J. Org. Chem. 1998, 63, 9031-9036
9031
Intramolecular Ketone-Nitrile Reductive Coupling Reactions Promoted by Samarium(II) Iodide Gary A. Molander* and Chad N. Wolfe Department of Chemistry and Biochemistry, University of Colorado at Boulder, Boulder, Colorado 80309-0215 Received July 31, 1998
Samarium(II) iodide (SmI2) has been successfully utilized as a reducing agent for the intramolecular coupling of ketones with nitriles. The use of visible light to promote the reductive coupling represents an improvement over previously reported protocols. The procedure also avoids overreduction of the resulting R-hydroxy ketones. Monocyclic, fused bicyclic, and bridged bicyclic R-hydroxy ketones composed of a number of substitution patterns have been synthesized in moderate to excellent yield via this method. A sequential reaction consisting of a nucleophilic acyl substitution followed by a ketyl-nitrile coupling has also been accomplished. Introduction Carbonyl coupling reactions passing through a ketyl intermediate constitute an important class of reactions in organic chemistry. Samarium(II) iodide (SmI2) has been shown to promote a wide variety of these reactions, including ketyl-olefin couplings1 and intramolecular pinacolic coupling reactions.1b,c,e Ketyl formation can also be achieved with other reductants1d,2 and by electrochemical3 and photochemical processes.4 The high degree (1) (a) Girard, P.; Namy, J. L.; Kagan, H. B. J. Am. Chem. Soc. 1980, 102, 2693. (b) Molander, G. A.; Kenny, C. Tetrahedron Lett. 1987, 28, 4367. (c) Molander, G. A.; Kenny, C. J. Org. Chem. 1988, 53, 2132. (d) Fevig, T. L.; Elliot, R. L.; Curran, D. P. J. Am. Chem. Soc. 1988, 110, 5064. (e) Molander, G. A.; Kenny, C. J. Am. Chem. Soc. 1989, 111, 8236. (f) Enholm, E. J.; Trivellas, A. Tetrahedron Lett. 1989, 30, 1063. (g) Enholm, E. J.; Trivellas, A. J. Am. Chem. Soc. 1989, 111, 6463. (h) Enholm, E. J.; Satici, H.; Trivellas, A. J. Org. Chem. 1989, 54, 5841. (i) Bannai, K.; Tanaka, T.; Okamura, N.; Hazato, A.; Sugiura, S.; Manabe, K.; Tomimori, K.; Kato, Y.; Kurozumi, S.; Noyori, R. Tetrahedron 1990, 31, 6689. (j) Molander, G. A.; Kenny, C. J. Org. Chem. 1991, 56, 1439. (k) Molander, G. A.; McKie, J. A. J. Org. Chem. 1992, 57, 3132. (l) Baldwin, J. E.; Mackenzie Turner, S. C.; Moloney, M. G. Tetrahedron Lett. 1992, 33, 1517. (m) Tadano, K.; Isshiki, Y.; Minami, M.; Ogawa, S. Tetrahedron Lett. 1992, 33, 7899. (n) Tadano, K.; Isshiki, Y.; Minami, M.; Ogawa, S. J. Org. Chem. 1993, 58, 6266. (o) Molander, G. A.; McKie, J. A. J. Org. Chem. 1994, 59, 3186. (p) Enholm, E. J.; Trivellas, A. Tetrahedron Lett. 1994, 35, 1627. (q) Baldwin, J. E.; Mackenzie Turner, S. C.; Moloney, M. G. Tetrahedron 1994, 50, 9411. (r) Baldwin, J. E.; Mackenzie Turner, S. C.; Moloney, M. G. Tetrahedron 1994, 50, 9425. (s) Molander, G. A.; McKie, J. A. J. Org. Chem. 1995, 60, 872. Reviews: (t) Kagan, H. B.; Namy, J. L. Tetrahedron 1986, 42, 6573. (u) Kagan, H. B. New J. Chem. 1990, 14, 53. (v) Molander, G. A. In The Chemistry of the Metal-Carbon Bond; Hartley, H. R., Patai, S., Eds.; J. Wiley & Sons: New York, 1989; Vol. 5, p 319. (w) Molander, G. A. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 1, p 251. (x) Soderquist, J. A. Aldrichimica Acta 1991, 24, 14. (y) Molander, G. A. Chem. Rev. 1992, 92, 29. (2) (a) Eakin, M.; Martin, J. J. Chem. Soc., Chem. Commun. 1965, 206. (b) Stork, G.; Malhorta, S.; Thompson, H.; Uchibayashi, M. J. Am. Chem. Soc. 1965, 87, 1148. (c) Sowinski, A. F.; Whitesides, G. M. J. Org. Chem. 1979, 44, 2369. (d) Pradhan, S. K.; Kadam, S. R.; Kolhe, J. N.; Radhakrishnan, T. V.; Shani, S. V.; Thaker, V. B. J. Org. Chem. 1981, 46, 2622. (e) Ikeda, T.; Yue, S.; Hutchinson, C. R. J. Org. Chem. 1985, 50, 5193. (f) Corey, E. J.; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821. (3) (a) Shono, T.; Nishiguchi, I.; Ohimizu, H.; Mitani, M. J. Am. Chem. Soc. 1978, 100, 545. (b) Fox, D. P.; Little, R. D.; Baizer, M. M. J. Org. Chem. 1985, 50, 2202. (c) Kariv-Miller, E.; Mahachi, T. J. J. Org. Chem. 1986, 51, 1041. (d) Little, R. D.; Fox, D. P.; Hijfte, L. V.; Dannecker, R.; Sowell, G.; Wolin, R. L.; Moens, L.; Baizer, M. M. J. Org. Chem. 1988, 53, 2287. (e) Kariv-Miller, E.; Maeda, H.; Lombardo, F. J. Org. Chem. 1989, 54, 4022.
of chemoselectivity exhibited by SmI2, however, provides several advantages over the aforementioned methods. For instance, a large number of organic functional groups are tolerated under the mild reaction conditions. Furthermore, the Sm(III) Lewis acid generated during the course of the reaction can be used as a template to control stereochemistry in appropriately designed substrates.1e,5 Differential reactivity of various reducible groups permits the sequencing of organic reactions with this reductant. Thus, complex products can be accessed from relatively simple precursors in a one-pot process.1j,k,6 Ketyls have also been coupled with nitriles, providing the same R-hydroxy ketone products as generated by an acyloin condensation. Although the acyloin condensation itself is an effective method for generating medium- and large-membered rings, it employs harsh reaction conditions and generally gives low yields when forming fiveand six-membered rings.7 This method also suffers from poor regiochemical and stereochemical control.7a,b,8 An intramolecular SmI2-promoted version of the acyloin condensation, employing an acyl anion derived from a carboxylic acid chloride, has also been studied.9 Synthesis of R-hydroxycyclopentanones by this route was not (4) (a) Belloti, D.; Cossy, J.; Pete, J. P.; Portella, C. Tetrahedron Lett. 1985, 26, 4591. (b) Belloti, D.; Cossy, J.; Pete, J. P.; Portella, C. J. Org. Chem. 1986, 51, 4196. (c) Cossy, J.; Belloti, D. Tetrahedron Lett. 1988, 29, 6113. (5) (a) Molander, G. A.; Etter, J. B.; Zinke, P. W. J. Am. Chem. Soc. 1987, 109, 453. (b) Molander, G. A.; Etter, J. B. J. Am. Chem. Soc. 1987, 109, 6556. (6) (a) Takai, K.; Nitta, K.; Fujimara, O.; Utimoto, K. J. Org. Chem. 1989, 54, 4732. (b) Curran, D. P.; Fevig, T. L.; Totelben, M. J. Synlett 1990, 773. (c) Molander, G. A.; Harring, L. S. J. Org. Chem. 1990, 55, 6171. (d) Curran, D. P.; Wolin, R. L. Synlett 1991, 317. (e) Baley, R. A.; Motherwell, W. B. Tetrahedron Lett. 1991, 32, 6649. (f) Enholm, E. J.; Jiang, S.; Abboud, K. J. Org. Chem. 1993, 58, 4061. (g) Yu, Y.; Lin, R.; Zhang, Y. Tetrahedron Lett. 1993, 34, 4547. (h) Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1995, 117, 3705. (i) Molander, G. A.; Harris, C. R. J. Am. Chem. Soc. 1996, 118, 4059. (j) Molander, G. A.; Harris, C. R. Chem. Rev. 1996, 96, 307. (k) Molander, G. A.; Harris, C. R. Tetrahedron 1998, 54, 3321. (7) (a) Sheenan, J. C.; O’Neill, R. C.; White, M. A. J. Am. Chem. Soc. 1950, 72, 3376. Reviews: (b) Finley, K. T. Chem. Rev. 1964, 64, 573. (c) Broomfield, J. J.; Owsley, D. C.; Nelke, J. N. In Organic Reactions; J. Wiley & Sons: New York, 1976; Vol. 23, p 259. (8) (a) Sheenan, J. C.; O’Neill, R. C. J. Am. Chem. Soc. 1950, 72, 4614. (b) Sheenan, J. C.; Coderre, R. C. J. Am. Chem. Soc. 1953, 75, 3997. (c) Gutsche, C. D.; Tao, I. Y. C.; Kozma, J. J. Org. Chem. 1967, 32, 1782.
10.1021/jo981537m CCC: $15.00 © 1998 American Chemical Society Published on Web 11/05/1998
9032 J. Org. Chem., Vol. 63, No. 24, 1998
possible because the conditions required for the generation of the requisite acid chlorides enolized the ketones, leading to the formation of enol lactones (eq 1).9 However, construction of six-membered rings was achieved in yields ranging from 36 to 82% (eq 2), as these substrates were not as prone to enolization.9
Ketyl-nitrile coupling reactions have been mediated by Zn/TMSCl,2f by SmI2,1e,10 and by electrochemical methods.11 Photochemically promoted ketyl-nitrile coupling reactions have proven unsuccessful.4b In some instances the SmI2-promoted reaction proceeds with much better stereochemical control than identical reactions promoted by electrochemical processes.11b The Sm(III) Lewis acid that is generated during the course of the reaction can chelate substrates to control the stereochemistry of the cyclization. Chelation control has not been studied in the Zn/TMSCl procedure, where only a single result has been reported.2f Although the SmI2 method generally proceeds with excellent diastereoselectivity,1e,10 the yields utilizing past experimental protocols were less than satisfactory (99% pure by gas chromatographic analysis: 1H NMR (300 MHz, CDCl3) δ 2.61 (s, 1H), 2.39-2.19 (m, 3H), 2.06-1.67 (m, 3H), 1.52-1.23 (m, 3H), 1.10 (s, 3H), 0.91 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 219.91, 79.09, 40.30, 39.07, 37.52, 34.06, 32.69, 32.10, 28.88, 26.23; IR (neat) 3425.9, 2953.0, 2933.0, 2869.5, 1747.9 cm-1; LRMS (EI+) m/z 168 (36), 112 (57), 97 (100); HRMS (EI+) calcd for C10H16O2 168.1150, found 168.1145. Ethyl (1R*, 2R*)-2-Hydroxy-1,2-dimethyl-3-oxocyclopentanecarboxylate (2m). 2m was prepared from keto nitrile 1m according to the general procedure for 2a. Purification by flash chromatography (40% EtOAc/hexanes) and Kugelrohr distillation (ot 55-65 °C at 0.01 mmHg) afforded 2m in 65% yield: 1H NMR (300 MHz, CDCl3) δ 4.15-4.07 (m, 2H), 2.85 (br s, 1H), 2.55-2.21 (m, 3H), 1.79-1.68 (m, 1H), 1.27 (s, 3H), 1.19 (t, J ) 7.22 Hz, 3H), 1.15 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 217.07, 175.13, 80.71, 61.07, 52.08, 31.65, 29.13, 19.30, 17.44, 13.93; IR (neat) 3480.0, 2981.1, 2941.2, 1738.2 cm-1; LRMS (EI+) m/z 155 (8), 144 (100), 98 (85), 43 (57); HRMS (EI+) calcd for C10H16O4 200.1049, found 200.1059. Anal. Calcd for C10H16O4: C, 59.98; H, 8.05. Found: C, 59.70; H, 8.07. (1R*,2R*)-N,N-Diethyl-2-hydroxy-2-methyl-3-oxocyclopentanecarboxylate (2o). 2o was prepared from keto nitrile 1o according to the general procedure for 2a. Purification by flash chromatography (100% EtOAc) and Kugelrohr distillation (ot 90-95 °C at 0.01 mmHg) afforded 2o in 89% yield: 1H NMR (500 MHz, CDCl ) δ 4.75 (br s, 1H), 3.33-3.19 (m, 3 4H), 2.89-2.86 (m, 1H), 2.50-2.43 (m, 1H), 2.21-2.14 (m, 1H), 2.06-1.99 (m, 2H), 1.16 (s, 3H), 1.12-1.09 (m, 3H), 1.01-0.99 (m, 3H); 13C NMR (125 MHz, CDCl3) δ 214.52, 173.17, 77.53, 46.65, 42.05, 40.17, 32.24, 22.04, 21.08, 14.52, 12.75; IR (neat) 3237.0, 2975.1, 2934.9, 1752.2, 1684.0 cm-1; LRMS (EI+) m/z 157 (71), 142 (27), 43 (65); HRMS (CI+) calcd for C11H20NO3 (M + H)+ 214.1443, found 214.1457. Anal. Calcd for C11H19NO3: C, 61.95; H, 8.98; N, 6.57. Found: C, 62.18; H, 9.22; N, 6.96. Ethyl cis-5-Hydroxy-4-oxobicyclo[3.3.0]octanecarboxylate (4). To Sm (0.740 g, 4.92 mmol) was added I2 (1.125 g, 4.43 mmol). Then 45 mL of dry THF was added. The resultant orange slurry was stirred vigorously for 2 h at rt. NiI2 (0.014 g, 0.044 mmol) was then added to the freshly generated SmI2. The resulting SmI2 solution had a deep bluegreen color. Keto nitrile 3 (0.401 g, 1.05 mmol) was added dropwise as a 0.05 M solution in dry THF. After 2 h, TLC showed complete consumption of the starting material. tBuOH (0.163 g, 2.20 mmol) was added, and the reaction mixture was cooled to 0 °C. The reaction mixture was irradiated with a 250 W flood lamp for 2 h at 0-10 °C. After 2 h, the reaction was found to be complete by TLC. The reaction was quenched with Rochelle’s salt,13 and the mixture was subjected to an aqueous workup. The crude product was purified by flash chromatography (40% EtOAc/hexanes) and Kugelrohr distillation (ot 70-80 °C at 0.01 mmHg) to afford 0.110 g of 4 (49% yield): 1H NMR (300 MHz, CDCl3) δ 4.12 (q, J ) 7.08 Hz, 2H), 3.00 (br s, 1H), 2.53-2.40 (m, 3H), 2.322.23 (m, 1H), 2.11-1.69 (m, 6H), 1.20 (t, J ) 7.08 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 216.36, 173.87, 89.58, 61.00, 36.84, 33.47, 33.05, 27.55, 22.86, 14.05; IR (neat) 3469.7, 2970.6, 1737.9 cm-1; LRMS (EI+) m/z 156 (100), 110 (78), 97 (23); HRMS (EI+) calcd for C11H16O4 212.1049, found 212.1054. Anal. Calcd for C11H16O4: C, 62.25; H, 7.60. Found: C, 62.17; H, 7.84.
Acknowledgment. We gratefully acknowledge the National Institutes of Health (GM 35249) for their generous support.
9036 J. Org. Chem., Vol. 63, No. 24, 1998 Supporting Information Available: Experimental details and characterization for substrates 1b, 1d-o, 3, 7, and their precursors and 1H and 13C NMR spectra for compounds without reported elemental analyses (52 pages). This material is contained in libraries on microfiche, immediately follows this
Molander and Wolfe article in the microfilm version of the journal, and can be ordered from the ACS; see any current masthead page for ordering information. JO981537M
