1307 can be seen i n the concentrated acetone photolysate after 2 and 3 hr.
Acknowledgment. This work was supported through grants from the U.S. Army Research Office, Durham,
which we gratefully acknowledge. Some preliminary studies were supported in part by an Institutional Grant to New York University by the National Science Foundation.
Steroids. CCCXVII. Photochemical Cycloadducts. 111. Addition of Ethylene and Maleic Anhydride to a Linear Dienone P. H. N e l ~ o n J. , ~ W. Murphy, J. A. Edwards, and J. H. Fried Contribution from the Institute of Steroid Chemistry, Syntex Research, Palo Alto, California. Received July 31, 1967 Abstract: The photochemical addition of ethylene to 17@-acetoxyandrosta-4,6-dien-3-one (I) gave approximately equal amounts of the 4&5a- and 4a,5a-ethylene adducts I1 and 111, and a small amount of the 6@,7@ adduct IV. Photochemical addition of maleic anhydride to I produced a mixture of the 4a,5a, 6a,7a, and 6&7@adducts in yields of 15, 19, and 577&respectively. The 6,7-maleic anhydride adducts were converted via the corresponding diacids Vb and VIb to the 6,7-vinyleneadducts VI11 and IX. A correlation between the maleic anhydride and ethylene additionsis described. The structures of the compounds are deduced mainly from their nmr and ORD spectra.
In order to obtain a larger proportion of addition ecently several reports of photochemically induced to the y,6 double bond, we next studied the photointermolecular cycloadditions of olefinic comchemical addition of maleic anhydride to I, in the pounds to unsaturated carbonyl systems have been expectation that excited maleic anhydride would add p ~ b l i s h e d . ~The method is of considerable utility for preferentially to the more electron-rich 6,7 double the preparation of cyclobutane compounds bearing a bond of the ground-state dienone. Irradiation of an wide variety of substituents. In the course of our inequimolar mixture of I and maleic anhydride under the vestigations of the photochemistry of s t e r o i d ~ , ~itJ same conditions as above led to rapid addition with became of interest to examine the addition of certain only a trace of starting material being detectable after olefins to an a,P,y,&unsaturated ketone. 17p-Ace40 min. The composition of the resulting mixture of toxyandrosta-4,6-dien-3-one(I) was chosen as a model anhydride adducts had to be determined after converunsaturated ketone and ethylene and maleic anhydride sion to the corresponding diesters by mild alkaline as addition substrates. It has been previously reported6 hydrolysis followed by diazomethane methylation, that dienones of this type will undergo dimerization since the primary products of addition were too easily when irradiated, but the addition of different olefinic hydrolyzed to be chromatographed. compounds has apparently not been studied. The major product, obtained in 55% yield, was 170Bubbling a stream of ethylene through an irradiated acetoxy-6/3,7/3-ethyleneandrost-4-en-3 -one-6'-exo-7'benzene solution of I, for a period of 6 hr, resulted in a exo-dicarboxylic acid dimethyl ester (Va). The corslow cycloaddition to give the trans-fused adduct 170responding 6a,7a isomer VIa was isolated in 19% acetoxy-4P,5a-ethyleneandrost-6-en-3-one(11) in 7 % yield, and the product resulting from addition to the yield, and the corresponding cis-fused adduct, 1704,5 double bond, 17P-acetoxy-4a,5a-ethyleneandrost-6acetoxy-4a,5a-ethyleneandrost-6-en-3-one (111), was isoen-3-one-4'-exo-5'-exo-dicarboxylic acid dimethyl lated in 5 % yield. In addition, ca. 1 % of the 6,7 cycloadduct 17P-acetoxy-6P,7~-ethyleneandrost-4-en-3-ester (VII), was obtained in 15% yield, in addition to ca. 5 % of recovered starting material. one (IV) and ca. 30% of recovered starting material Degradation of the 6,7-anhydride adducts appeared were also isolated, The remainder of the material was to be a useful route to the epimeric 6,7-vinylene and accounted for by several very polar products whose 6,7-ethylene adducts, as well as providing an opporisolation and characterization were not attempted. tunity to identify the minor product from photoaddition (1) Steroids. CCCXVI: L. Cuellar, H. Martinez, and P. CrabW, of ethylene to I, which had not been obtained in large Steroids, in press. (2) For part I1 see P. Sunder-Plassmann, P. H. Nelson, L. Durham, enough amounts or in sufficient purity' for conventional J. A. Edwards, and J. H. Fried, Tetrahedron Letters, 653 (1967). structure determination. The diacids Vb and VIb (3) Syntex Postdoctoral Fellow, 1965-1966. were isolated by preparative tlc of the crude mixture of (4) See, for example, E.J. Corey, J. D. Bass, R. LeMahieu, and R. B. Mitra, J. Amer. Chem. SOC., 86, 5570 (1964); R. L. Cargill, J. R. diacids obtained by mild hydrolysis of the total reaction Damewood, and M. M. Cooper, ibid., 88, 1330 (1966); Y. Yamada, products from maleic anhydride addition to I. The H. Uda, and K. Nakanishi, Chem. Commun., 423 (1966); J. J.
R
McCullough and J. M. Kelly, J . Amer. Chem. Soc., 88, 5935, (1966). (5) P. Sunder-Plassmann, J. Zderic, and J. H. Fried, Tetrahedron
Letters, 3451 (1966). (6) H. C. Thronsden, G. Carnelli, D. Arigoni, and 0. Jeger, Helv. Chim. Acta, 45,2342 (1962); M. B. Rubin, G. E.Hipps, and D. Glover, J . Org. Chem., 29, 68 (1964).
(7) This compound was contaminated with an impurity which could not be removed by recrystallization or chromatography. The nature of the impurity will be discussed later. (8) The more abundant diacid Va could also be obtained by direct crystallization of the crude hydrolysis mixture, or by hydrolysis of its
Nelson, et al.
Olefin Addition to a Linear Dienone
1308
&
0
0
I1
I
X
XIa, R = CsH17 b,R=OAc
0
IV
I11 OAc
J$P
&$ XI1
R
GCOnR
0
COzR VIa, R = CHo b,R=H
COzR Va,R = CH3 b,R=H
0
'
x1v
0 COZCHJ CO~CHI
VI11
VI1
OAc
IX separated diacids were each subjected to oxidative decarboxylation by lead tetraacetate in dioxane or tetrahydrofuran at 60-90°,9 the corresponding 6,7-vinylene compounds VI11 and IX being obtained in 30-40% yields. The 6P,7P-vinylene compound VI11 was reduced with tristriphenylphcsphinerhodium chloride and hydrogen l o to give compound IV, whose spectral and anhydride which crystallized directly from the photoaddition mixture in cu. 40 % yield. (9) These solvents were found to give higher yields, a cleaner product, and an easier work-up than those which have been used previously: (a) E. E. van Tamelen and S. P. Pappas, J . Amer. Chem. SOC., 85. 3297 (1963); (b) R. N. McDonald and C. R. Reineke, ibid., 87, 3020 (1965); (c) E. J. Corey and J. Casanova, Jr., ibid., 85. 165 (1963); (d) E. Grovenstein, Jr., D. V. Rao, and J. W. Taylor, ibid., 83, 1705 (1961); (e) C. A. Grob, M. Ohta, and A. Weiss, Angew. Chem., 70, 343 (1958). It was found that the cyclic ethers themselves react with lead tetraacetate to give the corresponding a-acetoxy compounds i and ii which were isolated and characterized by nmr and, in the case of ii,
1
ii
by acid hydrolysis to the known 4-hydroxybutanal, Due to the occurrence of this reaction no excess lead tetraacetate remained after the oxidative decarboxylation, thus greatly simplifying the isolation of the desired product. Compounds i and ii were removed by washing with dilute mineral acid.
Journal of the American Chemical Society
90:5
XlII
R Xv,R = C8HI7or OAc
chromatographic properties were identical with those of the minor product of addition of ethylene to the linear dienone I, neglecting those absorptions due to an impurity present in the ethylene adduct. Attempted hydrogenation of the 6P,7P-vinylene compound using conventional palladium-on-carbon, Lindlar, or platinum catalysts produced mixtures apparently of the di- and tetrahydro compounds. The 6a,7a-vinylene compound IX could not be reduced cleanly to the 6a,7a-ethylene adduct with either noble metal or Wilkinson catalysts. The structures of the ethylene addition products were determined by both chemical and physical methods. Compounds I1 and I11 were shown to be isomeric 4,5 adducts by their nmr spectra, which showed the resonances of the 6- and 7-vinylic protons, and also by their uv spectra, which had only n-r* carbonyl absorption. The mass spectra of these compounds were identical, presumably due to isomerization in the inlet system, since it was later found that the adduct I1 could be transformed quantitatively into 111 either by heating to 230" or by treatment with a catalytic amount of sodium methoxide in methanol at room temperature. These isomerization reactions indicate that the compounds differ in orientation at C4 and not at Cj. Although thermal epimerization at C 6 could conceivably occur via homolysis of either the C5-Cjt or C4-C5 bonds, base-catalyzed epimerization at Cs cannot take place. Since the heat-stable adduct I11 could be catalytically hydrogenated to 17P-acetoxy-4a,5a-ethyleneandrostan-3-one (X) (produced in 78 % yield by photochemical addition of ethylenes to testosterone (10) J. F. Young, I. A. Osborn, F. H. Jardine, and G. Wilkinson, Chem. Commun., 131 (1965); F.H. Jardine, J. A. Osborn, G. Wilkinson, and J. F. Young, Chem. Ind. (London), 560 (1965).
/ February 28, 1968
1309 Table I. Nmra and UvbSpectra of Maleic Anhydride Adducts and Related Compounds Compound
19-H, ppm
4-H,ppm
4-H half-band width, cps
6&7P-Anhydride XI11 6&7@-DiacidVbc 6fl,7P-Dimethyl ester Va 68,7D-Vinylene VI11 68,7@-Ethylene IV 6a,7a-Diacid VIbe 6a,7a-Dimethyl ester VIa &,7a-Vinylene IX
1.41 1.37 1.37 1.20 1.41 1.10 1.13 1.12
5.83 6.43 5.92 5.80 5.67 5.72 5.80 5.77
2.0 2.3 1.8 2.5 2.0 3.5‘ (doublet, J4,s= 2) (doublet, J4.s= 2)
Amax,
mp
241d 247 246 249 250 246 250 252
emax
20,600 13,100 16,500 14,200 14,700 14,900 11,100 13,500
In dimethyl-d6 sulfoxide. a Measured in deuteriochloroform unless otherwise stated. * Measured in ethanol unless otherwise stated. In dry dioxane; the dimethyl ester Va had A, 238 mp (e 17,100) in this solvent. e This half-band width corresponds to a coupling constant (J4.g) of approximately 2 cps which was not resolved, probably because of the high viscosity of the dimethyl sulfoxide solution. d
acetate), it must be a 4a,5a adduct, and the isomeric compound the 40,Sa-ethylene adduct. Optical rotatory dispersion (ORD) measurements on the 4a,5a-ethylene adducts I11 and X support the assignment of a rather than /3 stereochemistry. Both compounds show a weakly positive curve. The molecular amplitudes, which are smaller than would be expected for a Sa-substituted compound, indicate that ring A is in a boat conformation. In this conformation C4fand Cgrlie in a positive octant, their proximity to the 3-carbonyl group evidently just overriding the negative contribution of Cg, which lies in a negative octant. Thus a weakly positive curve is obtained (molecular amplitude a of I11 is +4 and of X is +26; cf. Sa-methylcholestan-3-one(XIa), a = +73).” A much greater amplitude would be expected for these adducts if ring A were in a chair conformation, since carbons 4’, 5, 5’, 6, and 7 would all lie in a positive octant. A 40,SP-ethylene adduct would be expected to have a negative Cotton effect of fairly high amplitude since Dreiding models show carbons 4’, 5, and 5’ to be in a negative octant. The 4/3,5a adduct I1 has a positive Cotton effect with amplitude +265, consistent with a model showing carbons 4’, 5, 5’, 6, 7, 10, and 19 in a positive octant. The nmr spectra of the ethylene adducts provide information as to the structures and conformations of these compounds in agreement with the foregoing ORD data. The 19-H resonances in the 4a,5a-ethylene adducts I11 and X occur at 0.74 and 0.78 ppm, respectively, compared to calculated values12 of 1.18 and 1.16 ppm for 17/3-acetoxy-5a-methylandrostan-3-one (XIb) and 170acetoxy-5a-methylandrost-6-en-3-one (XII), respectively. The relatively large amount of shielding experienced by the 19-H in the adducts is taken to indicate that ring A assumes a boat or a flexible conformation in which the 19-hydrogens are in the shielding zone of the 3-ketone. l 3 Examination of Dreiding models supports this conclusion. A model of the extremely strained 4&5a adduct I1 indicates a distorted half-boat conformation for ring A in which shielding of the 19-H by the 3(11) P. CrabW, “Optical Rotatory Dispersion and Circular Dichroism in Organic Chemistry,” Holden-Day Inc., San Francisco, Calif., 1965, pp 103-104. (12) N. S. Bhacca and D. H. Williams, “Applications of NMR Spectroscopy in Organic Chemistry,” Holden-Day Inc., San Francisco, Calif., 1964, pp 19-24. (13) J. A. Pople, Proc. Roy. SOC.(London), A239, 541, 550 (1957); L. M. Jackman, “Applications of NMR Spectroscopy in Organic Chemistry,” Pergamon Press, London, 1959, p 124. For use of this effect in conformational analysis see A. I).Cross and I. T. Harrison, J . Amer. Chem. SOC.,85, 3233 (1963); B. B. Dewhurst, D. S. E. Holker, A. Lablache-Combier, M. R. G. Leeming, J. Levisalles, and J. P. Pete, Bull. SOC.Chim. Fr., 3259 (1964).
ketone would not be expected, in accord with the observed position of the 19-H resonance (1.1 1 ppm) which is only slightly shielded relative to the reference compounds XIb and XII. The gross structure of the minor product of addition of ethylene to I was deduced from its uv spectrum (A, 250 mp (e ca. 10,000)) which indicated a 6,7 adduct, and by its mass spectrum (molecular ion 356 mass units, with a large peak corresponding to loss of C2H4). The orientation of addition was not, however, established until the spectra of this c o m p o ~ n dcould ’ ~ be compared with those of authentic IV (see below). The structures of the maleic anhydride adducts were deduced mainly from their nmr spectra and in particular by the positions of the 19-H resonances and the nature of the 4-H resonances. The relevant data are summarized in Table I, which also summarizes the uv spectra of the adducts and derived compounds. The relatively low-field positions of the 19-H resonances in the 6&7p adducts are thought to result from interaction of the quasi-axial 6 and 7 substituents with the 100-methyl group (a 60-methyl group produces a downfield shift of 008 ppm12 from the position (1.19 ppm) of the 19-H resonance in testosterone acetate (XIV)). In the 60,7/3-vinylene compound VI11 the 19-H is significantly shielded relative to all the other 6/3,7/3 compounds (see Table I). Examination of models shows that in this compound the 100-methyl group is directly in the shielding zone of the 6,7 double bond. l6 The 6a,7a compounds, on the other hand, exhibit small upfield shifts relative to the resonance position of the 19-H in testosterone acetate. The observed splitting or broadening of the C,-H signal in these compounds is also in accord with the assigned 6a,7a stereochemistry, since the measured C4H-CsH dihedral angle is larger in these adducts than in the 60,7/3 adducts (60” as against 30”) thereby leading to a resolvable coupling in two of the three a adducts. l6 (14) The identification of this compound was further complicated by the presence of an inseparable impurity whose molecular weight was apparently 2 mass units greater than IV. This contaminant is thought to be the hydroperoxide produced by photoaddition of oxygen to the dienone. This conclusion was supported by the presence of a weak OH band in the infrared spectrum of the impure sample of IV. (15) J. W. ApSimon, W. G. Craig, P. V. Demarco, D. W. Mathieson, L. Saunders, and W. B. Whalley, Tetrahedron, 23, 2357 (1967). (16) The relationship between allylic coupling constants and the dihedral angle between the relevant C-H bonds has been investigated in some detail. It has generally been found that the coupling constant reaches a maximum when the dihedral angle is 90” (S. Sternhell, Reo. Pure Appl. Chem., 14, 15 (1964)). J4.s in 6-substituted steroidal A4-3-ketones had previously been found to be resolvable only when the 6-hydrogen is in the (axial) orientation (T. A. Wittstruck, S. K. Malhotra, and H. J. Ringold, J . Amer. Chem. SOC., 85, 1699 (1963); D. J. Collins, J. J. Hobbs, and S. Sternhell, Australian J . Chem., 16, 1030 (1963)).
Nelson, et al.
O!eJn Addition to a Linear Dienone
1310
Table I1 ~~~
Protons x-y
4-6 6-6' 6-7 7-7'
70e
