Ring E degradation in the veratramine series

Ring E degradation in the veratramine series

463 RING E D E G R A D A T I O N IN T H E V E R A T R A M I N E S E R I E S ~ R i c h a r d W. F r a n c k , G e o r g e P. R i z z i and W i l l i...

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463

RING E D E G R A D A T I O N IN T H E V E R A T R A M I N E S E R I E S ~

R i c h a r d W. F r a n c k ,

G e o r g e P. R i z z i and W i l l i a m S. J o h n s o n

D e p a r t m e n t of C h e m i s t r y , S t a n f o r d U n i v e r s i t y , Stanford, California

Received August 3, 1964 Abstract N - C h l o r o v e r a t r a m i n e (I, R = C1), o b t a i n a b l e b y the a c t i o n of N - c h l o r o s u c c i n i m i d e on v e r a t r a m i n e (I, R = H), u n d e r g o e s a b a s e - p r o m o t e d f r a g m e n t a t i o n r e a c t i o n (see f o r m u l a C) to give the i m i n o a l d e h y d e D. A c i d - c a t a l y z e d h y d r o l y s i s of the l a t t e r a f f o r d s the a l d e h y d e II, w h i c h h a s b e e n d e g r a d e d to t h e m e t h y l k e t o n e HI. A similar ring E degradation sequence has been c a r r i e d out in the 5a, 6 - d i h y d r o v e r a t r a m i n e s e r i e s to p r o d u c e the a l d e h y d e IV a n d the k e t o n e V (R I = H, R z = -COCH3). Further degradation has been achieved by Beckmann reNOH a r r a n g e m e n t of t h e a c e t o x y o x i m e V (R 1 = Ac, R 2 = - 6 C H 3 ) to g i v e the a m i d e V (R 1 = Ac, R z = NHAc). A l k a l i n e h y d r o l y s i s of t h i s l a s t s u b s t a n c e a f f o r d s the a m i n e V (R 1 = H, R z = NH2) w h i c h h a s b e e n c o n v e r t e d , b y r e d u c t i o n of the d i a z o n i u m s a l t , i n t o the a l c o h o l V (R 1 = R z = H).

A s p a r t of a s t u d y a i m e d at the t o t a l s y n t h e s i s of v e r a t r a m i n e (I, R = H), we h a v e b e e n in s e a r c h of a f a c i l e m e t h o d f o r d e g r a d i n g the h e t e r o c y c l i c r i n g E to give a p r o d u c t w h i c h m i g h t s e r v e as a r e l a y s u b s t a n c e f o r c o m p a r i s o n w i t h t o t a l l y s y n t h e t i c m a t e r i a l as w e l l [email protected] f o r the r e - e l a b o r a t i o n of r i n g E.

T h e p u r p o s e of t h i s p a p e r is to

d e s c r i b e the r e a l i z a t i o n of t h i s o b j e c t i v e . In c o n s i d e r i n g the p r o b l e m a t h a n d , we n o t e d t h a t v e r a t r a m i n e

464

S T E R 0 I D S

4:4

CHO

HO

COCH3

HO H

is inert to periodic ment

of the amino

acid,

considered

proceeding

Another

formula

C,

dictable

from

shown

obvious

In considering

of the N-chloroamine,

the elimination

possible

moreover,

hydroxide

2 These

inappropriate.

B.

due to the antiparallel

functions;

ammonium

of products.

halogenation

and/or

presumably

and alcohol

tion of the quaternary zable mixture

HI

~ we

Hofmann

approaches

envisaged

was

involving

a fragmentation,

to give D,

Grob's

4 generalization.

N-Chloroamines

to be subject

decarboxylation

to fragmentation

of N-chloro

a-amino

reactions acids, s, 6

therefore

were

via dehydro-

the possibility

the imino

of elimination

degrada-

to an uncharacteri-

degradation

so as to produce mode

leads

arrange-

compound

of A

that depicted

of the type pre-

through

have the

been

in

Oct. 1 9 6 4

S T E R O I D S

465

A

B

C

D

Me

R

=

N-Chloroveratramine

(I, R = CI) w a s r e a d i l y f o r m e d b y s t i r r i n g

a s u s p e n s i o n of the a l k a l o i d in c h l o r o f o r m w i t h one m o l e - e q u i v a l e n t of N-chlorosuccinimide.

T h e c r u d e p r o d u c t w a s t h e n t r e a t e d in the c o l d

with s o d i u m methoxide.

A f t e r m i l d t r e a t m e n t w i t h a q u e o u s a c i d , in

o r d e r to h y d r o l y z e the i m i n e D, an o i l y p r o d u c t w a s o b t a i n e d , in 94% yield after chromatography,

w h i c h c r y s t a l l i z e d on s c r a t c h i n g but c o u l d

not be r e c r y s t a l l i z e d

from a solvent.

i n f r a r e d a n d n. m . r .

s p e c t r a l c h a r a c t e r i z a t i o n of t h i s c r y s t a l l i n e

product, m.p.

The c o m p o s i t i o n a l a n a l y s i s ,

144-148 °, c l e a r l y s h o w e d t h a t it w a s the a l d e h y d e II.

Its r e s i s t a n c e to r e c r y s t a l l i z a t i o n a n d f a i l u r e to f o r m n i c e l y b e h a v e d

466

S T E R 0 I D S

4:4

d e r i v a t i v e s i s u n d o u b t e d l y a s s o c i a t e d with t h e p r o b a b i l i t y t h a t the a l d e h y d e e x i s t s a s a m i x t u r e of e a s i l y i n t e r c o n v e r t i b l e Factors

C-20 epimers.

w h i c h m a y b e i n v o l v e d in f a v o r i n g t h e high y i e l d of the f r a g -

m e n t a t i o n c o u r s e of r e a c t i o n a r e (a) the r e l a t i v e l y high a c i d i t y of the alcoholic proton as compared

with t h o s e t h a t a r e a l p h a to the n i t r o g e n ,

(b) the p r o b a b l e d r i v i n g f o r c e f o r the I ~ p t u r e of the c a r b o n - t o - c a r b o n b o n d t h r o u g h the k e t o n i z a t i o n of the h y d r o x y l g r o u p , v and (c) the f a c t t h a t the s y s t e m s

c a n a d o p t the f a v o r e d g e o m e t r y f o r f r a g m e n t a t i o n . 4

Preliminary

experiments

have been carried

out on f u r t h e r

d e g r a d a t i o n of the a l d e h y d e II to the m e t h y l k e t o n e III. transformation

has been realized,

A l t h o u g h this

o p t i m u m conditions have not yet

b e e n w o r k e d out and the y i e l d i s p o o r .

O x i d a t i o n of t h e m o r p h o l i n e

e n a m i n e of I with s o d i u m d i c h r o m a t e in a c e t i c a c i d s a f f o r d e d 20% of recovered

a l d e h y d e and a 14%0 y i e l d of a n e w p r o d u c t ,

after purification. and n. m . r .

The compositional analysis,

spectral properties

w a s i n d e e d the k e t o n e III.

m.p.

ultraviolet,

1 4 8 - 1 5 0 °, infrared

c l e a r l y s h o w e d that t h i s l a t t e r p r o d u c t

A n o t h e r a p p r o a c h i n v o l v e d n i t r o s a t i o n of

the a l d e h y d e II with c o n c o m i t a n t c l e a v a g e to the o x i m e of III. 9 T h u s treatment

of the a l d e h y d e with s o d i u m m e t h o x i d e and n - b u t y l n i t r i t e

afforded alkali-soluble material

( c r u d e o x i m e ) in 50% y i e l d .

this f r a c t i o n it w a s p o s s i b l e to i s o l a t e a f o r m of the o x i m e , 253-255 ° .

From m.p.

T h e n e u t r a l f r a c t i o n f r o m the r e a c t i o n m i x t u r e a p p e a r e d

to b e the a c e t a l , was regenerated.

s i n c e on m i l d a c i d h y d r o l y s i s the s t a r t i n g a l d e h y d e When the n i t r o s a t i o n w a s p e r f o r m e d

in the p r e s e n c e

Oct. 1 9 6 4

S T E R O I D S

467

of s o d i u m n - b u t o x i d e in n - b u t y l a l c o h o l , w i t h the v i e w to r e t a r d i n g a c e t a l f o r m a t i o n , the a l k a l i - s o l u b l e f r a c t i o n a c c o u n t e d f o r 90% of the material.

H y d r o l y s i s of t h i s c r u d e o x i m e w i t h a q u e o u s h y d r o c h l o r i c

a c i d a f f o r d e d t h e k e t o n e III in o n l y 19% y i e l d .

It is s u s p e c t e d t h a t

s o m e of t h e o x i m e u n d e r w e n t B e c k m a n n r e a r r a n g e m e n t

and hydroly-

s i s to give t h e a m i n e l° w h i c h w a s l o s t in t h e a q u e o u s w a s h e s , b u t this possibility has not yet been studied.

/]"•CHO HO IV

V

A s i m i l a r d e g r a d a t i o n s t u d y h a s b e e n a p p l i e d to 5a, 6 - d i h y d r o v e r a t r a m i n e , zl T h u s t r e a t m e n t w i t h N - c h l o r o s u c c i n i m i d e f o l l o w e d b y s o d i u m m e t h o x i d e a f f o r d e d the c r u d e o i l y a l d e h y d e IV in 81% y i e l d . On t r e a t m e n t w i t h s o d i u m n - b u t o x i d e in n - b u t y l a l c o h o l , t h i s a l d e h y d e w a s c o n v e r t e d into a c r y s t a l l i n e o x i m e V (R I = H, R 2 = yield.

T h e p u r e s u b s t a n c e m e l t e d a t 239-241 °.

gOH

CHs) in 58%

H y d r o l y s i s of the

c r u d e o x i m e a f f o r d e d , in 65% y i e l d , c r y s t a l l i n e m e t h y l k e t o n e V (R I = H, R z = COCH3), m . p .

172-174 °, a f t e r p u r i f i c a t i o n .

In f u r t h e r d e g r a d a t i v e s t u d i e s the a l c o h o l V (R I = R z = H) w a s NOH ! p r e p a r e d a s f o l l o w s . T h e o x i m e V (R 1 = H, R 2 = -~CH3) w a s c o n v e r t e d ,

468

S T E R 0

by direct -

esterification,

CH3),

into the 3-acetoxy

oxychloride

compound

Rz = NHAc),

V (R 1 = Ac,

y i e l d of c r y s t a l l i n e

amide

sis of this product

afforded

m.p.

209-210.5 ° .

for the two steps

amide

acetate

w a s 73%.

The over-all

Alkaline

hydroly-

by reduction

of t h e

yield of crystalline

alcohol from

crude

w a s 53%.

10, 1 l b ~ - D i m e t h y l - 9 6a~, 1 laa, 1 lb-octahydroof 4.99

3~-hydroxy-

11H-benzo[a] fluorene

of chloroform

m.p. under

w a s a d d e d 1 . 6 8 g. o f N - c h l o r o s u c c i n i m i d e , at room

,

-(1 - f o r m y l e t h y l ) -

g. of v e r a t r a m i n e ,

a n d C o . ), in 100 m l .

30 m i n .

The over-all

i n t o t h e a l c o h o l V (R 1 = R z = H ) ,

Experimental

suspension

rearrange-

t h e a m i n o a l c o h o l V (R 1 = H , R z = N H z ) ,

salt with zinc and ethanol,

1 2 4 - 1 2 5 °.

Rz =

into the acetamido

2 3 5 . 5 - 2 3 7 °, w h i c h w a s in t u r n c o n v e r t e d ,

diazonium

V (R 1 = A c ,

by Beckmann

in p y r i d i n e , m.p.

4:4

compound

a n d t h i s in t u r n w a s t r a n s f o r m e d ,

ment with phosphorus

m.p.

I D S

temperature,

(II). -

an atmosphere m.p.

washed

sodium

over anhydrous

Penick

of nitrogen

148-150 ° .

the solution had become 30 r a i n .

dried

To a stirred

2 0 6 - 2 0 7 ° (S. B .

and was allowed to stand for an additional with water,

1, 2, 3 , 4 , 6, -

After

homogeneous

The solution was sulfate

and evapo-

Melting points were determined on a Kofler hotstage microscope. N. m . r . s p e c t r a w e r e d e t e r m i n e d u n d e r t h e s u p e r v i s i o n of D r . L . J . D u r h a m o n a V a r i a n A s s o c i a t e s A - 6 0 n. m . r . s p e c t r o m e t e r . Deuteriochloroform was employed as the solvent with tetramethylsilane as the internal reference. The chemical shifts are reported as 5-values in p. p . m . r e l a t i v e t o t e t r a m e t h y l s i l a n e = 0.

Oct. 1 9 6 4

S T E R O I D S

rated at reduced 0.1 ram.

pressure.

in o r d e r

anhydrous

to remove

of a b s o l u t e

for 1 hr.

traces

dioxane was added,

ice bath and stirred Z5 m l .

The residue

469

was dried for a while at

of chloroform;

and the suspension

t h e n 15 m l .

of

w a s c o o l e d in a n

w h i l e a s o l u t i o n o f 4 . 0 g. of s o d i u m m e t h o x i d e methanol

was added.

The mixture

was then stirred

a t Z5 °, at t h e e n d o f w h i c h t i m e t h e r e w a s n o c h l o r o a m i n e

remaining

as indicated by a negative test with starch-iodide.

A

s o l u t i o n o f 10 m l .

of concentrated

hydrochloric

water was added,

and the mixture

w a s a l l o w e d t o s t a n d at Z5 ° f o r

Z hr.

in

Water

was added,

organic layers

the mixture

were washed with water,

then dried over anhydrous evaporation

extracted

sodium

of the solvent under

graphed

on 175 g. o f F l o r i s i l .

benzene

amounted

a c i d in Z0 m l .

with ether,

and the

followed by saturated

sulfate.

reduced

The residue pressure

The fraction

on scratching,

(aldehyde C-H), 5.81 (C=O); k CSz

brine,

obtained upon

was chromato-

e l u t e d w i t h 4 - 8 % e t h e r in

t o 3 . 7 Z g. (94% y i e l d ) of c r u d e c o l o r l e s s

hyde which crystallized

of

m.p.

144-148°;

oily alde-

k CC14 3 . 7 4 max

3.74 ~, 5.81, 12. Z9, 12.69;

max

k

95% E t O H max

276 m ~ ( l o g ~

Anal. C, 81.85;

Calcd.

2.71),

267 ( 2 . 5 3 ) ,

f o r CzzH28Oz: C , 8 1 . 4 4 ;

254 ( 2 . 6 4 ) . H, 8 . 7 0 .

Found:

H, 8 . 5 . T h e n. m . r . s p e c t r u m

s i n g l e t a t 5 = 1 . 1 3 p. p . m . 1 . 3 3 (J = 7 c . p . s .

for 3 protons

as a

(CCH3), 3 p r o t o n s a s a d o u b l e t c e n t e r e d

) (CHCH3),

1 proton as an unresolved

showed absorption

3 protons

multiplet

at

a s a s i n g l e t a t Z. ZZ (ARCH,),

( q u a r t e t ) a t 5 . 4 3 (=CH),

Z protons

470

S T E R 0 I D S

4:4

a s an u n r e s o l v e d m u l t i p l e t ( q u a r t e t ) at 6 . 8 3 ( a r o m a t i c H), a n d 1 p r o ton as a d o u b l e t at 9 . 5 0 (J = 0 . 5 c. p. s. ) ( a l d e h y d e H). A l l a t t e m p t s to r e c r y s t a l l i z e solvents failed.

the a l d e h y d e f r o m v a r i o u s

The aldehyde readily formed a solid semicarbazone

a n d 2, 4 - d i n i t r o p h e n y l h y d r a z o n e w h i c h , h o w e v e r , c o u l d n o t be c r y s t a l l i z e d f r o m a n y of the s o l v e n t s e x a m i n e d . 9 - A c e t y l - 1 0 , 1 l b ~ - d i m e t h y l - 1 , 2 , 3, 4, 6, 6a~, 1 l aa, 1 l b - o c t a h y d r o - 1 1 H - b e n z o [ a ] f l u o r e n e (III). A__ z.

B y O x i d a t i o n of the E n a m i n e . 8

A m i x t u r e of 0 . 2 1 6 g. of t h e a f o r e m e n t i o n e d a l d e h y d e , 5 m l . of t o l u e n e a n d 0 . 2 m l . of m o r p h o l i n e w a s h e a t e d a t r e f l u x u n d e r an a t m o s p h e r e of n i t r o g e n f o r 2 h r . in an a p p a r a t u s e q u i p p e d w i t h a water separator.

The solvent was removed under reduced pressure

a n d the r e s u l t i n g c r u d e e n a m i n e , k 95% E t O H 265 m ~ (log c 3 . 9 6 ) , max film 6 . 0 bt (C=C-N), w a s d i s s o l v e d in 5 m l . of b e n z e n e ; t h e n a max s o l u t i o n of 0 . 4 0 g. of s o d i u m d i c h r o m a t e d i h y d r a t e in 2 m l . of a c e t i c a c i d a n d 1.6 m l . of b e n z e n e w a s a d d e d w i t h c o o l i n g . w a s s t i r r e d f o r 3 h r . at 0°;

The m i x t u r e

t h e n it w a s d i l u t e d w i t h e t h e r , w a s h e d

with water, followed by s a t u r a t e d brine and finally dried over anhydrous sodium sulfate.

T h e o i l y r e s i d u e o b t a i n e d on e v a p o r a t i o n

of t h e s o l v e n t a t r e d u c e d p r e s s u r e Florisil.

w a s c h r o m a t o g r a p h e d on Z0 g. of

T h e f r a c t i o n e l u t e d w i t h 5% e t h e r in b e n z e n e a m o u n t e d to

0 . 0 4 3 g. of c r u d e r e c o v e r e d a l d e h y d e .

F u r t h e r e l u t i o n w i t h 10-25%

e t h e r in b e n z e n e g a v e 0. 049 g. of c r u d e c r y s t a l l i n e k e t o n e , m . p . 150 °.

80-

R e c r y s t a l l i z a t i o n f r o m a c e t o n i t r i l e g a v e 0 . 0 3 0 g. of c o l o r l e s s

Oct 1964

rods,

S T E R O I D S

m.p.

A s a m p l e of t he s a m e m e l t i n g p o i n t w a s

148-150 ° .

obtained a f t e r two m o r e r e c r y s t a l l i z a t i o n s

Z59 m ~ (log~ 4.11);

471

k CHCI~

from acetonitrile,

k

95% E t O H max

5.95 ~, 6. Z4.

max

Anal. Calcd. for CzlHz6Oz: C, 81.25; C, 81.5;

H, 8.44.

Found:

H, 8.6.

The n. m. r. spectrum showed absorption for 3 protons as a s i n g l e t at 5 = 1 . 1 0 p . p . m .

(CCH3), 3 p r o t o n s a s a s i n g l e t at 2 . 3 8

(ARCH,), 3 p r o t o n s a s a s i n g l e t at 2 . 5 0 (CH3CO), 1 p r o t o n a s a n u n r e s o l v e d m u l t i p l e t ( q u a r t e t ) a t 5 . 4 8 (=CH),

1 proton as a doublet

c e n t e r e d at 6 . 9 0 (J = 8 c . p. s. ), and 1 p r o t o n a s a d o u b l e t c e n t e r e d at 7 . 4 0 (J = 8 c. p. s. ) ( a r o m a t i c H). W h e n t h e e n a m i n e o b t a i n e d f r o m 0. 090 g. of a l d e h y d e w a s treated for a 12-hr.

p e r i o d w i t h a r e a g e n t p r e p a r e d b y m i x i n g 0° 130 g.

of a n h y d r o u s c h r o m i c a n h y d r i d e and 1 . 0 m l . was obtained, after chromatography ketone, m.p.

1 2 0 - 1 5 0 °.

of d r y p y r i d i n e , ,z t h e r e

a s a b o v e , 0. 027 g. of t h e c r u d e

In a n o t h e r e x p e r i m e n t ,

of a l d e h y d e w a s t r e a t e d f o r a Z - h r .

e n a m i n e f r o m 0. 096 g.

p e r i o d with a r e a g e n t p r e p a r e d by

m i x i n g 0 . 2 5 0 g. of c h r o m i c a n h y d r i d e w i t h 2 m l . of p y r i d i n e ,

and in

t h i s c a s e 0. 031 g. of c r u d e k e t o n e w a s o b t a i n e d . B.

Via Nitrosation.

d e s c r i b e d 13 p r o c e d u r e

was used.

m e n t i o n e d a l d e h y d e in 2 m l . ice bath;

A m o d i f i c a t i o n of a p r e v i o u s l y A s o l u t i o n of 0. 090 g. of t he a f o r e -

of a n h y d r o u s m e t h a n o l w a s c o o l e d in an

t h e n 0 . 0 7 5 g. of a n h y d r o u s s o d i u m m e t h o x i d e w a s a d d e d ,

f o l l o w e d b y 0 . 2 m l . of n - b u t y l n i t r i t e u n d e r an a t m o s p h e r e

of n i t r o g e n .

47 2

S T E R O I D S

4:4

A f t e r s t a n d i n g f o r Z h r . at 0 °, t h e s o l u t i o n w a s d i l u t e d with e t h e r a n d e x t r a c t e d thoroughly with C l a i s e n ' s

a l k a l i . 14 T h e s e c o m b i n e d e x t r a c t s

w e r e chilled and kept cold while being c a r e f u l l y acidified with c o n c e n trated hydrochloric acid.

T h e m i x t u r e w a s t h e n e x t r a c t e d with e t h e r ,

a n d the c o m b i n e d o r g a n i c l a y e r s w e r e w a s h e d w i t h b r i n e a n d d r i e d over anhydrous sodium sulfate.

The c r u d e o x i m e of III o b t a i n e d u p o n

e v a p o r a t i o n of the s o l v e n t a t r e d u c e d p r e s s u r e poorly defined crystals,

m.p.

180-250 °.

a m o u n t e d to 0 . 0 4 5 g. of

Two recrystallizations

from

a b s o l u t e e t h a n o l a f f o r d e d 0o 015 g. of c o l o r l e s s r o d s w h i c h c h a n g e d to p l a t e s on h e a t i n g b e t w e e n 2 4 0 - 2 5 0 ° and t h e n m e l t e d at 250-255°o sample obtained by repeated recrystallizations

A

from absolute ethanol

melted at 253-255 ° . Anal. Caled° for CzIH27NOz: Found:

C, 77.2;

H, 8.45;

C, 77.50;

H, 8.36;

N, 4° 30.

N, 4.2.

The neutral ether solution remaining after the extraction with Claisen ts alkali was w a s h e d with water, followed by saturated brine and dried over anhydrous sodium sulfate. The oily residue amounted to 0. 054 g., k film 2.84 ~ (OH), 9.0 (ether C-O).

Since this product

max

appeared to contain acetal, it was w a r m e d

in a solution of 2 ml. of

dioxane, 0° 5 ml. of water and 0.5 ml. of concentrated hydroehlorie acid.

The product, which was isolated in the customary fashion by

ether extraction,

amounted to 0.045 g. of an oil, the infrared spectrum

of which was identical with that of the starting aldehyde. In another experiment,

a solution of 0o 080 g. of 53% sodium

O c t 1964

S T E R O I D S

hydride

in mineral

alcohol

was

hyde

added

II in i ml.

with 0.20

oil (Metal

ml.

with cooling

of n-butyl

temperature

solution

was

was

crystalline

oxime.

alcohol.

was

This 2 ml.

heated

with water, sodium

dissolved

of concentrated

with ether.

The

sulfate.

The

of the solvent

to 0.056

Ill as ascertained

elution with 5% ether

oxime,

crystalline ether

Finally, m.p.

fraction

in benzene,

yield of crude

210-240

ketone

10, 1 ib~ - D i m e t h y l -

was

of absolute

acid, added,

and the and the mix-

over

anhy-

pressure

was

was

chromato-

Further

0. 040 g. of ketone,

ether in benzene

upon

in

rich in the desired

chromatography.

m.p.

on

eluted with I% ether

gave

Rechromatography

g. of ketone,

was

in 20 ml.

and finally dried

on silicic acid yielded, 0.014

alkali, 14 and

washed

afforded

°.

The

were

fraction

elution with 10%

for 4 hr.

layers

g. of an oil which

in benzene

to stand at

(0. 182 g. ) obtained

reduced

by thin layer

then treated

allowed

organic

brine

The

was

to give 0. 277 g. of semi-

Water

oily residue under

g. of the alde-

hydrochloric

combined

by saturated

amounted

of crude

was

of n-butyl

with Claisen's

product

benzene

°.

extracted

above

on 15 g. of Florisil.

140-150

solution

as described

graphed

ketone

of 0.292

of nitrogen

at reflux for 3 hr.

followed

evaporation

This

in an atmosphere

isolated

containing

ture extracted

drous

to a solution

diluted with ether,

the product

solution

Inco ) in 5 ml.

of n_-butyl nitrite and the mixture

ice-bath

ethanol

Hydrides,

473

m.p. 0.029

g.

of the early nonelution with 5%

140-150

°.

Thus

the total

0. 054 g. 3~ - h y d r o x y -

9 - (1 - k e t o x i m i n o e t h y l ) -

i, 2, 3,4 -

474

S T E R O I D S

4:4

4aa, 5, 6, 6a~, l l a a , l l b - d e c a h y d r o - l l H - b e n z o [ a ] f l u o r e n e (V; R l = H, NOH R2 A Z. 1 4 - g . s p e c i m e n of 5a, 6 - d i h y d r o v e r a t r a m i n e , ii

_

=

m° p.

_

1 9 1 . 5 - 1 9 4 . 5 °, p r e p a r e d b y c a t a l y t i c h y d r o g e n a t i o n of v e r a t r a -

m i n e , ,1 w a s t r e a t e d with 0 . 8 2 g. of N - c h l o r o s u c c i n i m i d e

in 50 m l . of

c h l o r o f o r m j u s t a s d e s c r i b e d a b o v e in the e x p e r i m e n t with v e r a t r a m i n e . The c r u d e c h l o r o a m i n e

( 2 . 6 g. ) w a s t h e n d i s s o l v e d in 20 m l . of d i o x a n e

and 5 m l . of m e t h a n o l and t r e a t e d with 5 . 7 1 g. of s o d i u m m e t h o x i d e in 30 m l . of m e t h a n o l a s d e s c r i b e d a b o v e e x c e p t that the t e m p e r a t u r e w a s m a i n t a i n e d at 0 i n s t e a d of 25 °.

The product was hydrolyzed

w i t h 10 m l . of c o n c e n t r a t e d h y d r o c h l o r i c

a c i d and 20 m l . of w a t e r ,

a f t e r i s o l a t i o n a s d e s c r i b e d a b o v e , it w a s c h r o m a t o g r a p h e d of F l o r i s i l .

o v e r 30 g.

T h e f r a c t i o n e l u t e d with 5% e t h e r in b e n z e n e a m o u n t e d to

1 . 3 8 g. of c r u d e a m o r p h o u s

a l d e h y d e IV;

k CHC13 2 . 9 0 ~ (OH), 3 . 6 8 max

( a l d e h y d e CH), 5 . 8 1 ( a l d e h y d e C=O), 6 . 2 8 ( a r o m a t i c C=C); (c 1 . 3 1 ,

and,

CHCI~).

chromatography

This material

[a]~

+ 31 °

s h o w e d a s i n g l e s p o t on thin l a y e r

o v e r s i l i c a gel, Rf 0 . 5 0 (2:1 e t h y l a c e t a t e - b e n z e n e ) ,

b u t f a i l e d to g i v e a s a t i s f a c t o r y

compositional analysis after being

d r i e d f o r 12 h r . at 25 ° a n d 0 . 1 r a m .

(Found:

C, 7 8 . 6 ,

78.9;

H, 9 . 2 ;

9.0). J u s t a s d e s c r i b e d a b o v e f o r the v e r a t r a m i n e of 0. 555 g. of t h e c r u d e a l d e h y d e in 6 m l . with 15 m l .

case,

a solution

of n - b u t a n o l w a s t r e a t e d

of a s o l u t i o n p r e p a r e d b y d i s s o l v i n g 0 . 2 4 9 g. of 5 0 . 6 %

s o d i u m h y d r i d e (in m i n e r a l oil s u s p e n s i o n ) in 20 m l . of n - b u t a n o l . T h i s m i x t u r e w a s t h e n t r e a t e d with 0 . 3 0 m l . of n - b u t y l n i t r i t e .

The

Oct. 1964

S T E R O I D S

475

p r o d u c t , i s o l a t e d via C l a i s e n ' s alkalil%xtraction, a m o u n t e d to 0.320 g., m . p . Z08-Z27 °, with s o f t e n i n g at 190 °.

R e c r y s t a l l i z a t i o n f r o m 95%

e t h a n o l a f f o r d e d 0. 168 g. of c o l o r l e s s p l a t e s , m . p . 2 3 4 . 5 - 2 4 1 ° . R e p e a t e d r e c r y s t a l l i z a t i o n s f r o m the s a m e s o l v e n t gave m a t e r i a l , m . p . 239-241°;

k K B r 2.94 ~(OH), 6.13 (C=N), 11.0; max

[a]~+

36 °

(c 0.94, 95% ethanol). Anal. Calcd. f o r CzlHzgNOz: Found: C, 76.8;

H, 9.0;

C, 77.02;

H, 8.93;

N, 4 . 2 8 .

N, 4 . 0 .

The a l k a l i - i n s o l u b l e f r a c t i o n was c h r o m a t o g r a p h e d on 10 g. of Florisil.

The f r a c t i o n e l u t e d with 5% e t h e r in b e n z e n e a m o u n t e d to

0.17 g. of a m o r p h o u s m a t e r i a l .

Thin l a y e r c h r o m a t o g r a p h y on s i l i c a

gel (2:1 e t h y l a c e t a t e - b e n z e n e ) showed two m a j o r spots, one at Rf 0.50 ( s t a r t i n g a l d e h y d e ) and the o t h e r Rf 0.57 (possibly the n - b u t y l a c e t a l ) . 9 - A c e t a m i n o - 3 ~ - a c e t o x y - 1 0 , 1 i b ~ - d i m e t h y l - 1 , 2, 3, 4, 4aa, 5, 66a~,llaa, llb-decahydro-llH-benzo[a]fluorene

(V; R 1 = Ac, R z=

NHAc). - B e f o r e the o x i m e was s u b m i t t e d to B e c k m a n n r e a r r a n g e m e n t , the 3 - h y d r o x y l g r o u p was p r o t e c t e d by d i r e c t e s t e r i f i c a t i o n ,

A

slow s t r e a m of d r y n i t r o g e n was p a s s e d t h r o u g h a s o l u t i o n of 0. 082 g. of the aforementioned oxime, m.p.

234.5-241 °, in 8 ml. of acetic acid

(distilled f r o m triacetyl borate) for 5 rain. at 25 °.

The solution was

then saturated with hydrogen chloride and allowed to r e m a i n at 25 ° for 15 hr.

T h e mixture was then diluted with 100 ml. of benzene and

evaporated to dryness under reduced pressure at 70 °.

T h e residue

was ehromatographed on 5 g. of Florisil, and the fraction eluted with

476

S T E R O I D S

4:4

10-50% e t h e r in h e x a n e a m o u n t e d to 0. 083 g. of a c o l o r l e s s f o a m ; kCHC13 3 . 0 5 ~ ( o x i m e OH), 5 . 8 0 , max

8.10 (acetate).

Thin l a y e r chro-

m a t o g r a p h y on s i l i c a gel (2:1 e t h y l a c e t a t e - b e n z e n e ) s h o w e d two m a j o r s p o t s at Rf 0 . 6 8 and 0 . 6 2 ,

w h i c h p r e s u m a b l y w e r e the s y n a n d a n t i

f o r m s of the a c e t o x y o x i m e V (R 1 = Ac, R 2 = -CCH3). h y d r o x y o x i m e e x h i b i t e d a s i n g l e s p o t a t Rf 0 . 4 8 .

The s t a r t i n g

Since a t t e m p t s to

c r y s t a l l i z e the a c e t o x y o x i m e f a i l e d , the c r u d e p r o d u c t w a s u s e d d i r e c t l y in t h e B e c k m a n n r e a r r a n g e m e n t

a c c o r d i n g to a p r e v i o u s l y

d e s c r i b e d m e t h o d . 15 A s o l u t i o n of 0. 083 g. of the c h r o m a t o g r a p h e d a c e t o x y o x i m e in 1 m l . of a n h y d r o u s p y r i d i n e w a s s t i r r e d at 0 ° in an a t m o s p h e r e of n i t r o g e n w h i l e a c o l d s o l u t i o n of 0 . 5 m l . of p h o s p h o r u s o x y c h l o r i d e in 1.5 m l . of p y r i d i n e w a s s l o w l y a d d e d o v e r a 1 3 - r a i n . p e r i o d .

The

m i x t u r e w a s s t i r r e d f o r 3 h r . at 0 °, t h e n a d d e d d r o p w i s e to a b o u t 50 g. of i c e .

T h e m i x t u r e w a s a c i d i f i e d with 10 m l . of 10% h y d r o -

c h l o r i c a c i d , a n d the p r o d u c t e x t r a c t e d with e t h y l a c e t a t e .

The c o m -

b i n e d o r g a n i c l a y e r s w e r e w a s h e d t h o r o u g h l y with w a t e r , f o l l o w e d b y saturated brine, then dried over anhydrous sodium sulfate.

The brown

f o a m y r e s i d u e o b t a i n e d on r e m o v a l of the s o l v e n t a t r e d u c e d p r e s s u r e w a s c h r o m a t o g r a p h e d o v e r 5 g. of F l o r i s i l .

The f r a c t i o n e h t e d with

10% e t h e r in b e n z e n e a n d 100% e t h e r a m o u n t e d to 0. 067 g. of c r y s t a l l i n e a m i d e V (R I = Ac, R z = N H A c ) , at 190°o

m.p.

200-207.5 °, with softening

Recrystallization f r o m b e n z e n e - hexane afforded 0. 061 go of

colorless prisms,

m.p.

205-209 °.

Two

further recrystallizations

Oct. 1 9 6 4

S T E R O I D S

477

f r o m the s a m e s o l v e n t p a i r g a v e c o l o r l e s s c l u s t e r s of e l o n g a t e d p r i s m s , m.p.

209-210.5°;

k CHCI~ 5.81 ~, 8 . 1 0 ( a c e t a t e ) , 6 . 0 0 , max

[a]~

+ 29 ° (c 1 . 3 6 , CHC13). A n a l . C a l c d . f o r Cz3HslNO3:

Found:

C, 7 4 . 7 ;

H, 8 . 5 ;

C, 7 4 . 7 6 ;

6.65 (amide);

H, 8 . 4 6 ;

N, 3 . 7 9 .

N, 4 . 0 .

9 - A m i n o - 1 0 , 1 l b ~ - d i m e t h y l - 3 ~ - h y d r o x y - 1, 2, 3, 4, 4 a a , 5, 6, 6 a ~ llaa, llb-decahydro-llH-benzo[a]fluorene 0.174-g.

(V;

R I = H, R z = NHz). - A

s a m p l e of t h e a f o r e m e n t i o n e d a m i d e , m . p .

2 0 7 . 5 - 2 0 9 °, w a s

a d d e d to a s o l u t i o n of 1 . 4 6 g. of 85% p o t a s s i u m h y d r o x i d e in 7 m l . of e t h y l e n e g l y c o l , t h e n the m i x t u r e w a s h e a t e d at r e f l u x f o r 2 h r . in an a t m o s p h e r e of n i t r o g e n .

The n e a r l y c o l o r l e s s r e a c t i o n m i x t u r e was

diluted with w a t e r and e x t r a c t e d with ethyl acetate° o r g a n i c l a y e r s w e r e w a s h e d t h o r o u g h l y with water,

The c o m b i n e d followed by

saturated brine, and dried over anhydrous sodium sulfate.

The r e s i -

due o b t a i n e d on r e m o v a l of the s o l v e n t at r e d u c e d p r e s s u r e

amounted

to 0 . 1 4 0 g. of p a l e y e l l o w c r y s t a l s , at 212 °.

2 1 8 - 2 3 4 . 5 °, w i t h s o f t e n i n g

R e c r y s t a l l i z a t i o n f r o m 95% e t h a n o l a f f o r d e d 0. 077 g. of pale

yellow prisms, prisms,

m.p.

m.p.

m.p.

231-235 °.

225-231°,

An a d d i t i o n a l 0. 037 g. of c o l o r l e s s

w a s o b t a i n e d as a s e c o n d c r o p .

c r y s t a l l i z a t i o n s of the f i r s t - c r o p

Two re-

material gave colorless stout prisms,

m.p. 235.5-237°; k 95% E t O H 236 m ~ (log c 3.92), 290 (3.29); max

kKBr max

2.94 ~t (OH and NH), 6.14, 8.24 (amine); [a]~ + 29 ° (c 0.75,

95% ethanol). Anal, Calcd. for C19HzTNO: C, 79.95; H, 9.54.

Found:

478

S T E R O ID

C, 79.6;

S

4:4

H, 9.8.

i0, 1 I b ~ - D i m e t h y l - 3 ~ - h y d r o x y - I, 2, 3, 4, 4aa, 5, 6, 6a~, 1 laa, 11bdecahydro-I IH-benzo[a] fluorene (V; R I = R z = H).

- A modification

of a previously described procedure 16 w a s employed.

A suspension of

0. I13 g. of the crude a m i n o a l c o h o l V (R l = H, R z = N H 2 ) in 3 ml. of water w a s treated with I. 5 ml. of 4 8 % fluoboric acid.

T h e slurry of

a m i n e fluoborate w a s then stirred at 0 ° while 0.80 ml. of I. 03 M aqueous s o d i u m nitrite w a s added dropwise over a 5-rain. period. T h e mixture w a s stirred at 0 ° for an additional 15 rain. ; then the d i a z o n i u m salt w a s separated and w a s h e d once with water b y centrifugation.

T h e crude salt w a s dried for 30 rain. at 0 ° and 0.1 m m .

;

then 0. 654 g. of reagent grade zinc dust and 5 ml. of absolute ethanol w e r e added.

T h e mixture w a s heated at reflux for i. 8 hr. ; then it

w a s cooled, diluted with ethanol and ether, and filtered.

Concen-

tration of the filtrate u n d e r reduced pressure afforded 0.093 g. of a pale b r o w n glass w h i c h w a s c h r o m a t o g r a p h e d

on 5 g. of Florisil.

The

fraction eluted with 1 0 0 % benzene and 2 % ether in benzene a m o u n t e d to 0. 057 g. of colorless crystals.

Recrystallization f r o m hexane

afforded 0.040 g. o f l o n g c o l o r l e s s needles, m . p . additional 0. 012 g., m . p .

IZ4.5-126.5 °.

An

IZ0-1Z6.5 ° , w a s obtained as a second crop.

Recrystallization of the first-crop material f r o m hexane gave long colorless needles, m . p .

lZ4-1Z5°;

k 95% E t O H

Z65 m ~

(logo Z.76),

max

273 (2.74); k CHCI~ 2 . 9 0 ~ (OH), 6. Z9 ( a r o m a t i c C=C), 9 . 7 0 (C-O); max kCSz 12.75 ~, 13.24 13.99 ( s u b s t i t u t e d a r o m a t i c ring); [a]~ + 32 ° max

AJ

Oct 1964

479

S T E R O I D S

(c 1 . 0 8 ,

CHC13). A n a l . C a l c d . f o r C19Hz60: C, 8 4 . 3 9 ;

C, 8 4 . 5 ;

H, 9 . 6 9 .

Found:

H, 9 . 9 .

9 - A c e t y l - 1 0 , 1 l b ~ - d i m e t h y l - 1, 2, 3, 4, 4 a a , 5, 6, 6a~, l l a a , l l b decahydro-llH-benzo[a]

f l u o r e n e (V;

R 1 = H, R z = COCH3).

-

The

g e n e r a l m e t h o d of H e r s h b e r g 17 w a s e m p l o y e d f o r h y d r o l y s i s of t he o x i m e . A m i x t u r e of 0 . 0 4 7 g. of t he h y d r o x y o x i m e V (R 1 = H, R z = NOH - ~ C H s ) , m . p . 2 3 4 . 5 - 2 4 1 °, 0. 186 g. of 99% p y r u v i c a c i d , Z m l . of g l a c i a l a c e t i c a c i d a n d 2 m l . of w a t e r w a s h e a t e d a t r e f l u x f o r 3 h r . in a n a t m o s p h e r e

of n i t r o g e n .

The mixture was then made strongly

a l k a l i n e b y t h e d r o p w i s e a d d i t i o n of s a t u r a t e d s o d i u m h y d r o x i d e w i t h cooling.

S u f f i c i e n t 95% e t h a n o l w a s a d d e d t o r e n d e r t he s o l u t i o n h o m o -

geneous,

w h i c h w a s t h e n a l l o w e d to s t a n d f o r 20 m i n . at 25 °.

The

m i x t u r e was diluted with w a t e r and e x t r a c t e d with e t h e r .

The com-

bined o r g a n i c l a y e r s w e r e w a s h e d t h o r o u g h l y with w a t e r ,

followed by

saturated brine,

and d r i e d o v e r a n h y d r o u s s o d i u m sulfate.

The semi-

c r y s t a l l i n e r e s i d u e o b t a i n e d u p o n e v a p o r a t i o n of t h e s o l v e n t at r e d u c e d pressure with

was chromatographed

on 5 g. of F l o r i s i l .

The fraction eluted

5 - 1 0 % e t h e r in b e n z e n e a m o u n t e d to 0 . 0 2 9 g. of c o l o r l e s s

crystals. needles,

Crystallization m.p.

f r o m a c e t o n i t r i l e g a v e 0. 016 g. of c o l o r l e s s

167.5-173 °.

An a d d i t i o n a l 0 . 0 0 9 g . , m . p .

w a s o b t a i n e d as a s e c o n d c r o p . material

Two recrystallizations

afforded colorless needles,

m.p.

172-174°;

167.5-172.5 °,

of t h e f i r s t - c r o p k

95% E t O H max

ZlZ m ~ (log ~ 4. Z9), Z58 (4.05); k CHCI3 2.95 ~ (OH), 5.99 (conjumax

480

S T E R O I D S

g a t e d C=O), 6 . 2 9 ( a r o m a t i c C=C), 9o69 (C-O);

4:4

[a]~ +

39 ° (c 1.04,

H, 9 . 0 3 .

Found:

CHC13). Anal. C a l c d . f o r C21H28Oz: C, 80.73; C, 81.1; H, 9.2.

Acknowledgments We w i s h to thank the U. S. P u b l i c Health S e r v i c e and the N a t i o n a l S c i e n c e F o u n d a t i o n f o r a s s i s t i n g this s t u d y .

References .

2. .

A p o r t i o n of this w o r k has b e e n d e s c r i b e d in a p r e l i m i n a r y c o m m u n i c a t i o n : F r a n c k , R. W. and J o h n s o n , W. S . , T E T R A H E D R O N L E T T E R S , No. 9, 545 (1963). P e r s o n a l c o m m u n i c a t i o n f r o m D r . O. W i n t e r s t e i n e r . R u s c h i g , H . , F r i t s c h , W . , S c h m i d t - T h o m d , J . and H a e d e , W . , B E R . , 88, 883 (1955).

4.

Grob, C. A . , (1960).

5.

Langheld,

6.

van T a m e l e n , E. E. and H a a r s t a d , V. B . , L E T T E R S , 390 (1961).

7.

Cf. C l a y t o n , R. B . , H e n b e s t , H. B. and Smith, M . , J . CHEM. S O C . , 1982 (1957).

K.,

B U L L . SOC. CHIM. F R A N C E , 27, 1360

CHEM. B E R . ,

42, 2360 ( 1 9 0 9 ) . TETRAHEDRON

.

Cf. S h e p h e r d , D. A . , Donia, R. A . , C a m p b e l l , J . A . , J o h n s o n , B. A . , H o l y s z , R. P . , Slomp, G . , J r . , Stafford, J. E . , P e d e r s o n , R. L. and Ott, A . C . , J . AM. CHEM. S O C . , 77, 1212 (1955).

.

Cf. W o o d w a r d , R. B. and D o e r i n g , W. E . , J. AM. C H E M . S O C . , 67, 860 (1945).

i0. Cf. the rearrangement of the oxime of 2-methylacetophenone s i m p l y on t r e a t m e n t with a q u e o u s h y d r o c h l o r i c acid,

Oct. 1 9 6 4

S T E R O I D S

v. A u w e r s , K . , L e c h n e r ,

481

M. and B u n d e s m a n n ,

H., BER.,

58, 36 (19z5). 11.

Saito, K . , B U L L . C H E M . SOC. J A P A N ,

15, 22 (1940).

12.

P o o s , G. I . , Arth, G. E . , B e y l e r , R. E. and S a r e t t , L. H . , J . AM. C H E M . S O C . , 75, 422 (1953).

13. B i r c h , A. J . and L a h e y , F. N . , A U S T R A L . J . C H E M . , 6,

379 (1953). 14. F i e s e r , L. F . , " E X P E R I M E N T S IN ORGANIC C H E M I S T R Y , u D. C. H e a t h and C o . , B o s t o n , M a s s . , 1955, 3rd edition,

p. 310. •

r

15. S c h m l d t - T h o m e , J . , 16.

BER.,

Roe, A. and G r a h a m ,

J.R.,

88, 895 (1955). J. AM. C H E M . S O C . , 74,

6297 (1952). 17. H e r s h b e r g , E . B . ,

J. ORG. C H E M . ,

13, 542 (1948).

482