Base-Catalyzed Stereoselective Isomerization of Electron-Deficient Propargylic Alcohols to E-Enones
SCHEME 1. E-Enone B
Isomerization of Propargylic Alcohol A to
SCHEME 2.
Nineham-Raphael Reaction
John P. Sonye and Kazunori Koide* Department of Chemistry, UniVersity of Pittsburgh, 219 Parkman AVenue, Pittsburgh, PennsylVania 15260
[email protected] ReceiVed February 14, 2006
We have developed highly stereoselective methods to isomerize electron-deficient propargylic alcohols to E-enones under mild conditions (EWG ) electron-withdrawing group). Among weak bases we screened, catalytic (10-20 mol %) 1,4-diazabicyclo[2.2.2]octane (DABCO) was found to be effective in most cases. When the substrate is conjugated with an amide, the addition of sodium acetate catalyzed the isomerization. γ-Oxo-R,β-(E)-alkenyl esters (B, Scheme 1) are substrates for many types of organic reactions including Diels-Alder cycloadditions1 and cyclopropanations.2 These esters are also part of peptidomimetic3 and natural products such as pyrenophorin4 and macrosphelide B.5 Compounds B, particularly those with R ) aryl, are biologically and medicinally important small molecules.6 While compounds B can be formed by means of (1) (a) Angell, E. C.; Fringuelli, F.; Guo, M.; Minuti, L.; Taticchi, A.; Wenkert, E. J. Org. Chem. 1988, 53, 4325-4328. (b) Kowalski, C. J.; Lal, G. S. J. Am. Chem. Soc. 1988, 110, 3693-3695. (c) Molander, G. A.; Harris, C. R. J. Org. Chem. 1998, 63, 812-816. (2) Hirayama, T.; Oshima, K.; Matsubara, S. Angew. Chem., Int. Ed. 2005, 44, 3293-3296. (3) Vabeno, J.; Brisander, M.; Lejon, T.; Luthman, K. J. Org. Chem. 2002, 67, 9186-9191. (4) Nozoe, S.; Hirai, K.; Tsuda, K. Tetrahedron Lett. 1965, 6, 46754677. (5) (a) Hayashi, M.; Kim, Y. P.; Hiraoka, H.; Natori, M.; Takamatsu, S.; Kawakubo, T.; Masuma, R.; Komiyama, K.; Omura, S. J. Antibiot. 1995, 48, 1435-1439. (b) Takamatsu, S.; Kim, Y. P.; Hayashi, M.; Hiraoka, H.; Natori, M.; Komiyama, K.; Omura, S. J. Antibiot. 1996, 49, 95-98. (6) (a) Tomassini, J.; Selnick, H.; Davies, M. E.; Armstrong, M. E.; Baldwin, J.; Bourgeois, M.; Hastings, J.; Hazuda, D.; Lewis, J.; McClements, W. Antimicrob. Agents Chemother. 1994, 38, 2827-2837. (b) Ozeki, K.; Ishizuka, Y.; Sawada, M.; Shimamura, H.; Ichikawa, T.; Sato, M.; Yaginuma, H. Yakugaku Zasshi 1987, 107, 268-273. (c) Anderson, B. M.; Tanchoco, M. L.; Dal Pozzo, A. Biochim. Biophys. Acta 1982, 703, 204211.
Wittig-type condensations,3 they can also be generated by the isomerization of readily accessible7 γ-hydroxy-R,β-alkynyl esters A. In 1949, the first example of such an isomerization was reported by Nineham and Raphael (Scheme 2),8 whereby 1 was subjected to excess Et3N at 23 °C and the subsequent distillation afforded E2. The high E-selectivity is presumably due to the isomerization of Z2 to E2 at elevated temperature in the presence of Et3N as indicated in more recent literature.9 Although an alternative stereoselective isomerization of A to B is known, calling for 3 mol % of Rh(PPh3)3Cl and air-sensitive10 tri-n-butylphosphine at 110 °C,11 currently the Nineham-Raphael method appears to be the method of choice.9,12 Additional methods continue to emerge as isomerization of propargylic alcohols to enones is an important topic in organic synthesis.13 The currently used, modified Nineham-Raphael method requires a high temperature (60 °C) and stoichiometric Et3N in limited substrates, which prompted us to develop a more convenient method for the conversion of A to B. We found that treatment of 1 with 10 mol % of Et3N in CH2Cl2 at 23 °C gave a mixture of E2 and Z2 in 70% yield with an E/Z ratio of 2:1. To optimize the reaction conditions, we screened organic bases (DBU, DMAP, DABCO, Et3N, iPr2NEt) with 1 (initially at 0.25 M) in NMR tubes with various solvents at 23 °C, the result of which is summarized in Table 1. The conversion of 1 to E2 and Z2 was catalyzed by DBU with moderate E-selectivity in CDCl3 (entry 1, E/Z ) 5:1). Under these conditions, the E/Z ratio remained the same even after the starting material was consumed, excluding the isomerization of Z2 to E2. Although the DBU-catalyzed redox isomerization was facile (t1/2 < 0.3 h), less basic and more selective catalysts would be more desirable. Treatment of 1 with DMAP, a milder base, generated an intractable mixture (entry 2) that did not contain either E2 (7) (a) Midland, M. M.; Tramontano, A.; Cable, J. R. J. Org. Chem. 1980, 45, 28-29. (b) Shahi, S. P.; Koide, K. Angew. Chem., Int. Ed. 2004, 43, 2525-2527. (8) Nineham, A. W.; Raphael, R. A. J. Chem. Commun. 1949, 118121. (9) Bernotas, R. C. Synlett 2004, 2165-2166. (10) Buckler, S. A. J. Am. Chem. Soc. 1962, 84, 3093-3097. (11) Saiah, M. K. E.; Pellicciari, R. Tetrahedron Lett. 1995, 36, 44974500. (12) Coelho, A.; Sotelo, E.; Ravina, E. Tetrahedron 2003, 59, 24772484. (13) (a) Trost, B. M.; Livingston, R. C. J. Am. Chem. Soc. 1995, 117, 9586-9587. (b) Ishikawa, T.; Mizuta, T.; Hagiwara, K.; Aikawa, T.; Kudo, T.; Saito, S. J. Org. Chem. 2003, 68, 3702-3705. (c) Erenler, R.; Biellmann, J.-F. Tetrahedron Lett. 2005, 46, 5683-5685. (d) Tanaka, K.; Shoji, T. Org. Lett. 2005, 7, 3561-3563. 10.1021/jo060304p CCC: $33.50 © 2006 American Chemical Society
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Published on Web 07/07/2006
TABLE 1. Redox Isomerization Optimizationa entry
base
solvent
t1/2 (h)
E2/Z2
1 2 3 4 5 6 7 8 9 10 11 12
DBU DMAP Et3N Et3N Et3N iPr NEt 2 iPr NEt 2 iPr NEt 2 DABCO DABCO DABCO DABCO
CDCl3 CDCl3 CDCl3 C6D6 DMSO-d6 CDCl3 C6D6 DMSO-d6 CDCl3 C6D6 DMSO-d6 CD3CN
10:1
17 16 1.5 60 126 12 0.7
a Conditions: initial [1] ) 0.25 M, base (10 mol %), solvent (1.0 mL), 23 °C.
or Z2. Although Et3N-catalyzed reactions were nearly quantitative in various solvents (entries 3-5), the E/Z ratios were low (∼1.7:1). It is noteworthy that despite the poor selectivity the reaction in DMSO (entry 5) was significantly faster than those in less polar solvents (CDCl3, C6D6; entries 3 and 4). Interestingly, bulkier iPr2NEt (entries 6-8) reversed the stereoselectivity, generating E2 and Z2 in 1:1-1.6 ratios. These reactions were again nearly quantitative; however, they were sluggish, requiring 12-126 h for 50% conversion. During these iPr2NEtcatalyzed reactions, the E/Z ratios remained the same for at least 96 h. The isomerization did not proceed in the presence of DABCO in CDCl3 and C6D6 (entries 9 and 10). However, a desirable isomerization protocol was finally found: treatment of 1 with 10 mol % of DABCO in DMSO-d6 at 23 °C afforded E2 and Z2 in nearly quantitative combined yield with a 33:1 E/Z ratio (the yield and ratio were determined by NMR analysis). This operation is convenient because it requires only inexpensive DABCO and relatively nontoxic DMSO and does not require an inert atmosphere. In CD3CN, the treatment of 1 with 10 mol % of DABCO generated 2 with a high E-selectivity (>10:1) but in somewhat lower yield (60-70% determined by 1H NMR; entry 12). Suitable concentrations of 1 were determined to be 0.2-0.25 M; at higher concentrations (>0.5 M), the yield of E2 is significantly lower, and at lower concentrations (
