431

APPLICATION

OF THE WITTIG-HORNER Ernst

D.

of

Organic

Department Received:

Bergmann

REACTION

* and

Chemistry,

A.

TO STEROID

KETONES

Solomonovici

Hebrew

University,

Jerusalem

6/2/75 ABSTRACT

The applicability ketosteroids has been shown to exist. The has It

Wittig

been was

ketones react

with been

ref.

14).

studied

prepare

other

hand,

in

the

Mechoulam

(2,3)

of

at

the

we have

steroid

series

C6,C7,Cl7

differentiation,

They with and

C20 (II)

at

field

steroids,

of

dedicated

to

4/6/75.

his

because

memory

is of by

that

with of

the

his the

its

last

favorite other

well 4-13).

side

chains

the

(1). steroid

diketones This

method

(see

also

applicability

of

has by

been

Bose

and

(saturated) (I),

whilst

the

other

and

C20ketones

smaller

volume.

article

of

subjecta.This author.

as

(15,16),

only

C3,C17

Barton

saturated

especially

on

by

ref.

investigated

refractory;

reacts

one

also

phosphonoacetate

are

This

both

reaction,

concluded

1956

series,as

sporadically,

triethyl

probably

Deceased

only

a number of have been

(C6H5) 3P=CHR

in

unsaturated

recently

to

type

that

this

Wittig-Horner

systems

react

with

the first

(see

sterols

cyanomethylphosphonate

-

and

of

ketones,

3-ketones

(13,17,18).

3-ketosteroids

*

steroid

Sondheimer

to

other

co-workers

groups

various

reaction regularities

of

phosphoranes

triphenylphosphine-methylene used

to

Wittig-Horner A number

with

4,5-unsaturated

On the which

to

by

and

has

reaction

applied

found

of the studied.

E.D.

hand

keto diethyl without

Bergmann article

in is

the

S

432

T=EOXDb

H5C200C*CH2*;

(OC2H5) 2

NCCH2.;

(OC2H5) 2

0

0

I

II

p-NC ‘C6H4CH2$

(OC2H5) 2

(H5C20)

2CHCH2

‘$ (OC2H5) 2

b

0

III We have compounds

I

made and

a somewhat

II

diethyl

phosphonoacetaldehyde these

reagents

(pregnenolone estrone

more

extensive

were

in

and

study,

p-cyanobenzylphosphonate

diethylacetal

acetate,

(VIII)

IV

(IV).

the

first

line

V),

4-cholesten-j-one

androsterone

The

in

(III)

and

steroidal

addition

to

diethyl

substrates

for

3B-acetoxy-5-pregnen-20-one (VI),

5-cholesten-3-one(VII),

(Ix).

H O’..

0

The

using

phosphonate

5-cholesten-j-one conditions smoothly sodium

was with

hydride)

I

did

not

(VII) tried.

react

or

and

estrone

On the

phosphonate gave

I -

with

(VIII),

other in

after

pregnenolone although

hand,

DMSD or

acetate

hydrolysls

a large

androsterone

toluene -

(in the

(V),

(IX) the

acid

variety reacted

presence X,

of

characterized

of

S by combustion

analysis

It

222nm). steric

hindrance; in

Diethyl does

al 1 ready

of

sodium by

B-unsaturated

compound

(IX)

the

the

reaction

surprisingly to

the

in

is

(V)

to

in

yield

on

the

compounds

I,

dimethoxyethane

the

(18) from

at

noteworthy

carrying

of

known

III in

compound

the

same

giving

the

220nm, that

out

experiments

keto-aldehyde

XIV

conditions,

either

-

both

aidehyde

give

the

the

aompounds

acids.

combustion Recently

have

between

steroids

in

the

idene

The

analyses,

reaction

bufadienol

unlike

absorption It

series

corresponding their

for

based

and

IV,

the

XI

which

was

but

under

reactants

the

product

XII,

characteristic

Nagata

and

ofa,

Hayase react

Wittig-Horner

as

(21) ion

with

XIII.

of

reacted

explanation

analogously,

ultraviolet

recently

A further reaction

(II),

Dahi 11

reacted

nitriles. very

an explanation,

conditions.

Androsterone by

and

spectrum(Xmax.

observed.

(50%)

Bose

ultraviolet

sustain

no other

acetate

hydride

reaction

succeeded

we have

pregnenolone

and to

we have

reactivity

prepared

indicated

infrared

difficult

however,

with

different

433

cyanomethylphosphonate

react

presence

the

therefore,

is,

differences

and

WDEOIDrn

been

the

22).

with

only

the

to

and

the

otherwise

XV and

XVI

which

and

UV spectra

ester some

their the

of

W tt ig-Horner

or

-

to

somewhat

unreactive

were the

According

I.

group

keto

hydrolysed products,

to

group the

together

characterisation.

application

analogue

the

phosphonate

aldehyde

published

of

devoted

the

permitted

methyl

synthesis (21,

IR

was

of

of ester

14 CL bufadienolids

the I

Wittig-Horner

and

21

-

aldehyde

and

4(s)-dehydro-

with

EXPERIMENTAL The melting uncorrected.

points

are

determined

on a Bilchi

apparatus

and

are

3a-Hydroxy-5a-pregn-17-en-21-oic acid (X). A suspension of 0.369. of sodium hydride (50%) in 25 ml. of DMSO was heated at 800 in a nitrogen atmosphere until the evolution of hydrogen ceased, and solutions of 4.489. of triethyl phosphonoacetate (I) in 5 ml. of DMSO and of 1.459. of androsterone (IX) in 30 ml. of the same solvent were added. The mixture was heated at 1000 for 16 hours and poured into 150 ml. of water. The oily product was separated (1 .5g.), dissolved in 10 ml. ethanol and refluxed for 6 hours with 1.59. of sodium hydroxide in 15 ml. of water. The solution was acidified with cont. hydrochloric acid and the product (X) recrystallized from benzene; 1.39. (53%) of m.p. 257-25g”. A word should be said on the acid X. Marker and co-workers (19) , have synthesized by different routes both the 30. - and the 38 - isomer of the acid X and have indicated the melting points 232-235O and 24g”, respectively. We have no explanation of this discrepancy unless we assume that these authors did not succeed in obtaining the two acids in pure form; the roperties of our product are undoubtedly consistent with E g 222 nm (loge=4.13). formula X. A,:: ‘b/$L 3400 and 2940(free OH),

.

169O(carbonyl),

164O(c=C),

144O(C-O) ,

102O(C-C),

870(olefin=C-H)cm-1,

Ax

Calcd.

for

C2,H3203:

C,

75.9;

H,

9.7

Found:

C,

76.1;

H,

9.6.

~-Hydroxy-~-pregn-17-en-21-nitrile (XII). In the manner described in the preceding paragraph, starting with 0.969. of NaH, 3.549. of diethyl cyanomethlphosphonate (II) in 10 ml. tetrahydrofuran and 1.459 androsterone in 15 ml. DMSO and 15 ml. tetrahydrofuran were condensed 30 After dilution with 200 ml. of water, mins. at 800 and 12 hrs. at 25O filtration and recrystallization from cyclohexane, 1.49. (89%) of ound XII, m.p. 177-179O, was obtained. XEtoH 220nm (loge-4.13); ;iBe 3400 and 2940(free OH), 22lO(CaN), 163O’p@Z), 144O(C-0), 1l75(C-C) , l?;l%[C-C), 9lO(olefinic=C-H)cm-1. Am. H,

9.7;

Calcd. N,

for

C21H3,NO:

C,

80.5;

H,

10.0;

4.5.

Found:

C,

80.0;

4.7.

solution of - choladienonitrile(XI).A 3a - Hydroxy-23-nor-5,20(22) 3.549. of diethyl cyanomethylphosphonate in 5 ml. dimethoxyethane was added to a stirred suspension of 0.969. of sodium hydride (50%) in the same solvent; after one hour, 1.89. pregnenolone acetate (V> in 30 ml. of the same solvent was added and the mixture refluxed for 12 hrs. in an atmosphere of nitrogen and diluted with 150 ml. of water. The solid product was recrystallized from ace one and melted at 185-18i” (lit. 18): 186-187’); yield, 1.29. (63%). XEtdH 221 nm (logc=4 .O8) ; 3ia: 3400 22lO(CaN), 16lO(C=C), T@~(cH~). 117O(C-0 and / or bH), (free OH), g60(A22)cm-l.

H,

Anal. 9.6;,

Calcd. 4.1.

for

C22H33NO:

C,

80.7;H,

10.2;

N,

4.3.

Found:

C,

80.9;

- choladienate (XV, R = C,H ). The enolate, Ethyl 3-0x0-4,22 dimethoxyethane and prepared from 0.539. of sodium hydride in 25 ml. -b2.59. of triethyl phosphonoacetate (I) in 5 ml. of the same solvent, was brought to reaction with 3.619. of the ketoaldehyde XIV (purchased from by refluxing the mixture for Upjohn Co.) in 35 ml. of dimethoxyethane The product precipitated upon dilution with water; it was filtered, 8 hrs. dissolved in benzene and chromatographed on neutral alumina, benzene The ester XV (R=C H5) was recrystallized from ethanol serving as eluent. 3.49. P80%). When the reaction was carried and melted at l59-161°; yield, out in a DMSO-THF mixture as solvent, the yield of the ethyl ester was 82%. $,igH 218 nm (logs=4.l6)i 238 nm (logc=4.13). SKBr 2940(C-H), 1720 164o(c=c) ,yt50(CH3), 12OO(C-0), (car6oxyl ic C=O)221670(A -3 ketone), 104O(C-C) , ggO(A ), 875(olef inic=CH)cm-l . fi.

(0.59.) of lg.

Calcd.

for

C26H3803:

3-Oxo-4,22-choladienic acid was refluxed for II hours of potassium hydroxide in

C,

78.4;

H,

9.6.

Found:

C,

78.6;

H,

9.9.

(XV, R=H). The ethyl ester (XV,ReC2H5) of ethanol and a solution with 12 ml. The acidif ied product 10 ml. of water.

S

436

72DEOID1

was recrystallized from ethanol, m.p. 214-216O* ,&ed, 0.49. (87%). $$",H 220 nm (loge=2.20); 240 nm (loge=4.19).,.'$ 3450 and 2940 (carboxylic OH), 1700 (carboxylic C-O), 1670 (Aqa$etone), 164O(C=C), 1455(CH3), 124O(C-0), Y80(A22), 87O(olefinic=CH)cm-'. Anal.

Calcd.

for

C,

C24H3403:

77.8;

H, 9.2.

Found:

C,

77.6;

H, 9.0.

Ethyl 3-(carboxymethylene)-4,22 choladienate (XVI, R=C,H ). The best yield is achieved by the following procedure: The condensatTo * of 4.489. (0.02mole) ketoaldehyde XIV in 15 ml. DMSO and 15 ml. THF was carried out at room temperature (12 hrs.) in the presence of 0.969. (0.02mole) of sodium hydride (50%). After dilution with water, one obtained a mixture of solids which was dissolved in benzene and chromatographed on neutral alumina, the eluent being hexane-benzene (1:2). There were two distinct fractions, the second being XV (R=C2H5), m.p. 159-161°; yied 35%. The first fraction (XVI R=C H ) was recrystallized from ethanol; m.p. 1181200; yield, 41%. &OH $25 nm (logc=4.27); 280 nm (logc=3.92). S/,$i$$ 2150(C-H), 1750 andm$~20(carboxylic C=O) 1645(C=C), 1430(CH3), 1795(C-C), 104O(C-0 and/or OH), 995(A22), 870(olefiAic=CH)cm-1. Anal.

Calcd.

for

C30H4404:

C, 76.9;

H, 9.5.

Found:

C,

77.3;

9.2.

3-(Carboxymethylene)-4,22-choladienic acid (XVI, R=H). The ethyl ester (XVI, RaC2H ) (0.3g.) was hydrolysed by refluxing it for 8 hours with a solution o 3 0.89. of potassium hydroxide in 10 ml. of water. The product obtained by acidification with concentrated hydrochloric aci EgOWas recrystallized from methanol, m.p. 255-25 O; yield, 0.259. (96%). X, lBr 3400(free OH), 2Y50(C-i!Xor 213 nm (logc94.17); 278 nm (loge 4.29). amax free OH), 1700(carboxylic C=C), 1645(C=C), 1450(CH3), 124O(C-0), YYO(A22), 870(olefinic=CH)cm'l. REFERENCES 1.

Barton, 3500

D.H.R.,

Campos-Never,

A.S.

and

Cookson,

R.C.,

J.CHEM.

SOC.,

(1956).

2.

Sondheimer,

F. and

Mechoulam,

R.,

J.AMER.CHEM.SOC.,

79,

5029

(1956).

3.

Sondheimer,

F. and

Mechoulam,

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80,

3087

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Levine,

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Fagerlund,

6.

Idler,

7.

Bergmann,

W.

and

Dusza

8.

Bergmann,

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and

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S.G.,

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U.H.M.

D.R.

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and

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U.H.M.,

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(1958).

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6473

(1957).

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603,

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W.

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J.P.,

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E.P.,

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N.

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D.J.

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Haede, W., 149 (1971).

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