Organocatalysis in Ionic Liquids: Highly Efficient l-Proline-Catalyzed Direct Asymmetric Mannich Reactions Involving Ketone and Aldehyde Nucleophiles

Abstract

Proline-catalyzed direct asymmetric Mannich reactions of N-PMP protected α-imino ethyl glyoxylate with various aldehydes and ketones in ionic liquids afforded both α- and β-amino acid derivatives with excellent yields and enantioselectivities, providing facile product isolation, catalyst recycling, and significantly improved reaction rates, ca 4- to 50-fold. Three component Mannich reactions involving other imines also worked well in ionic liquids. Significant advantages and limitations of ionic liquid solvents in this reaction have been revealed.

Key words

proline - enamine - Mannich reaction - ionic liquids - green chemistry

References

• 1a Mannich C. Krosche W. Arch. Pharm.  1912,  250:  647 
• 1b Kleinmann EF. Comprehensive Organic Synthesis   Vol. 2:  Trost BM. Fleming I. Pergmon Press; New York: 1991.  Chap. 4.1.
• 1c Williams RM. Hendrix JA. Chem. Rev.  1992,  92:  889 
• 2a Yamasaki S. Iida T. Shibasaki M. Tetrahedron  1999,  55:  8857 
• 2b Juhl K. Gathergood N. Jorgensen KA. Angew. Chem. Int. Ed.  2001,  40:  2995 
• 2c Notz W. Sakthivel K. Bui T. Barbas CF. Tetrahedron Lett.  2001,  42:  199 
• 2d Córdova A. Notz W. Zhong G. Betancort JM. Barbas CF. J. Am. Chem. Soc.  2002,  124:  1842 
• 2e List B. J. Am. Chem. Soc.  2000,  122:  9336 
• 2f List B. Pojarliev P. Beller WT. Martin HJ. J. Am. Chem. Soc.  2002,  124:  827 
• 3a Córdova A. Watanabe S.-I. Tanaka F. Notz W. Barbas CF. J. Am. Chem. Soc.  2002,  124:  1866 
• 3b Córdova A. Barbas CF. Tetrahedron Lett.  2002,  43:  7749 
• 3c Watanabe S.-I. Córdova A. Tanaka F. Barbas CF. Org. Lett.  2002,  4:  4519 
• 3d Córdova A. Barbas CF. Tetrahedron Lett.  2003,  44:  1923 
• 4a McNamara CA. Dixon MJ. Bradley M. Chem. Rev.  2002,  102:  3275 
• 4b Song CE. Lee S.-G. Chem. Rev.  2002,  102:  3495 
• 5 Zhong G. Hoffmann T. Lerner RA. Danishefsky S. Barbas CF. J. Am. Chem. Soc.  1997,  119:  8131 
• 6a List B. Lerner RA. Barbas CF. J. Am. Chem. Soc.  2000,  122:  2395 
• 6b Sakthivel K. Notz W. Bui T. Barbas CF. J. Am. Chem. Soc.  2001,  123:  5260 
• 6c Cordova A. Notz W. Barbas CF. J. Org. Chem.  2002,  67:  301 
• 6d Chowdari NS. Ramachary DB. Cordova A. Barbas CF. Tetrahedron Lett.  2002,  43:  9591 
• 6e Betancort JM. Sakthivel K. Thayumanavan R. Barbas CF. Tetrahedron Lett.  2001,  42:  4441 
• 6f Betancort JM. Barbas CF. Org. Lett.  2001,  3:  3737 
• 6g Thayumanavan R. Ramachary DB. Sakthivel K. Tanaka F. Barbas CF. Tetrahedron Lett.  2002,  43:  3817 
• 6h Ramachary DB. Chowdari NS. Barbas CF. Tetrahedron Lett.  2002,  43:  6743 
• 6i Chowdari NS. Ramachary DB. Barbas CF. Org. Lett.  2003,  5:  1685 
• 6j For key references to studies from other laboratories see ref. and following references: Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  6798 
• 6k Northrup AB. MacMillan DWC. J. Am. Chem. Soc.  2002,  124:  2458 
• 6l Bogevig A. Juhl K. Kumaragurubaran N. Zhuang W. Jorgensen KA. Angew. Chem. Int. Ed.  2002,  41:  1790 
• 6m Halland N. Hazell RG. Jorgensen KA. J. Org. Chem.  2002,  67:  8331 
• 6n Enders D. Seki A. Synlett  2002,  26 
• 6o Nakadai M. Saito S. Yamamoto H. Tetrahedron  2002,  58:  8167 
• 7a Welton T. Chem. Rev.  1999,  99:  2071 
• 7b Wasserscheid P. Keim W. Angew. Chem. Int. Ed.  2000,  39:  3772 
• 7c Sheldon RA. Chem. Commun.  2001,  2399 
• 10 Hoffmann T. Zhong G. List B. Shabat D. Anderson J. Gramatikova S. Lerner RA. Barbas CF. J. Am. Chem. Soc.  1998,  120:  2768 
• 11a Loh TP. Feng LC. Yang HY. Yang JY. Tetrahedron Lett.  2002,  43:  8741 
• 11b Kotrusz P. Kmentova I. Gotov B. Toma S. Solcaniova E. Chem. Commun.  2002,  2510 

8

General experimental procedure: To a glass vial charged with l-proline (3 mg, 0.025 mmol) was added [bmim]BF₄ (1 mL) followed by α-imino ethyl glyoxylate (104 mg, 0.5 mmol), aldehyde (1.5 equiv) or ketone (1 mL) and the reaction was stirred at r.t. for 30 min. After completion of the reaction (as monitored by TLC), the product was isolated by extraction with Et₂O (4 × 5 mL). The combined Et₂O extracts were concentrated to obtain the Mannich product. The ionic liquid containing l-proline was dried under vacuum prior to reuse.

9

General experimental procedure for three component Mannich reaction (Table 3): To a glass vial charged with l-proline (3 mg, 0.025 mmol) were added [bmim]BF₄ (1 mL), p-anisidine (68mg, 0.55 mmol), aldehyde (0.5 mmol) and ketone (1 mL) and the reaction was stirred at r.t. After completion of the reaction (as monitored by TLC), the product was isolated by extraction with Et₂O (4 × 5 mL). The combined ether extracts were concentrated and chromatographed to obtain the Mannich product.