Dynamic Study of Cyclic-Open Tautomerism in a Warfarin Analog

The more polar product of the Michael addition of 4-hydroxycoumarin to mesityl oxide, an analog of warfarin, crystallizes as the racemic cyclic coumarin hemiketal 2-hydroxy-2,4,4-trimethyl-3,4-dihydro-2 H ,5 H -pyrano[3,2-c][1] benzopyran-5-one. Crystals occur in the monoclinic system, space group P 2(1)/ n , with a 6.6655(4)Å, b 12.9450(7)Å, c 14.5809(7)Å, β 97.909(5)°, Z = 4. In solution by nuclear magnetic resonance (400 MHz), a dynamic equilibrium exists between the enantiomeric coumarin hemiketals through an unobserved intermediate open tautomer. Diastereomeric methylene and methyl Hs exchange slowly in non-polar solvents (acetic acid and chloroform), much faster in polar, aprotic solvents (acetone and dimethylsulfoxide). In methanol, dynamic behavior begins in the slow-exchange region at 288–310 K, with signal coalescence at 310.5 K, followed by fast-exchange behavior. The barrier to cyclic-open-cyclic (racemization) was found to be ΔG ‡ = + 63(1) kJ/mol (in CD 3 OD), with a racemization rate of 30 s −1 at 298 K, 155 s −1 at 310.5 K. Density functional theory (DFT) computations modelling the open and cyclic coumarin tautomers, including solvent fields, confirms that the open-form is 60–70 kJ/mol higher in energy than the cyclic hemiketal. Additionally, modelling supports the contention that chromone tautomers are insignificant participators in solution. An operative gem -dimethyl effect, supported by the proximity of the methyls to the coumarin carboxy oxygen, apparently favors rotamers that bring the side-chain ketone into proximity with the coumarin enolic hydroxy. The less-polar by-product of the Michael addition has been characterized by spectroscopy and crystallography as 2,2,4-trimethyl[2 H ,5 H ]pyrano[3,2-c][1]benzopyran-5-one. Computations on the alkyl warfarin analog 2-hydroxy-2,4-dimethyl-3,4-dihydro-2 H ,5 H -pyrano[3,2-c] [1]benzopyran-5-one, lacking the gem -dimethyl effect significantly stabilizes the intermediate open coumarin form, which accords with open-form observations in solution for this analog and for warfarin reported in the literature. Graphical Abstract