Using hyperpolarised NMR and DFT to rationalise the unexpected hydrogenation of quinazoline to 3,4-dihydroquinazoline

Abstract

PHIP and SABRE hyperpolarized NMR methods are used to follow the unexpected metal-catalysed hydrogenation of quinazoline (Qu) to 3,4-dihydroquinazoline as the sole product. A solution of [IrCl(IMes)(COD)] in dichloromethane reacts with H2 and Qu to form [IrCl(H)2(IMes)(Qu)2] (2). The addition of methanol then results in its conversion to [Ir(H)2(IMes)(Qu)3]Cl (3) which catalyses the hydrogenation reaction. Density functional theory calculations are used to rationalise a proposed outer sphere mechanism in which (3) converts to [IrCl(H)2(H2)(IMes)(Qu)2]Cl (4) and neutral [Ir(H)3(IMes)(Qu)2] (6), both of which are involved in the formation of 3,4-dihydroquinazoline via the stepwise transfer of H+ and H-, with H2 identified as the reductant. Successive ligand exchange in 3 results in the production of thermodynamically stable [Ir(H)2(IMes)(3,4-dihydroquinazoline)3]Cl (5).

Scheme 1. Solvent dependent reaction of 1 with quinazoline and H₂ leads to 2 in dichloromethane and unstable 3 in methanol-d₄.

Fig. 1. Typical ¹H NMR spectra of the aromatic region of a sample consisting of Qu (0.1 M) and 1 (5 mM) in dichloromethane-d₂: (A) magnetisation at thermal equilibrium and (B) hyperpolarised magnetisation created by SABRE at 65 G.

Fig. 2. Plot of a series of expansions of the aromatic region of five ¹H NMR spectra that track the conversion of quinazoline into 3,4-dihydroquinazoline in methanol over a 24 h period.

Scheme 2. Route for the outer-sphere conversion of quinazoline into 3,4-dihydroquinazoline by 3 as determined by DFT.