3484
J. Am. Chem. SOC.1993,115, 3484-3493
Selective Aromatization of the A-Ring of Steroids through C-C, C-H, and C-0 Bond Activation by an Electrophilic Ruthenium Complex Francisco Urbanos, Malcolm A. Halcrow, Juan Fernandez-Baeza, Franqoise Dahan, Daniel Labroue, and Bruno Chaudret’ Contribution from the Laboratoire de Chimie de Coordination du CNRS, U.P. 8241 lile par conventions h I’Universitk Paul Sabatier et a l’lnstitut National Polytechnique, 205 route de Narbonne. 31 077 Toulouse Cedex, France Received October 15, 1992
Abstract: The Cp*Ru+fragment (1) generated by the protonation of [Cp*Ru(OMe)]z by CF3SO3H reacts with oestradiol and oestrone in THF or CH2C12 at 293 K to form mixed sandwich [Cp*Ru($-aryl steroid)]+ products. Reaction of 1 with testosterone, progesterone, cholesterol, dehydroisoandrosterone, or androsterone at 90-1 20 “ C leads to selective and (except for androsterone) near-quantitative aromatization of the A-ring of the steroid substrates via C-0, C-H and C-C bond activation, affording $-aryl derivatives as above and CH4, H2, and/or H2O as byproducts. The reactions with testosterone and progesterone proceed through a hydrido cyclohexadienyl intermediate, whereas those with cholesterol and dehydroisoandrosterone occur via a triene intermediate. In the latter case, the triene has been trapped by reaction with NaOMe, which leads to addition of a methoxo group to the carbon C6 of the steroid; the single crystal X-ray structure of the resultant metal complex is presented. Cp*Ru+ forms a 1:l adduct with prednisolone; reaction of 2 equiv of 1 with prednisolone causes fragmentation of the steroid.
Introduction While the creation of new chemical bonds is obviously more important to the organic synthesist, the discovery of new bond activation reactions has led toseveral new developments in organic chemistry.’ For example, activation of C-H bonds2 has been achieved by oxidative addition to low-valent electron-rich complexes in the presence or absence of an alkene as hydrogen a ~ c e p t o r using , ~ electrophilic early transition-metal complexes via a u-bond metathesis mechanism: or even in the presence of cationic platinum(1V) or palladium(I1) derivative^,^-* both of which were able to activate methane.2a,2e These elementary processes are now used for productive organic transformations such as d e h y d r o g e n a t i ~ n ,carbonylati~n,~-l~ ~.~~ or silylationlO of alkanes using a rhodium complex as photocatalyst, alkylation of pyridine by zirconium derivatives,12 and chlorination of alkanes by platinum salts.2f At the same time, another important challenge for the organometallic chemist has been the activation of carbon-carbon (1) Collman, J. P.; Hegedus, L. S . ; Norton, J. R.; Finke, R. G. Principles and applications of organotransition metal chemistry; University Science
Books: Mill Valley, CA, 1987. (2) For recent reviews, see: (a) Shilov, A. E. The actiuation of saturated hydrocarbons by transition metal complexes; D. Riedel Publishing Co.: Dordrecht, Holland, 1984. (b) Crabtree, R. H. Chem. Rev. 1985, 85, 245. (c) Rothwell, I. P. Polyhedron 1985, 4 , 177. (d) Ephritikhine, M. New J . Chem. 1986, 10, 9. (e) Sen, A. Acc. Chem. Res. 1988, 21, 421. (f) Shilov, A. E.; Shul’pin, G. B. Russ. Chem. Reu. 1990, 59, 853. (3) Janowicz, A. H.; Bergman, R. G. J . Am. Chem. SOC.1983,105,2829. (4) Thompson, M. E.; Baxter, S . M.; Bulls, A. R.; Burger, B. J.; Nolan, M. C.; Santarsiero, B. D.; Schaefer, W. P.; Bercaw, J. E. J . Am. Chem. SOC. 1987, 109, 203. (5) Shul’pin, G. B.; Skripnik, S . Y.; Deiko, S . A,; Yatsimirskii, A. K., Metalloorg. Khim. 1989, 2, 1301. (6) Labinger, J. A,; Herring, A. M.; Bercaw, J. E. J . Am. Chem. SOC.1990, 112, 5628. (7) Kao, L-C.; Hutson, A. C.; Sen, A. J . Am. Chem. SOC.1991,113,700. ( 8 ) Gretz, E.; Oliver, T. F.; Sen, A. J . Am. Chem. SOC.1987, 109, 8109. (9) Nomura, K.; Saito, Y. J . Mol. Catal. 1989, 54, 57. (10) Sakakura, T.; Sodeyama, T.; Sasaki, K.; Wada, K.; Tanaka, M. J . Am. Chem. SOC.1990. 112. 7221. (1 1) Maguire, J. A:; Boese, W. T.; Goldman, A. S . J . Am. Chem. SOC. 1989. 111. 7088. (12) (aj Jordan, R. F.; Taylor, D. F. J . Am. Chem. SOC.1989, 111, 778.
(b) Jordan, R. F.; Bradley, P. K.; Lapointe, R. E.; Taylor, D. F. New J . Chem. 1990, 14, 505. (c) Guram, A. S.; Jordan, R. F. Organometallics 1991, 10, 3470.
0002-786319311515-3484$04.00/0
bonds.l3 While cleavage of strained C-C bonds is common,’3 the reaction is rare for unstrained C-C bonds,l3 whether using electron-rich or electrophilic transition-metal centers. Only highly Lewis acidic species such as ~ c a n d i u m ( I I 1 )or ~ ~ dicationic palladium(II)2ederivatives have been shown to initiate reactions such as isomerization of pentadiene or tert-butylethene. We have recently demonstrated that the protonation of [Cp*Ru(OMe)]z(Cp*- = C5Me5-) by triflic acid affords the electrophilic fragment Cp*Ru+ ( l ) ,in fact a mixture of complexes exhibiting varying degrees of solvation and/or triflate ion coordination which react instantaneously and quantitatively with acetonitrile or benzene to give the expected triacetonitrile or $benzene d e r i v a t i v e ~ .The ~ ~ fragment 1 is able to aromatize CS hydrocarbons through activation of C-H, C-0, C-C1, or even C-C bonds, a driving force for these reactions being the high affinity of 1 for aromatic hydrocarbons.16J7 In particular, we showed that enones containing two geminal methyl substituents (e.g., isophorone or 4,4’-dimethylcyclohexenone) were selectively demethylated under relatively mild conditions to form the corresponding substituted phenols.’5b (13) See, for example: (a) Periana, R. A.; Bergman, R. G. J . Am. Chem. SOC.1986, 108, 7346. (b) Flood, T. C.; Slater, J. A. Organometallics 1984, 3,1795. (c) Benfield, F. W. C.; Green, M. L. H. J . Chem.Soc.,Dalton Trans. 1974, 1325. (d) Eilbracht, P. Chem. Ber. 1976,109, 1429; 1976,109,3136; 1980,113,542; 1980,113,1033;1980,113,1420;1980,113,2211.
(e)Suggs,
J. W.; Cox, S. D. J . Organomet. Chem. 1981,221,199. (f) Crabtree, R. H.; Dion, R. B.; Gibboni, D. J.; McGrath, D. V.; Holt, E. M. J . Am. Chem. SOC. 1986,108,7222. (9) Watson, P. L.; Roe, D. C. J. Am. Chem. SOC.1984,104, 647 1. (h) Geiger, W. E.; Salzer, A,;Edwin, J.; Von Philipsborn, W.; Piantini, V.; Rheingold, A. L. J . Am. Chem. SOC.1990, 112, 7113. (14) Bunuel, E.; Burger, B. J.; Bercaw, J. E. J . Am. Chem. SOC.1988,110, 976. (15) (a) Chaudret, B.; Dahan, F.; He,X. D. J . Chem.SOC.,Chem. Commun. 1990, 1111. (b) Rondon, D.; Chaudret, B.; He, X. D.; Labroue, D. J . Am. Chem. SOC.1991, 113, 5671. (c) Rondon, D.; He, X-D.; Chaudret, B. J . Organomet. Chem. 1992, 433, C18. (16) (a) Fagan, P. J.; Ward, M. D.; Caspar, J. V.; Calabrese, J. C.; Krusic, P. J. J . Am. Chem. SOC.1988, 110, 2981. (b) Fagan, P. J.; Ward, M. D.; Calabrese, J. C. J . Am. Chem.Soc. 1989,111,1698. (c) Fagan, P. J.; Mahoney, W. S . ; Calabrese, J. C.; Williams, I. D. Organometallics 1990, 9, 1843. (17) (a) Chaudret, B.; Chung, G.; Huang, Y . S . J. Chem. SOC.,Chem. Commun. 1990,749. (b) Chaudret, B.; Jalon, F.; Perez-Manrique, M.; Lahoz, F. J.; Plou, F. J.; Sanchez-Delgado, R. New J . Chem. 1990,14, 331. (c) He, X. D.; Chaudret, B.; Dahan, F.; Huang, Y .S . Organometallics 1991,10,970.
0 1993 American Chemical Society
Selective Aromatization of the A-Ring of Steroids
J . Am. Chem. SOC..Vol. 115, No. 9, 1993 3485
aromatization of the A-ring of steroid enones via elimination of Whilst examining possible applications for this novel organoCH4, and selective aromatization of the A-ring of sterols through metallic process, we considered the reactions of 1 with steroids. multistep reactions involving elimination of CH4, H20, and/or Steroids are large multifunctional molecules with a great diversity of structures; however, the A-ring of steroids generally contains H2. A preliminary report of some of these reactions has been published:32a aromatization at the B-ring of 5,7-dienyl steroids alcohol, enone, or similar functionality which can coordinate to by 1 is also described in a companion paper.32b a transition-metal center as well as a quaternary carbon atom linked to a methyl group. Aromatization of the A-ring requires Results and Discussion rupture of this latter carbonxarbon bond. This is a difficult process, which is achieved in nature by a cytochrome P-450 enzyme (1) Coordination of Cp*Ru+ (1) to Estrogens. As discussed (P-450 aromatase) via successive oxidation steps:]*a model study above, Jaouen et al. have coordinated Cp*Ru+ (1) to estradiol of this process was recently r e ~ 0 r t e d . lReductive ~ aromatization and some of its derivatives using either the cationic precursor by reaction with lithium has been used to aromatize the A-ring [Cp*Ru(NCMe)3]+ or zinc reduction of [Cp*RuC12], followed of dienone-containing steroids.20 by anion exchange.27 Since the activation reactions reported The pioneering work of Birch and colleagues has shown that hereafter were expected to lead to a-complexes of estradiol or attachment of [Fe(CO)3] fragments could favor the cleavage of estrone derivatives, we first investigated the simple coordination C-H and C-0 bonds of hexadienes using various chemical of 1 to these steroids using our methodology, Le., protonation of reagents.21 q4-a-Complexes of dienyl steroids with organometallic [Cp*Ru(OMe)]2 by CF3SO3H in THF followed by addition of fragments such as [Fe(C0)3] have been widely studied for the aromatic steroid, in order to prepare and study the spectrosynthetic purposes, the metal fragment acting both as a protecting scopic properties of authentic samples of these products. group for the diene functionality and to control the site of attack at the dienyl moiety by incoming n ~ c l e o p h i l e s . ~ ~ More ~ ~ ~ ~ ~ 2 3 The reaction of 1 with estradiol at room temperature for 5 h is quantitative and yields a 60:40mixtureof the previously reported recently, a number of $-complexes of oestrogens with Cr, Ru, complexes a- and p- [Cp*R~(q~-estradiol)]CF3SO3~’ (2a and 26) or Rh moieties have been prepared by the groups of Jaouen and by IH N M R spectroscopy. Recrystallization from THF/Et20 Moriarty,2”28 who studied the functionalization of the steroid affords an analytically pure sample showing some enrichment in ligands by nucleophilic attack at the benzylic position of the thea-isomer (2a:2@,2:1). This differs significantly from Jaouen’s *-coordinated A-ring26 as well as the potential utility of these result (2a:2&85:15)27and probably originates from the increased For example, the a-arene substances in biological systems. rate of coordination of 1 compared to [Cp*Ru(NCMe)3]CF3complex [Cr(CO)3(q6-oestradiol)]has been used as a marker in SO3. In refluxing T H F or acetonitrile, the formation of the molecular biology.24 Other known examples of reactions of thermodynamically more stable a-isomer is probably favored. organometallics with steroids include dehydrogenation of the We have previously reported the reaction of [Cp*Ru(OMe)]2 alcohol function of the A-ring through hydrogen transfer catalyzed with phenol, which leads to a r-bonded phenoxo derivative.17c by ruthenium complexes,29aromatization by cleavage of a C-0 The same reaction using estradiol leads to an analogous estradionyl bond,30 and the formation of clusters containing 17-CY-alkynyl derivative [Cp*Ru($-estradionyl)] (3; 3a:3@,80:20)which are steroidal m o i e t i e ~ . ~ ’ the deprotonated forms of 2a and 2p. As observed for simple We report in this paper new reactions leading to coordination phenoxo33 and a l k ~ x adducts o ~ ~ and in agreement with similar of the [Cp*Ru]+ fragment to estrone and estradiol, selective observations by J a o ~ e ncompound , ~ ~ ~ ~3~is hydrogen-bonded to (18) (a) Thompson, E. A.; Siiteri, P. K. J . Biol. Chem. 1974, 249, 5364; a free estradiol molecule, whose ‘H N M R spectrum differsslightly 1974, 249, 5373. (b) Meyer, A. S. Biochem. Biophys. Acta 1955, 17, 441. (c) Arigoni, D.; Bataglia, R.; Akhtar, M.; Smith, T. J . Chem. SOC.Chem. in the aromatic region from that of free estradiol ( 6 7.16, d, J = Commun. 1975, 185. 8.5 Hz, H1; 6.74, dd, J = 8.5 and 1 Hz, H2; 6.59, d, J = 1 Hz, (19) Watanabe, Y.; Ishimura, Y. J . Am. Chem. SOC.1989, 1 1 1 , 8047. H4). (20) Dryden, L. H.; Webber, G. M.; Wieczorek, J. J. J. Am. Chem. SOC. 1964, 86, 742. The complexation of estrone by Cp*Ru+ is similar to that of (21) (a) Birch, A. J.; Cross, P. E.;Lewis, J.; Wild, S. B. J. Chem. SOC.A estradiol. Thus reaction of 1 with estrone in CH2C12 is 1968, 332. (b) Birch, A . J.; Chamberlain, K. B.; Haas, M. A.; Thompson, quantitative, yielding [Cp*Ru($-estrone)]CF$303 (4; 4a:4P, D. J. J . Chem. SOC.,Perkin Trans. I 1973,1882. (c) Birch, A . J.; Williamson, D. H. J . Chem. Soc., Perkin Trans. I 1973, 1892. (d) Birch, A. J.; Kelly, 2:l). Recrystallization from THF/Et20 affords a 60% yield of L. F. J . Organomet. Chem. 1985, 285, 267. a 9:l mixture of 4a and 4P, a good separation of the isomers. As (22) Pearson, A . J. Acc. Chem. Res. 1980, 13, 463. for similar a-arene derivatives, the lH N M R spectrum of 4a (23) (a) Alper, H.; Huang, C-C. J. Organomet. Chem. 1973,50,213. (b) Evans, G.;Johnson, B. F. G.;Lewis, J. J . Organomet. Chem. 1975,102,507. shows the coordinated aromatic ring protons near 6 6 ( 6 6.15, d, (c) Barton, D. H. R.; Gunatilaka, A . A . L.; Nakanishi, T.; Patin, H.; J = 6.3 Hz, H1; 5.88, dd, J = 6.3 and 1.8 Hz, H2; 5.84, d, J = Widdowson, D. A,; Worth, B. R. J. Chem. SOC.,Perkin Trans. 1 1976, 821. 1.8 Hz, H4), the hydrogen atoms bound to C6 near 6 3 (6 3.1, (d) Collins, D. J.; Jackson, W. R.; Timms, R. N. Aust. J . Chem. 1977, 30, 2167. (e) Trost, B. M.; Verhoeven, T. J . Am. Chem. SOC.1978, 100, 3435. m, H6a; 2.8, dd, H6/3), the 18-methyl group at 6 1.02 (s), and (24) (a) Jaouen, G.; VessiBres, A,; Top, S.; Ismail, A. A,; Butler, I. S. J . the Cp* ligand at 6 2.04 (s). 13C N M R data are listed in the Am. Chem. SOC.1985, 107, 4778. (b) Top, S.; Jauoen, G.; VessiBres, A,; Experimental Section, together with assignments where these Abjean, J. P.; Davoust, D.; Rodger, C. A,; Sayer, B. G.; McGlinchey, M. J. Organometallics 1985, 4 , 2143. (c) Jaouen, G.; Vessibres, A. Pure Appl. could be made. As observed in similar systems, there is an upfield Chem. 1989, 61, 565. shift of ca. 40 ppm for the a-coordinated ring carbons (6 130.13, (25) (a) Moriarty, R. M.; Ku, Y. Y.; Gill, U. S.; Gilardi, R.; Perrier, R. C3; 100.57 and 94.33, C5 and C10; 84.34,76.87, and 76.39, C1, E.;McGlinchey, M. J. Organometallics 1989, 8, 960. (b) Moriarty, R. M.; C2, and C4). Guo, L.; Ku, Y. Y.; Gilardi, R., J. Chem. SOC.,Chem. Commun.1990, 1765. (26) (a) Top, S.; VessiBres, A,; Abjean, J-P.; Jaouen, G. J . Chem. SOC., As with estradiol, estrone reacts with [Cp*Ru(OMe)12to yield Chem. Commun.1984,429. (b) Jaouen, G.; Top, S.;Laconi, A,; Couturier, the corresponding a-complexes of the deprotonated form of D.; Brocard, J. J. Am. Chem. SOC.1984, 106, 2207. estrone, namely 5a and Sp, which exhibit properties similar to (27) (a) Vichard, D.; Gruselle, M.; El Amouri, H.; Jaouen, G. J . Chem. SOC.,Chem. Commun.1991, 46. (b) Vichard, D.; Gruselle, M.; El Amouri, those of 3a and 3p. In particular, hydrogen bonding of 5 to a H.; Jaouen, G.; Vaisserman, J. Organometallics 1992, I!, 976. free estrone molecule is also observed. These hydrogen bonds (28) El Amouri, H.;Gruselle, M.; Jackson, P. A.; Jaouen, G.;Vaissermann, are important not only for the biological properties of these J. Organometallics 1990, 9, 2871. (29) Sharpless, K. B.;Akashi, K.; Oshima, K. Tetrahedron Lett. 1976,29, 2503. (30) Birch, A . J.; Cross, P. E.;Connor, D. T.;Subba Rao, G. S. R. J . Chem. SOC.C 1966, 54. (31) (a) Vessibres,A.;Tondu,S.;Jaouen,G.;Top,S.;Ismail,A. A.;Teutsch, G.; Moguilewsky, M. Inorg. Chem. 1988, 27, 1852. (b) Top, S.; Gunn, M.; Jaouen, G.; Vaisserman, J.; Daran, J-C.; Thornback, J. R.; McGlinchey, M. J. Organometallics 1992, 11, 1201.
(32) (a) Urbanos, F.; Fernandez-Baeza, J.; Chaudret, B. J . Chem. SOC. Chem. Commun. 1991, 1739. (b) Halcrow, M. A,; Urbanos, F.; Chaudret, B. Organometallics, in press. (33) Cole-Hamilton, D. J.; Young, R. J.; Wilkinson, G. J. Chem. SOC., Dalton Trans. 1976, 1995. (34) Kegley, S. E.; Schaverien, C. J.; Freudenberger, J. H.; Bergman, R. G.; Nolan, S. P.; Hoff, C. D. J. Am. Chem. SOC.1987, 109, 6563.
3486 J. Am. Chem. Sot., Vol. 115, No. 9, 1993
Oestradiol
Urbanos et al.
Oestrone
Testosterone
&& 22
2 F ~H z ~
24
16
8 l4
2 H
0
3
4
\5
Progesterone
15
8 l4
2
6
HO
18zk=o
&160@H
16
IS
8 l4
2
15
2 /
g l4 I5
3 4
5\6
H
0
3
4
'
s
6
4
Cholesterol Dehydroisoandrosterone Androsterone Figure 1. Steroid substrates used in this work with atom numbering scheme employed.
7 6
Prednisolone
Table I. Conditions Employed and Yields Obtained for Reactions Discussed in This Paper
steroid estradiol
estrone
testosterone
solvent THF"
T (K)
reaction time (h)
293
5
gases detected
ligand transformation (%)
products
100
2a
28
THFb
293
16
50
CH2C12"
293
5
100
THFb
293
16
50
3a 38 4a 48 5a
CH2C12"
393
40
CH4
30
5s 2a
THF"
413
70
CH4
100
6a
progesterone
THF"
413
40
CH4
cholesterol
THF"
383
24
H2 + CH4
100
dehydroisoandrosterone
CH2C12" THF' THF' THF'
383 393 413 393
40 40 40 40
CH4 CH4 CH4 H2 + CH4
100 100 100 80
THF"
413
40
CH4
THF" THF" CH2C12" THF" THFC
433 293 393 413 413
40 5 40 40 40
androsterone prednisolone
H2 + CH4
co co
95
80 15 100 100 100 100
2a
28 6a 68 7a 78 8a 88 13a 14a 13a 13a 13a 16a 17a 16a 168 16a 18
spectroscopic yields (7%)
isolated yields (%)
60 40 79d 21d 67 33 7 9 25d 22 8 62
45 22 61d 12d 54 6 56d 16d 42
8 27 3 66 1 19 3 68 32 100 100 100 52 28 56 24 15 100
18 55 6 16 2 40 18 30 48 36 4 46
5 12
e e
19
75
35
Reaction with 1. Reaction with [Cp*Ru(OMe)]2. Reaction with 2 molar equiv of 1. Yields with respect to initial weight of steroid. e Complex mixture of products. a
molecules,27bbut they also control the self-assembly of organic and organometallic compounds in the solid state. The N M R spectra of 5 resemble those of 3 (5a:6 5.54, d, J = 6.5 Hz, H1; 4.75, dd, J = 1.7 and 6.5 Hz, H2; 4.70, d, J = 1.7 Hz, H4. 5@: 6 5.40, d, J = 6.6 Hz, H1; 4.60, d, J = 1.8 Hz, H4; 4.50, dd, J = 1.8 and 6.6 Hz, H2). As with other known ?r-phenoxo complexes, protonation of 3 and 5 with CF3S03H yields 2 and 4 without changing the a:@ isomer ratio. (2) Reactions of Cp*Ru+ (1) with Steroids Containing an Enone Function on the A-Ring. We have previously shown that demethylation of cyclic enones by 1 leads to coordinated phenol derivative^.'^^ It was of interest to test this type of reaction with important biological compounds such as testosterone and proges-
terone, both of which possess other reactive functionalities (Figure 1). Furthermore, demethylation of testosterone would yield estradiol in one step, a transformation usually achieved using multistep oxidation. The reaction conditions employed and yields obtained are summarized in Table I. All the reactions examined afforded methane, the presence of which was confirmed and quantified by GC. The highest yields of aromatized products were obtained in THF because of competitive C-Cl activation reactions in CH2Clz which lead to chloromethylidene ~ 1 u s t e r s . lThe ~ ~ highest yield was obtained at a temperature of 120 "C for a reaction time of 70 h, in which case the testosterone was quantitatively converted to estradiol and derivatives. N M R analysis of the reaction products shows, in addition to
J . Am. Chem. SOC.,Vol. 115, No. 9, 1993 3481
Selective Aromatization of the A - Ring of Steroids Table 11. Bond Lengths (A) for IS with Estimated Standard Deviations in Parentheses Ru-C(1) Ru-C(2) Ru-C( 3) Ru-C(4) Ru-C(5) C(l)-C(2) cwc(3) C(3)-C(4) C(4)-C(5) C(5)-C( 10) C( 10)-C( 1) C(5)-C(6) C(6)-C(7) C(6)-0 O-C(28) C (7 )-C( 81 C(8)-C(9) C(9)-C( 10) C( 10)-C( 19) C( 8)-C( 14) C(9)-C(11) C(29)-C(30) C(30)-C(31) C(31)-C(32) C(32)-C(33) C(33)-C(29)
2.201(4) 2.160(4) 2.159(5) 2.163(4) 2.222(4) 1.417(7) 1.388(6) 1.397(7) 1.410(7) 1.525 (6) 1.5 13(6) 1.519(6) 1.521(7) 1.426(5) 1.388( 6) 1.526(6) 1.53 l(6) 1.539(7) 1.546(7) 1.533(6) 1.527(6) 1.400(8) 1.398(9) 1.409(11) 1.388 ( 10) 1.410(8)
Ru-C(29) Ru-C( 3) Ru-C(3 1) Ru-C( 32) Ru-C( 33) C( 1I)*( 12) C(12)-C(13) C( 13)-C( 14) C( 13)-C(17) C( 13)-C( 18) C( 14)-C(15) C( 15)-C( 16) C( 16)-C( 17) C( 17)-C(20) C(2O)-C(21) C(2O)-C(22) C(22)-C(23) C (2 3)-C (24) C(24)-C(25) C(25)-C(26) C(25)-C(27) C(29)-C(34) C(30)-C(35) C(3 1)-C(36) C(32)-C(37) C( 33)-C( 3 8)
2.196(4) 2.198 (4) 2.171(7) 2.161 (6) 2.1 7 3( 6) 1.536(7) 1.525(7) 1.5 16(6) 1.552(6) 1.55l(6) 1.517(6) 1.535 (7) 1.551(6) 1.546(7) 1.501(6) 1.564(6) 1.479(8) 1.524(7) 1.520(7) 1.474(7) 1.516(8) 1.489(7) 1.495(7) 1.5 14(9) 1.463(7) 1.499(8)
the byproduct 6 (vide infra), the presence of 2a and 2P in a ratio of 6:1 for reaction at 100 O C and 8:l at 120 OC. These product ratios are different from that observed in the simple roomtemperature complexation of estradiol discussed earlier and are now similar to that obtained by Jaouen in refluxing MeCN of 85: 15. This may imply that equilibration between the isomers occurs at high temperatures (vide infra) or alternatively that attack on the a-face of testosterone is preferred because of the steric hindrance created by the 19-methyl group on the P-face of the molecule. In the latter case the carbon-carbon bond activation step would occur when the ruthenium center is bound to the a-face of the steroid, opposite the 19-methyl group, consistent with homolytic rupture of the carbon-carbon bond. The observed presence of 10-15% ethane in addition to methane in the gas phase is in agreement with this proposal, which was previously formulated for the aromatization of cyclic enones purely on the basis of gas-phase analysis. Together with compound 2,another very similar complex ( 6 ) is formed during these reactions in ca. 30% yield with respect to 2. 6 is present as a mixture of isomers in a ratio similar to that of 2 (6~x68, ca. 8:l). The IH N M R spectrum of 6a resembles that of 2a (6 2.07, CsMe5; 0.91, Me-18) except in the phenyl region, which consists of a complex multiplet at 6 6.0-6.3 and a singlet at 6 3.97 attributed to a methoxy group. 6/3 is a very minor component of the reaction mixture but is still identifiable by IH N M R (6 4.00, OMe; 2.09, C5Me5; 1.05, Me-18). Recrystallization from THF/Et20 produces a microcrystalline solid in ca. 60% yield. While the a:@ ratio is enhanced by recrystallization, the 2:6ratio is unaffected; we have been unable to separate 2 and 6. 6 was thus identified as a *-complex of the methyl ether derivative of estrone; such methyl ether derivative byproducts were also observed in the aromatization of simple cyclic enones by l.lSb For that reaction, it was shown that formation of the ether functionality occurred at an early stage of the aromatization process, before the C-C activation step. Analogous reactions were carried out using progesterone, which differs from testosterone by the presence of an acyl functionality at the 17-carbon atom compared to an hydroxyl group (Figure 1). This reaction is smoother than that observed for testosterone, and complete transformation of progesterone occurs after 40 h at 120 "C. As for the preceding reaction, four products are observed, viz. the products of aromatization at the A-ring (7; 7a:7&8:1) and their methyl ether derivatives (8; 8a:8j3,8-10:1;
7a:8a, 10:3). The IH and I3CN M R data for 7 and 8 are very similar to those of 2 and 4 and are given in the Experimental Section. N o side reactions such as decarbonylation of the acyl group are observed: G C analysis of the reaction mixture shows the presence of methane and ethane as before but no carbon monoxide. Reaction of 1 with testosterone in T H F at 293 K for 15 h clearly shows by IH N M R spectroscopy, in addition to unreacted steroid, the presence of two metal hydride species (9 and 10) at 6 5.21 (d, J = 6.7 Hz, H2), 5.17 (s, H4), and -5.70 (br s), and at 6 4.96 (d, J = 7.1 Hz, H2), 4.91 (s, H4), and -6.96 (d, J = 6.6 Hz), respectively. A similar reaction of 1 with progesterone allowed the observation of 11 and 12 at 6 5.22 (d, J = 6.7 Hz, H2), 5.19 (s, H4), 3.47 (d, J = 6.7 Hz, H l ) , and -5.68 (br s) and a t 6 4.98 (d, J = 6.9 Hz, H2), 4.93 (s, H4), 3.29 (dd, 6.9, J = 6.1 Hz, H l ) , and -6.96 (d, J = 6.1 Hz). These hydride resonances arevery similar to those observed for theintermediates [C~*RU'~(H)(?~-~,~-M~~C~H~OR)]+ ( R = H, Me) in the aromatization of 4,4'-dimethylcyclohexenone by and are in agreement with the formation of a hydrido q5-complex on which the C10-Cl9 bond cleavage has not yet occurred. Given this evidence, together with the similarity of the products observed in the two cases (CH4 and C2H6 in the gas phase, methyl ether derivatized byproducts), we propose that an analogous mechanism operates for these steroid transformations, i.e., coordination of Cp*Ru+ to the dienol form of the steroid enone, partial attack of methanolat the hydroxyl functionality of thecoordinated dienol to form the methoxy derivative, activation of a C-H bond to give the observed cyclohexadienyl hydride species, and finally rupture of the C10-Cl9 bond to yield methane and a ?r-arene complex (Figure 2). (3)Reactions of Cp*Ru+ (1) with Cholesterol and Dehydroisoandrosterone. The reactions described in the preceding section were an extension of previous work on cyclic enones and involved only a short sequence of mechanistic steps. In order to extend the scope of the aromatization reactions, we considered the case of sterols bearing unsaturation on the B-ring, such as cholesterol and dehydroisoandrosterone (Figure 1). In this case, aromatization of the A-ring could involve migration of the C5
