J. zyxwvutsrq Org. zyxwvutsr Chem. zyxwvu 1989,54, zyxwvut 5763-5768 Reaction of Arylglyoxals with 2-Amino Heterocycles' 5763 Benito Alcaide,* Joaquin Plumet, Miguel A. Sierra, and Cristina Vicent Departamento de Qulmica Orgdnica, Facultad de Qulmica, Universidad Complutense, 28040-Madrid, Spain Received March 23, 1989 The reaction of some arylglyoxals with a variety of 2-amino heterocycles,including pyridine, diazine, and azole derivatives, has been studied, with or without BF3.Et20complex as catalyst. On the basis of the isolation of different intermediate carbinolamines and of some crossover cyclization experiments, a reasonable mechanism zy has been proposed for all these processes. In addition,some structural features of the resulting bicyclic imidazo[l,2-a] derivatives having a potential hydroxyl group in position 3 are discussed. Introduction The reaction of some glyoxal derivatives with different 2-amino heterocycles in acidic media has been investigated previously by several authors. Thus, Goto et a1.2 have reported the synthesis of compounds 1 and 2 (Chart I), the model compounds of Cypridina l~ciferine,~ by heating 2-aminopyridine or aminopyrazines with both phenyl- glyoxal and pyruvaldehyde in aqueous acid solution. Later, Barlin et al.4 described the synthesis of compounds 2 (R' zyxwvu = Ph, R2 = H) and 3 by reacting phenylglyoxal with 2- aminopyrazine and 3-aminopyridazines, respectively, in ethanolic solution and in the presence of concentrated hydrochloric acid. In all these cases the observed regio- chemistry is accounted for through an intermediate a- ketimine aldehyde arising from initial condensation of the amino group with the keto group of the a-keto aldehyde (Scheme I). On the other hand, in early reports no tau- tomeric studies have been made to provide some evidence for the assigned structures. As part of our systematic study on the reactions of a- dicarbonyl compounds with heterocyclic amines we have explored the reaction of some arylglyoxals with various 2-amino heterocycles. In a preliminary communication' we reported the reaction of phenylglyoxal with 2-amino- pyridine in benzene and, on the basis of UV data, the structure 2-phenyl-lH-imidazo[ 1,2-a] pyridinium-3-olate (4a, NH meso-ionic tautomer) instead of the structure 1 (R = Ph) of hydroxy tautomer2p5 was proposed. On the other hand, isolation and characterization of the inter- mediate carbinolamine 5a and identification of the final structure as 4a allowed us to propose tentatively the re- action pathway shown in Scheme I1 for this reaction. In this paper we have extended the above reaction to other arylglyoxals and to a series of representative 2-amino heterocycles with the aim of studying its scope and gen- erality for the synthesis of bicyclic meso-ionic imidazo- [1,2-a]derivatives and, if possible, to elucidate the reaction course for all these processes. Results and Discussion We began this investigation by examining the reaction between several para-substituted phenylglyoxals6 and a (1) For a preliminary communication see: Alcaide, B.; Pgrez-Ossorio, R.; Plumet, J.; Sierra, M. A. Tetrahedron Lett. 1986, 27, 1627. (2) (a) Inoue, S.; Sugiura, S.; Kakoi, H.; Goto, T. Tetrahedron Lett. 1969, 1609. (b) Sugiura, S.; Kakoi, H.; Inoue, S.; Goto, T. Yakugaku Zasshi, 1970,90, 441. (3) Yamaguchi, I. Biochem. J. 1975, 151, 9. (4) Barlin, G. B.; Brown, D. J.; Kadunc, Z.; Petric, A.; Stanovnik, B.; Tisler, M. Aust. J. Chem. 1983, 36, 1215. (5) The synthesis of 4a and some derivatives by reaction of phenacyl bromides with 2-aminoppidine 1-oxide has been also described. See: (a) Deady, L. W.; Stanborough, M. S. J. Heterocycl. zyxwvutsrq Chem. 1979,163,187. (b) Deady, L. W.; Stanborough, M. S. Aust. J. Chem. 1981, 34, 1295. Chart I Q ? + R on 0 1, R = Me, Ph 2, R' = Me, Ph; R2 = H, Ph, Me 3, R = H, C1 Scheme I x v % R-CO-CCIO ky,N (X,Y: CH,N) Scheme I1 @r + xm - 5a series of representative C-substituted 2-aminopyridines. By reacting equimolar amounts of the arylglyoxal and the 2-aminopyridine in benzene or methylene chloride a t room temperature and in the absence of any catalyst, we ob- tained in fair to excellent yields either carbinolamines 5 or imidazo[ 1,2-a]pyridinium-&olates 4a-f, depending on the nature of the substituents on both aromatic rings. On the other hand, compounds 4 were the only isolated products when the reaction was carried out in the presence of a catalytic amount of BF3.Et20. Carbinolamines 5 in turn cyclized to the related 4 with yields identical with those obtained from the reagents in the presence of the same catalyst, with the only exception being compound 5k, which did not react even after prolonged reaction time. Table I shows physical data and reaction conditions for compounds 4, along with those for compounds 10 and 11. Compounds 4 were obtained as hydrates, and the cor- responding anhydrous products, generally orange or red powdery solids, were sparingly soluble in most usual or- ganic solvents and could not be recrystallized as such. (6) The arylglyoxals were used in all cases as hydrates given their greater stability and easier handling. The results obtained with free arylglyoxals were identical in the cases for which both forms were tested. 0022-3263/89/1954-5763$01.50/0 0 1989 American Chemical Society