3,5,5-Trisubstituted Hydantoins from Activated (Benzyloxycarbonyl­amino)­malonic Acids

Abstract

Diethyl 2-alkyl-2-(benzyloxycarbonylamino)malonates were saponified, activated with oxalyl chloride, and treated with primary aromatic amines. This gave 3,5-disubstituted hydantoin-5-carboxamides. As second products, 2-alkyl-2-formamido-N ¹,N ³-bis(aryl)malonamides were isolated. The formation of both types of products is expected to include a cyclization to 2-alkoxyoxazol-5(4H)-ones, acting as precursor for the hydantoins, or a further transformation to N-carboxy anhydrides, their chloride-promoted ring opening, and subsequent conversion to give the bis(aryl)malon­amides.

Key words

hydantoins - malonic acids - oxazolones - nitrogen heterocycles - ring closure - ring opening

• References

• 1 Meusel M, Gütschow M. Org. Prep. Proced. Int. 2004; 36: 391
• 2 Meusel M, Ambrożak A, Hecker TK, Gütschow M. J. Org. Chem. 2003; 68: 4684
• 3 Gütschow M, Hecker T, Thiele A, Hauschildt S, Eger K. Bioorg. Med. Chem. 2001; 9: 1059
• 4a Gütschow M, Hecker T, Eger K. Synthesis 1999; 410
• 4b Ambrożak A, Gütschow M. J. Heterocycl. Chem. 2006; 43: 807

For recent examples, see:
• 5a Volonterio A, de Arellano CR, Zanda M. J. Org. Chem. 2005; 70: 2161
• 5b Ignacio LM, Macho S, Marcaccini S, Pepino R, Torroba T. Synlett 2005; 3051
• 5c Olimpieri F, Volonterio A, Zanda M. Synlett 2008; 3016
• 5d Olimpieri F, Bellucci MC, Volonterio A, Zanda M. Eur. J. Org. Chem. 2009; 6179
• 5e Attanasi OA, De Crescentini L, Favi G, Nicolini S, Perulli FR, Santeusanio S. Org. Lett. 2011; 13: 353
• 5f Miura T, Mikano Y, Murakami M. Org. Lett. 2011; 13: 3560
• 5g Marcelli T, Olimpieri F, Volonterio A. Org. Biomol. Chem. 2011; 9: 5156
• 6 Jacob LA, Chen BL, Stec D. Synthesis 1993; 611

For the formation of 2-alkoxyoxazol-5(4H)-ones through activation of N-protected amino acids, see, for example:
• 7a Jones JH, Witty MJ. J. Chem. Soc., Chem. Commun. 1977; 281
• 7b Plucińska K, Liberek B. Tetrahedron 1987; 43: 3509
• 7c Benoiton NL, Chen FM. Int. J. Pept. Protein Res. 1993; 42: 455
• 7d Coste J, Frérot E, Jouin P. J. Org. Chem. 1994; 59: 2437

For the hydantoin cyclization of (alkoxycarbonyl-amino)carboxamides, see, for example:
• 8a Akhtar MS, Brouillette WJ, Waterhous DV. J. Org. Chem. 1990; 55: 5222
• 8b Maji SK, Halder D, Velmuguran D, Rajakannan V, Banerjee A. Lett. Pept. Sci. 2002; 8: 61
• 8c Du Y, Creighton CJ, Yan Z, Dauthier DA, Dahl JP, Zhao B, Belkowski SM, Reitz AB. Bioorg. Med. Chem. 2005; 13: 5936
• 9 Carter RE. Acta Chem. Scand. 1968; 22: 2643
• 10 Liler M. J. Chem. Soc., Perkin Trans. 2 1972; 720
• 11 Bloemendal M, Sijpkes AH, Somsen G. J. Solution Chem. 1986; 15: 81
• 12 Angus PM, Fairlie DP, Jackson WG. Inorg. Chem. 1993; 32: 450
• 13 Nakanishi H, Roberts JD. Org. Magn. Reson. 1981; 15: 7
• 14 CCDC 854013 (11f) and 854014 (12f) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif
• 15a Adams R, Ulich LH. J. Am. Chem. Soc. 1920; 42: 599
• 15b Mobashery S, Johnston M. J. Org. Chem. 1985; 50: 2200
• 15c Kitagawa T, Ito J, Tsutsui C. Chem. Pharm. Bull. 1994; 42: 1931

For the formation of NCAs from 5(4H)-oxazolones, derived from carbamate-protected amino acids, see:
• 16a Wilder R, Mobashery S. J. Org. Chem. 1992; 75: 2755
• 16b Frérot E, Coste J, Poncet J, Jouin P, Castro B. Tetrahedron Lett. 1992; 33: 2815
• 16c Fiammengo R, Licini G, Nicotra A, Modena G, Pasquato P, Broxterman QB, Kaptein B. J. Org. Chem. 2001; 6: 5905
• 16d Frizler M, Lohr F, Lülsdorff M, Gütschow M. Chem.–Eur. J. 2011; 17: 11419
• 17 For a review on NCAs, see: Kricheldorf HR. Angew. Chem. Int. Ed. 2006; 45: 5752 ; Angew. Chem. 2006, 118, 5884
• 18a Benoiton NL, Lee YC, Chen FM. Int. J. Pept. Protein Res. 1993; 41: 587
• 18b Cynkowski T, Cynkowska G, Aston P, Crooks PA. J. Chem. Soc., Chem. Commun. 1995; 2335
• 18c Hollweck W, Burger K. J. Prakt. Chem. 1995; 337: 391
• 19 Cai L, Han Y, Ren S, Huang L. Tetrahedron 2000; 56: 8253
• 20 Mukherjee-Müller G, Heimgartner H, Schmid H. Helv. Chim. Acta 1979; 62: 1429
• 21 Dutta AS, Giles MB, Williams JC. J. Chem. Soc., Perkin Trans. 1 1986; 1655