A bifunctional iminophosphorane squaramide catalyzed enantioselective synthesis of hydroquinazolines via intramolecular aza-Michael reaction to α,β-unsaturated esters

Abstract

An efficient synthesis of enantioenriched hydroquinazoline cores via a novel bifunctional iminophosphorane squaramide catalyzed intramolecular aza-Michael reaction of urea-linked α,β-unsaturated esters is described. The methodology exhibits a high degree of functional group tolerance around the forming hydroquinazoline aryl core and wide structural variance on the nucleophilic N atom of the urea moiety. Excellent yields (up to 99%) and high enantioselectivities (up to 97 : 3 er) using both aromatic and less acidic aliphatic ureas were realized. The potential industrial applicability of the transformation was demonstrated in a 20 mmol scale-up experiment using an adjusted catalyst loading of 2 mol%. The origin of enantioselectivity and reactivity enhancement provided by the squaramide motif has been uncovered computationally using density functional theory (DFT) calculations, combined with the activation strain model (ASM) and energy decomposition analysis (EDA).

Fig. 1. Representative pharmaceutically active compounds containing a hydroquinazoline core.

Scheme 1. Previous enantioselective syntheses of hydroquinazoline.

Scheme 2. (A) Scope of the BIMP-catalyzed intramolecular aza-Michael reaction to α,β-unsaturated ester. [a] Reaction carried out at 80 °C. [b] Reaction carried out at 40 °C. [c] 30 hours reaction time. [d] 48 hours reaction time. [e] 72 hours reaction time. [f] 5 mol% cat. K was used. [g] Reaction carried out at 50 °C. [h] Reaction carried out at 60 °C. [i] 120 hours reaction time. [j] 216 hours reaction time. (B) Preparative scale synthesis of 2j. Stereochemical configuration was assigned by analogy with (R)-2j (determined by single crystal X-ray diffraction studies).

Scheme 3. Derivatization of enantioenriched 2j. [a] (i) TFA, CH₂Cl_2, 0 °C to RT, 5 h. (ii) SOCl₂, MeOH, 20 h. [b] (i) TFA, CH₂Cl₂, 0 °C to RT, 5 h. (ii) (COCl)₂, DMF (cat.), CH₂Cl₂, 2 h. (iii) BnNH₂, Et₃N, CH₂Cl₂, 18 h. [c] 1-Methyl-1H-pyrazole-3-boronic acid pinacol ester, Pd(dppf)Cl₂CH₂Cl₂, Cs₂CO₃, 1,4-dioxane, H₂O. [d] Erlotinib (HCl complex), PdCl₂(PPh₃)₂, CuI, PPh₃, Et₃N.

Scheme 4. (A) Lowest energy TS structure for the formation of (R)-product and (B) lowest energy TS structure for the formation of (S)-product of the BIMP squaramide-catalyzed intramolecular aza-Michael reaction computed at COSMO(toluene)-ZORA-M06-2X/TZ2P//COSMO(toluene)-ZORA-BLYP-D3(BJ)/DZP. Energies (kcal mol⁻¹) and forming bond lengths (Å) of TS geometries are provided in the insert.

Scheme 5. (A) Interaction energies and the energy decomposition analysis (EDA) of the hydrogen bond donor–methyl acrylate complexes (HB–MA). (B) Energy barriers of the aza-Michael reaction transition structures and the activation strain analysis (ASA) and the energy decomposition analysis (EDA). (C) Molecular orbital diagram and the most significant occupied orbital overlaps computed at COSMO(toluene)-ZORA-M06-2X/TZ2P//COSMO(toluene)-ZORA-BLYP-D3(BJ)/DZP. Energies (kcal mol⁻¹) are provided in the insert.