s t r e t c h )
(hexane)
228 n'm (e 3 .7 8 ) Amax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
193 (3 2 .3 % );.
123 (22.1% );
122 (32%);
97 (100%);
96 (51.2% );
70
(23%)
A n a l:
C a lc 'd f o r C-j9H-|gON;
C 7 4 .5 6 ;
H 9 .9 0 .
Found: C 7 6 .9 0 ; H 10.26.
P r e p a ra tio n o f S - A c e t y l - I - ( I - P y r r o l i d i n y l ) C y c l o h e x e n e [ 4 1 ]
Using th e general p y r o l y s i s p ro c e d u re , 5 .0 grams (0.025 mole) o f
p y r r o l i d i n e enamine was placed in th e 15 ml round bottom f l a s k and f o l ­
lo w in g th e c o n d it io n s p r e v io u s ly d e s c r ib e d , p y r o l y s i s was i n i t i a t e d .
60
A f t e r th r e e hours the apparatus was cooled and the crude p y r o ly s i s
p ro d u c t was removed, y i e l d i n g 5 grams o f an a i r s e n s i t i v e produ ct
which had to be s to re d under n i t r o g e n .
Glc a n a ly s is in d ic a t e d a
homogeneous compound, and high vacuum d i s t i l l a t i o n
c l e a r y e llo w l i q u i d , b .p .
tio n .
(N ote:
tilla tio n
^
gave 4 .3 grams o f a
135° C, a y i e l d o f 86% a f t e r d i s t i l l a ­
0.61 grams o f polym e rized re s id u e s remained in the d i s ­
fla s k .)
3
3 ,4 ,5 ,6 ,9 ,1 0
Chemical
S h i f t (6)
Number
o f Protons
Nature
o f Peaks
I .0 8 -2 .4 6
11
m u ltip le t
2
4.28
I
mu I t i p l e t
7
2.14
3
s in g le t
8,11
2.89
4
mu I t i p l e t
I . R. ( f i l m ) cm
2890;
1698 (C O s t r e t c h ) ;
1639 (D O s t r e t c h ) ;
1 395;
1351;
1163;
61
7 5 4 .7 ;
.
;
'
U.V.
2082 C==Cxu s t r e t c h )
11
. ’
■
^
(hexane)
227 nm (e3.81);
281 nm (el .62), Xmax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
193 (21%);
(8.9 % );
A n a l:
1 7 8 (8 .2 % );
70 (44%);
1 5 0 (1 0 0 % );
1 0 8 (6 .3 % );
123 (42.6% );
80
43 (57.6%)
C a lc 'd f o r CpH^gNO;
C 7 4 .5 8 ;
H, 9 .9 0 .
Found:
C 7 4 .6 8 ;
H5
9.6 8
P r e p a ra tio n o f 3 - A c e ty l cyclohexanone [3 6 ]
4 .0 grams (0.020 mole) o f f r e s h l y - d i s t i l l e d 5 - a c e t y l - I - p y r r o l i d in e -rl-c y c lo h e x e n e were d is s o lv e d in 50 ml o f d ry benzene.
The r e s u l t ­
in g s o l u t i o n was placed under a n it r o g e n atmosphere to which was added
10 ml o f a 5% aqueous s u l f u r i c a c id and r e f lu x e d f o r a p e rio d o f 24
h ou rs, a f t e r which th e s o l u t i o n was cooled and e x t r a c te d th re e times
w it h 100 ml p o r t io n s o f e t h e r .
The combined e t h e r e x t r a c t s were washed
th re e tim es w i t h 100 ml p o r t io n s o f s a tu r a te d sodium b ic a rb o n a te , d r ie d
o ver anhydrous magnesium s u l f a t e and the s o lv e n t removed under reduced
p re s s u re .
The re m a in in g re s id u e was vacuum d i s t i l l e d
(w a te r a s p i r a t o r )
to g iv e a c o l o r l e s s l i q u i d , b .p . 124° C, 2.11 grams, a y i e l d o f 73%.
Spectra was i d e n t i c a l t o t h a t p r e v io u s ly d iscu sse d .
62
P r e p a ra tio n o f 2 - M e th y l-5 -A c e ty lc y c lo h e x a n o n e [4 0 ]
3 .0 grams (0.015 mole) o f 5 - a c e t y l - I - p y r r o l id i n e - 1 - c y c lo h e x e n e
were d is s o lv e d in 50 ml o f d r y benzene, and the e n t i r e s o l u t i o n was
placed under a n i tr o g e n atmosphere.
W hile s t i r r i n g , 2.12 grams (0.015
mole) o f methyl io d id e were i n je c t e d o v e r a p e rio d o f 1/2 hour.
The
r e s u l t i n g m ix t u r e was then a llo w e d to r e f l u x f o r 24 h o u rs , a t the end
o f which tim e 10 ml o f aqueous 5% s u l f u r i c a c id was added.
The
r e s u l t i n g s o l u t i o n was f u r t h e r r e f l u x e d f o r an a d d i t i o n a l f i v e hours
to a f f e c t h y d r o l y s i s .
The r e s u l t i n g o ra n g e -c o lo re d s o l u t i o n was cooled
and e x t r a c te d th r e e tim es w i t h 100 ml p o r t io n s o f e t h e r .
The combined
e t h e r e x t r a c t s were washed th re e tim es w i t h 100 ml p o r t io n s o f
s a tu r a te d sodium b ic a r b o n a t e , d r ie d o v e r anhydrous magnesium s u l f a t e
and the e t h e r removed under reduced p re s s u re .
was vacuum d i s t i l l e d
The r e s u l t i n g re s id u e
to y i e l d a c o l o r l e s s l i q u i d , b .p .
C, 1.81 grams (76%).
^
131-132°
Glc a n a ly s is i n d ic a t e s o n ly one compound p re s e n t.
n
^
U
\ /
6
5\
7
Il
O
/ 8
\
63
Number .
o f Protons
Chemical
S h i f t (6)
Nature
o f Peaks
8
2.18
3
s in g le t
9
0.92
3
m u lt i pi e t
(both isomers p re s e n t)
8
m u lt i pi e t
3 ,4 ,5 ,6 ,2
1 .1 2 -2 .5 5
( f i l m ) , cm""^
2924;
1712-1689 (C=O s t r e t c h ) ;
1456;
1429;
1359;
1266; . 1176;
965.3
U.V.
(hexane)
290 nm ( s 3 .7 2 ) Xtnax.
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
43 (100%);
55 (72%);
96 (65.6% );
111 (57.8% );
139 (15.6% );
154
(19.6%)
A n a l:
C a lc 'd f o r CgH-j^Og;
N
C, 7 0 .1 0 ;
H, 9 .1 4 .
Found:
C, 69.-82; H, 8.53
REFERENCES
REFERENCES
K
• D. L e d n ic e r , " L a t e n t F u n c t i o n a l i t y in Organic S y n t h e s i s Advances
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2.
A. I . Meyers, H e te ro c y c le s in O rganic S y n th e s is , J. W ile y , 1974.
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D. L. D a lrym p le , I . L. Kruger and W. N. W hite, The Chem istry o f th e
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7.
K. B. L i p k o w it z , Ph.D. T h e s is , Montana S ta te U n i v e r s i t y , 1975.
8.
K. B. L ip k o w it z and B. P. Mundy, T e t . L e t t . , in p re s s .
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(1963 ).
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H. A h lb r e c h t
and G. Papke, T e t ., L e t t . ,
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and S. F is c h e r , T e i x ,
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and S. F is c h e r , T e t . ,
3 0 , 2571 (1974)
h.
H. Qust and A. H e u b le in , Chem. B e r . , 108, 2574 (1974).
10. D. S. Black and A. M. Wade, Chem. Comm., 871 (1970 ).
11. R. K. H i l l
and G. R. Newhom, T e t . L e t t . , 5059 (1968)
12. R. K. Bramley and G. G rig g , Chem. Comm. , 99 (1969 ).
66
13.
D. F e l i x , K. Gschwend-Steen, A. E. Wick and A. Eschenmeser, Helv.
Chim. A c t a , 52^, 1030 (1969 ).
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R. K. H i l l
15.
a.
E. J. Corey, R. D. Cramer and W. Howl, J . Amer. Chem. S o c.,
94, 440 (1972 ).
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E. J. Corey, R. D. Cramer and W. Howl, J. Amer. Chem. S o c.,
94, 431 (1972 ).
and N. W. Gilm an, l e t . L e t t . , 1421 (1967 ).
16.
L. B i r k o f f e r and D. Daum, Chem. B e r . , 9 5 , 183 (1962 ).
17.
D. E. Pearson and C. A. B u e h le r , "Potassium T e r t - B u to x id e in
S y n th e s is , " Chem. Rev. , 7 4 , 45 (1974).
18.
D. Y. C u r t i n , E. J. Grubbs, C. G. McCarty,
88, 2775 (1966 ).
19.
W. B. Jenninqs and D. R. Boyd, J . Amer. Chem. S o c ., 94, 7187
(1971 ).
20.
a.
R. B. Woodward and R. Hoffman, The C o nservation o f O r b it a l
Symmetry, Academic P ress, New York (1971).
b.
T. L. G i l c h r i s t and R. C. S t o r , Organic Reactions and O r b i t a l
Symmetry, Cambridge U n i v e r s i t y Press, New York (1972).
c.
I.
Amer. Chem. Soc. ,
Flem ing, F r o n t i e r O r b i t a l s and O rganic Chemical R e a c tio n s ,
John W ile y , New York (1976 ).
d.
K. F u k i , Theory o f O r i e n t a t i o n and S t e r e o - S e l e c t io n , S p r in g e r V e r la g , New York (1975 ).
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J. E. Baldwin and R. H. F lem ing, J_. Amer. Chem. Soc. , 94, 2140
(1972).
f .
G. K. Klopman ( E d . ) , Chemical R e a c t i v i t y and R e action P a th s,
John W ile y and Sons, New York (1974 ), p. 129.
21.
W. J. LeNoble , H i g h l ig h t s o f O rganic C h e m is try , Marcel Dekker,
New York (1 9 7 4 ).
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a.
S. J. Rhoads and N. R. Raul i n s , O rg. R e a c tio n s , 22_, I (1975 ).
67
22.
b.
M. J. S. Dewar and L. E. Wade, J r . , J. Amer. Chem. S o c ., 95,
290 (1973 ).
•c. ■ M. J. S. Dewar and L. E. Wade, J r . , J. Amer. Chem. S o c ., 99,
4417 (1977 ).
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W. D. G urow itz and M. A. Joseph, J_. O rg. Chem. , 32, 3289 (1967).
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G. 0. Dudek and R. H. Holm,
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b.
G. 0. Dudek and R. H. Holm, J_. Amer. Chem. Soc. , 8 3 , 2914
(1963 ).
a.
Y. A. Ovchinnkov and G. P. Kugatwa-Shemyakina, J e t . , 23, 697
(1962 ).
b.
G. M. N ik o la e v and G. P. Kugatwa-Shemyakina, l e t . , 2 3 , 2987
' (1967 ).
c.
G. M. N ik o la e v and G. P. Kugatwa-Shemyakina, T e t . , 23^, 2721
■ (1967).
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Amer. Chem. Soc. , 8 3 , 2099
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A. DeSavignac and A. L a t , Comptes Rendus, S e rie s C, 277, 1367
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Academic Press, New York (1970 ).
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a.
A. G. Cook, Enamines: S y n th e s is , S t r u c tu r e and R e a c tio n s ,
Marcel D ekker, New York (1969 ).
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S. F. Dyke, The C hem istry o f Enamines, Cambridge U n iv e r s it y
Press, New York (1973).
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D. J. Dunham and R. G. Lawton, J_. Amer. Chem. Soc. , 9 3 , 2074
(1971 ).
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a.
T. K. Devon and A. I . S c o t t , Handbook o f N a t u r a l l y O ccu rrin g
Compounds, V o l . I I , Academic Press, New York (1972 ).
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K o ji Nakanishi and T i s h io Goto, N a tural Products C h e m is try , .
V o l . I , Academic P ress, New York (1974).
31.
J. ApSimon, The T o ta l S yn th e sis o f N a tu ra l P r o d u c ts , V o l . I I ,
W ile y I n t e r s c i e n c e , New York (1973 ).
68
32.
R. M. Coates and J. E. Shaw, J_. O rq. Chem., 35, 2597 (1970).
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E. P ie rs and K. F. Cheng, Can.
34.
J. K. Roy, Chem. and I n d . , 1393 (1954 ).
35.
K. K le in and W. Rojahn, l e t . L e t t . , 279 (1970 ).
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G. Desemoni and G. T a c c o n i, "H e te ro d ie n e S yn th e sis w i t h a ,B U n satu ra ted Compounds, " Chem. Rev. , 75, 651 (1 9 7 5 ).
37.
"a,B-Unsaturated Carbonyl Compounds as D ie n e s ," J. Colonge and
G. Descotes, 1 , 4 - C y c lo a d d it io n R e a c tio n s , Jan. Hamer ( E d . ) ,
Academic Press, New York (1 9 6 7 ).
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B. P. Mundy, K. B. L ip k o w it z and G. W. D i r k s , H e te r o c y c le s , 6_,
51 (1977).
39.
B. P. Mundy, K. B. L ip k o w it z and G. W. D ir k s , " C y c lo a d d it io n
R eactions Leading to Pyran D e r i v a t i v e s , " ( s u b m it te d ) .
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K. A l d e r , H. Offermanns and E. Ruder, Chem. B e r . , 74^, 905 (1941 ) .
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Chem., 46, 377 (1968 ).
A MEW SYNTHESIS OF BREVICOMIN
C hapter I
HISTORICAL
The western pine bark b e e t l e , D endvoaotonus b v e v ia o m is , has
been r e s p o n s ib le f o r mass d e s t r u c t i o n o f the ponderosa p in e in both
the U n ited S ta te s and Canada.
The in v a s io n and even tua l d e s t r u c t i o n o f
the t r e e by D. b v e v ia o m is occurs in two phases.
in itia l
In th e f i r s t , an
a t t a c k i s made by a few b e e tle s which bore i n t o the t r e e and
c o n s t r u c t a n u p t i a l chamber.
f r a s s , a m ix tu re o f f e c a l
In t h i s p e rio d o f a c t i v i t y , they expel
p e l l e t s and wood fra g m e n ts .
The fr a s s con­
t a in s a t h i r d component, a sex pheromone^ which in t u r n t r i g g e r s the
secondary massive in v a s io n which u nd oubtedly k i l l s
the t r e e .
In 1968, S i l v e r s t e i n 2 and coworkers i s o l a t e d 2 mg o f the agg re ­
g a tin g sex pheromone o f D. b v e v ia o m is from 1.6 kg. o f f r a s s and
re p o rte d the s t r u c t u r e as e x o - 7 - e t h y l - 5 - m e t h y l- 6 , 8 - d i o x a b i c y c l o [ 3 . 2.1 ) octane ( I ) o r e x o -b re v ic o m in .
71
Because one co u ld a c t u a l l y use e x o - b r e v ic o m in f o r the mani­
p u l a t io n o f the m ating h a b its o f D. b v e v io o m is one co u ld p o t e n t i a l l y
p r o v id e the F o re s t S e rv ic e w ith an e c o l o g i c a l l y advantageous means o f
p o p u la tio n c o n t r o l
f o r t h is s p e c ific in s e c t.
I t is i n t e r e s t i n g to
note t h a t th e re are no e f f e c t i v e means o f c o n t r o l l i n g D. b re v io o m is
up to t h i s p o i n t .
Thus, a t t e n t i o n was then turn e d toward the t o t a l
s y n th e s is o f b re vico m in because o f the obvious i s o l a t i o n problem s,
e s p e c i a l l y in la r g e q u a n t i t i e s .
As Mundy
3
has p o in te d o u t in a re c e n t r e v ie w , r e t r o - s y n t h e t i c
a n a ly s is o f the 7 - e t h y l - 5 - m e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] octane r in g
s k e le to n re v e a ls two p o s s ib le ro u te s f o r the c o n s t r u c t i o n o f the k e ta l
m oiety o f t h i s m o le cu le .
In ro u te [ a ] , the s y n t h e t ic s t r a t e g y demands the c o n s t r u c t io n
72
i
o f a m olecule w i t h ketone and g ly c o l f u n c t i o n a l i t y , w h il e ro u te [ b ]
c o n s is ts o f th e c o n s t r u c t i o n o f a d ih y d ro p y ra n c a r b i n o l .
In 1969, S i l v e r s t e i n
4
p u b lis h e d the f i r s t s y n th e s is o f b r e v i -
comin in which the s y n t h e t i c s t r a t e g y c o n s is te d o f the p r e p a ra tio n Of
the e th y le n e k e ta l
(3J o f 6^bromohexane-2-one ( 2 ) , f o llo w e d by t r e a t ­
ment w i t h t r i p h e n y l phosphine t o y i e l d the phosphomiurn s a l t ( 4 ) .
Con­
d e n s a tio n o f (4) w i t h p r o p i nonaldehyde y ie ld e d a m ix tu re o f c is and
tra n s non-6 -en e-2 -on e e th y le n e k e ta l
(5^), which upon t re a tm e n t w it h
m -c h lo ro p e rb e n z o ic a c id gave the c i s and tra n s epoxides ( 6 )
separated by g l c .
H y d ro ly s is gave th e in te r m e d ia te d i o l
clo sed t o the b i c y c l i c k e t a l .
which were
( 7) which
73
^
o
CH3-C-(CH2)4-Br H°
r-\
r~ \Q
° H' H% CH3-C -(C H 2)4-B r
CH3-C ^(C H 2)4- P +O3
r n
o
-----------> CH03-C-(CH 2)3-CH-CH-CH 2-C h 3 m-C'C6H4C0?- ^ CH3-C-(CH 2)3CH-CH-CH2-C h 3
2 .) C H 3 - C H 2 -C H O
3
^ 3
H 2 SO4 Z H 2O
----------------> CH3-C -(C H 2) 3-C H -C H -C H 2- C h 3
A c e to n e
L
I
OH
F ig u re 29.
» 1
S i l v e r s t e i n ' s B revicom in S y n th e s is .
An a l t e r n a t i v e approach taken by S i l v e r s t e i n in v o lv e d the a c id
h y d r o ly s is o f 2 - a c e t y l b u t y r o la c to n e ( 8 ) , which when f o llo w e d by k e t a l i z a t i o n gave 5-brom o pentan-2-one, e th y le n e k e ta l
(9) in 60% y i e l d .
Treatment o f 9 w i t h NaZNH3 and 1 -b u tyn e gave the n o n -6 -yn -2 -o n e e t h y l ­
ene k e ta l
in 16.7% y i e l d .
T his was reduced w i t h n i c k e l t e t r a ­
a c e ta te and sodium b o ro h y d rid e to g iv e c is -n o n -6 -e n e -2 -o n e e th y le n e
k e ta l
(2) in 80% y i e l d .
74
o
\\
x o y ^o
8
o H ,
CH3-C -C H 2-C H 2-C H 2-Br
1.
) H Br1 H2O
2.
) H ( T l) H , H+
No, NH3
CH3CH2 C=CH^
9
^
r\
O
H2l Ni-(OAc)4
°x
^
CH3-C -(C H 2)3-C = C -C H 2-C H 3 —
------> CH3 -C -(C H 2)3-C H =CH-C h 2-CH 3
Ox
IO
F ig u re 30.
S i l v e r s t e i n ' s A l t e r n a t e Scheme.
5
Working along the same l i n e s , Wasserman
and coworkers a l k y l ­
ated a c e t o a c e tic e s t e r w it h c i s - 1 -bromo-3-hexene (TJJ w h ic h , f o llo w e d
by s a p o n i f i c a t i o n and d e c a r b o x y la t io n , gave c is -n o n -6 -e n e -2 -o n e (1 2 ).
The ketone ( I j H was t r e a t e d w i t h m -c h lo ro p e rb e n z o ic a c id to g iv e the
c is - e p o x id e ( U ) which upon sealed tube p y r o ly s i s a t 210°C gave b r e v i comin in a 95% y i e l d :
w i t h an exo/endo r a t i o o f 90:10.
+ CH3- ^ - C H 2- H - O C H 2 CH3
Br
Il
75
-> ( I )
9 0 % Exo
I 0 % Endo
F ig u re 31.
Wasserman S yn th e sis o f B r e v icomin.
S i l v e r s t e i n 6 and c o w o rk e rs , in 1971, were a b le to g r e a t l y
improve t h e i r o r i g i n a l
(14) to i t s
s y n th e s is by the con ve rsio n o f c i s - 3 - h e x e n e - l- o l
t o s y l a t e e s t e r ( 1 5 J , which was used to a l k y l a t e e th y l
a c e to a c e ta te .
T h is , f o llo w e d by a c id h y d r o ly s is and d e c a rb o x y la tio n
y ie ld e d ( 1 2 ) , c i s - 6 - n o n e n e - 2 - o l , in 37% y i e l d .
Treatment o f 12 w i t h
m -c h lo ro p e rb e n z o ic a c id in benzene a t 15°C gave c i s-6 ,7 -o xe d o n o n a n -2 one, which in t u r n was r e f l u x e d in benzene to g iv e I a 55% y i e l d
o f which was exo and 5% e n d o ).
(95%
76
Ch 3-C H 2 -CH = C H -(C H 2)2-OH
T tC I
CH3-C H 2-CH=CH-(CH 2)2 OTs
80%
15
14
O
Il
C H 3 - C - C H 2- C - O E l
IN
NoOH
37%
12
OH, re flu x
F ig u re 32.
Improved S i l v e r s t e i n
S yn the sis o f B revicom in.
In 1976, P. L. K o cienski and R. W. Ostrow7 p u b lis h e d y e t a n o th e r
s y n th e s is o f b re v ic o m in based on the ketone d i o l synthon developed by
S i ! v e rs te in .
y ie ld e d H k
The Eschenmoser fra g m e n ta tio n o f the epoxy ketone (15)
K e ta ly z a t io n o f 1_5 gave the S i l v e r s t e i n in t e r m e d ia t e ,
6-nonyn-2-one e th y le n e k e t a l , ( 1 0 ) .
Reduction o f the a c e t y le n ic k e ta l
(10) by BH3 -Me2S f o llo w e d by p r o t o n a t io n gave the S i l v e r s t e i n i n t e r ­
m edia te , c is - n o n - 6 - e n e - 2 - o n e , ( 5 ) .
S t e r e o s p e c if ic a c id cleavage o f the
c is epoxide (6) w i t h co n co m ita n t h y d r o l y s is o f the k e t a l gave the keto
d io l
in t e r m e d i a t e ,
(7 ).
77
O
Ii
:o
P-Ts-NHNH2
0
----------------- > CH3-C(CH2) 3-C iC -C H 2 -CH 3
CH2CI2 , HO-Ac
15
F ig u re 33.
16
K o cienski S y n th e sis o f B r e v icomin.
The S i l v e r s t e i n in te r m e d ia te was s t i l l
to be used in an o th e r
78
s y n th e s is o f b re vico m in in 1977 by Coke^, which c o n s is te d o f the a l k y l a ­
t i o n o f 1 ,3 -c y c lo h e x a n e d io n e w it h e t h y l
io d id e to g iv e 2 - e t h y l - 1 ,3 -
cyclo h e xa n e d io n e , which when fo llo w e d by tre a tm e n t w i t h phosphorous
t r i c h l o r i d e y ie ld e d th e c h l o r i d e ( 1 7 ) .
Treatment o f YJ_ w i t h m e th y l-
l i t h i u m , fo llo w e d by p y r o l y s i s , g ives 16.
This a c e t y le n ic ketone was
reduced t o the c i s o l e f i n w i t h 10% p a lla d iu m on barium s u l f a t e .
T re a t­
ment o f 12 w i t h m -ch lo ro p e rb e n z o ic a c id y ie ld e d the S i l v e r s t e i n i n t e r ­
m edia te , ( 1 3 ) ;
w h ic h , when heated a t 21O0C gave both exo and endo
b re vico m in in a 9:1 r a t i o .
O
Il
CH %- C - (CHg)^-CEC -CHg-C H^
O
_Ha______
CH3 -H -(C H g )3-C H = C H -C H g -C H 3
Pd(BaSO4)
12
16
Fn-ClC6H4CO3H
(I )
CH2CI2
F ig u re 34.
Coke S yn th e sis o f B revicom in.
79
Now t u r n in g o u r a t t e n t i o n t o the second r e t r o s y n t h e t i c r o u t e ,
b, H. C. Brown^ p ro v id e d the i n i t i a l
s y n t h e t ic impetus in a paper pub­
li s h e d in 1970, in which c y c l i c e th e rs were c o n s tr u c te d from unsatu­
ra te d a lc o h o ls v ia o r g m e r c u r a tio n / d e m e r c u r a tio n .
1. ) Hg(OAc)2
>
2 . ) OH- ZNoBH4
: oh
The mechanism f o r t h i s r e a c t io n was th o u g h t to proceed along
the l i n e s o f f i r s t e l e c t r o p h i l i c a t t a c k by the m e rc u ria c e ta te c a t io n
to form the in te r m e d ia te c y c l i c m ercu riniu m io n which then undergoes
subsequent i n t r a m o le c u la r n u c l e o p h i l i c a t t a c k o f the hyd ro xyl group.
Demercuration and d e p ro to n a tio n gave a f i ve-membered c y c l i c e t h e r .
In a s e r ie s o f papers f i r s t p u b lis h e d in 1971 M undy^ demon­
s t r a t e d a t h r e e - s t e p s y n th e s is o f b re v ic o m in .
The s y n t h e t i c s t r a t e g y
developed from the -n j* s + Trg2 c y c lo a d d i t i o n o f methyl v i n y l
ketone and
a c r o l e i n to y i e l d 2 - f o r m y l- 6 - m e t h y l- 2 , 3 - d ih y d r o - 2 H - p y r a n , ( 1 9 ) .
The
G rignard r e a c t io n o f e th y lm a g n e s iurn bromide w it h lj) gave both isomers
o f 2 - ( 2 - h y d r o x y e t h y l) - 6 - m e t h y l- 2 , 3 - d ih y d r o - 2 H - p y r a n , ( 2 0 j .
C y c l iz a t i o n
o f the p y ra n y l c a r b i n o l , ( 2 0 ) , v ia the o x y m e rc u ra tio n /d e m e rc u ra tio n
80
method o f Brown gave exo/endo b re vico m in in a 1:1 r a t i o .
EtMgBr
I . IHg(OAc)
2.) HO- ZNa BH
F ig u re 35.
Mundy S y n th e sis o f B revicom in.
Mundy has a ls o demonstrated t h a t tre a tm e n t o f 20 w i t h p - to lu e n e s u l f o n i c a c id in benzene g iv e s b re v ic o m in in 87% y i e l d w i t h a 64:36
r a t i o o f exo to endo isom ers.
I t i s a ls o w o r th w h ile to mention t h a t u n l ik e any o f the b e fo r e mentioned syn th e s e s , Kossanye11 re p o r te d a q u i t e novel s y n th e s is o f
b re vico m in in 1977.
Here the s e l e c t i v e i r r a d i a t i o n o f 2 - p r o p i o n y l- 6 -
methyl - 2 , 3 - d ih y d r o - 4 H - p y r a n , (21_), by s i n g l e t s e n s i t i z a t i o n and t r i p l e t
quenching by I - m e th y ln a p th a !ene gave the s t e r e o s e l e c t i v e exo-isom ers o f
I - m e t h y l - 6 - e x o - e t h y l- 7 , 8 - d i o x a b i c y c l i c [ 3 . 2 . I ] o c t - 2 - e n e , ( 2 2 ) , in 23%
y ie ld .
y ie ld .
C a t a l y t i c hydro g e n a tio n o f 22 gave exo b r e v i c o m i n , ( I j , in 95%
81
X> 3 0 0 mm
vycor filter
H2
>
Pd/C
Pentane
• P * -
22
F ig u re 36.
I
Kassanye S y n th e sis o f B r e v icomin.
Thus, in a c o n t in u in g e f f o r t in our la b o r a t o r y to improve the
o rig in a l
Mundy s y n th e s is o f b r e v ic o m in , a search f o r a b e t t e r e l e c t r o ­
p h i l i c reage nt was begun.
C a reful
i n v e s t i g a t i o n o f the l i t e r a t u r e
re ve a le d such an e l e c t r o p h i l e in p h e n y ls e le n y l c h l o r i d e .
Sharpless
In 1974, K. B.
re p o r te d a new ro u te f o r th e s y n th e s is o f a l l y l i c
the e l e c t r o p h i l i c a d d i t i o n o f v a r io u s *Sex reagents (where x =
o r oAc) t o a lk e n e s .
e th e rs by
c l , Br
These reagents always undergo tra n s -1 ,2 a d d it io n s
to g iv e the a d d u c t, ( 2 3 ) , which i s q u i t e s t a b le when x = oAc, b u t is
both t h e r m a lly and s o l v o l y t i c a l I y u n s ta b le when x = c l o r Br.
A d d it io n
o f an a lc o h o l gave the p h e n y ls e le n o e th e r , ( 2 4 ) , which when o x id iz e d w i t h
30% H2O2 in THF a t room tem p era ture gave 25.
n a tio n v ia 26 to g iv e the a l l y l i c
e th e r,
This underwent syn e l i m i ­
( 2 7 ) , in 93% y i e l d .
82
F ig u re 37.
Sharpless S y n th e s is o f C y c lic E th e rs .
Based on t h i s work o f V e m u ra ^ , N i c o l a o u ^ re p o r te d in 1977
t h a t tre a tm e n t o f u n s a tu ra te d a lc o h o ls such as 28 w i t h p h e n y lse le n yI
c h l o r i d e in methylene c h l o r i d e a t -78°C a f fo r d e d the p h e n y lseleno
e th e rs , (30).
e th e r,
O x id a tio n o f 30 w i t h 30% H2O9ZTHF gave the a l l y l i c
( 3 2 ) , in 87% y i e l d .
Raney n i c k e l
Treatment o f the phe nylse le n o e t h e r w it h
in THF a t 25°C r e d u c t i v e l y removed the p he nylse leno group
to g iv e the b i c y c l i c e t h e r ,
(31_), in 95% y i e l d .
53
F ig u re 38.
N icolaou S y n th e sis o f B i c y c l i c E th e rs .
The mechanism f o r t h i s r e a c t io n was again p o s t u la te d to proceed
v ia an i n i t i a l
a t t a c k o f the h i g h l y e l e c t r o p h i l i c <j>Secl on the double
bond fo llo w e d by the in t r a m o le c u la r n u c l e o p h i l i c a t t a c k by the h ydroxyl
group, v ia 29.
R e a liz in g the im portance o f these e x p e rim e n ta l f i n d i n g s ,
the q u e s tio n we addressed o u rs e lv e s to was, can the a d d i t i o n o f <f>Secl
to d ih y d ro p y ra n c a r b in o ls produce a b i c y c l i c k e t a l , and, i f so, can we
in f a c t s y n th e s iz e b re v ic o m in .
C hapter 2
RESULTS AND DISCUSSION
Ic
The D i e l s - A ld e r r e a c t io n 0 o f I -b u te n e -3 -o n e gave 2 - a c e t y l - 6 m e th y l- 3 ,4 - d ih y d r o - 2 H - p y r a n in 85% y i e l d .
p r o p i o n y l- 6 - m e t h y l- 3 ,4 -d ih y d ro - 2 H -p y r a n
w it h a p p ro x im a te ly equal e f f i c i e n c y .
and Doud
17
21
The a c tu a l p r e p a r a t io n o f 2was accom plished in two ways
The f i r s t method was t h a t o f S to rk
which c o n s is te d o f th e fo r m a tio n o f the c y c lo h e x y li mine o f
2 3 , f o llo w e d by the a d d i t i o n o f e t h y l magnesium bromide which y i e l d s the
enamine, ( 23a) .
A l k y l a t i o n o f 23a w i t h methyl io d id e a t 0°C, fo llo w e d
by h y d r o l y s is w i t h one e q u iv a le n t o f 5% aqueous a c e t ic a c id gave 21_ in
81% y i e l d .
The second method in v o lv e d the d i r e c t a l k y l a t i o n o f the
p y r r o l i d i n e enamine, ( 2 4 J , a t O0C w i t h methyl i o d id e , aga in fo llo w e d by
c a r e f u l h y d r o l y s is w i t h one e q u iv a le n t o f 5% aqueous a c e t i c a c id t o g iv e
21_ in 88% y i e l d .
One must be c a r e f u l
in the a c id h y d r o l y s i s , o th e rw is e
Ig
the 2 - p r o p i o n y l - 6 - m e t h y l- 3 , 4 - d ih y d r o -2 H - p y ra n , (21_), r i n g w i l l open.
85
/
F ig u re 39.
S yn th e sis o f 2-P ro p io n y l- 5 - M e t h y l- 3 , 4 -D ih yd ro -2 H -
P yran.
The n o n - s t e r e o s p e c if ic r e d u c t io n
d ih y d ro -2 H -p y ra n ,
19
o f 2 - p r o p i o n y l- 6 - m e t h y l- 3 , 4 -
( 2 1 J , by sodium b o ro h y d rid e in is o p ro p y l a lc o h o l a t
O0C gave both isomers 2- ( 2- h y d r o x y e t h y l) - 6 - m e t h y l- 3 , 4 - d ih y d r o - 2 H - p y r a n ,
( 2 0 ) , in a 1:1 r a t i o ;
determ ined by g lc on 15% 0V-101 a t I l O 0C.
ment o f 20 w i t h I e q u iv a le n t o f p h e n y ls e le n y l c h l o r i d e a t -78°C in
T re a t­
86
methylene c h l o r i d e c o n t a in in g two e q u iv a le n t s o f potassium carbonate
gave 4 - p h e n y ls e le n o - 5 - m e th y l- 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ]octa ne ( 3 8 )
in q u a n t i t a t i v e y i e l d .
K e t a l i z a t i o n was evidenced by th e appearance o f
f o u r i n f r a r e d a b s o rp tio n s in the 1200-1050 cm ^ r e g i o n s , c h a r a c t e r i s t i c
o f c y c lic k e ta ls .
Both n u c le a r m agnetic resonance and mass s p e c tr a l
data su pp orted t h i s c o n c lu s io n .
Treatm ent o f 38^ w i t h a c t iv a t e d Raney
N icke l in THF a t room tem p era ture gave both endo and exo isomers o f
7 - e t h y l - 5 - m e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1]o c ta n e , ( Tj , in 92% y i e l d .
The
exo and endo isomer r a t i o was determ ined to be in I :1 by g l c a n a ly s is
on 5% SE-30.
O x id a tio n o f 38 w i t h 30% hydrogen p e ro x id e in THF a t room
tem p era ture w i t h p e r i o d i c c o o lin g gave th e expected p r o d u c t, 5-methyl 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1] o c t - 3 - e n e , ( 2 2 ) , in o n ly 29% y i e l d .
The
m ajor p r o d u c t . o f th e r e a c t io n was 5 - m e t h y l - 7 - e t h y l - 6 , 8 - d io x a b i c y c lo [3 .2 .1 ]o c ta n e -4 -o n e ,
( 3 9 ) , in 71% y i e l d .
C a t a l y t i c h y d ro g e n a tio n o f .22
w it h 10% Pd/C in e t h y l a c e ta te gave a 91% y i e l d o f I w i t h a 1:1 isomer
ra tio .
87
F ig u re 40.
Navel S y n th e tic Approach to B r e v icomin.
O x id a tio n o f 38 w i t h m -c h lo ro p e rb e n z o ic a c id in methylene
c h l o r i d e a t 25°C gave 2^2 in 86% y i e l d w it h an exo/endo isomer r a t i o o f
I :I .
In the o x i d a t io n r e a c t io n o f 4 - p h e n y ls e l e n o -5 -m e th y l- 7 - e t h y l 6 , 8 - d io x a b ic y c l o [ 3 . 2 . 1 ] o c t a n e w it h 30% hydrogen p e r o x id e , we can r a t i o n ­
a l i z e the fo rm a tio n o f 5 - m e t h y l - 7 - e t h y l - 6 , 3 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t- 3 - e n e
by th e syn e l i m i n a t i o n o f the s e le n o x id e , ( 4 0 ) , in the same fa s h io n as
those re p o r te d by Reich
a c id .
w ith c o n co m ita n t fo rm a tio n o f p h e n y ls e le n ic
88
■>
/
+ 0SeOH
0
Tl
n
F ig u re 41.
Reaction Mechanism f o r the Formation o f 5 - M e th y l- 7 E th y l-6 ,3 -D io x a b ic y c lo [3 .2 .1 ]o c t-3 -e n e .
The fo rm a tio n o f the m ajor p ro d u c t o f the r e a c t io n 39^ was
20
p o s tu la te d to be d e r iv e d from a Pummer-Iike ' rearrangem ent.
P rotona­
t i o n o f the s e le n o x id e g iv in g 41 which upon e l i m i n a t i o n o f w a ter gives
the Pummer in te r m e d ia te ( 4 3 ) .
H y d r o ly s is o f t h i s
in te r m e d ia te ,
f o llo w e d by a hydrogen t r a n s f e r to the p h e n y ls e le n id e g ives a species
which e v e n t u a ll y leads to H
20
39
OH
o
Ii
- H 2O
4l7|
n
n
F ig u re 42.
Reaction Mechanism f o r the Form ation o f 5 -M e th y l- 7 E th y l- 6 ,8 -D io x a b ic y c lo [3 .2 .I ]o c t-4 -o n e .
The r o l e o f the w a te r h y d r o l y s is in the Rummer rearrangem ent was
confirm ed w i t h the o x i d a t i o n o f 38 w i t h one e q u iv a le n t o f m -c h lo ro p e rbenzoic a c id which o n ly gave one p r o d u c t, 2 2 , in 36% y i e l d .
C hapter 3
EXPERIMENTAL
■
-
‘
■
P re p a ra tio n o f 2 - p r o p i o n y l- 5 - m e t h y l- 3 ,4 -d i.hydro-2H -pyran
T h is compound was prepared by two methods o u t l i n e d below.
Method A
15.0 grams (0.0 77 mole) o f the p y r r o l i d i n e enamine o f 2 - a c e t y l 6 - m e th y l- 3 ,4 -d ih y d ro - 2 H -p y r a n was placed in d ry benzene and cooled to
0°C.
W hile the m ix tu r e was s t i r r i n g under a n itr o g e n atmosphere, 11.00
grams (0.0 77 mole) o f methyl io d id e were added o v e r a p e r io d o f t h i r t y
m in u te s.
A f t e r s t i r r i n g f o r one hour a t O0C, the m ix t u r e was r e f lu x e d
f o r t w e n t y - f o u r h o u rs ;
a t the end o f which tim e th e s o l u t i o n was cooled
to O0C and h y d ro ly z e d by one e q u iv a le n t o f a 5% aqueous s o l u t i o n o f
a c e t ic a c id (4 .6 2 grams o f a c e t ic a c id in 87.9 ml o f w a t e r . )
This
m ix tu re was then a llo w e d to s t i r f o r 45 m inutes a t th e end o f which tim e
the s o l u t i o n was e x t r a c t e d w it h f o u r 100 ml p o r t io n s o f e t h e r which was
washed w i t h two 15 ml p o r t io n s o f sodium b ic a r b o n a te , d r ie d over anhy­
drous magnesium s u l f a t e , f i l t e r e d and the e t h e r removed under vacuum
v ia a r o t a t o r y e v a p o r a to r.
The re s id u e was vacuum d i s t i l l e d
to g iv e
10.44 grams o f a c o l o r l e s s l i q u i d , b .p . 84°C, 88% y i e l d .
>
Method B
20 grams (0.1 42 mole) o f 2 - a c e t y l- 6 - m e t h y l- 3 , 4 r d ih y d r o - 2 H - p y r a n
and 14.1 grams (0.1 42 mole) o f c y c lo h e x y l amine was placed in 200 ml o f
91
d ry benzene and r e f lu x e d w it h a Dean-Stark w a ter s e p a ra to r f o r tw e n ty f o u r hours a t the end o f which tim e the benzene was removed under
reduced pressure v ia r o t a t o r y e v a p o r a to r and the r e s id u e was vacuum d i s ­
tille d
to y i e l d 29.2 g o f a c l e a r l i q u i d , b . p . ^
95-96°C.
14 grams (0.0 63 mole) o f the c y c lo h e x y li mine o f 2 - a c e t y l - 6 m e th y l- 3 ,4 - d ih y d r o - 2 H - p y r a n were added to a s o l u t i o n o f 150 ml o f d ry
THF and 9.23 grams (0.069 moles) o f ethylmagnesium brom ide.
This s o l u ­
t i o n was r e f l u x e d f o r f i v e h o u rs , a t the end o f which tim e the s o l u t i o n
was cooled to O0C and 8.94 grams (0.0 63 m oles) o f methyl io d id e were
added o v e r a p e rio d o f one hour.
This m ix tu re was then a llo w e d to s t i r
a t room tem p era ture f o r t w e n t y - f o u r h o u rs .
The m ix tu re was then cooled
to 0°C and h y d ro ly z e d w i t h I e q u iv a le n t o f 5% aqueous a c e t i c a c id (3 .7 8
grams, in 71.87 m l) f o r t h i r t y m in u te s .
The m ix tu re was e x t r a c te d w i t h
f o u r 100 ml p o r t io n s o f e t h e r , washed tw ic e w it h 50 ml p o r t io n s o f 5%
sodium b ic a rb o n a te d r ie d o v e r magnesium s u l f a t e f i l t e r and the e t h e r was
removed under vacuum v ia r o t a t o r y e v a p o r a to r.
d is tille d
The re s id u e was vacuum
to y i e l d 81% o f a c o l o r l e s s l i q u i d , b .p . 84°C.
Products from both r e a c t io n s were i d e n t i f i e d by IR , NMR, UV and
mass s p e c tra d a ta .
A n a ly s is by g lc on 15% SE-30 a t I 30°C showed the
compounds to be i d e n t i c a l .
NMR Data
,
92
Chemical
S h i f t (<s)
Number
o f Protons
Nature
o f Peaks
10
1 .7
3
s in g le t
4
4.44
I
m u lt i p i e t
2,,3
1.92
4
m u lt i pi e t
I
4.16
I
m u ltip le t
8
2.5
2
q u a r t e t (J=7.2 H2 )
9
1 .03
3
t r i p l e t (J=7.2 H2 )
'
L R . . ( t h i n f i l m ) cm ^
2882, 1712, 1678; 1449; 1385; 1355; 1299; 1241; 1190; 1167; 1111; 1071;
929. 4; 3 9 9 .3 ; 8 1 5 .7 ; 751 .9.,
U.V. Data (cyclohe xane)
208(=2100) 281(=38) 1 5 5 (4 .2 ) ;;
1 5 4 (2 8 .1 ); 112
( 3 . 4 ) ; 1 1 1 ( 2 8 .6 ) ; 9 8 ( 1 1 . 1 ) ; 9 7 (1 0 0 ); 9 5 ( 1 8 . 2 ) ; 9 3 ( 1 0 . 1 ) ; 8 3 ( 1 1 .4 ) ; 81
( 1 3 . 4 ) ; 7 9 ( 1 6 . 2 ) ; 7 1 ( 1 1 . 1 ) ; 7 0 ( 1 6 . 0 ) ; 69 ( 3 2 . 1 ) ; 6 7 ( 1 4 . 6 ) ; 5 7 ( 1 6 .6 ) ; 55
( 3 6 . 2 ) ; 5 3 ( 1 9 .1 ) ; 4 3 ( 4 2 . 6 ) ; 4 1 ( 2 9 .3 ) .
C a lc u la t e d :
Found:
C 70.10%;
C 70.07%;
H 9.14%
H 9.35%
P re p a ra tio n o f 2 - ( 2 - h y d r o x y e th y l) - 6 - m e th y 1 - 3 ,4 - d ih y d r o - 2 H - p y r a n ( 20)
To a s t i r r e d s o l u t i o n o f 100 ml o f is o p ro p y l a lc o h o l and 14.0
grams (0.0 90 mole) o f , 2 - p r o p io n y l- 5 - m e t h y l- 3 ,4 -d ih y d ro -2 H -p .y ra n , which
was e x t e r n a l l y cooled to 0°C, was added 3.45 grams (0.0 90 mole) o f
93
sodium b o ro h y d rid e o v e r a p e rio d o f one hour.
The r e a c t io n m ix tu re was
a llo w e d to s t i r f o r two hours a t O0C a t the end o f which tim e 15 ml o f
20% aqueous sodium h y d ro x id e were added.
a d d itio n a l
S t i r r i n g was c o n tin u e d f o r an
two hours a f t e r which the s o l u t i o n was poured i n t o 200 ml o f
d i s t i l l e d w a te r and e x t r a c t e d w it h f o u r 100 ml p o r t io n s o f e t h e r , which
were combined, d r ie d o ver anhydrous magnesium s u l f a t e and the s o lv e n t
removed under reduced p ressure to y i e l d a re s id u e which was vacuum d i s ­
tille d
to y i e l d 12.19 grams (86%) o f a c l e a r c o l o r l e s s l i q u i d , b .p .
84°C.
Glc a n a ly s is on 15% 0V-101 a t I l O 0C showed the two a lc o h o l i s o ­
mers in a r a t i o o f 1 :1 .
NMR Data
M
Cr
6
9
i
OH
IO
11
4
2,3,8
1,7
Nature
o f Peaks
Chemical
S h i f t (6)
Number
o f Protons
1 .7
3
s in g le t
4.40
I
mul t i p l e t
I .1-2.2
6
m u ltip le t
3.18-3.71
2
mul t i p l e t
9
I .02
3
tr ip le t
10
2.98
I
broad s i n g l e t
94
I . R . Data ( t h i n f i l m ) cm~
3367; 2890; 1678; 1449; 1385; 1292; 1241; 1171; 1964; 9 8 0 .4 ; 943.3;
8 7 7 .2 ; 758.7
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
1 5 6 ( 1 8 .3 ) ; 1 4 1 ( 1 . 6 ) ; 1 2 7 ( 2 .1 ) ; 1 2 3 ( 1 . 2 ) ; 114 ( T l . 3 ) ; 1 0 9 ( 2 . 3 ) ; 9 9 ( 3 1 . 2 ) ;
9 8 ( 9 1 . 2 ) ; 9 7 (1 0 0 );
95 (3 3 ); 8 6 (2 1 .3 ); 8 5 (4 2 .6 ); 8 4 (5 2 .3 );.8 3 (1 0 .4 );
8 1 (1 3 .3 ); 7 9 (6 .3 ); 7 2 (1 2 .3 ); 7 1 (3 4 .3 ); 7 0 (7 .3 ); 6 9 (4 1 .3 ); 6 7 (8 .6 );
5 7 ( 1 3 .9 ) ; 5 5 ( 1 0 .3 3 ) ; 4 3 ( 6 1 . 4 ) ; 4 1 (1 2 .9 )
C a lc u l a t e d :
Found:
C 69.2%;
C 69.01%;
H 10.31%
H 10.61%
P re p a ra tio n o f 4 - p h e n y ls e le n o - 5 - m e th y l- 7 - s t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] octane (38)
A s o l u t i o n o f 100 ml o f d ry methylene c h l o r i d e and 8 .2 grams
(0.052 mole) o f 2 - ( 2 - h y d r o x y e t h y l) - 6 - m e t h y l- 3 , 4 - d ih y d r o - 2 H - p y r a n , ( 2 0 ) ,
and 20 grams o f anhydrous potassium carbonate was prepared and placed
in a 200 m l, th re e -n e c k e d ,ro u n d -b o tto m f l a s k equipped w i t h an i n j e c t i o n
septum, mechanical s t i r r e r and r e f l u x condenser.
The e n t i r e apparatus
was evacuated and placed under a n it r o g e n atmosphere surrounded by a
tem p era ture bath o f acetone and d ry ic e (-7 8 ° C ).
W hile s t i r r i n g , a
s o l u t i o n o f 10 ml o f d ry methylene c h l o r i d e and 10 grams (0.052 mole)
o f p h e n y ls e le n y l c h l o r i d e was i n j e c t e d .
The r e s u l t i n g o ra n g e -c o lo re d
s o l u t i o n was a llo w e d to s t i r a t -78°C f o r f o u r hours and then a t room
95
tem p era ture f o r 24 hours a t the end o f which tim e the r e a c t io n m ix tu re
was removed and f i l t e r e d .
The methylene c h l o r i d e was removed under
reduced p ressure v ia the r o t a t o r y e v a p o ra to r and then column chromato­
graphed on a 2.5 cm x 48 cm s i l i c a
w i t h methylene c h l o r i d e .
gel column which had been prepacked
The column was e lu te d w i t h methylene c h l o r i d e .
C o ll e c t i o n o f the compound and removal o f the methylene c h l o r i d e under
reduced p ressure v ia r o t a t o r y e v a p o ra to r l e f t a red o i l .
chromatography on s i l i c a gel
R^r 0 .712.
Thin la y e r
IB/CHgClg showed o n ly one compound p r e s e n t,
The y i e l d was q u a n t i t a t i v e .
NMR Data
,,
„
Chemical S h i f t (6)
Number o f Peaks
Mature o f Peaks
I .1-2.01
6
m u ltip le t
I
3.99
I
mu I t i p l e t
7
3.80
I
m u ltip le t
10
0.88
3
trip le t
11
1.35
3
s in g le t
12
7.48
2
mul t i p l e t
13
7.19
3
m u ltip le t
4
3.26
I
m u ltip le t
2 ,3 ,9
96
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
311(12.3% ); 269(6.3% ); 268(3.2% ); 253(16.3% ); 156(55.2% ); 155(12.3%);
126(6.7% ); 113(26%); 112(19.3% ); 97(32%); 34(19.3% ); 83(42.3% ); 66
(36.2% ); 43(100%); 41(17.4%)
O x id a tio n o f 4 - p h e n y ls e le n o - 5 - m e th y l- 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] octane w i t h 30% Hydrogen Peroxide .
In a 12 5 ml Erlenmeyer f l a s k equipped w i t h a m agnetic s t i r r e r ,
was placed 75 ml o f d ry THF and 4 .0 grams (0.012 moles) o f 4-phenyl s e le n o - 5 - m e th y l- 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . I ]o c ta n e .
added o ver a p e r io d o f 20 m inutes 1.36 ml
30% HgOg.
To t h i s was
(0.408 grams, 0.012 mole) o f
E x te rn a l c o o lin g became necessary d u r in g th e r e a c t io n to
m a in ta in 25°C.
A f t e r f o u r hours o f s t i r r i n g , the m ix tu r e was added to
250 ml o f d i s t i l l e d w a te r and potassium carbonate was added u n t i l a
b a s ic pH was m a in ta in e d .
The r e s u l t i n g s o l u t i o n was then e x t r a c te d
w i t h th re e 150 ml p o r t io n s o f e t h e r , d r ie d o ver anhydrous magnesium
s u l f a t e , f i l t e r e d and e t h e r removed under reduced p re s s u re v ia r o t a t o r y
e v a p o r a to r.
The r e s id u e was vacuum d i s t i l l e d to y i e l d two f r a c t i o n s :
(I)b .p .
64°C, which corresponds t o 22^ (29%);
68°C, which corresponds to 39^ (71%).
and ( I I )
b .p .
97
NMR Data: 5-m ethyl - 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t - 4 - o n e
Z
5- S O6
9
10
Chemical
S h i f t (6)
Number
o f Protons
Nature
o f Peaks
1 .1 -2 .0 4
6
mu I t i p l e t
I
3.97
I
mult i p l e t
7
3.70
I
mu I t i p l e t
10
0.90
3
trip le t
11
1.35
3
s in g le t
2 ,3 ,9
I .R . Data ( t h i n f i l m ) cm"^
2899; 1767; 1453; 1381; 1351; 1241; 1176; 1111; 1075; 1033; 970.9;
9 2 7 .6 ; 8 8 1 .1 ; 847.5
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
170(6.8% ); 154(7.1% ); 142(5.3% ); 128(6.33% ); 114(37.2% ); 99(8.4% );
98(22.3% ); 86 (2 1 .3 % ); 85(100%); 72(6 .1 % ); 71(12.3% ); 69(44.2% );
68(39.2% ); 58(13 .1% ); 57(24%); 5 5(12 .3% ); 43(91.2% ); 42(20%); 41(6.3%)
98
MMR D a ta : 5 - m e t h y l - 7 - e t h y l - 6 , 8 - d i o x a b i c y c 1 o [ 3 . 2 . I ] o c t - 3 - e n e (22)
3
4
2
I
O --------
6
7
y
I9
H
MO
Chemical
S h i f t (6)
3,4
2,9
5.66
I .30-2.81
Number
o f Protons
Nature
o f Peaks
2 ( v in y l)
m u ltip le t
4
mu I t i p l e t
I
4.08
I
broad s i n g l e t
7
3.64
I
mult i p l e t
10
0.90
3
trip le t
11
I .40
3
s in g le t
L R . Data ( t h i n f i l m ) cm ^
3050; 1642; 1385; 1194; 1179; 1109; 1036; 1014; 9 7 4 .4 ; 9 3 2 .6 ; 8 8 0 .8 ;
712
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
154(3.2% ); 127(3.6% ); 98(18.4% ); 86(32 .4% ); 85(39 .2% ); 56(19.4% );
114 (36.1% ); 43(100%)
99
P re p a ra tio n o f e x o / e n d o - 7 - e t h y l- 5 - m e t h y l- 6 , 8 - d io x a b i c y c lo [ 3 . 2 . 1 ] o c t a n e
111
In 200 ml o f d ry THF
was d is s o lv e d 4 .0 grams (0.0 12 mole) o f
4 - p h e n y ls e l e n o -5 -m e th y l- 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t a n e to which
was added 25 grams o f a c t iv a t e d Raney n i c k e l c a t a l y s t which was s t i r r e d
under n it r o g e n f o r 24 hours a t the end o f which tim e the c a t a l y s t was
removed from the r e a c t io n m ix tu re by f i l t r a t i o n , and the THF was then
removed under reduced p ressure v ia the r o t a t o r y e v a p o r a to r.
was then chromatographed on a 46 cm x 2.5 cm s i l i c a
The re s id u e
gel column prepacked
w it h methylene c h l o r i d e o f which s o lv e n t was used to e l u t e the column.
The purpose o f the column chromatography was to remove the p h e n yls e le n o l
which remains behind in the s i l i c a
g e l.
The methylene c h l o r i d e was
then removed under reduced p re ssu re v ia the r o t a t o r y e v a p o ra to r le a v in g
a l i g h t y e llo w r e s id u e which upon d i s t i l l a t i o n
c o l o r l e s s l i q u i d , b .p .
gave 1.72 g o f c le a r
( i g mm) 64°C, a y i e l d o f 91.8%.
Glc a n a ly s is on
15% SE-10 dem onstrated the two isomers o f 7 - e t h y l - 5 - m e t h y l - 6 , 8 - d io x a b i c y c l o [ 3 . 2 . 1 Joctane in a 1:1 r a t i o .
NMR Data
3
100
Chemical
S h i f t (6)
Number
o f Protons
Nature
o f Peaks
I
3.98
I
m u ltip le t
7
3.79
I
m u lt i pi e t
10
0.88
3
trip le t
11
I .38
3
s in g le t
8
m u ltip le t
2,3,4,9
1 .1 - 1 .9 8
.
L R . Data ( t h i n f i l m ) cm™^
2899; 1462; 1383; 1333; 1238; 1190; 1176; 1109; 1032; 1006; 9 70 .9;
9 2 7 .6 ; 9 0 0 .9 ; 880. .3; 8 5 1 .8 ; 782.5
Mass Spectrum m/e ( r e l a t i v e i n t e n s i t y )
156(4.7% ); 127(4.3% ); 114(28%); 9 9(6.3% ); 98(14.8%); 86(10.3% ); 85
(32%); 7 2(3.4% ); 7 1(7.8% ); 68(14.1% ); 57(10%); 55(6 .3 % ); 43(100%);
41(13.4%)
C a lc u la tio n s :
Found:
C, 6 9 .2 0 ;
C, 6 9 .1 7 ;
H, 10.31
H, 10.45
O x id a tio n o f 4 - p h e n y ls e le n o - 5 - m e th y l- 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] 0
octane w i t h m -c h lo ro p e rb e n z o ic a c id
To a s o l u t i o n o f 1 .0 grams (0.0032 mole) o f 4 - p h e n y ls e le n o -5 m e th y l- 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ]o c ta n e in 25 ml o f d ry methylene
c h l o r i d e was s lo w ly added w h ile s t i r r i n g a s o l u t i o n o f 0.63 grams
(0.0032 mole) o f m -c h lo ro p e rb e n z o ic a c id o ver a p e r io d o f 30 m in u te s ,
101
w ith p e r io d ic c o o lin g to m a in ta in the r e a c t io n tem p era ture a t 25°C.
A f t e r -one hour the r e a c t io n was stopped w i t h the a d d i t i o n o f 20 ml
o f 10% aqueous sodium s u l f i t e .
S e p a ra tio n o f the m ethylene c h l o r i d e
la y e r f o llo w e d by washing w it h th r e e 50 ml p o r t io n s o f 5% aqueous sodium
b ic a rb o n a te , d r ie d o v e r anhydrous magnesium s u l f a t e and removal o f the
methylene c h l o r i d e under reduced p ressure v ia the r o t a t o r y e v a p o ra to r
l e f t a re s id u e which upon d i s t i l l a t i o n
c o l o r l e s s l i q u i d b .p .
gave 0.42 grams o f a c l e a r ,
64°C which corresponds to the p r e v io u s ly
is o l a t e d 5 - m e t h y l- 7 - e t h y l- 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . 1 ] o c t - 3 - e n e in 86% y i e l d
by NMR, IR and mass s p e c t r a l d a ta .
H yd rog enolysis o f 5 - m e t h y l - 7 - e t h y l - 6 , 8 - d i o x a b i c y c l o [ 3 . 2 . I ] o c t- 3 - e n e (22)
0 .5 grams (0.0032 mole) o f 5 - m e t h y l - 7 - e t h y l - 6 , 8 - d io x a b i c y c lo [ 3 .2 .1 ] o c t- 3 - e n e was placed i n 50 ml o f r e d i s t i l l e d e t h y l a c e ta te w i t h
0 .5 grams o f 10% Pd/C.
This was then placed in a P a rr C a t a l y t i c
H ydrogenation apparatus under a hydrogen atmosphere o f 45 lb s .
A fte r
shaking a t room tem p era ture f o r 24 h o u rs , the r e a c t io n was stopped and
the c a t a l y s t f i l t e r e d from the r e a c t io n m ix tu re and the e t h y l a c e ta te
removed under reduced p re s s u re .
The rem a in in g re s id u e was d i s t i l l e d -
under vacuum to y i e l d 0.46 grams o f a c l e a r c o l o r l e s s l i q u i d , b .p .
64°C which was i d e n t i c a l
in NMR, IR , g lc and mass s p e c t r a l data ( I ) .
^
REFERENCES
REFERENCES
I.
W. D. Redard and D. I . Wood, M. C. B irc h Ed. "Pheromones, " American
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R.. M. S i ! v e r s t e i n , R. G. Brownlee, I . E. B e l l a s , D. I .
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R. M. Si I v e r s t e i n , J. Chem. E d . , 45, ?94 (1968 ).
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B. P. Mundy, K. B. L ip k o w itz and G. W. D ir k s , H e te r o c y c le s , 6, 51
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T. E. B e l l a s , R. G. Brownlee and R. M. S i ! v e r s t e i n , T e t r .
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H. C. Brown, P. J. Geoghegan, J. T. Kurek and G. J. Lynch, Q rg.
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B. P. Mundy, R. D. O tzenberger and A. R. D e be rn a rd is , J. O rg.
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K. C. N icolaou and Z. Lysenko, T e t r .
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V o l. I ,
MONTANA STATE UNIVERSITY LIBRARIES
3 1 762 1001 2 8 8 9 9
N378
Bornmann, William G
New synthetic
m e t h o d o l o g i e s for
B616
C O T ).
2
natural products
IS S U E D TO
DATE
n
J t f H a i t
.ife»
4
/ / = P / <4
/2 /
z z/
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