Efficient One-pot Three-component Synthesis of 7-Oxo-1,7,8,8a-tetra­hydroimidazo[1,2-a]pyrimidines

Abstract

1-Methyl imidazole reacts smoothly with dialkyl acetyl­enedicarboxylates in the presence of isocyanates to produce dialkyl 1-methyl-7-oxo-1,7,8,8a-tetrahydroimidazo[1,2-a]pyrimidine-5,6-dicarboxylates in excellent yields.

isocyanates - cyclizations - heterocycles - imidazoles - alkynes

References

1 Swinbourne JF. Hunt HJ. Klinkert G. Adv. Heterocycl. Chem.  1987,  23:  103 

2 Sliskovic DR. In Comprehensive Heterocyclic Chemistry   Vol. 8:  Katritzky AR. Rees CW. Scriven EVF. Pergamon Press; London: 1996.  p.345 ; and references therein

3 Greenhill JV. In Comprehensive Heterocyclic Chemistry   Vol. 5:  Katritzky AR. Rees CW. Pergamon; London: 1984.  p.607 

4 Rupert KC. Henry JR. Dodd JH. Wadsworth SA. Cavender DE. Olini GC. Fahmy B. Siekierka JJ. Bioorg. Med. Chem. Lett.  2003,  13:  347 

5 Abignente E. Arena F. Luraschi E. Saturnino C. Berrino L. De Santis D. Marmo E. Farmaco Ed. Sci.  1987,  42:  657 

6 Loiseau PR. Payard M. Grassy G. Pinto ZD. Advenier C. Gnassounou JP. Adams Y. Eur. J. Med. Chem.  1987,  22:  457 

7 Rival Y. Grassy G. Taudou A. Escalle R. Eur. J. Med. Chem.  1991,  26:  13 

8 Gala D. DiBenedetto DJ. Kugelman M. Mitchell MB. Tetrahedron Lett.  2003,  44:  2721 

9

The procedure for the preparation of dimethyl 1-methyl-7-oxo-8-phenyl-1,7,8,8a-tetrahydroimidazo[1,2-a]pyr-imidine-5,6-dicarboxylate (4a) is described as an example. To a magnetically stirred solution of phenyl isocyanate (0.119 g, 1 mmol) and 1-methyl imidazole (0.082 g, 1 mmol) in anhyd CH₂Cl₂ (5 mL) was added dropwise a mixture of DMAD (0.142 g, 1 mmol) in CH₂Cl₂ (2 mL) at -5 ºC for 10 min. The reaction mixture was allowed to warm to r.t. and stirred for 1 h. The solvent was removed under reduced pressure and the residue was crystallized from hexane-EtOAc (1:1). The product 4a was obtained as pale red crystals; yield: 99% (0.34 g); mp 113-116 ºC. IR (KBr): 1755, 1722, 1670, (C=O), 1616, 1371, 1155, 842 cm^-1. ¹H NMR (500 MHz, CDCl₃): δ = 3.69 (s, 3 H, NCH₃), 3.83, 3.88 (2 s, 6 H, 2 × OCH₃), 5.47 (s, 1 H, N₃CH), 6.74, 6.81 (2 nearly br s, 2 H, NCH=CHN), 7.26 (d, 2 H, J = 7.8 Hz, o-CH), 7.32 (t, 1 H, J = 7.4 Hz, para CH), 7.39 (dd, 2 H, J = 7.8 Hz, J = 7.4 Hz, m-CH). ¹³C NMR (125 MHz, CDCl₃, the signals have been assigned using 2D ¹H-¹³C COSY): δ = 35.11 (NCH₃), 51.78, 52.78 (2 × OCH₃), 113.82 (N₃CH), 124.92 (NCH=CHN), 128.02 (Ph, o-CH), 128.22 (Ph, p-CH), 128.57 (NCH=CHN), 129.52 (Ph, m-CH), 138.46, 141.06 (2 × C), 146.78 (NC=C), 160.13, 163.92, 165.26 (3 × C=O). MS: m/z (%) = 343 (5) [M⁺], 284 (30), 252 (8), 175 (7), 144 (10), 109 (100), 77 (20). Anal. Calcd for C₁₇H₁₇N₃O₅ (343.34): C, 59.47; H, 4.99; N, 12.24. Found: C, 59.5; H, 5.0; N, 12.2.

10 Acheson RM. Foxton MW. Abbott PJ. Mills KR. J. Chem. Soc. C  1967,  882 

11 Friebolin H. Basic One- and Two-Dimensional NMR Spectroscopy   3rd ed.:  Wiley-VCH; Weinheim: 1998.