Reaction between N-Isocyaniminotriphenylphosphorane, Aldimines, Meldrum’s Acid and Water: Diastereoselective Synthesis of 3,4-Disubstituted N-Aminopyrrolidine-2,5-diones

Abstract

A multicomponent synthesis of 3,4-disubstituted N-aminopyrrolidine-2,5-diones is described. A mixture of N-isocyan­iminotriphenylphosphorane, an aldimine and Meldrum’s acid undergoes an addition reaction under mild conditions in aqueous THF to produce 1-amino-4-aryl-2,5-dioxo-N ^³-aryl-3-pyrrolidinecarboxamides diastereoselectively in good to excellent yields. ^¹H NMR analysis showed that the two substituents on C-3 and C-4 ­positions of the obtained pyrrolidine-2,5-diones are trans.

Key words

N-isocyaniminotriphenylphosphorane - aldimines - Meldrum’s acid - 3,4-disubstituted N-aminopyrrolidine-2,5-diones - diastereoselective synthesis - multicomponent reactions

References and Notes

• 1 Hargreaves MK. Pritchard JG. Dave HR. Chem. Rev.  1970,  70:  439 
• 2 Galatina AI. Derkach LG. Kilimenchuk HD. Kondratyeva RV. Novikova NS. Jarovoy JK. Liq. Cryst.  2000,  27:  1229 
• 3a Malawska B. Curr. Top. Med. Chem.  2005,  5:  69 
• 3b Kornet MJ. J. Pharm. Sci.  1983,  73:  405 
• 3c Kaminski K. Obniska J. Acta Pol. Pharm. Drug Res.  2008,  65:  457 
• 4a Brière JF. Charpentier P. Dupas G. Quèguiner G. Bourguignon J. Tetrahedron  1997,  53:  2075 
• 4b Reddy PY. Kondo S. Toru T. Ueno Y. J. Org. Chem.  1997,  62:  2652 
• 4c King RW. Tetrahedron Lett.  1981,  22:  2837 
• 4d Reuschling D. Mitzlaff M. Kühlein K. Tetrahedron Lett.  1976,  4467 
• 5 Obrecht D. Abrecht C. Altorfer M. Bohdal U. Grieder A. Kleber M. Pfyffer P. Müller K. Helv. Chim. Acta  1996,  79:  1315 
• 6 Abell AD. Oldham MD. J. Org. Chem.  1997,  62:  1509 
• 7 Whomsley R. Smith HJ. Nicholls PJ. Nazareth W. Ahmadi M. J. Enzyme Inhib. Med. Chem.  1993,  6:  317 
• 8 Fredenhagen A. Tamura SY. Kenny PTM. Komura H. Naya Y. Nakanishi K. Nishiyama K. Sugiura M. Kita H. J. Am. Chem. Soc.  1987,  109:  4409 
• 9a Needham J. Kelly MT. Ishige M. Andersen RJ.
  J. Org. Chem.  1994,  59:  2058 
• 9b Oclarit JM. Okada H. Ohta S. Kaminura K. Yamaoka Y. Iizuka T. Miyashiro S. Ikegami S. Microbios.  1994,  78:  7 
• 10 Liu X. Fortin PD. Walsh CT. Proc. Natl. Acad. Sci. U.S.A.  2008,  105:  13321 
• 11 Robert F. Gao HQ. Donia M. Merrick WC. Hamann MT. Pettetier J. RNA  2006,  12:  717 
• 12 Malochet-Grivois C. Roussakis C. Robillard N. Biard JF. Riou D. Debitus C. Verbist JF. Anticancer Drug Des.  1992,  7:  493 
• 13 Sandler SR. Karo W. In Organic Functional Group Preparations   Vol. 3, 3rd ed.:  Blomquist AT. Wasserman H. Academic Press; New York: 1972.  p.241 
• 14 Reddy PY. Kondo S. Toru T. Ueno Y. J. Org. Chem.  1997,  62:  2652 ; and references cited therein
• 15a Zerrer R. Simchen G. Synthesis  1992,  922 
• 15b Darcy PJ. Heller HG. Patharakorn S. Piggott RD. Whittall J. J. Chem. Soc., Perkin Trans. 1  1986,  315 ; and references cited therein
• 16 Hatakeyama S. Sugawara K. Takano S. J. Chem. Soc., Chem. Commun.  1992,  953 
• 17 Leigh WJ. Mitchell DS. J. Am. Chem. Soc.  1992,  114:  5005 
• 18 Furukawa I. Abe T. Fujisawa H. Ohta T. Tetrahedron  1997,  53:  17643 
• 19a Souldozi A. Ramazani A. Bouslimani N. Welter R. Tetrahedron Lett.  2007,  48:  2617 
• 19b Souldozi A. Ramazani A. Tetrahedron Lett.  2007,  48:  1549 
• 20a Adib M. Riazati Kesheh M. Ansari S. Bijanzadeh HR. Synlett  2009,  1575 
• 20b Adib M. Ansari S. Feizi S. Bijanzadeh HR. Synlett  2010,  921 
• 20c Adib M. Ansari S. Fatemi S. Bijanzadeh HR. Zhu LG. Tetrahedron  2010,  66:  2723 
• 21a Adib M. Mohamadi A. Sheikhi E. Ansari S. Bijanzadeh HR. Synlett  2010,  1606 
• 21b Adib M. Ansari S. Mohamadi A. Bijanzadeh HR. Tetrahedron Lett.  2010,  51:  30 
• 21c Adib M. Ansari S. Feizi S. Asgarian Damavandi J. Mirzaei P. Synlett  2009,  3263 
• 21d Adib M. Sheibani E. Bijanzadeh HR. Zhu LG. Tetrahedron  2008,  64:  10681 
• 21e Adib M. Mohammadi B. Bijanzadeh HR. Synlett  2008,  3180 
• 21f Adib M. Mohammadi B. Bijanzadeh HR. Synlett  2008,  177 
• 21g Adib M. Sayahi MH. Ziyadi H. Bijanzadeh HR. Zhu LG. Tetrahedron  2007,  63:  11135 
• 23a Matsuo T. Bull. Chem. Soc. Jpn.  1964,  37:  1844 
• 23b Stamboliyska BA. Binev YI. Radomirska VB. Tsenov JA. Juchnovski IN. J. Mol. Struct.  2000,  516:  237 
• 24a Ugi I. Isonitrile Chemistry   Academic Press; London: 1971. 
• 24b Ugi I. Angew. Chem., Int. Ed. Engl.  1982,  21:  810 
• 24c Walborsky HM. Periasamy MP. In The Chemistry of Functional Groups, Supplement C   Patai S. Rappaport Z. Wiley; New York: 1983.  Chap. 20. p.835-837 
• 24d Dömling A. Chem. Rev.  2006,  106:  17 
• 24e Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3169 

22

General Procedure for the Preparation of Compounds 4a-i: A mixture of N-isocyaniminotriphenylphosphorane (1 mmol), the appropriate imine (1 mmol) and Meldrum’s acid (1 mmol) in THF (5 mL) was stirred at ambient temperature for 48 h. The progress of the reaction was monitored by TLC. Then, the solvent was removed under the reduced pressure and the residue was purified by column chromatography using n-hexane-EtOAc (3:1) as eluent. The solvent was removed and the product was recrystallized from n-hexane-EtOAc (1:1).
1-Amino-4-(4-methylphenyl)-2,5-dioxo- N ^³ -phenyl-3-pyrrolidinecarboxamide (4c):
yield: 0.28 g (86%); colorless crystal; mp 152-154 ˚C. IR (KBr): 3340, 3275, 3192 (NH), 1772, 1693 (C=O), 1600, 1534, 1438, 1312, 1191, 1106, 903, 815, 748, 691 cm^-¹. ^¹H NMR (500.1 MHz, DMSO-d ₆): δ = 2.28 (s, 3 H, Me), 4.01 (d, J = 5.0 Hz, 1 H, CH), 4.34 (d, J = 5.0 Hz, 1 H, CH), 5.16 (br s, 2 H, NH₂), 7.09 (t, J = 7.4 Hz, 1 H, CH), 7.17-7.21 (m, 4 H, 4 × CH), 7.33 (dd, J = 8.1, 7.7 Hz, 2 H, 2 × CH), 7.59 (d, J = 7.7 Hz, 2 H, 2 × CH), 10.49 (s, 1 H, NHCO). ^¹³C NMR (125.8 MHz, DMSO-d ₆): δ = 20.53 (Me), 47.26, 54.72 (2 × CH), 119.19, 123.97, 127.95, 128.79, 129.30 (5 × CH), 133.41, 137.02, 138.21 (3 × C), 164.82, 171.06, 174.59 (3 × C=O). EI-MS: m/z (%) = 323 (10) [M⁺], 279 (13), 236 (9), 203 (21), 167 (31), 149 (86), 115 (17), 97 (23), 83 (37), 71 (42), 69 (78), 57 (89), 55 (65), 43 (100), 41 (72). Anal. Calcd for C₁₈H₁₇N₃O₃ (323.35): C, 66.86; H, 5.30; N, 13.00. Found: C, 67.0; H, 5.4; N, 12.8.
1-Amino-4-(4-chlorophenyl)-2,5-dioxo- N ^³ -phenyl-3-pyrrolidinecarboxamide (4e): yield: 0.33 g (96%); colorless crystal; mp 172-174 ˚C. IR (KBr): 3321, 3234, 3172 (NH), 1787, 1704, 1667 (C=O), 1603, 1537, 1493, 1440, 1414, 1321, 1257, 1215, 1094, 1051, 1007, 965, 830, 790, 743, 693, 658 cm^-¹. ^¹H NMR (500.1 MHz, DMSO-d ₆): δ = 4.04 (d, J = 5.3 Hz, 1 H, CH), 4.45 (d, J = 5.3 Hz, 1 H, CH), 5.15 (s, 2 H, NH₂), 7.09 (t, J = 7.4 Hz, 1 H, CH), 7.33 (dd, J = 8.1, 7.7 Hz, 2 H, 2 × CH), 7.38 (d, J = 8.5 Hz, 2 H, 2 × CH), 7.45 (d, J = 8.5 Hz, 2 H, 2 × CH), 7.59 (d, J = 7.7 Hz, 2 H, 2 × CH), 10.50 (s, 1 H, NHCO). ^¹³C NMR (125.8 MHz, DMSO-d ₆): δ = 46.93, 54.39 (2 × CH), 119.30, 124.09, 128.76, 128.89, 130.25 (5 × CH), 132.56, 135.34, 138.27 (3 × C), 164.75, 171.00, 174.27 (3 × C=O). EI-MS: m/z (%) = 345 (13) [M⁺ + ^³7Cl], 343 (35) [M⁺ + ^³5Cl], 315 (31), 295 (11), 284 (7), 273 (17), 236 (15), 223 (53), 207 (32), 196 (29), 179 (24), 165 (48), 152 (17), 137 (33), 111 (22), 102 (33), 93 (47), 83 (43), 77 (45), 69 (80), 57 (100), 43 (98), 41 (84). Anal. Calcd for C₁₇H₁₄ClN₃O₃ (343.77): C, 59.40; H, 4.10; N, 12.22. Found: C, 59.4; H, 4.0; N, 12.1.