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Totally synthetic steroid hormones. XI. Observations on the condensation of 1-vinyl-1-tetralols with 2-alkylcyclopentane-1, 3-diones
309
TOTALLY SYNTHETIC STWOID HORMUNXS. XI.
1
OBSRRVATIONS ON THE CONDENSATION OF 1-VINYL-l-TEIRALOLSWITH 2-ALLXnCICLOPE~~-1,3-DlONES. D.P. Strike, T.Y. Jen, G.A. Hughes, G.H.
Douglas, and Herchel Smith
Research Division, Wyeth Laboratories Inc., Radnor, Pennsylvania
Received May 23, 1966
The condensation of a 6-oxygenated 1-vinyl-l-tetralolI (R=IiO, .
CH30, C6H5CH20, 2-tetrahydropyranyloxy-;R'=H) with a 2-alkylcyclopentane or hexane-1,3-dione to give the corresponding seco-steroid of type II has provided a highly efficient means of generating the correctly substituted carbon skeleton of estrone, D-homo-estroneand related struc2-7 tures.
This reaction is closely related, at least formally, to the
long-known condensation of l-phenylallyl alcohol and ethyl acetoacetate 8 in the presence of potassium acetate giving cinnsmylacetone which has been recently extended' to the preparation of precursors of a variety of diphenyls. Here we report findings bearing on its mechanism and the geometric structure of the products. We have previously found that the best yields of seco-steroidsof type II are obtained when the reaction is carried out in refluxing methanol with a trace of base,' generally potassium or sodium hydroxide or hydrogen carbonate. Using essentially these conditions, 75"80% yields of the seco-steroid II (R=CH30; Rl=H; R2=CH3; n=l), the precursor of estrone, can be obtained even on the pilot plant scalelo (Ku0 --• et al 7 have reported obtaining yields of no better than SO-60% in this reaction). The
STEROIDS
310
8:3
method fails with I-vinyl-l-tetralol I (R=Rl=H) and its 5-methoxy derivative I (R=H; Rl=C
0), but a reaction occurs between the former and 2l-3
ethylcyclopentane-1,3_dione
when the neat reactants are kept with or with-
11 out base at 150-170' for several hours, and between the latter and 2-methylcyclopentane-1,3-dione
in refluxing ethylene glycol.
The success of
the reaction in the absence of base has been recently confirmed.
7
We believe the foregoing results to be consistent with an anionotropic displacement mechanism similar to that associated with the rearrangements of l- to 3-phenylallyl
alcohols.
=,f3
In such processes the
ease and extent of the reaction is enhanced by electron release, particularly of the conjugative type, to the carbon which loses the hydroxyl. In the present examples, mesomeric release of negative charge to the lposition (naphthalene numbering) is possible with a 6- but not a 5-methoxy-1-tetralol.
We prefer to summarize the mechanism by the expression
III, in which the proton is derived from another molecule of the acidic dione.
14
Such an expression need not necessarily represent a fully con-
certed process.
An analogous expression, in which the enol form of the
dione is substituted for the enolate anion, can be written for the reaction in the absence of base. et al. --
After the formulation of our views, Kuo
reported that the reaction between I (R=CH30; R'=H) and e-methyl-
cyclopentane-1,3-dione
is acid catalysed, and presented evidence that
the reaction proceeds through an intimate ion-pair intermediate.
Since
reaction occurs in its absence, one beneficial function of the base may be to buffer the acidity of the dione (which is expected to approach acetic acid in acidic strength) and thereby limit the formation of by-products through decomposition of the acid-sensitive tetralol (cf.15). Such acid-sensitivity would be decreased by removal of the 6-methoxy group.
Sept. 1966
STEROIDS
311
16 Whitehurst has suggested that seco-steroids of type II are formed by simple displacement of hydroxide anion from the vinyl tetralol I by the cyclopentane-l,+dione enolate anion, whilst ascribing quite novel character to the overall reaction. Such a mechanism, in which an anion is displaced by one of much lower basicity in homogeneous solution, is excluded by the failure of the reaction between the alcohol I (R=CH30; Rl=H) and 2-ethylcyclopentane-1,3-dionein the presence of 1 mol. of base reported here, and of that between the same alcohol and 27 methylcyclopentane-1,3-dioneindependentlyobserved by Kuo -et al.
For
the condensation between the tetralol I (R=OH; Rl=H) and 2-methylcyclo2e pentane-1,3-dione,Torgov and his colleagues have suggested a mechanism involving loss of hydroxide ion followed by Michael addition of the dione to the resulting tetraenone IV, but this mechanism is not so satisfactorily applied to reactions involving the substrates I (&Rl=H, R=CH30; Rl= H,and R=H; R1=C%O) as that suggested here. Cyclization of the dione 6a If (R=H; Rl=CqO; R2=CH+ n=l) with hot ethanolic hydrochloric acid gave the expected pentaenone (V).
312
STEROIDS
8:3
&I I
m
Ho
Hb
P
R
P
Hb
Sept. 1966
STEROIDS
313
Seco-steroids of type II may theoretically exist with the Cll-proton 3yn- or anti- to the aromatic nucleus. Examination of a typical Dreiding model of II and of possible transition states for its formation suggests that the former configuration should be predominantly produced whether the reaction is thermodynamicallyor kinetically controlled. Evidence supporting this suggestion has been adduced as follows. Vinylic proton resonances occur as two doublets at 6 4.85 and 5.35 in the proton NMR spectrum of a preparation consisting mainly of the olefin VI (made through the Wittig reaction between 6-methoxy-1-tetraloneand methyltriphenylphosphoniumbromide). Proton Ha is nearer to the aromatic nucleus 18,19 and should therefore be the more deshielded; therefore, the foregoing two signals can be assigned to protons Hb and H ar respectively. These signals are to be compared with the multiplet centered at 6 5.73 that we found for the endocyclic vinylic proton in the known dihydronaphtha20 lene (VII).
Knowing that the NMR signals for the co-protonss-
and
anti- to the aromatic nucleus in styrene are shifted downfield by 0.5 and 0.6 ppm, respectively, in trans- and
propenylbenzene,respectively,18
it can be predicted that the signals for protons Ha and Hb in the alkylsubstituted derivatives VIII and IX should occur at 6 5.85 and 5.45, respectively. In fact, the vinyl proton in the mixture of diols X [made by lithium aluminum hydride reduction of the seco-steroid II (R=CH30; R1=H; R2=CH3; n=l)] occurs as a triplet-likemultiplet centered at 6 6.07, thereby clearly favoring a configuration for the seco-steroid in which the Cll-hydrogen is E-
to the aromatic nucleus. That the 9(11)-double
bond had remained intact in the preparation of the diol X (rather than having rearranged to the 8-position) is shown by the signal for the Clproton,which occurs as a doublet centered at 6 7.52. This signal is to
STEROIDS
314
8:3
to be compared with those for the C ll-proton in the precursor and the analogous C -proton (naphthalene numbering) in the dihydronaphthalene
4
VII, which occur as doublets centered at 6 7.39 and 7.14, respectively. The dione II (R=CH30; Rl=H; R2=C H3; n-l) was deemed unsuitable for comparison because of its capability of existing in conformations in which the diamagnetic anisotropic effect of the carbonyl groups could seriously influence the NMR resonance signal of the Cll-proton, and it is notable that this signal occurs as a triplet-like multipl&t at 6 5.65 in the dione II (R=C?O;
R1=H; R2=CH3; n=l) and as a similar multiplet at 6 5.82 in
the corresponding ketol II (R=CH30; R1=H; R2=CH ; n=l).
21
3
ACKNOWLEDGEMENT
We thank Dr. H. Gibian and his colleagues, Schering AG, Berlin, for providing a manuscript of their paper before publication.
EXPERIMENTAL
22
~-Methox~-8,1~-secoestra-1,3,5(10),9(11)-tetraene-1~,17-dione II (R=H; Rl=CH 0; R2=CH ; n=l). - 5-Methoxytetralone (1.14 g.) in tetrahydrofuran (15 m 2 .) was aaded to vinylmagnesium bromide in tetrahydrofuran (25 ml. of 1.2M) and the mixture refluxed for 3.5 hr. The cooled mixture was diluted with water and extracted with ether. The extract was washed successively with 2N HCl and water, dried, and evaporated to give the crude 5-methoxy-1-vinyl-1-tetralol (1.26 g.). An aliquot (0.83 g.) was stirred under N2 with 2-methylcyclopentane-1,3-dione (0.82 g.) and potassium hydroxide (0.1 g.) in ethylene glycol (5 ml.) at 150' for 2 hr. Water was added to the cooled solution, the mixture was extracted with ether, and the ether solution was washed successively with 5% aqueous RHCO and water, and dried. The product was chromatographed on neutral a4 umina, elution with benzene-hexane (1:3) giving material which was recrystallized twice from hexane-acetone to give the dione (0.25 g.), m.pRBJ3-75". The analytical sample (from acetone-hexane) had m.p. 83-84*, &,,,x 5.82, 6.38, 7.95 p; hax 224 and 261 rnp (s 27,600 and 12,500). w. 7.71.
Calcd. for ClgHi203: C, 76.48;H, 7.43. Found: C, 76.24; H,
Sept. 1966
STEROIDS
315
(f)-4-Methoxyestra-1,3,5(10),8,14-pentaen-17-one (V). - The foregoing dione (.19 g.) was refluxed in ethanol (10 ml.)-1lN HCl for 1 hr. The cooled solution was diluted with water and the product extracted mm. followed by three recrywith ether. Sublimation at 180-200cj/o.1 stallizations from hexane-acetone gave pink crystals, which were sublimed at 130014O'b.l rmn.to give the pentaene (.036 g.), m.p. 155-157'; hXBr 5.76, 6.27, 6.40, 7.95 IJ~; hax 230, 247, 297, 307, and 320 9 (:?7,900, 9,900, 21,600, 24,300, and 16,600). &. 7.12.
Calcd. for ClgH2002: C, 81.39;H, 7..19.Found: C, 81.48; H,
6-Methoxy-l-methylene-1,2,3,4tetrahydronaphthaleneVI. - Butyl lithium in hexane (38.5 ml. of 15.2% I/W> was added under nitrogen, with stirring, to methyltriphenylphosphoniumbromide (35.7 g.) in ether (0.5 1.). Stirring was continued at 25O for 3 hr. and to the resulting suspension was added 6-methoxy-1-tetralone(10 g.) in ether (200 ml.). The mixture was stirred for 4 hr. and kept at room temperature overnight. Most of the ether was evaporated, tetrahydrofuran (300 ml.) was added, and the mixture refluxed for 2 hr. Ether was added to the cooled mixture, which was washed with water, dried and evaporated. Distillation of the residue gave the crude olefin (1.4 g.), b.p. 80-82°/o.05 mm.; Lax 265 rnp (a 13,700); NMR: 3 proton singlet 6 3.76 (OCH3), 0.8 proton doublets 6 4.85 and 5.35 (:CH2, J=1.5 cps. for both), 0.8 proton doublet 6 7.59 (C, - H; J=8 cps). Gas-liquid chromatography,run using a Perkin-Elmer Vapor Fractometer Model 154-C with a sample in CH2C12 at a flow rate of 24 ml/&n. of He on a 2-meter column (external diameter 0.25 in.) at 220' packed with Celite containing 3% I& fluorosilicone QF-1 as stationary phase, showed the product to contain 82% of pure VI (retention time 3 min., 9 sec.) with two other components, one estimated at 11% (retention time 2 min., 9 sec.) and the other at 7% (retention time 10 min.). m.
Calcd. for C=Hl40: C, 82.72;H, 8.10. Found: C, 82.28;H, 8.33.
(+) 3-Methoxy-8,14-secoestra-1,3,5(10),9(ll)-tetraen-14~,17~-d~~ls. - ~)~3~methoxy-8,14-secoestra-1,3,5(10),9(11)-tetraen-14,17-dione (2 g.) was refluxed for 2 hr. with lithium aluminum hydride (1 g.) in tetrahydrofuran (100 ml.). The excess of reducing agent was decomposed by adding ethyl acetate, water was added and the mixture extracted with ether. Distillation of the ;T$ct at 200' (bathfi.2 mm. gave the H. mixture of diols as a gum; Amax 3.00 p with no absorption in the 5.75 )I region; NMR: singlets at S 0.78 and 0.94 (Cl3 - CH3), singlet at 6 3.76 (OCH3) triplet-likemultiplet centered at 6 7.52 (Cl - H; J=8 cps). Anal. Calcd. for Cl9H2603: C, 75.46;~, 8.67. Found: C, 75.37;H, 8.42.
REFERENCES
1. Part X. Buzby, G.C., Jr., Walk, C.R., and Smith, H., J. MED. CHJZM., in the press.
316
STEROIDS
8:3
2. (a) Ananchenko, _ ._ S.N., and Torgov, I.V., DOKL. AKAD. NAUK SSSR., 127, 553 (1959); (b) Ananchenko, S.N., Leonov, V.N., Platonova, A.V., ana. Torgov, I.V., IBID., 135, j3 (1960); (c).Ananchenko,S.N.; Limanov, V.Y., Leonov, V-N., Rzheznikov, V.N., and Torgov, I.V., TETRAHEDRON, l8, 1355 (1962); (d) Ananchenko, S.N., Torgov, I.V., T~RDRON LEITERS, 1553 (1963); (e) Zakharychev, A.V., Ananchenko, S.N., and Torgov, I.V., STEROIDS, 3, 31 (1964). 3. Crispin, D.J., and Whitehurst, J.S., PROC. CHEM. SOC., 22 (1963). 4. Miki, T., Hiraga, K., and Asako, T., IBID., p. 139. 5.
Windholz, T.B., Fried, J.H., and Patchett, A.A., J. ORG. CHEM., 28, 1092 (1963).
6.
(a) Douglas, G-H., Graves, J.M.H., Hartley, D., Hughes, G.A., McLoughlin, B.J., Siddall, J., and Smith, H., J. CHEM. SOC., 5072, (1963); (b) Smith, H., Hughes, G.A., Douglas, G-H., Hartley, It., McLaughlin, B.J., and Siddall, J.B.; Wendt, G.R., Buzby, G.C., Jr., Herbst, D.R., Ledig, K.W., McMenamin, J.R., Pattison, T.W., Suida, J., Tokolics, J., and Edgren, B.A.; Jansen, A.B.A., Gadsby, G., Watson, D.H.R., and Phillips, P.C., EKPERIENTIA,l9, 394 (1963); (c) Smith, H., Hughes, G.A., Douglas, G.H., Wendt, G-R., Buzby, G-C ., jun., Edgren, B.A., Fisher, J., Foell, T., Gadsby, B., Hartley, D., Herbst, D., Jansen, A.B.A., Ledig, K., McLaughlin, B. J-, McMenamin, J., Pattison, T.W., Phillips, P.C., Rees, R., Siddall, J., Siuda, J., Smith, L.L., Tokolics, J., and Watson, D.H.P., J. CHEM. XX., 4472 (1964).
7.
Kuo, C.H., Taub, D., and Wendler, N.L., ANGEW. CHEM., 77, 1142 (1965).
8.
Carroll, M.F., J. CHEM. SOC., I.266(1940).
9.
Colonge, J., and Brunie, J-C., COMPT. REND., 253, 2709 (1961).
10.
Private co~nication from Dr. C.C. Christman, Development Division, Wyeth Laboratories Inc., West Chester, Pennsylvania.
11.
Hughes, G.A., and Smith, H., Belgian Patent 632,348 (1963), priority from May 16, 1962.
12.
Ingold, C.K., "Structure and Mechanism in Organic Chemistry," G. Bell and Sons Ltd., London, 1953, pp. 590-591.
13. de la Mare, P.B.D., in nMolecular Rearrangements," edited de Mayo, P ., Interscience Publishers, New York, 1963, pp. 76-80. 14‘ This mechanism was considered in lectures given by one of us (H.S.) to the Philadelphia Section of the American Chemical Society, November 15, 1962 and to the Section of Chemical Sciences, New York Academy of Sciences, January 5, 1965.
Sept. 1966
STEROIDS
317
15. Robins, P.A., and Walker, J., J. CHKM. SOC., 3249 (1956). 16. Whitehurst, J.S., ANN. REPT. PROGR. CHEM., 60, 426 (1963). 17. Eschenmoser, A., Schreiber, J., and Julia, S.A., HRLV. CHIM. ACTA, 9, 482 (1953). 18. Pople, J.A., Schneider, W.G., and Bernstein, H.J., "High Resolution Nuclear Magnetic Resonance," McGraw-Hill, New York, 1959, p. 239. 19. Rottendorf, H., Sternhell, S., and Wilmshurst, J.R., AUSTRALIAN J. CHKM. 18, 1759 (1965). 20. Stork, G., Meisels, A., and Davies, J.E., J. AMER. CHRM. SOC., 85, 3419 (1963). 21. Gibian, H., Kieslich, K., Koch, H.J., Kosmol, H., Rufer, C., Schrb'der,E., and Vossing, R., TETRAHEDRON LETTERS, NO. 21, 2321 (1966). 22. Proton NMR spectra were measured on the Varian A-60 Spectrometer using 5-10% solutions in CDCl containing tetramethylsilane(TMS) as internal reference standara'. Chemical shifts are expressed in 8 units measured downfield from the reference, and coupling constants, J., in cps. The former should be accurate to f 0.01 ppm, the latter to ?!0.5 cps. Ultra-violet absorption spectra were measured in 95% ethanol.
TOTALLY SYNTHETIC STWOID HORMUNXS. XI.
1
OBSRRVATIONS ON THE CONDENSATION OF 1-VINYL-l-TEIRALOLSWITH 2-ALLXnCICLOPE~~-1,3-DlONES. D.P. Strike, T.Y. Jen, G.A. Hughes, G.H.
Douglas, and Herchel Smith
Research Division, Wyeth Laboratories Inc., Radnor, Pennsylvania
Received May 23, 1966
The condensation of a 6-oxygenated 1-vinyl-l-tetralolI (R=IiO, .
CH30, C6H5CH20, 2-tetrahydropyranyloxy-;R'=H) with a 2-alkylcyclopentane or hexane-1,3-dione to give the corresponding seco-steroid of type II has provided a highly efficient means of generating the correctly substituted carbon skeleton of estrone, D-homo-estroneand related struc2-7 tures.
This reaction is closely related, at least formally, to the
long-known condensation of l-phenylallyl alcohol and ethyl acetoacetate 8 in the presence of potassium acetate giving cinnsmylacetone which has been recently extended' to the preparation of precursors of a variety of diphenyls. Here we report findings bearing on its mechanism and the geometric structure of the products. We have previously found that the best yields of seco-steroidsof type II are obtained when the reaction is carried out in refluxing methanol with a trace of base,' generally potassium or sodium hydroxide or hydrogen carbonate. Using essentially these conditions, 75"80% yields of the seco-steroid II (R=CH30; Rl=H; R2=CH3; n=l), the precursor of estrone, can be obtained even on the pilot plant scalelo (Ku0 --• et al 7 have reported obtaining yields of no better than SO-60% in this reaction). The
STEROIDS
310
8:3
method fails with I-vinyl-l-tetralol I (R=Rl=H) and its 5-methoxy derivative I (R=H; Rl=C
0), but a reaction occurs between the former and 2l-3
ethylcyclopentane-1,3_dione
when the neat reactants are kept with or with-
11 out base at 150-170' for several hours, and between the latter and 2-methylcyclopentane-1,3-dione
in refluxing ethylene glycol.
The success of
the reaction in the absence of base has been recently confirmed.
7
We believe the foregoing results to be consistent with an anionotropic displacement mechanism similar to that associated with the rearrangements of l- to 3-phenylallyl
alcohols.
=,f3
In such processes the
ease and extent of the reaction is enhanced by electron release, particularly of the conjugative type, to the carbon which loses the hydroxyl. In the present examples, mesomeric release of negative charge to the lposition (naphthalene numbering) is possible with a 6- but not a 5-methoxy-1-tetralol.
We prefer to summarize the mechanism by the expression
III, in which the proton is derived from another molecule of the acidic dione.
14
Such an expression need not necessarily represent a fully con-
certed process.
An analogous expression, in which the enol form of the
dione is substituted for the enolate anion, can be written for the reaction in the absence of base. et al. --
After the formulation of our views, Kuo
reported that the reaction between I (R=CH30; R'=H) and e-methyl-
cyclopentane-1,3-dione
is acid catalysed, and presented evidence that
the reaction proceeds through an intimate ion-pair intermediate.
Since
reaction occurs in its absence, one beneficial function of the base may be to buffer the acidity of the dione (which is expected to approach acetic acid in acidic strength) and thereby limit the formation of by-products through decomposition of the acid-sensitive tetralol (cf.15). Such acid-sensitivity would be decreased by removal of the 6-methoxy group.
Sept. 1966
STEROIDS
311
16 Whitehurst has suggested that seco-steroids of type II are formed by simple displacement of hydroxide anion from the vinyl tetralol I by the cyclopentane-l,+dione enolate anion, whilst ascribing quite novel character to the overall reaction. Such a mechanism, in which an anion is displaced by one of much lower basicity in homogeneous solution, is excluded by the failure of the reaction between the alcohol I (R=CH30; Rl=H) and 2-ethylcyclopentane-1,3-dionein the presence of 1 mol. of base reported here, and of that between the same alcohol and 27 methylcyclopentane-1,3-dioneindependentlyobserved by Kuo -et al.
For
the condensation between the tetralol I (R=OH; Rl=H) and 2-methylcyclo2e pentane-1,3-dione,Torgov and his colleagues have suggested a mechanism involving loss of hydroxide ion followed by Michael addition of the dione to the resulting tetraenone IV, but this mechanism is not so satisfactorily applied to reactions involving the substrates I (&Rl=H, R=CH30; Rl= H,and R=H; R1=C%O) as that suggested here. Cyclization of the dione 6a If (R=H; Rl=CqO; R2=CH+ n=l) with hot ethanolic hydrochloric acid gave the expected pentaenone (V).
312
STEROIDS
8:3
&I I
m
Ho
Hb
P
R
P
Hb
Sept. 1966
STEROIDS
313
Seco-steroids of type II may theoretically exist with the Cll-proton 3yn- or anti- to the aromatic nucleus. Examination of a typical Dreiding model of II and of possible transition states for its formation suggests that the former configuration should be predominantly produced whether the reaction is thermodynamicallyor kinetically controlled. Evidence supporting this suggestion has been adduced as follows. Vinylic proton resonances occur as two doublets at 6 4.85 and 5.35 in the proton NMR spectrum of a preparation consisting mainly of the olefin VI (made through the Wittig reaction between 6-methoxy-1-tetraloneand methyltriphenylphosphoniumbromide). Proton Ha is nearer to the aromatic nucleus 18,19 and should therefore be the more deshielded; therefore, the foregoing two signals can be assigned to protons Hb and H ar respectively. These signals are to be compared with the multiplet centered at 6 5.73 that we found for the endocyclic vinylic proton in the known dihydronaphtha20 lene (VII).
Knowing that the NMR signals for the co-protonss-
and
anti- to the aromatic nucleus in styrene are shifted downfield by 0.5 and 0.6 ppm, respectively, in trans- and
propenylbenzene,respectively,18
it can be predicted that the signals for protons Ha and Hb in the alkylsubstituted derivatives VIII and IX should occur at 6 5.85 and 5.45, respectively. In fact, the vinyl proton in the mixture of diols X [made by lithium aluminum hydride reduction of the seco-steroid II (R=CH30; R1=H; R2=CH3; n=l)] occurs as a triplet-likemultiplet centered at 6 6.07, thereby clearly favoring a configuration for the seco-steroid in which the Cll-hydrogen is E-
to the aromatic nucleus. That the 9(11)-double
bond had remained intact in the preparation of the diol X (rather than having rearranged to the 8-position) is shown by the signal for the Clproton,which occurs as a doublet centered at 6 7.52. This signal is to
STEROIDS
314
8:3
to be compared with those for the C ll-proton in the precursor and the analogous C -proton (naphthalene numbering) in the dihydronaphthalene
4
VII, which occur as doublets centered at 6 7.39 and 7.14, respectively. The dione II (R=CH30; Rl=H; R2=C H3; n-l) was deemed unsuitable for comparison because of its capability of existing in conformations in which the diamagnetic anisotropic effect of the carbonyl groups could seriously influence the NMR resonance signal of the Cll-proton, and it is notable that this signal occurs as a triplet-like multipl&t at 6 5.65 in the dione II (R=C?O;
R1=H; R2=CH3; n=l) and as a similar multiplet at 6 5.82 in
the corresponding ketol II (R=CH30; R1=H; R2=CH ; n=l).
21
3
ACKNOWLEDGEMENT
We thank Dr. H. Gibian and his colleagues, Schering AG, Berlin, for providing a manuscript of their paper before publication.
EXPERIMENTAL
22
~-Methox~-8,1~-secoestra-1,3,5(10),9(11)-tetraene-1~,17-dione II (R=H; Rl=CH 0; R2=CH ; n=l). - 5-Methoxytetralone (1.14 g.) in tetrahydrofuran (15 m 2 .) was aaded to vinylmagnesium bromide in tetrahydrofuran (25 ml. of 1.2M) and the mixture refluxed for 3.5 hr. The cooled mixture was diluted with water and extracted with ether. The extract was washed successively with 2N HCl and water, dried, and evaporated to give the crude 5-methoxy-1-vinyl-1-tetralol (1.26 g.). An aliquot (0.83 g.) was stirred under N2 with 2-methylcyclopentane-1,3-dione (0.82 g.) and potassium hydroxide (0.1 g.) in ethylene glycol (5 ml.) at 150' for 2 hr. Water was added to the cooled solution, the mixture was extracted with ether, and the ether solution was washed successively with 5% aqueous RHCO and water, and dried. The product was chromatographed on neutral a4 umina, elution with benzene-hexane (1:3) giving material which was recrystallized twice from hexane-acetone to give the dione (0.25 g.), m.pRBJ3-75". The analytical sample (from acetone-hexane) had m.p. 83-84*, &,,,x 5.82, 6.38, 7.95 p; hax 224 and 261 rnp (s 27,600 and 12,500). w. 7.71.
Calcd. for ClgHi203: C, 76.48;H, 7.43. Found: C, 76.24; H,
Sept. 1966
STEROIDS
315
(f)-4-Methoxyestra-1,3,5(10),8,14-pentaen-17-one (V). - The foregoing dione (.19 g.) was refluxed in ethanol (10 ml.)-1lN HCl for 1 hr. The cooled solution was diluted with water and the product extracted mm. followed by three recrywith ether. Sublimation at 180-200cj/o.1 stallizations from hexane-acetone gave pink crystals, which were sublimed at 130014O'b.l rmn.to give the pentaene (.036 g.), m.p. 155-157'; hXBr 5.76, 6.27, 6.40, 7.95 IJ~; hax 230, 247, 297, 307, and 320 9 (:?7,900, 9,900, 21,600, 24,300, and 16,600). &. 7.12.
Calcd. for ClgH2002: C, 81.39;H, 7..19.Found: C, 81.48; H,
6-Methoxy-l-methylene-1,2,3,4tetrahydronaphthaleneVI. - Butyl lithium in hexane (38.5 ml. of 15.2% I/W> was added under nitrogen, with stirring, to methyltriphenylphosphoniumbromide (35.7 g.) in ether (0.5 1.). Stirring was continued at 25O for 3 hr. and to the resulting suspension was added 6-methoxy-1-tetralone(10 g.) in ether (200 ml.). The mixture was stirred for 4 hr. and kept at room temperature overnight. Most of the ether was evaporated, tetrahydrofuran (300 ml.) was added, and the mixture refluxed for 2 hr. Ether was added to the cooled mixture, which was washed with water, dried and evaporated. Distillation of the residue gave the crude olefin (1.4 g.), b.p. 80-82°/o.05 mm.; Lax 265 rnp (a 13,700); NMR: 3 proton singlet 6 3.76 (OCH3), 0.8 proton doublets 6 4.85 and 5.35 (:CH2, J=1.5 cps. for both), 0.8 proton doublet 6 7.59 (C, - H; J=8 cps). Gas-liquid chromatography,run using a Perkin-Elmer Vapor Fractometer Model 154-C with a sample in CH2C12 at a flow rate of 24 ml/&n. of He on a 2-meter column (external diameter 0.25 in.) at 220' packed with Celite containing 3% I& fluorosilicone QF-1 as stationary phase, showed the product to contain 82% of pure VI (retention time 3 min., 9 sec.) with two other components, one estimated at 11% (retention time 2 min., 9 sec.) and the other at 7% (retention time 10 min.). m.
Calcd. for C=Hl40: C, 82.72;H, 8.10. Found: C, 82.28;H, 8.33.
(+) 3-Methoxy-8,14-secoestra-1,3,5(10),9(ll)-tetraen-14~,17~-d~~ls. - ~)~3~methoxy-8,14-secoestra-1,3,5(10),9(11)-tetraen-14,17-dione (2 g.) was refluxed for 2 hr. with lithium aluminum hydride (1 g.) in tetrahydrofuran (100 ml.). The excess of reducing agent was decomposed by adding ethyl acetate, water was added and the mixture extracted with ether. Distillation of the ;T$ct at 200' (bathfi.2 mm. gave the H. mixture of diols as a gum; Amax 3.00 p with no absorption in the 5.75 )I region; NMR: singlets at S 0.78 and 0.94 (Cl3 - CH3), singlet at 6 3.76 (OCH3) triplet-likemultiplet centered at 6 7.52 (Cl - H; J=8 cps). Anal. Calcd. for Cl9H2603: C, 75.46;~, 8.67. Found: C, 75.37;H, 8.42.
REFERENCES
1. Part X. Buzby, G.C., Jr., Walk, C.R., and Smith, H., J. MED. CHJZM., in the press.
316
STEROIDS
8:3
2. (a) Ananchenko, _ ._ S.N., and Torgov, I.V., DOKL. AKAD. NAUK SSSR., 127, 553 (1959); (b) Ananchenko, S.N., Leonov, V.N., Platonova, A.V., ana. Torgov, I.V., IBID., 135, j3 (1960); (c).Ananchenko,S.N.; Limanov, V.Y., Leonov, V-N., Rzheznikov, V.N., and Torgov, I.V., TETRAHEDRON, l8, 1355 (1962); (d) Ananchenko, S.N., Torgov, I.V., T~RDRON LEITERS, 1553 (1963); (e) Zakharychev, A.V., Ananchenko, S.N., and Torgov, I.V., STEROIDS, 3, 31 (1964). 3. Crispin, D.J., and Whitehurst, J.S., PROC. CHEM. SOC., 22 (1963). 4. Miki, T., Hiraga, K., and Asako, T., IBID., p. 139. 5.
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(a) Douglas, G-H., Graves, J.M.H., Hartley, D., Hughes, G.A., McLoughlin, B.J., Siddall, J., and Smith, H., J. CHEM. SOC., 5072, (1963); (b) Smith, H., Hughes, G.A., Douglas, G-H., Hartley, It., McLaughlin, B.J., and Siddall, J.B.; Wendt, G.R., Buzby, G.C., Jr., Herbst, D.R., Ledig, K.W., McMenamin, J.R., Pattison, T.W., Suida, J., Tokolics, J., and Edgren, B.A.; Jansen, A.B.A., Gadsby, G., Watson, D.H.R., and Phillips, P.C., EKPERIENTIA,l9, 394 (1963); (c) Smith, H., Hughes, G.A., Douglas, G.H., Wendt, G-R., Buzby, G-C ., jun., Edgren, B.A., Fisher, J., Foell, T., Gadsby, B., Hartley, D., Herbst, D., Jansen, A.B.A., Ledig, K., McLaughlin, B. J-, McMenamin, J., Pattison, T.W., Phillips, P.C., Rees, R., Siddall, J., Siuda, J., Smith, L.L., Tokolics, J., and Watson, D.H.P., J. CHEM. XX., 4472 (1964).
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Private co~nication from Dr. C.C. Christman, Development Division, Wyeth Laboratories Inc., West Chester, Pennsylvania.
11.
Hughes, G.A., and Smith, H., Belgian Patent 632,348 (1963), priority from May 16, 1962.
12.
Ingold, C.K., "Structure and Mechanism in Organic Chemistry," G. Bell and Sons Ltd., London, 1953, pp. 590-591.
13. de la Mare, P.B.D., in nMolecular Rearrangements," edited de Mayo, P ., Interscience Publishers, New York, 1963, pp. 76-80. 14‘ This mechanism was considered in lectures given by one of us (H.S.) to the Philadelphia Section of the American Chemical Society, November 15, 1962 and to the Section of Chemical Sciences, New York Academy of Sciences, January 5, 1965.
Sept. 1966
STEROIDS
317
15. Robins, P.A., and Walker, J., J. CHKM. SOC., 3249 (1956). 16. Whitehurst, J.S., ANN. REPT. PROGR. CHEM., 60, 426 (1963). 17. Eschenmoser, A., Schreiber, J., and Julia, S.A., HRLV. CHIM. ACTA, 9, 482 (1953). 18. Pople, J.A., Schneider, W.G., and Bernstein, H.J., "High Resolution Nuclear Magnetic Resonance," McGraw-Hill, New York, 1959, p. 239. 19. Rottendorf, H., Sternhell, S., and Wilmshurst, J.R., AUSTRALIAN J. CHKM. 18, 1759 (1965). 20. Stork, G., Meisels, A., and Davies, J.E., J. AMER. CHRM. SOC., 85, 3419 (1963). 21. Gibian, H., Kieslich, K., Koch, H.J., Kosmol, H., Rufer, C., Schrb'der,E., and Vossing, R., TETRAHEDRON LETTERS, NO. 21, 2321 (1966). 22. Proton NMR spectra were measured on the Varian A-60 Spectrometer using 5-10% solutions in CDCl containing tetramethylsilane(TMS) as internal reference standara'. Chemical shifts are expressed in 8 units measured downfield from the reference, and coupling constants, J., in cps. The former should be accurate to f 0.01 ppm, the latter to ?!0.5 cps. Ultra-violet absorption spectra were measured in 95% ethanol.