Base-Promoted Michael Reaction Concomitant with Alkylation of Cyclic-1,3-diones, an Efficient Approach to 2-Substituted Vinylogous Esters

Abstract

Vinylogous esters can be synthesized by a base-promoted Michael reaction concomitant with alkylation of the cyclic 1,3-dione substrate. The methodology provides a wide range of 2-substituted vinylogous esters in good to excellent yields.

Key words

vinylogous esters - cyclohexenones - Michael reaction - alkylation - diones

• References and Notes


For examples of alkylative 1,3-carbonyl transpositions in vinylogous esters, see:
• 1a Corey EJ, Crouse D. J. Org. Chem. 1968; 33: 298
• 1b Stork G, Danheiser RL. J. Org. Chem. 1973; 38: 1775
• 1c Quesada ML, Schlessinger RH. Synth. Commun. 1976; 6: 555
• 1d Tobin PS, Basu SK, Grosserade RS, Wheeler DM. S. J. Org. Chem. 1980; 45: 1250
• 1e For recent applications in total syntheses, see: White DE, Stewart IC, Grubbs RH, Stoltz BM. J. Am. Chem. Soc. 2008; 130: 810
• 1f Bisai A, West SP, Sarpong R. J. Am. Chem. Soc. 2008; 130: 7222
• 2a Smith AB. III. Evolution of a Synthetic Strategy: Total Synthesis of (±)-Jatrophone. In Strategies and Tactics in Organic Synthesis. Lindberg T. Academic; New York: 1984: 224-254 , Chap. 9
• 2b For numerous examples, see: Nicolaou KC, Sorensen EJ. Classics in Total Synthesis . 1st ed Wiley-VCH; New York: 1996
• 2c Nicolaou KC, Snyder SA. Classics in Total Synthesis II . 1st ed Wiley-VCH; Weinheim: 2003
• 2d Nicolaou KC, Chen JS. Classics in Total Synthesis III . 1st ed Wiley-VCH; Weinheim: 2011
• 2e Mohr PJ, Halcomb RL. J. Am. Chem. Soc. 2003; 125: 1712
• 3a Szychowski J, MacLean DB. Can. J. Chem. 1979; 57: 1631
• 3b Oppolzer W, Petrzilka M. Helv. Chim. Acta 1978; 61: 2755
• 4a Linghu X, Kennedy-Smith JJ, Toste FD. Angew. Chem. Int. Ed. 2007; 46: 7671
• 4b Kozak JA, Dake GR. Angew. Chem. Int. Ed. 2008; 47: 4221
• 5 Staben ST, Kennedy-Smith JJ, Huang D, Corkey BK, LaLonde RL, Toste FD. Angew. Chem. Int. Ed. 2006; 45: 5991
• 6 Shigeyama T, Katakawa K, Kogure N, Kitajima M, Katayama H. Org. Lett. 2007; 9: 4069
• 7a Harayama T, Takatani M, Inubushi Y. Tetrahedron Lett. 1979; 4307
• 7b Harayama T, Takatani M, Inubushui Y. Chem. Pharm. Bull. 1979; 27: 726
• 8 For isolation of huperzine W, see: Tan CH, Ma XQ, Chen GF, Jiang SH, Zhu DY. Chin. Chem. Lett. 2002; 13: 331
• 9a For synthesis of (R)-5-methyl-2-alkylcyclohexen-2-ones 2 from (R)-pulegone, see: Caine D, Procter K, Cassel RA. J. Org. Chem. 1984; 49: 2647
• 9b For the use of 2-iodo-2-cyclohexenones of the type 4c in cross-coupling, see: Pandey G, Balakrishnan M. J. Org. Chem. 2008; 73: 8128
• 10a Carlone A, Marigo M, North C, Landa A, Jørgensen KA. Chem. Commun. 2006; 4928
• 10b Marigo M, Wabnitz TC, Fielenbach D, Jørgensen KA. Angew. Chem. Int. Ed. 2005; 44: 794
• 11a Pandey G, Hajra S, Ghorai MK, Kumar KR. J. Am. Chem. Soc. 1997; 119: 8777
• 11b Bisai V, Sarpong R. Org. Lett. 2010; 12: 2551
• 11c For the synthesis of 1a and 1b, see: Patterson JW. Tetrahedron 1993; 49: 4789
• 11d Rajamannar T, Palani N, Balasubramanian KK. Synth. Commun. 1993; 23: 3095

For recent examples, see:
• 12a Bennett NB, Hong AY, Harned AM, Stoltz BM. Org. Biomol. Chem. 2012; 10: 56
• 12b White DE, Stewart IC, Seashore-Ludlow BA, Grubbs RH, Stoltz BM. Tetrahedron 2010; 66: 4668
• 12c Petrova KV, Mohr JT, Stoltz BM. Org. Lett. 2009; 11: 293
• 12d Levine SR, Krout MR, Stoltz BM. Org. Lett. 2009; 11: 289
• 13a For synthesis of bicyclic vinylogous esters, see: Smith III. AB, Dorsey BD, Ohba M, Lupo AT. Jr, Malamas MS. J. Org. Chem. 1988; 53: 4314
• 13b For use of vinylogous esters in organic synthesis, see: Masalov N, Feng W, Cha JK. Org. Lett. 2004; 6: 2365
• 13c Nicolaou KC, Montagnon T, Vassilikogiannakis G, Mathison CJ. N. J. Am. Chem. Soc. 2005; 127: 8872
• 13d Grundl MA, Trauner D. Org. Lett. 2006; 8: 23
• 13e For a review, see: Rubinov DB, Rubinova IL, Akhrem AA. Chem. Rev. 1999; 99: 1047
• 14 Under base-catalyzed conditions it has been reported that cyclohexane-1,3-dione can follow double Michael reactions with acrylates, for example, see: Konno M, Nakae T, Sakuyama S, Imaki K, Nakai H, Hamanaka N. Synlett 1997; 1472

For reviews of diterpenoids having gem-dimethyl cyclohexane motifs, see:
• 15a Majetich G, Shimkus JM. J. Nat. Prod. 2010; 73: 284
• 15b Simmons EM, Sarpong R. Nat. Prod. Rep. 2009; 26: 1195

For diterpenoids having the gem-dimethyl cyclohexane motif, see:
• 16a Banerjee M, Mukhopadhyay R, Achari B, Banerjee AK. Org. Lett. 2003; 5: 3931
• 16b Fillion E, Fishlock D. J. Am. Chem. Soc. 2005; 127: 13144
• 16c Tang SC, Xu YF, He JM, He YP, Zheng JY, Pan XF, She XG. Org. Lett. 2008; 10: 1855
• 16d Tapia R, Guardia JJ, Alvarez E, Haidöur A, Ramos JM, Alvarez-Manzaneda R, Chahboun R, Alvarez-Manzaneda E. J. Org. Chem. 2012; 77: 573 ; and references cited therein
• 17 Synthesis of Vinylogous Esters; General Procedure: A flame-dried, round-bottomed flask was charged with cyclic 1,3-dione (1 mmol) and ethyl acrylate (1.3 mmol) in DMSO (5 mL). To this solution was added NaH or Cs₂CO₃ (1.2 mmol) and the reaction mixture was stirred at 80 °C for the indicated time. Upon completion of the Michael reaction (typically, TLC showed complete conversion of starting materials after 3 h of reaction), alkyl halide (1.2 mmol) was added and the reaction mixture was heated at 80 °C for the indicated time (typically 1 h). Upon completion of the alkylation (TLC), the reaction mixture was acidified with 2 M HCl. The resulting mixture was extracted with EtOAc (4 × 20 mL) and the combined organic layers were dried over MgSO₄ and concentrated under vacuum. The crude product was purified by flash chromatography (petroleum ether–EtOAc) to give the pure product. Ethyl 3-{2-[(2-Bromoallyl)oxy]-6-oxocyclohex-1-en-1-yl}propanoate (5a): R_f = 0.54 (EtOAc–hexane, 50%); ¹H NMR (400 MHz, CDCl₃): δ = 5.95 (m, 1 H), 5.69 (m, 1 H), 4.63 (t, J = 1.44 Hz, 2 H), 4.10 (q, J = 7.12 Hz, 2 H), 2.65 (m, 2 H), 2.55 (t, J = 6.2 Hz, 2 H), 2.34–2.38 (m, 4 H), 1.99 (m, 2 H), 1.24 (t, J = 7.16 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 197.9, 173.4, 170.2, 126.5, 119.0, 117.9, 70.4, 60.1, 36.3, 33.0, 25.1, 20.9, 18.0, 14.2; IR (film): 2939, 1728, 1628, 1589, 1446, 1385, 1354, 1277, 1169, 1072, 1041, 856 cm^–1; HRMS (ESI): m/z [M + Na]⁺ calcd for [C₁₄H₁₉BrO₄+Na]⁺: 353.0359; found: 353.0342. Ethyl 3-[2-(Allyloxy)-6-oxocyclohex-1-en-1-yl]propanoate (5b): R_f = 0.59 (EtOAc–hexane, 50%); ¹H NMR (400 MHz, CDCl₃): δ = 5.88–5.98 (m, 1 H), 5.31–5.36 (m, 1 H), 5.24–5.28 (m, 1 H), 4.55 (m, 2 H), 4.08 (q, J = 7.12 Hz, 2 H), 2.59–2.64 (m, 2 H), 2.55 (t, J = 6.24 Hz, 2 H), 2.33 (m, 4 H), 1.95 (m, 2 H), 1.22 (t, J = 7.16 Hz, 3 H); ¹³C NMR (100 MHz, CDCl₃): δ = 198.0, 173.6, 171.8, 132.8, 118.2, 117.5, 68.1, 60.1, 36.3, 33.1, 25.3, 20.9, 17.9, 14.2 cm^–1; IR (film): 2931, 1724, 1597, 1438, 1385, 1265, 1184, 1076, 1030, 930, 860 cm^–1; HRMS (ESI): m/z [M + H]⁺ calcd for [C₁₉H₂₁O₄+Na]⁺: 313.1434; found: 313.1273.