One-Pot, Three-Component, Highly Diastereoselective Metal-Free Synthesis of 2,3,4,5-Tetrasubstituted Pyrrolidines

Abstract

An extremely efficient, highly diastereoselective, metal-free synthesis of 2,3,4,5-tetrasubstituted pyrrolidines is described. The three-component reaction between aldehydes, aminomalonates, and nitroalkenes proceeds with high diastereoselectivities and high yields.

Key words

metal-free - cycloaddition - three component - pyrrolidines - stereoselectivity

References and Notes

• 2a For an excellent review of enamine catalysis, see: Erkkila A. Majander I. Pihko P. Chem. Rev.  2007,  107:  5416 
• 2b For an excellent review of asymmetric synthesis enabled by metal-free catalysis, see: Lelais G. MacMillan DWC. Aldrichimica Acta  2006,  3:  79 
• 2c For an excellent review of Michael additions, see: Tsogoeva SB. Eur. J. Org. Chem.  2007,  1701 
• 3 Pandey G. Banerjee B. Gadre SR. Chem. Rev.  2006,  106:  4484 
• 4a Hanessian S. Baykadarian M. Luo X. J. Am. Chem. Soc.  2002,  124:  4716 
• 4b DeGoey DA. Chen H.-J. Flosi WJ. Grampovnik DJ. Yeung CM. Klein LL. Kempf DJ. J. Org. Chem.  2002,  67:  5445 
• 4c Zaccardi J. Alluri M. Ashcroft J. Bernan V. Korshalla JD. Morton GO. Siegel M. Tsao R. Williams DR. Maeiese W. Ellestad GA. J. Org. Chem.  1994,  59:  4045 
• 4d Scott JD. Williams RM. Chem. Rev.  2002,  102:  1669 
• 4e Hanessian S. ChemMedChem  2006,  1:  1300 
• 4f da Silva KP. Godoi MN. Correia CRD. Org. Lett.  2007,  9:  2815 
• 4g Morita Y. Tokuyama H. Fukuyama T. Org. Lett.  2005,  7:  4337 
• 5a Najera C. Sansano JM. Angew. Chem. Int. Ed.  2005,  44:  6272 
• 5b Hucinec S. Savic V. Tetrahedron: Asymmetry  2005,  16:  2047 
• 6a Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2001,  40:  3726 
• 6b Duthaler RO. Angew. Chem. Int. Ed.  2003,  42:  975 
• 6c Dalko PI. Moisan L. Angew. Chem. Int. Ed.  2004,  43:  5138 
• 6d Enders D. Grondal C. Huttl MRM. Angew. Chem. Int. Ed.  2007,  46:  1570 
• 7a Garner P. Ho WB. Shin C. J. Am. Chem. Soc.  1993,  115:  10742 
• 7b Coldham I. Crapnell KM. Fernandez J.-C. Moseley JD. Rabot R. J. Org. Chem.  2002,  67:  6181 
• 7c Pandey G. Banerjee P. Kumar R. Puranik VG. Org. Lett.  2005,  7:  3713 
• 7d Hong SW. Yang JH. Weinreb SM. J. Org. Chem.  2006,  71:  2078 
• 8a Jem WS. Wiener JJM. MacMillan DWC. J. Am. Chem. Soc.  2000,  122:  9874 
• 8b Rios R. Ibrahem I. Vesely J. Zhao G.-L. Cordova A. Tetrahedron Lett.  2007,  48:  5701 
• 9 Vicario JL. Reboredo S. Badía D. Carrillo L. Angew. Chem. Int. Ed.  2007,  46:  5168 
• 10a Ibrahem I. Rios R. Vesely J. Cordova A. Tetrahedron Lett.  2007,  48:  6252 
• 10b Rios R. Ibrahem I. Vesely J. Sundén H. Cordova A. Tetrahedron Lett.  2007,  48:  8695 
• 11 Viranyi A. Marth G. Dancso A. Blasko G. Toke L. Nyerges M. Tetrahedron  2006,  62:  8720 ; and references cited therein

1

ICREA Researcher at University of Barcelona.

12

Chloroform was bought from Aldrich and was used as received.

13

Typical Experimental Procedure for the Three-Component Synthesis of Pyrrolidine Derivatives
To a stirred solution of aldehyde 3 (0.375 mmol, 1.5 equiv) in CHCl₃ (0.5 mL) at r.t., diethyl 2-aminomalonate (2a, 0.375 mmol, 1.5 equiv) was added. The reaction was stirred at r.t. for 30 min and then nitroalkene 1 was added. The reaction was then stirred at r.t. overnight. Next the crude was purified by silica gel column chromatography to afford the pyrrolidine derivative 4.
Compound 4d: colorless oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.48-7.44 (m, 2 H), 7.33-7.28 (m, 7 H), 5.58 (dd, J = 6.8, 8.0 Hz, 1 H), 5.46 (d, J = 8.4 Hz, 1 H), 5.12 (d, J = 7.2 Hz, 1 H), 4.42-4.21 (m, 2 H), 3.91 (q, J = 7.6 Hz, 1 H), 3.46 (q, J = 7.6 Hz, 1 H), 1.29 (t, J = 7.6 Hz, 3 H), 0.78 (t, J = 7.6 Hz, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 171.1, 168.4, 135.7, 134.9, 132.4, 131.6, 130.9, 128.9, 128.7, 128.6, 128.3, 122.9, 93.5, 75.9, 63.8, 62.2, 62.0, 51.9, 14.0, 13.3.