MOLECULAR SCAFFOLDS .2. INTRAMOLECULAR HYDROGEN-BONDING IN 1,2-DIAMINOETHANE DIUREAS

Intramolecular hydrogen bonding creates remarkably stable folded structures in diurea derivatives of substituted 1,2-diaminoethanes. 1,2-Diaminoethane diureas 2 [PhN(CONHR(1))CH2CH2N(CONHR(2))CH2CH2CN; 2a, R(1) = R(2) = Ph; 2b, R(1) = (S)-CH(CH(2)Ph)CO2CH3, R(2) = (S)-CH(i-Pr)CO2CH3; 2c, R(1) = R(2) = (S)-CH(CH(2)Ph)CO2CH3; 2d, R(1) = R(2) = CH3] are prepared in high yield by reaction of diamine 4 (PhNHCH(2)CH(2)NHCH(2)CH(2)CN) with isocyanates. The differing reactivities of the two amino groups in 4 permit the preparation of diureas bearing different substituents R(1) and R(2) (e.g., 2b) with greater than or equal to 95% regioselectivity. The N-phenyl substituent on the 1,2-diamine backbone of diureas 2 helps maintain conformational homogeneity by controlling the direction of the urea group that bears this substituent (NCONHR(1)). Intramolecular hydrogen bonding aligns the other urea group (NCONHR(2)). Infrared and H-1 NMR spectroscopic studies indicate ureas 2 are largely or wholly hydrogen bonded (ca. 75-100%) in chloroform solution, whereas the homologous 1,3-diaminopropane diureas 1 [PhN(CONHR(1))CH2CH2CH2N(CONHR(2))CH2CH2CN] exhibit a lesser degree of intramolecular hydrogen bonding (25-80%). These findings indicate that the 9-membered hydrogen-bonded ring structures of 1,2-diaminoethane diureas 2 are more stable than the 10-membered hydrogen-bonded ring structures;of 1,3-diaminopropane diureas 1. H-1 NMR and X-ray crystallographic studies establish that the 1,2-diaminoethane backbone of diureas 2 adopts an anti conformation, both in solution and in the solid state.