Thieme Chemistry Journals Awardees – Where Are They Now?
Phospha-Münchnone 1,3-Dipolar Cycloaddition with Alkenes: A One-Pot Approach to 2-Pyrrolines from Imines, Acid Chlorides and Alkenes

Abstract

We describe herein studies on the cycloaddition of phospha-Münchnones and alkenes, and the factors that influence selectivity between 2-pyrrolines and bicyclic products. Coupling this cycloaddition with the formation of the dipoles can provide a one-pot route to synthesize 2-pyrrolines in moderate yield from imines, acid chlorides and alkenes.

Key words

1,3-dipole - cycloaddition - alkene - pyrrolines - regioselectivity

• References and Notes

• 1a Moya P, Cantin A, Castillo M.-A, Primo J, Miranda MA, Primo-Yufera E. J. Org. Chem. 1990; 63: 8530
• 1b Carmeli S, Moore RE, Patterson GM. L. Tetrahedron 1991; 47: 2087
• 1c Antonow D, Thurston DE. Chem. Rev. 2011; 111: 2815
• 2a Marti C, Carreira EM. J. Am. Chem. Soc. 2005; 127: 11505
• 2b Stepankova J, Studenovsky M, Malina J, Kasparkova J, Liskova B, Novakova O, Ulbrich K, Brabec V. Biochem. Pharmacol. 2011; 82: 227
• 2c Rahman KM, James CH, Bui TT, Drake AF, Thurston DE. J. Am. Chem. Soc. 2011; 133: 19376
• 2d Nasakin OE, Lyshchikov AN, Kayukov YS, Sheverdov VP. Pharm. Chem. J. 2000; 34: 170
• 2e Nagy A, Armatic P, Schally AV. Proc. Natl. Acad. Sci. U.S.A. 1996; 93: 2464
• 2f Li W, Khullar A, Chou S, Sacramo A, Gerratana B. Appl. Environ. Microbiol. 2009; 75: 2869
• 2g Langlois N, Rojas-Rousseau A, Gaspard C, Werner GH, Darro F, Kiss R. J. Med. Chem. 2001; 44: 3754
• 2h Cui C.-B, Kakeya H, Osada H. Tetrahedron 1996; 52: 12651
• 2i Antonow D, Kaliszczak M, Kang GD, Coffils M, Tiberghien AC, Cooper N, Barata T, Heidelberger S, James CH, Zloh M, Jenkins TC, Reszka AP, Neidle S, Guichard SM, Jodrell DI, Hartley JA, Howard PW, Thurston DE. J. Med. Chem. 2010; 53: 2927
• 3a Wilson KE, Kempf AJ, Liesch JM. J. Antibiot. 1983; 36: 1109
• 3b Sunagawa M, Matsumura H. J. Antibiot. 1995; 48: 408
• 3c Sato H, Sakoh H, Hashihayata T, Imamura H, Ohtake N, Shimizu A, Sugimoto Y, Sakuraba S, Bamba-Nagano R, Yamada K, Hashizume T, Morishima H. Bioorg. Med. Chem. 2002; 10: 1595
• 3d Kahan JS, Kahan FM, Goegelman R, Currie SA, Jackson M, Stapley EO, Miller TW, Miller AK, Hendlin D, Mochales S, Hernandez S, Woodruff HB, Birnbaum J. J. Antibiot. 1979; 32: 1
• 4a Ye Z, Shi L, Shao X, Xu X, Xu Z, Li Z. J. Agric. Food Chem. 2013; 61: 312
• 4b Cantin A, Moya P, Miranda MA, Primo J, Primo-Yufera E. J. Agric. Food Chem. 2000; 48: 3682

For representative examples, see:
• 5a Haimowitz T, Fitzgerald ME, Winkler JD. Tetrahedron Lett. 2011; 52: 2162
• 5b Piva O, Bressy C, Menant C. Synlett 2005; 577
• 5c Herzon SB, Myers AG. J. Am. Chem. Soc. 2005; 127: 5342
• 5d Martin R, Jager A, Bohl M, Richter S, Fedorov R, Manstein DJ, Gutzeit HO, Knolker HJ. Angew. Chem. Int. Ed. 2009; 48: 8042
• 6 For a review, see: Bellina F, Rossi R. Tetrahedron 2006; 62: 7213
• 7a Yu YF, Shu C, Zhou B, Li JQ, Zhou JM, Ye LW. Chem. Commun. 2015; 51: 2126
• 7b Yin Y, Ma W, Chai Z, Zhao G. J. Org. Chem. 2007; 72: 5731
• 8 Sonesson C, Hallberg A. Tetrahedron Lett. 1995; 36: 4505
• 9a Stevens RV, Wentland MP. J. Am. Chem. Soc. 1968; 5580
• 9b Jacoby D, Celerier JP, Haviari G, Petit H, Lhommet G. Synthesis 1991; 884
• 9c Wurz RP, Charette AB. Org. Lett. 2005; 7: 2313
• 9d Ding C.-H, Dai L.-X, Hou X.-L. Tetrahedron 2005; 61: 9586
• 9e Ghorai MK, Tiwari DP. J. Org. Chem. 2013; 78: 2617
• 9f Feng JJ, Lin TY, Zhu CZ, Wang H, Wu HH, Zhang J. J. Am. Chem. Soc. 2016; 138: 2178
• 10 Kinderman SS, Maarseveen JH. v, Schoemaker HE, Hiemstra H, Rutjes FP. J. T. Org. Lett. 2001; 3: 2045

For alternative approaches, see:
• 11a Magedov IV, Luchetti G, Evdokimov NM, Manpadi M, Steelant WF, Van Slambrouck S, Tongwa P, Antipin MY, Kornienko A. Bioorg. Med. Chem. Lett. 2008; 18: 1392
• 11b Guo C, Xue M.-X, Zhu M.-K, Gong L.-Z. Angew. Chem. Int. Ed. 2008; 47: 3414
• 11c Zhou X, Zhang H, Yuan J, Mai L, Li Y. Tetrahedron Lett. 2007; 48: 7236
• 12 Gotthardt H, Huisgen R, Schaefer FC. Tetrahedron Lett. 1964; 487

For reviews on Münchnone reactivity, see:
• 13a Gribble GW In Oxazoles: Synthesis, Reactions, and Spectroscopy, Part A. John Wiley & Sons, Inc; New York: 2003: 473
• 13b Gingrich HL, Baum JS In Chemistry of Heterocyclic Compounds. Vol. 45. Turchi IJ. John Wiley & Sons, Ltd; New York: 1986: 731
• 13c Reissig H.-U, Zimmer R. Angew. Chem. Int. Ed. 2014; 53: 9708

For examples, see:
• 13d Yebdri O, Henri-Rousseau O, Texier F. Tetrahedron Lett. 1983; 24: 369
• 13e Gotthardt H, Huisgen R. Chem. Ber. 1970; 103: 2625
• 13f Myers JA, Wilkerson WW, Council SL. J. Org. Chem. 1975; 40: 2975
• 13g Baggi P, Clerici F, Gelmi ML, Mottadelli S. Tetrahedron 1995; 51: 2455
• 14a St Cyr D, Arndtsen BA. J. Am. Chem. Soc. 2007; 129: 12366
• 14b Krenske EH, Houk KN, Arndtsen BA, St Cyr D. J. Am. Chem. Soc. 2008; 130: 10052
• 14c Lu Y, Arndtsen BA. Org. Lett. 2009; 11: 1369
• 14d St Cyr D, Morin MS, Belanger-Gariepy F, Arndtsen BA, Krenske EH, Houk KN. J. Org. Chem. 2010; 75: 4261
• 15 Morin MS, St Cyr D, Arndtsen BA, Krenske EH, Houk KN. J. Am. Chem. Soc. 2013; 135: 17349

Electron-deficient chlorocyanoethylene and vinyl phosphonium salts react with phospha-Münchnones to form pyrroles upon HX elimination. See refs 14a, 14d and:
• 16a Morin MS. T, St Cyr D, Arndtsen BA. Org. Lett. 2010; 12: 4916
• 16b Kayser LV, Vollmer M, Welnhofer M, Krikcziokat H, Meerholz K, Arndtsen BA. J. Am. Chem. Soc. 2016; 138: 10516
• 17a Morin MS, Aly S, Arndtsen BA. Chem Commun. 2013; 49: 883
• 17b Morin MS, Arndtsen BA. Org. Lett. 2014; 16: 1056
• 18a Nan’ya S, Goto S, Butsugan Y. J. Heterocycl. Chem. 1990; 27: 1519
• 18b Gribble GW, Sponholtz III. WR, Switzer FL, D’Amato FJ, Byrn MP. Chem. Commun. 1997; 993
• 19 As discussed in ref. 15, cycloaddition to form the product expected from the electron bias in the 1,3-dipole is asynchronous, while that forming the isomer with the ester unit on the ylidic carbon is much more concerted.
• 20 1,3-Dipolar Cycloaddition Chemistry . Vol. 1. Padwa A. John Wiley & Sons; New York: 1984
• 21 Typical Experimental Procedure: In a glovebox, p-tolyl(H)C=NEt (59 mg, 0.40 mmol) and p-toluoyl chloride (68 mg, 0.44 mmol) were mixed in CH₂Cl₂ (1 mL) for 30 min, followed by the addition of PhP(2-catechyl) (95 mg, 0.44 mmol). The reaction mixture was stirred at ambient temperature for 2 h. DBU (152 mg, 1.00 mmol) was added to the solution and the final volume was adjusted to 2 mL. After 15 min, dimethyl furmarate (66 mg, 0.46 mmol) in CH₂Cl₂ (2 mL) was transferred to a 3-mL syringe and added to the reaction mixture via syringe pump over 6 h. The reaction mixture was allowed to stir for 16 h before the crude solution was concentrated in vacuo. Due to the sensitivity of many of these products, and to more accurately determine product composition, all yields were determined by ¹H NMR analysis by filtration of a toluene solution of the product through alumina and ¹H NMR analysis relative to an internal hexamethylbenzene standard (70% yield 3a). The product was isolated by flash chromatography on silica using toluene–EtOAc as the eluent to afford 3a in 56% isolated yield as a light yellow solid. ¹H NMR (500 MHz, CDCl₃): δ = 7.46 (2 H), 7.32 (d, J = 8.1 Hz, 2 H), 7.11 (d, J = 4.9 Hz, 2 H), 7.09 (d, J = 4.9 Hz, 2 H), 5.02 (d, J = 7.7 Hz, 1 H), 4.41 (d, J = 7.7 Hz, 1 H), 3.63 (s, 3 H), 3.46 (s, 3 H), 2.95 (dq, J = 14.5, 7.2 Hz, 1 H), 2.66 (dq, J = 14.5, 7.2 Hz, 1 H), 2.21 (s, 3 H), 2.18 (s, 3 H), 0.73 (t, J = 7.1 Hz, 3 H). ¹³C NMR (126 MHz, C₆D₆): δ = 175.51, 165.83, 163.60, 139.94, 139.60, 138.43, 130.50, 130.10, 129.50, 128.91, 128.81, 128.72, 128.53, 128.43, 127.62, 98.87, 69.42, 57.92, 52.43, 50.68, 41.47, 21.91, 21.69, 13.24. HRMS (APCI): m/z calcd for C₂₄H₂₇NO₄H⁺: 394.20128; found: 394.20069.