An efficient preparation of macrocycles 7 and 9 bearing vinamidine moieties is described. The key to the preparation is the (2:2) cyclocondensation of malonaldhyde derivatives 1 and 8 and 1,w-diaminoalkanes 6.Vinamidine (1,5-diazapentadiene) and vinamidinium salts are unique conjugate systems 1 because electron-donating and electron-withdrawing groups are separately attached to a carbon-carbon double bond. Vinamidinium salts have been used for the preparation of heterocycles, while vinamidine derivatives were rarely used for the synthetic purpose. 2 We have recently been studying an efficient preparation of N,N'-diaryl-3-cyanovinamidines 5a by the reaction of 3-butoxy-2-cyanoacrolein 1, a synthetic equivalent of cyanomalonaldehyde 2, with two molar equivalents of arylamine 3a via the initially formed product 4a. 3 Similar reaction of acrolein derivative 1 with aliphatic primary amines, such as benzyl-3b, cyclohexyl3c, and (R)-1-phenylethyl-amine 3d, also gave vinamidine derivatives 5b-d in good yields (Scheme 1). In our continuing study on the synthetic utility of malonaldehydes, we examined the reaction of acrolein derivative 1 and (methoxycarbonyl)malonaldehyde 8 4 with 1,w-diaminoalkanes 6 expecting to form cyclic products bearing vinamidine moieties.
Scheme 1To a solution of 3-butoxy-2-cyanoacrolein 1, generated by the acid treatment of commercially available 1,3,3-tributoxy-2-cyanopropene, 5 in acetonitrile were added 1.2 equivalents of 1,6-diaminohexane (6e). The resultant mixture was refluxed for 8 hours and the solvent was evaporated to dryness, and the white solid was crystallized from methanol to give an unexpected (2:2) cyclic product 7e in 78% yield. The structure of 7e was confirmed on the basis of its analytical and spectroscopic data; in its IR spectrum characteristic absorption bands due to N-H and CN stretching were observed. The simple signal patterns in the 1 H and 13 C NMR spectra of product 7e implied that it has a symmetrical structure and, especially, its mass spectra showed the proposed molecular ion peaks [354 (M + ) for EI and 355 (MH + ) for CI]. Similar reaction of 1 with 1,2-diaminoethane (ethylenediamine) 6a, 1,4-diaminobutane 6c, 1,5-diaminopentane (gadaverine) 6d, and 1,12-diaminododecane 6f gave the corresponding (2:2) cyclic products 7a, 7c, 7d, and 7f in moderate to good yields (Scheme 2, Tables 1, 2). In addition, the reaction of 1 with 1,5-diaminopentane 6d gave another product 7d' along with product 7d. Product 7d' could not be isolated in its pure form; 7d' in deuteriochloroform and methanol was not stable and gradually converted to 7d within a few days on standing at room temperature. A prolonged reaction in refluxing acetonitrile (72 hours) gave only 7d (Table 1, run 4). The 1 H and 13 C NMR spectra of 7d' were almost consistent with those of 7d over the whole region. These findings suggest that product 7d' is a conformational isomer of 7d.(Methoxycarbonyl)malonaldehyde 8 was also reacted with diaminoalkanes 6a, 6c, 6e, and 6f; the same type of (2:2) cyclic products 9a, 9c...
