J. Org. Chem. 1992,57,1733-1740 160.0553, found 160.0549. Anal. Calcd for C,H1202S: C, 52.50; H, 7.50. Found C, 52.77; H. 7.56. -~ -(&)-3,3-Dimethyl-2-tetrahydrothiopheneacetic acid (50): 587 mg (3.37 mmol, 75%)from 41;mp 55-56 "C (hexane-ether); IR (CHClJ 3500-2300,1715,1390,1370cm-'; 'H NMR (CDC1,) 6 11.10 (bs, 1 H), 3.33 (dd, 1 H, J = 10.8, 3.7 Hz), 2.81 (m, 2 H), 2.75 (dd, 1 H, J = 16.5,3.7 Hz), 2.43 (dd, 1 H, J = 16.5,10.8 Hz), 1.83 (m, 2 H), 1.11 (s,3 H), 0.96 (s,3 H); '% NMR (CDC1,) 6 178.7, 51.8,44.3,44.1,237.4,28.7,26.0,20.9; HRMS mle for C8H1,O2S calcd 174.0714, found 174.0709. Anal. Calcd for C8H1402S:C, 55.14;H, 8.09. Found C, 55.84; H, 8.09. (f)-2-Thiaspiro[4.5]deane-l-aoetic acid (51): 683 mg (3.20 mmol, 71%) from 42;mp 101-102 OC (hexane-ether); IR (thin film)3520-2880,1725 cm-'; 'H NMR (CDC13) 6 12.40-11.60 (bs, 1 H), 3.36 (dd, 1 H, J = 11.4, 3.6 Hz), 2.81 (m, 2 H), 2.76 (dd, 1 H, J = 15.9, 3.6 Hz), 2.40 (dd, 1 H, J = 15.9, 11.4 Hz), 1.93 (m, 1 H), 1.77 (m, 1 H), 1.57-1.25 (cplx, 10 H); 13CNMR (CDCl,) 6 178.5,64.0,50.8,47.8,38.0,34.9,30.6,28.2,26.4,23.3, 23.1; HRMS mle for CllH1802Scalcd 214.1022, found 214.1006. Anal. Calcd for CllH180&3: C, 61.65; H, 8.47. Found C, 61.84, H, 8.35. (&)-4,4-Dimethyl-2R-tetrahydrothiopyran-2-acetic acid (52): 662 mg (3.52 mmol, 78%) from 43;mp 96-97 OC (hexane-ether); IR (CHClJ 3500-2100,1720,1395,1375 cm-l; 'H N M R (CDC13)6 11.35 (bs, 1 H), 3.31 (m, 1 H), 2.91 (dt, 1 H, J = 13.5, 2.7 Hz), 2.44 (m, 3 H), 1.66 (m, 2 H), 1.44 (dt, 1 H, J = 13.2, 3.9 Hz), 1.24 (t, 1 H, J = 12.6 Hz), 0.93 (e, 3 H), 0.91 (8, 3 H); 13C NMR (CDCl3) 6 177.7, 46.8,40.9,39.0,33.7, 33,3, 30.6, 25.4, 23.7; HRMS mle for CBHIBOZS calcd 188.0871, found 188.0870. Anal. Calcd for CgH1602S:C, 57.42; H, 8.56. Found C, 57.35; H, 8.64. (+2-Methyl-2~-tetrahydrothiopheneacetic acid (53): 576 mg (3.60 mmol, 80%)from 45;mp 33-34 "C (pentane-ether); IR (CHClJ 3700-2200, 1710, 1376 cm-'; 'H NMR (CDC13) 6 11.2E4-10.92 (bs, 1 H), 2.96 (m, 2 H), 2.76 (s, 2 H), 2.11 (m, 2 H), I
1783
2.03 (m, 1 H), 1.95 (m, 1 H), 1.56 (8, 3 H); lSC NMR (CDClS) 6 177.2,53.7, 48.0,44.0,33.3, 29.6,29.5; HRMS mle for CIHl20# calcd 160.0558, found 160.0557. Anal. Calcd for C1Hl2O2S: C, 52.43; H, 7.55. Found C, 52.58; H, 7.64. Reaction Chronology Studies. A. Nitrogen Heterocycles. A 5-mL EtOH solution of 0.57 g (0.62 mL, 5.00 mmol) of ethyl crotonate,0.54 g (0.55 mL, 5.00 m o l ) of benzylamine, 1.06 g (0.74 mL, 5.00 "01) of l-iodohexane, and 0.56 g (0.77 mL, 5.50 mmol) of triethylamine was heated at reflux according to the standard heterocyclization procedure. The reaction was monitored by GC analysis of 0.15-pL aliquots removed from the reaction at 30-min intervals during the f i t 3 h and at l-h intervals thereafter. After 12 h, all of the benzylamine and l-iodohexane had been consumed. A significant amount (ca. 75%) of the ethyl crotonate remained unreacted after this time. B. S u l f u r Heterocycles. A mixture of 1.24 g (5.00 mmol) of ethyl of benzylisothiouronium bromide and 0.88 g (5.00 "01) cinnamate was stirred at 23 OC with 20% KOH in 4:l water/ EtOH. The reaction was monitored by TLC at 15min intervals for disappearance of the reactants. After 40 min, the ethyl cinnamate had been completely consumed. Benzyl mercaptan and its cinnamate addition product were formed to only a minor extent during this period.
Acknowledgment. Support of this work by the Oklahoma Center for the Advancement of Science and Technology (Nos. HR8084 and HR1-035) is greatly appreciated. The authors also acknowledge partial support by NSF grants DMB-8603864 and CHE-8718150 in the upgrade of our NMR facility and BSS-8704089 for our mass spectrometry facility. Supplementary Material Available: High-field 'H NMR 36,37,38, and 13CNMR spectra for 9, 11, 13,15,20,22,24,28a, 39,41,42,43,and 44 (32 pages). Ordering information is given on any current masthead page.
Silyl Group-Transfer-MediatedSerial Michael Additions Peter G. Klimko' and Daniel A. Singleton* Department of Chemistry, Texas ABM University, College Station, Texas 77843 Received September 26, 1991 Three protocols have been developed for achieving ordered, multiple (serial) Michael reactions initiated by silyl enol ethers or silyl ketene acetals. Anion (fluoride or m-chlorobenzoate) catalysis was most effective for reactions of silyl ketene acetal 2 with bis diesters, aa in the highly selective formation of 3. Lewis acid (ZnIz) catalysis was more general than anion catalysis and afforded stereochemically complementary products with lower selectivity. The use of SnC12-trityl chloride was effective in reactions of both silyl ketene acetals and silyl enol ethers with bis enones. Very high stereoselectivity was generally observed in the formation of cyclopentanes. The products of serial Michael reactions of bis enones could be regiospecifically cyclized to bicyclic enones. Overall, it was found that the serial Michael reactions initiated by silyl enolates can be used to form efficiently and selectively complex cyclics from simple acyclic precursors.
Introduction Ordered sequences of Michael reactions, in which each intermediate Michael addition initiates a specific subsequent addition, are a potentially powerful tool for the synthesis of cyclics and polycyclics. The utility of these 'serial Michael additions" has been exemplified by t h e use of sequential inter- and intramolecular Michael reactions in t h e total syntheses of 3-de~methylaflavinine~ a n d di(1) NSF Pre-doctoral Fellow, 19-1991.
hydronepat~lactone,~ 'double Michael" reactions as Diels-Alder equivalents in several syntheses? and the sequencing of up to three intermolecular Michael reactions by P o s n e ~ . ~In principle, large and varied arrays of (2) Danishefsky, S.; Chackalamannil, S.; Harrison, P.; Silvestri, M.; Cole, P. J . Am. Chem. Soc. 1985,107,2474. (3) Uyehara, T.;Shida, N.; Yamamoto,Y. J. Chem. SOC.,Chem. Commun. 1989, 113. (4) Ihara, M., Suzuki, M.; Fukumoto, K.; Kabuto, C. J. Am. Chem. SOC.1990, 112, 1164, and references cited therein. Roberta, M. R.; Schlessinger, R. H. J . Am. Chem. SOC. 1981, 103, 724.
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electrophilic olefins can undergo serial intramolecular Michael additions terminated by protonation or reaction with other electrophiles. However, such sequences are subject to the limitations of Michael methodology. “Traditional” Michael conditions (catalytic amounts of base,protic solvent)have been used in most intramolecular Michael reactions! but are not generally suitable for serial Michael additions due to rapid protonation of intermediate carbanions. “Kinetic” Michael reactions (stoichiometric anions) have been central to the aforementioned serial reactions. However, such sequences must be carefully planned to avoid polymerization, proton transfers, competitive l,a-addition,and retrograde Michael reactions, and yields have often been These problems, general to base-promoted Michael reactions, are much less prevalent in Michael additions initiated by silyl enol ethers and silyl ketene acetals. The addition of silyl enolates to activated olefins may be catalyzed by Lewis acids, as in the “Mukaiyama-Michael” reaction! or anions (often fluoride) as in “group-transfer polymerization” (GTP).’OJ1 The likely suitability of these reactions for serial Michael additions heis been established in recent variations which allow the isolation or subsequent in situ reaction of silyl enol ethers derived fr6m these conjugate additions.12J3 In this paper, we describe a series of methods for achieving sequential silyl-mediated intermolecular and intramolecular Michael reactions with sim(5) (a) Posner, G. H.; Asirvatham, E. Tetrahedron Lett. 1986,27,663. (b) Posner, G. H.; Webb, K. 5.;Aeirvatham, fi.; Jew, S.; Degl’Innocenti, k J. Am. Chem. Soc. 1988,110,4754. (c) Posner, G. H.; Shulman-Ruskea, E. M. J. Org. Chem. 1989,54, 3514. (6) For examples, see: (a) Stork, G.; Taber, D. F.; Manr, M. Tetrahedron Lett. 1978, 2445. (b) Stork, G.; Shiner, d. S.; Winkler, J. D. J. Am. Chem. SOC.1982,104,310. (c) Stork, G.; Winkler, J. IY.; Saccomano, N. A. Tetrahedron Lett. 1983,465. (d) Stork, G.; Saccomano, N. Nouu. J. Chim. 1986,10,677. (e) Barton, D. H. R.; Campos-Neves, A. D. S.; Scott, A. I. J. Chem. SOC. 1967, 2698. (fj Alexakis, A.; Chapdlaine, M. J.; Posner, G. H. Tetrahedron Lett. 1978,4209. (9) Gregory, B.; Bullock, E.; Chen, T. J. Chem. SOC., Chem. Commun. 1979,1070. (h) Lombardo, L.; Mander, L. N.; Turner, J. V. J. Am. Chem. SOC.1980,102,6626. (i) Brattesani, D. N.; Heathcock, C. H. J. Org. Chem. 1975, 40, 2165. (j) Johnson, W. S.; Shulman, S.; Williamson, K. L.; Pappo, R. J.Org. Chem. 1962,27,2015. (k) Trost, B. M.; Suey, C. D.; DiNinno, F. J.Am. Chem. SOC. 1979,101,1284. (7) An intermolecular Michael addition-intramolecular alkylation or Claisen o r d u r e . termed ‘Michael-Initiated Rinn Cloeure” by Little, has been ued for the synthesis of three-to seven-membered rings; sometimea with excellent diastereoselectivity. (a) Cooke, M. P. Tetrahedron Lett. 1979,2199. (b) Little, R. D.; D a m n , J. R. Tetrahedron Lett. 1980,2609. (c) Little, R. D.; Verhre, R.; Monte, W. T.; Nugent, S.; Dawson, J. R. J. Org. Chem. 1982,47, 362. (d) Nugent, W. A,; Hobbs, F. W., Jr. J. Org. Chem. 1983,48,5364. (e) Crimmins, M. T.; Mascarella, S. W.; DeLoach, J. A. J. Org. Chem. 1984,49,3033. (fj Yamaguchi, M.; Tsukamoto, M. Hirao, I. Tetrahedron Lett. 1986, 1723. (9) See ref 5a-c. (8)For a recent review on the intramolecular Michael reaction and other ring-closure methods, see: Thebtaranonth, C.; Thebtaranonth, Y. Tetrahedron 1990,46, 1385. (9) (a) Naraaaka, K.; Soai, K.; Mukaiyama, T. Chem. Lett. 1974,1223. (b) Mukaiyama, T. Angew. Chem., Int. Ed. Engl. 1977,16,817. (10) Anion-catalpd grouptransfer polymerization (GTP) of activated olefins: (a) Webeter, 0. W.; Hertler, Sogah, D. Y.; Farnham, W. B.; RajanBabu, T. V. J. Am. Chem. SOC.1983,105, 5706. (b) Sogah, D. Y.; Hertler, W. R.; Webster, 0. W.; Cohen, G. M. Macromolecules 1987,20, 1473. (c) Hertler, W. R. Macromolecules 1987,20,2976. (d) Hertler, W. R.; RajanBabu, T. V.; Ovenall, D. W.; Reddy, G. S.; Sogah, D. Y. J. Am. Chem. SOC.1988, 110, 5841. (e) Brittain, W. J.; Dicker, I. B. Macromolecules 1989,22,1054. (f) Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1988,27, 994. (11) Lewis acid-catalyzed GTP of activated olefins: Hertler, W. R.; Sogah, D. Y.; Webster, 0. W.; Trost, B. M. Macromolecules 1984, 17, 1415. (12) (a) Rajanbabu, T. V. J. Org. Chem. 1984,49,2083. (b) Kita, Y.; Segawa, J.; Haruta, J.; Fujii, T.; Tamura, Y. TetrahedronLett. 1980,3779. (c) Kita, Y.; Segawa, J.; Hruuta, J.; Yasuda, H.; Tamura, Y. J. Chem. Soc., Perkin Trans. 1 1982, 1099. (d) Bunce, R. A.; Schled, M. F.; Dauben, W. G.; Heathcock, C. H. Tetrahedron Lett. 1983,24,4943. (e) Yamamoto, Y.; Maruyama, K.; Mateumoto, K. Ibid. 1984,25, 1075. (13) (a) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1986, 953. (b) Kobayashi, S.; Mukaiyama, T. Chem. Lett. 1986, 221.
Klimko and Singleton Table I. Anion-Catalyzed Serial Michael Additions Initiated by 2 acceptor procedure” yield product(s)
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