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.
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