March 5 , 1957
SYNTHESIS OF A
THIOPHENE ANALOGO F
3a-Methyl-d3-trans-hexahydroindan (IV) .-The Clemmensen conditions described for the reduction of XXXVII were duplicated for the reduction of XLV. The attempt was equally unsuccessful. Using the procedure described immediately above, 0.95 g. (6.0 mole) of XLV, 1.2 g. of 857' potassium hydroxide and 0.9 ml. of hydrazine hydrate (857') in 8 ml. of diethylene glycol gave 0.48 g. (3.0 mole, 5lTO)of IV, b.p. 70" (21 mm.), ~ * S D 1.4669, d254 0.8923. Anal. Calcd. for C ~ O H I ~ DC, B : 85.02; H , 13.08; D/ H + D , 16.7; R Z 543.98. ~ Found: C , 85.33; H, 13.27; D / H f D , 15.8 =I= 0.2: R Z 6 ~ 43.92. , Reduction of XXVIII to XXIX and XXX with Lithium in Anhydrous Ammonia.-In a 2-1. flask insulated with rock wool and equipped with a mercury sealed stirrer, Dry Ice condenser protected with a soda lime drying tube, dropping funnel and nitrogen inlet were placed 500 ml. of anhydrous ammonia, and 55.56 g. (0.25 mole) of XXVIII (b.p. 146149' (1.5 mm.)) dissolved in 100 ml. of anhydrous ether. Ten and one-half grams (1.5 atoms) of lithium was added in small pieces over 0.5 hr. The usual blue color of alkali metalammonia solutions became evident only after an amount in excess of two equivalents of lithium had dissolved. The solution was stirred for 1 hr. after the addition of the metal, whereupon 81 g. of absolute ethanol was added dropwise over a period of 75 minutes followed by 70 g. of ammonium chloride. The ammonia was then allowed t o evaporate rapidly, the residue being treated with 250 ml. of ether and 100 ml. of water. A water-cooled condenser was utilized while the mixture was cautiously acidified with dilute ( 2 : 1) hydrochloric acid. The complete operation through the acidification was carried o u t with stirring under a slow stream of dry nitrogen. The aqueous phase from the acidified mixture was removed and extracted three times
[CONTRIBUTION FROM
THE
3-DESOXYISOEQUILENIN
1103
with 100-ml. portions of ether which were combined with the original organic layer and washed once with 50 nil. of water followed by half-saturated sodium bicarbonate solution until alkaline t o litmus. The ethereal solution was dried, concentrated on the steam-bath and finally distilled. The product boiling between 115-155' (0.3-1.0 mm.) was collected and weighed 31.5 g. This material was definitely composed of two substances easily separable by fractionation. However, infrared spectra showed the lower-boiling material to be mainly ketonic while the higher-boiling fraction was strongly hydroxylic and that little, if any, starting material was present. The distillate was dissolved in 70 ml. of acetic acid and added dropwise while cooling in ice t o 13.8 g. of chromium(V1) oxide dissolved in 280 ml. of acetic acid containing 7 ml. of water a t such a rate that the temperature did not rise above 30". The mixture was allowed t o stand a t room temperature for 1 hr., then 40 ml. of ethanol was added. After standing an additional 15 minutes, the mixture was poured into 1 liter of water and extracted four times with 100-ml. portions of petroleum ether (b.p. 30-40'). The combined extracts were washed with m-ater, half-saturated sodium bicarbonate solution until the washings were alkaline t o litmus, dried and concentrated on the steam-bath. Vacuum distillation resulted in 17.7 g. (0.08 mole, 327') of the mixture of X X I X and X X X , b.p. 120-123" (1.2 mm.). Anal. Calcd. for CI3H20O3:C, 69.61; H , 8.99. Found: C, 69.75; H , 8.91. From 1.12 g. of this product, 0.5 g. (38Yc) of semicarbazone was obtained. Two recrystallizations from 9570 ethanol raised the melting point t o 163-1645' dec. Anal. Calcd. for C14H21K308:C , 59.76; H , 8.24; K, 14.94. Found: C,60.14; H,8.23; IY,15.01. BROOKLYN, IYT~1vYORK
CHEMISTRY LABORATORIES O F FORDHAM UNIVERSITY
AND
SETON HALLUNIVERSITY]
Heterocyclic Analogs of the Estrogenic Steroid Hormones. I. Synthesis of a Thiophene Analog of 3-Desoxyisoeq~ilenin~~~ BY ROBERT J. COLLINS AND ELLISv. BROWN3 RECEIVED JUSE 21, 1956 A thiophene analog of 3-desoxyisoequilenin has been prepared. The required intermediate, 4-keto-1,2,3,4-tetrahydrodibenzothiophene, was prepared both by a modification of the synthesis of Buu-Hoi and Cagniant and by a new route. Application t o this material of an equilenin synthesis of Johnson gave the desired final compound. Along with the structural proof inherent in the synthesis both chemical and spectrophotometric evidence were considered. In the course of this work two new fused ring systems have been prepared for which are proposed both systematic and trivial names.
Replacement of the benzene ring in many physio- cyclic analogs of estrogenic steroid hormones, we logically active compounds by heterocyclic rings have undertaken to prepare a 3-desoxyequilenin often has led to interesting variations in activity analog in which a thiophene ring replaces the benand sometimes to antimetabolite behavior. Ap- zene "B" ring, cis and trans-16-cyclopentano[c]plications of this approach to the estrogenic hor- 10,11,12,13,14,15-hexahydro-12-methyldibenzothiomones have been limited to the synthetic estrogens,4 phene. The hitherto unknown cyclopentanoand although several active estrogens have been [ c Jdibenzothiophene system has been tentatively produced, no effective hormonal antagonists have assigned a numbering system which resembles that been obtained. of the steroid hormones. As part of a general program to prepare hetero0 (1) Supported in part by a grant in aid from the National Cancer Institute (C-1390) of the National Institute of Health, Public Health Service. (2) Presented a t the 125th meeting of the American Chemical Society, Kansas City, March, 1954. After this paper had been submitted to the JOURNAL, an abstract of a paper presented a t the 42nd Session of the Indian Science Congress, Baroda, January, 1955, came to our attention. This paper by R. B. Mitra and B. D. Tilak (J.Sci. Ind. Research, 14B, 132 (1955)) reaches the same conclusions as our work except that the 154.5' melting reduction product is reported to be the thiophene analog of 3-desoxyequilenin. (3) T o whom inquiries should be addressed, Chemistry Department, Seton Hall University, South Orange, N. J. (4) N. P. Buu-Hoi and H. Hoan, J . Org. Chem., 17, 350 (1952); W.P. Biggerstaff and 0. L. Stafford, THISJOURNAL, 74, 419 (1952); J. Sice and M. Mednick, ibid., 78, 1628 (1953).
I I C H 11~ A'+ 121
101
Of the three excellent syntheses of the equilenins which are a ~ a i l a b l e ,all ~ beginning with a sub( 5 ) (a) W. E. Bachmann, W. Cole and A. L. Wilds, ibid., 62, 824 (1940); (b) W. S. Johnson, J. W. Petersen and C. D. Gutsche, ibid., 69, 2924 (1947); (c) W. S. Johnson and V . L. Stromberg, i b i d . , 78, 505 (1950).
ROBERTJ. COLLINSAND ELLISV. BROWN
1104
V
VI
stituted ketotetrahydrophenanthrene, the first synthesis of Johnsonbb \\-as considered best suited to our requirements. The required intermediate, 4-keto-l,2,3,4-tetrahydrodibenzothiophene has been prepared6 by a succinoylation of thianaphthene, reduction of the resulting ketoacid and cyclization of the acid to the ketone. However, in our hands neither of the Friedel-Craft succinoylations6 gave the reported yields of P-(3-thianaphthoyl)-propionic acid and, because this product was formed along with the %isomer, separations were required which on a large scale became tedious. As an alternate route, 3-bromothianaphthene (prepared by the method of Komppa7 in 97y0 yields) was converted to the Grignard reagent which, when reacting with succinic anhydride, furnished the keto acid in 66y0 yield. This acid was reduced by a modification of the Clemmensen reduction of Buu-Hoi and Cagnito a 91% yield of y-thianaphthylbutyric acid. This in turn was cyclized t o the ketone, through the acid chloride, by a modification of the FriedelCrafts method of Cagniant and Cagniant6b in 95% yicld. The butyric acid also could be cyclized directly t o the ketone in 90Tc yields by a short treatment with commercial polyphosphoric acid. The ketone I could thus be obtained in an over-all yield of 57y0 from thianaphthene. Treatment of I with ethyl formate and sodium methylate gave a 97% yield of 3-hydroxymethylcne - 4 - keto - 1,2,3,4 - tetrahydrodibenzothiophene (111). When crude 11, as obtained from the reaction mixture, was treated with hydroxylamine hydrochloride, an 88% yield of 9,10-dihydrodiI~enzothiopheno-3,4-(d)-isoxazole (111), a representative of a new ring system, was obtained. The isoxazole was cleaved to 4-keto-3-cyano-1,2,3,4tetrahydrodibenzothiophene (IV) by the action of sodium methylate and this ketonitrile reacted i i 2 situ as the 3-sodio derivative to produce 4keto-3-methyl -3-cyano - 1,2,3,4-tetrahydrodibenzothiophene (V) in 77% over-all yield from the i soxazole. Stobbe condensation of V with diethyl succinate in the presence of potassium t-butylate furnished :in Slyo yield of ethyl 13,14-dehydro-16-cyclo( G ) (a) N. P. Buu-Hoi and P. Cagniant, Bcr., 76B, 1269 (1913); (11) P. Caxniant and M. Cagniant, BrlZ. soc. chim., 336 (1952). (7) 0. Komppa, J . p r a k t . Chcm., 192, 319 (1929).
VI1
Vol. 70
VI11
IX
pentano[ c ] - 12 -methyl - 10,11,12,13,14,15- hexahydrodibenzothiophene-14-carboxylate (VI) referred to in this paper as ethyl 3-desoxy-13,13-dehydrothiaquilenin- 14-carboxylate. Hydrolysis of the ciehydro-ester VI with bariuiii hydroxide gave 75% of the 3-desoxy-14,15-dehydrothiaquilenjncarboxylic acid (VII). I n alkaline solution the acid was oxidbed rapidly with the formation of a deep purple solution, and for this reason the hydrolysis was conducted under nitrogeii with the rigid exclusion of air. Decarboxylation of the acid VI1 with pyridine and hydrochloric acid produced a 91y0 yield of crude material melting a t 163-168" with some previous softening. Recrystallization from petroleum ether (90-100') furnished a 61(2 yield of a compound melting 173-174.3", found to be 3-desoxy13,14dehydrothiaquilenin (VIII) . The 14,l.j-dehydro compound, if present in the mother liquor, could not be isolated. The 13,14-dehydro compound VI11 purified by vacuum sublimation was hydrogenated a t rootn temperature and atmospheric pressure over 10% palladium-on-charcoal t o give a 95% yield of pink crystals. The product, m.p. 90 0-91.5', after recrystallization from methanol, was believed to be the cis compound IX. Attempts to obtain the trans form from this reaction were unsuccessful. Hydrogenations of VIIL over 30y0 Pd IC resulted in more rapid hydrogen absorption and gave 20% of the cis compound and 10% of a material, m.p. 131.0-142.5°, which could not be further purified. Reduction of VI11 over 30% Pd/C in the presence of a trace of hydrochloric acid, t o favor formation of the trans product, gave 37.5y0 of IX and 20yo of a crude material, m.p. 143.0-147.5". Repeated recrystallization of the latter compound raised the melting point to 154.0-154.5'. This product was shown to be polymorphic with the dehydro-compound VIII. Structural Proofs Ultraviolet Spectroscopy.-Assignment of the double bond in the Stobbe condensation ester VI a t the 13,14-position was based on the intense ultraviolet absorption at 320 mp (Fig. 1) which was believed t o be characteristic of such a thianaphthyl-Bacrylic acid system. This belief was substantiated when a model compound, methyl thia-
March 5, 1957
4.50
SYNTHESIS OF A
THIOPHENE ANALOGOF 3-DESOXYISOEQUILENIN
c
1105
1
..-\
4.50
4.00
ki M
3
3.50 I
220
260
300 340 MLI. Fig. l.-Ethyl-3-desoxv-13,14-deh~drotl~~aquile~~in-l4carboxylate, (VI) - - - -; methy-o-(2-thianaphthyl)acrylate (X) -. .-. ; 3-desoxy-13,14-dehydrothiaquilenin, (VIII) -. 220
naphthyl-2-acrylate, was prepared and was found to have an equally intense absorption a t 320 mp.
Of*;
. :. .. :.
\J\S/-C&CLCOOCHs €1 H
X
Hydrolysis of the dehydro-ester (VI) gave the acid VI1 which was completely lacking in strong absorption above 275 mp (Fig. 2), suggesting that the ethylenic bond had shifted to the 14,15-position. An a,@-unsaturatedketone of this type with a P-carboxy substituent has been estimated to absorb below 220 mp. Further evidence of the position of the ethylenic bond in VI1 is the remarkable resemblance (Fig. 2) of its absorption curve to that of the reduced compound I X . The ethylenic bond in VIII, the compound produced by decarboxylation of the acid VII, was assigned the 13,14-dehydro position because of the intense absorption a t 298 mp. The spectrum of the compound resembled that of ester VI and the model acrylic ester, except that the maximum had shifted probably due to the bathochromic influence of the ester groups. Analogous bond migrations have been shown to occur in the equilenin and 3-desoxyequilenin seriessb and in the 3-desoxy-6-methoxyequilenin series8 Infrared Spectra.-The correlation of infrared absorptions with specific structural features in steroids has been investigated extensively by Jones and associate^.^ Based on this background, structural assignments have been made for the (8) R . Hirschmann and W. S. Johnson, THIS JOURNAL, IS, 326 (1951). (9) R . N. Jones and H. Herlin, J . Org. Chem., 19, 1252 (1954).
260
300
340
mfi.
Fig. 2.-3-Desoxy-14,l~-dchydrothiaquileniii-l4-~arboxylic acid (1'11) -. , 3-desoxyequilenin thiophene analog (IX), -. , tliinnaphthene -
--
bands exhibited by the dehydrocompound VI11 and the desoxyisoequilenin analog IX (Table I). These assignments are compatible with the ethylenic bond positions determined from the ultraviolet spectra. The absorption of the keto group in VI11 a t 17413 cm.-' supported the assignment of the double bond a t the 13,14-position, P - 7 to the ketone. The predicted value for such a ketone would be 1752-1754 em.-' while a ring "D" ketone with an a,P-doublc In the hydrobond should absorb a t 1716 cni.-'. genation product IX (m.p. 91.5') carbonyl stretching occurred a t 1736 cm.-', in the normal range for steroids having a saturated ring "D." Identity of the 154.5" Reduction Product.-The ketone, m.p. 154.5', obtained by acid hydrogenation of VI11 showed an ultraviolet spectrum resembling that of VI11 particularly in the twinned absorption maxima a t 291 mp (log E 4.2) arising from a conjugated double bond. The infrared absorption spectrum resembled that of VI11 in major details, including carbonyl absorption a t 1749 cm.-', when crystalline material in KBr pills was examined. The spectra of VI11 and the 154.5" ketone became identical when carbon tetrachloride solutions were examined. Although the two forms had different melting points, a mixed melting point caused no depression. The foregoing evidence indicated that the 154.5' ketone was a polymorphic modification of the unchanged starting material VIII.
1106
ROBERTJ. COLLINSAND ELLIS V. BROWN
Experimental
VOl. 79
nitrile 1. \\as76.9Oj,. Repeated rccrj stalliL&tion from 15 parts methanol raised the melting point to 112.0-114.0" 4-Keto-1,2,3,4-tetrahydrodibenzothiophene (1).-@-(3(hexagonal plates). Thianaphthoyll-propionicacid68 was prepared in 66Yc yield A n a l . Calcd. for C I , H I I S S O : C ,ii9.69; H , 4.%!(5; S , from 3-bromothianaphthene,7 magnesium and succinic anhy- 3.81. Found: C,60.66; H , 4 . 6 0 ; S , 5 . 2 5 . dride in anisole a t 0", reduced by the Clemmensen method to \Vhen the meth5-lated compound Y \vas rccrystallizctl y(3-thianaphthyl)-butyric acid6bin 91 yo yield and cyclized from more concentrated solution, such as 10 parts of methato the ketone6b in 90y0 yield by the Friedel-Crafts process (SnClr) or with commercial polyphosphoric acid at 70-80". nol or less, it cr~-stallizedin a polymorphic modification as small platelets, m . p . 8.5-100". This form, when allowed t o 3-Hydroxymethylene-4-ket0-1,Z ,3,4-tetrahydrodibenzothiophene (II).-Ethyl formate, 5.4 g . (0.113 mole) and 6.1 stand under the mother liquor, reverted to the higher meltg. (0.113 mole) of commercial sodium methylate were dis- ing hexagonal plates in from 12 hr. to 7 clays. Ethyl 3-Desoxy-13,14-dehydrothiaquilenin-14-carboxylate solved in 132 ml. of dry benzene and the system flushed with dry nitrogen while connected to a mercury trap. T o this (VI) .--X 500-ml. three-necked flask with ground glass joints solution was added with swirling a solution of 10.3 g . (0.051 was fitted xvith a Hershberg wire stirrer and a special seal could function under reduced pressure. It was also inole) of compound I in 161 ml. of dry benzene. This ivas which :illowed to stand at room temperature for 5 hr. mith ncca- fitted with a reflux condenser, to the top of which vas COIIyional swirling (nitrogen passed in the first hour, mercury nccted a ?-way stopcock connected in turn to a source of nitrogen and vacuum. The apparntuh v,-its flame dried and trap connected through the entire period.) inole) of pijtassiuni metal and 60 .it the end of 5 hr. the greenish yellow precipitate \vas hy- charged with 1.1g . (0.0:36 ml.of dri- t-butyl a k l J h i ~ i .T h e flask was evacuated and fillctl drolyzed by the addition of 300 ml. of ice-water. .After with nitrogen and then refluxed gently until all the potu>complete solution of the solid, the organic layer was sepa- hium had dissolved' (:ihiiut 3 1ir.j. After cooling, nitrogen rated and n-ashcd with two 60-ml. portions of 5ycsodium hydroxide which were combined u-ith the original 300 ml. of al- v-as added to equalizi. r h c pressure. T h e flask w:ts tlieti with 4.11 g. (O.Ul66i n o k I o f the meth! 1 kekaline solution and the whole washed twice with ether. The quicklj- charged and 13.2 1111. ( I F tlictlij-l iuccirinte (0.08d niislc.). ;ilkaline solution was then slowl>- acidified with 6 S hydro- tonitrilc IT system was tlicn evacu:itid until tlic solvetit began ti! chloric acid with stirring and ice cooling. The yellow crys- Tlie talline powder was filtered, washed well with water arid air- boil, filled with nitrogcti anti allrxved to stir :it room teiiiper.iturc for 7 hr. .lftcr :30 iniiiutcs the solid rrieth\-l ketonitrilc dried. The yield a a s 11.4 g . (972C;.), m . p . 109.5-110.5°, had dissolved to fnrin a deep red solution arid after an addiri.itli slight previous softening. Recrystallization from cyclotioiial hour an orange precipitate appeared. hexane gave >-ellowrhombic crj-stals, m.p. 114.5-116.5". .After an elapsed time of 7 hr. t h e iriisture vias sIri\vl!. - 1 7 z i i l . Calcd. for ClaHloS02: C ,67.83; H , 4.35. I ~ o u n d : acidified with 35 ml. of dilute (1: 1) hydrochhric acid. DurC,(23.18; 13, 4.15. ing the acidification tlie orange precipitate dissolved and a yellow precipitate appeared with el-olution of carbon dios\\-hen t h e compound was erJ.stallized from ethanol-water, itle. Most of the alcohol \vas theii reiniived a t reduced pres< t polyin(irphic modification resulted, a reddish-bronm britsure, the residue taken u p in a mixture of benzene and ether, tle mass of crystals, m.p. 126.0-128.5". Recrystallization of this material from cyclohexane again produced the form, washed well Lvith water, twice with 5yc HC1, then thrcc times with KOH, then again ivith Jvatcr and the organic i11.1). 111.5116.5°. Both forms gave an olive-green color solution dried over sodium sulfate. wit11 rilcoholic ferric chloride. Evaporation of tlie solvciit undcr reduced pressure depos9,10-Dihydrodibenzothiopheno-3,4,(d)-isoxazole(111).Tlie hydroxymethylene ketone (11), 14.3 g. (0.062 mole), ited 4.38 g. (81.0ycjnf thc dehydro keto-ester 1.1 as orange needles, m . p . 150.j-1 ,j4.,5' with me previous softening. m . p . 109.L5-110.50, and 6.6g. of dry hydroxylamine hydrorts of cyclohexane gax'e chloride were dissolved in 350 ml. of glacial acetic acid. The Several recrystallizations fro the compound as y l l m v mi les , ni .p . lt54.O-1 ,55 .,5'. flask wits then introduced into an oil-bath preheated to 170" and maintained at this temperature. STithin 5 min.4nul. Caicd. for Clllils utes the mixture refluxed with much foaming and was then 0.84. Found: C , G!S.89; H?3.36; S,Il.SR. kept at reflux for 10 minutes. n'hile still hot, 150 ml. of In attempts to recrj-stallize the ester from nicthaiiol, tiehiding water was added to the mixture with swirling and composition occurred arid the ester could be recovered 011ly the whole then allowed to cool. Precipitation of the lustrous to the extent of 60-705. Evaporation of these mother liqt a n platelets began immediately. The mixture was cooled uors t o dryness ~-ieldecla red oil with a fruit>-odor which was :it .ifor o 2 1 hr. and then the product filtered, washed with a not further identified. little cold 257" acetic acid, then with a little cold water, The acid atid water iushiiigs m d rcsiducs from the abo1.i. \licked drl- and air dried. The jield was 12.4 g. (87.87,), reaction werc com1,incti and a n aliquot tested for nitrogen I)>iii.p. 130.?-149.3". This mnterial was of suflicient purity a modified Dumas method. It m-as found that about 869; for tlic liest jtcp. of the theoretical a i i i o u i i t of pi~ssiblci i i t r o g e ~ released ~ in the re:rctioti n-as presetit, .l7Zi//. Calctl. for C l i l l s S S O : C, 3-Desoxy-14,15-dehydrothiaquilenin-14-carboxylicAcid ti.lti. I'
