7-Dimethylamino-4-Hydroxycoumarin and Derivatives: Enhanced β-Chain Hydrogen-Bonding

Abstract

The crystal and molecular structure of 7-dimethylamino-4-hydroxycoumarin as its hydrate (1, C₁₁H₁₁NO₃ • H₂O) has been determined. Crystals are monoclinic, space group P2(1)/n with a = 7.1435(4) Å, b = 20.1763(6) Å, c = 7.8590(3) Å, β = 110.018(5)^o and V = 1064.28(8)ų for 4 formula units per cell. Both coumarin enol ester hydroxy and carboxy groups engage in hydrogen-bonding with the water of crystallization. Several 3-substituted derivatives were prepared from this material including 7-dimethylamino-3-benzyl-4-hydroxycoumarin (2) and 7-dimethylaminowarfarin (4). Compound 2 (C₁₈H₁₆NO₃) crystallizes in the triclinic system, space group P-1, with a = 7.0180(7) Å, b = 7.8143(7) Å, c = 14.3158(10) Å, α = 90.586(6)^o, β = 94.738(5)^o, γ = 104.639(7)^o, and V = 756.57(9) ų for 2 molecules in the cell. For compound 2, the crystal structure shows infinite hydrogen-bonded translational β-chains linking well aligned hydroxy and ester carboxy groups with a repeat distance of 7.018 Å. The dipolar nature of the substituted 4-hydroxycoumarin strengthens the β-chains compared to unsubstituted systems in which the repeat is longer and weaker at 7.17 Å. Computations (DFT) support the bond length changes due to a dipolar influence of the 7-dimethylamino group (compared to the unsubstituted compounds), and a more negative carboxy oxygen hydrogen-bond acceptor. For compound 4 (C₂₁H₂₁NO₄), a stereoselective synthesis allowed preparation of the (S)-isomer which crystallized in the orthorhombic system, space group P2(1)2(1)2(1), with a = 6.7857(3) Å, b = 14.7140(5) Å, c = 17.4652(7) Å and V = 1743.81(12) ų for 4 molecules in the cell. Compound 4 forms the trans cyclic hemiketal from methanol in the crystal. In CDCl₃ solution (298 K), 4 exists as an equilibrium mixture of three tautomers: 12.8% open form, 45.5% cis hemiketal and 41.7% trans hemiketal (coumarin forms).

Graphical Abstract

Elisei Cosovan, Victor Cosovan, Daniel A. Osborne, David H. Magers, Edward J. Valente-3-Benzyl-4-hydroxy-7-dimethylaminocoumarin forms enhanced translational β-chain hydrogen-bonded arrays in the crystal