CH C(CONH2)COMe NO2 CH(OH)CH(CONH2)COMe NO2 1 2 78 J. CHEM. RESEARCH (S), 1997 J. Chem. Research (S), 1997, 78–79 J. Chem. Research (M), 1997, 0643–0649 2-Hydroxy-2-methyl-2H-1-benzopyran-3-carboxamide Derivatives produced by Knoevenagel Condensation Conor N. O’Callaghan* and T. Brian M. McMurry University Chemical Laboratory, Trinity College, Dublin 2, Ireland The reaction of 2-hydroxybenzaldehydes with 3-oxobutanamide affords 2,4-dihydroxy-2-methyl-2H-3,4-dihydro- 1-benzopyran-3-carboxamides and 2-hydroxy-2-methyl-2H-1-benzopyran-3-carboxamides, depending on the particular aldehyde and the experimental conditions used.Many benzopyran derivatives occur in nature,1 and 2,2-disubstituted 2H-1-benzopyrans are of considerable biological importance. The tocopherol (vitamin E) compounds have been known for many years,2 and more recently 7-methoxy- 2,2-dimethyl-2H-1-benzopyran was shown to inhibit insect hormone activity.3 At present there is widespread interest in the potassium channel modulatory (antihypertensive) activity of a range of 3-hydroxy-2,2-dimethyl-2H-1-benzopyran derivatives, 4 which have been developed following the discovery of cromakalim.5 New 2,2,3-tri- and 2,2,3,4-tetra-substituted benzopyran derivatives, obtained by the reaction of 2-hydroxybenzaldehydes with 3-oxobutanamide, are now reported. 3-Oxobutanamide has been little studied in the Knoevenagel condensation, but it is clearly less reactive than the classical activated methylene derivatives normally cited,6 and is more sensitive to alterations in reaction conditions. Thus, for example, reaction with o-nitrobenzaldehyde under normal basic conditions affords the expected product 1, but in mildly acid solution two diastereoisomeric racemates 2 are obtained.There is a considerable literature describing the Knoevenagel condensations of salicylaldehyde 3a.6,7 With methylene compounds activated by, e.g., C�N and CO2R groups, the reaction affords, almost invariably, coumarin-type products or products derived from these.Initial examination of the reaction of salicylaldehyde with 3-oxobutanamide 4 indicates that it fits into this pattern. Even under very mild Knoevenagel conditions, the only stable, solid product (obtained in very small yield) is the benzopyranopyridine derivative 13 (R=coumarin-3-yl). Under less mild conditions, a complex solid foam is obtained, the two main components of which are the bridged tricyclic derivatives 14 (R=coumarin-3-yl) where Rp=OH and NH2 respectively.All three of these products have previously been shown to be obtained from the reaction of 3-acetyl-2H-1-benzopyran-2-one 10a with ammonia.8 *To receive any correspondence. Scheme 1 a X=H; b X-6-Cl; c X=8-OMe; d X=7-OMe; e X=6,8-Br2; f X=(5,6)-CH�CH·CH�CH (benzopyran numbering)H HO H2NOC O OH Me H In contrast to this, the sole product formed from the reaction of salicylaldehyde with 3-oxobutanamide in ethanol containing acetic acid and minimal piperidine is the crystalline dihydroxy derivative 6a.The observed vicinal coupling constant, 10.5 Hz, for the pyran ring protons H3 and H4 establishes that the latter are trans, with H3 axial and H4 quasiaxial. It is most likely that the 2-hydroxy group is also axial, as shown in Fig. 1 (cf. ref. 9). The fully saturated compound 6a is stable in the solid state and is recrystallisable, but when the [2H6]DMSO NMR solution is stored, it is clear that it undergoes dissociation into the original two components within 48 h.The reaction of 5-chloro-2-hydroxybenzaldehyde 3b with 3-oxobutanamide under similar conditions affords the analogous dihydroxy compound 6b as the main product. NMR confirms this formulation, but shows that in solution in [2H6]DMSO the pyran ring rapidly undergoes ring-opening. Two racemic openchain compounds 5b are present in solution, but these intermediate decomposition products are too unstable to be isolated; further decomposition, with liberation of the original aldehyde, is evident within 2 h.The instability of the compounds 6 in solution is discouraging, but other, substituted o-hydroxybenzaldehydes afford products which are considerably more stable. In contrast to salicylaldehyde and 5-chloro-2-hydroxybenzaldehyde, the reaction of 2-hydroxy-3-methoxybenzaldehyde with 3-oxobutanamide (in methanol containing catalytic piperidine) affords the 2,2,3-trisubstituted product 9c and a little of the coumarin-type product 10c.The compounds 9 and 10 are much more stable than the saturated structures 6 (which are formed without dehydration), and rapid ring-opening and decomposition reactions are not evident. 2-Hydroxy-1-naphthaldehyde behaves like 2-hydroxy- 3-methoxybenzaldehyde, affording the 3,3-disubstituted tricyclic product 12 in moderate yield. Two other aldehydes which afford the same type of product (9e and 9d respectively) but in much smaller yield, are 3,5-dibromo- and 2-hydroxy- 4-methoxybenzaldehyde; in the case of the latter, the 2-oxo derivative 10d is the main product formed.The isolation of the two types of product 9 and 10 shows that the initial condensation can result in the formation of both of the possible stereoisomers 7 and 8. The sequence of formation of the various products can be summarised as shown in Scheme 1. Techniques used: IR, mp, 1H and 13C NMR, elemental analysis References: 12 Schemes: 1 Figures: 1 Received, 29th October 1996; Accepted, 9th December 1996 Paper E/6/07362J References cited in this synopsis 1 E.E. Schwiezer and D. Meeher-Nycz, in Chromenes, Chromanones and Chromones, ed. G. P. Ellis, Wiley, New York, 1977, p. 29. 2 See, e.g. K. Mukai, J. Kageyama, T. Ishida and K. Fukuda, J. Org. Chem., 1989, 54, 552; T. Rosenan and W. D. Habicher, Synlett., 1996, 427. 3 T. R. Kasturi and T. Manithomas, Tetrahedron Lett., 1967, 2573; D. R. Boyd, N. D. Sharma, R. Boyle, T. A. Evans, J. F. Malone, K. M. McCombe, H. Dalton and J. Chima, J. Chem. Soc., Perkin Trans. 1, 1966, 1757. 4 See, e.g., F. Cassidy, J. M. Evans, M. S. Hadley, A. H. Haladi, P. E. Leach and G. Stemp, J. Med. Chem., 1992, 35, 1623. 5 cf. C. J. Roxburgh, Synthesis, 1996, 307. 6 G. Jones, Org. React. (N.Y.), 1967, 15, 204. 7 C. N. O’Callaghan, T. B. H. McMurry and C. J. Cardin, J. Chem. Res., 1990, (S) 132; (M) 0901. 8 C. N. O’Callaghan and T. B. H. McMurry, J. Chem. Res., 1989, (S) 329; (M) 2501. 9 W. D. Cotterill, D. A. Johnston and R. Livingstone, J. Chem. Res., 1995, (S) 226; (M) 1466. 10 N. P. Buu-Hoi, T. B. Loc and N. D. Xuong, Bull. Soc. Chim. Fr., 1957, 561. 11 P. Czerney, H. Hartmann and J. Liebscher, Ger. (East) Pat. 140,252, 1980 (Chem. Abstr., 1980, 93, 114 327). 12 E. Knoevenagel and R. Schroeter, Ber. Dtsch. Chem. Ges., 1904, 37, 4484. J. CHEM. RESEARCH (S), 1997 79 Fig. 1 Probable conformation of the dihydroxy derivat