Mutual Kinetic Resolution of Racemic 3,4‐Dihydro‐3‐methyl‐2H‐[1,4]benzoxazines with Acyl Chlorides of Racemic O‐Phenyllactic Acids and DFT Modelling of Transition States

Abstract

The effect of the electronic nature of the para substituent on the aromatic ring of 2‐aryloxypropionyl chlorides on the stereochemical outcome of the acylation of 3,4‐dihydro‐3‐methyl‐2H‐[1,4]benzoxazine and its 7,8‐difluoro‐containing analogue has been studied. The geometries of the diastereoisomeric transition states and the corresponding Gibbs free enthalpies of activation were determined through DFT calculations at the COSMO‐CH2Cl2‐B3LYP‐D3‐gCP/def2‐TZVP (or def2‐SVP)//B3LYP‐D3‐gCP/def2‐SVP level of theory. It has been found that a low‐cost quantum chemical calculation at a chosen level of theory describes well the quantitative dependence of the selectivity of acylation on the structures of the reagents. The obtained results indicate that aromatic interactions between the reagents play a significant role in the process of stereodifferentiation, ensuring high selectivity of the acylation of benzoxazines with 2‐aryloxyacyl chlorides.

Kinetic Resolution of Racemic 2‐Aryloxy Propionyl Chlorides Using Enantiopure (S)‐3,4‐Dihydro‐3‐methyl‐2H‐[1,4]benzoxazines

“…The selectivity factor is the ratio of the rate constants of individual enantiomers ( s = k fast/ k slow) . We used an approach based on the interaction of racemic reagents, as previously described . In this case, the ratio of the diastereoisomeric amides formed is equal to the selectivity factor; moreover, ratio of the starting reagents, their concentration and the reaction duration do not affect the stereochemical outcome of the process, and therefore, the s value can be determined quite accurately …”

“…KR of racemic acyl chlorides 3 a,b,d,f under the action of enantiopure ( S )‐amines 1 a and 1 b (99 % ee ) was carried out according to the method we used to assign the configuration of the synthesized amides (see Scheme ), except that the acylation was carried out at −20 °C, since lowering the reaction temperature, as we showed earlier,– leads to better stereochemical results. For KR of racemic acyl chlorides 3 a and 3 b , we used fluorinated amine ( S )‐ 1 b ; for KR of compounds 3 d and 3 f , benzoxazine ( S )‐ 1 a (Scheme , Table ).…”

“…We have previously found that the interaction of amines 1 a and 1 b with 2‐(1‐naphthyloxy)propionyl chloride 3 g leads to the predominant formation of (3 R *,2’ R* )‐amides 4 g and 5 g , respectively; while acylation of these amines with 2‐(4‐nitrophenyloxy)propionyl chloride 3 f leads to the (3 S *,2’ R *)‐diastereoisomers of amides 4,5 f as the major products …”

“…We have previously studied acylative KR of racemic heterocyclic amines with chiral acid derivatives . We have also performed the DFT‐based simulation of the transition states in the acylation of 3‐methylbenzoxazines 1 a,b (Figure ) with 2‐aryloxy acyl chlorides and suggested an explanation of the observed stereoselectivity . At the same time, the task of preparation of individual enantiomers of 2‐arylroxy acids as a result of KR with enantiopure amines was not posed.…”

Mutual kinetic resolution: probing enantiorecognition phenomena and screening for kinetic resolution with racemic reagents

“…Acylation of the analogues system were also extensively studied. 20,21 Mutual kinetic resolution as a screening method for kinetic and parallel kinetic resolutions Mutual kinetic resolution can be a key initial evaluation method to assess the level of the enantiorecognition of the reagents. The levels of enantiorecognition are quantified by the stereoselectivity factor E, 5 which is determined from the product distribution using 1 H NMR spectroscopic analysis (i.e., ratio of the major diastereoisomeric product to the minor diastereoisomeric product).…”