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Wang et al. Chem Synth 2023;3:9 https://dx.doi.org/10.20517/cs.2022.44 Page 3 of 9

Scheme 2. Organocatalytic reactions of benzoxazinanone-related compounds.

unsaturated carbonyl derivatives 2 or 4 (0.2 mmol) and quinidine C5 (0.01 mmol, catalyst). The mixture was
stirred at 35 °C for 96 h. After removing the solvent under vacuum, the residue was purified by flash
chromatography (petroleum ether/ethyl acetate = 4/1, v/v) to afford the desired products 3 or 5.

RESULTS AND DISCUSSION
At the outset, we wanted to develop an organocatalytic [4 + 4]-annulation of 2-(4H-benzo[d][1,3]oxazin-
E
4-yl)acrylates w i t h 2 - [aryl(tosylimino)methyl]acrylates . x c e p t i o n a l l y , m e t h y l
[16]
2-[phenyl(tosylimino)methyl]acrylate 2a was found to act as a two-atom synthon in the N,
N-dimethylpyridin-4-amine (DMAP) catalyzed reaction of methyl 2-(2-phenyl-4H-benzo[d][1,3]oxazin-4-
[17]
yl)acrylate 1a, leading to the formation of racemic 1,2,3,4-tetrahydroquinoline-3-carboxylate 3aa . To
achieve an organocatalytic asymmetric [4 + 2]-annulation for the construction of chiral 1,2,3,4-
tetrahydroquinolines, we then started our investigation with a model reaction between methyl 2-(2-phenyl-
4H-benzo[d][1,3]oxazin-4-yl)acrylate 1a and methyl 2-[phenyl(tosylimino)methyl]acrylate 2a in the
presence of different chiral amines C in dichloromethane (CH Cl ) at room temperature (rt) for 24 h.
2
2
Initially, the C1-catalyzed formal [4 + 2]-annulation furnished the desired product 3aa in 60% yield with
18% ee and > 20:1 dr [Table 1, entry 1]. Other chiral organocatalysts C2-3 bearing pyridine ring also
afforded unsatisfactory enantioselectivity, respectively [Table 1, entries 2-3]. An essential enhancement of
enantioselectivity was achieved when quinine C4 was employed as a catalyst, giving the desired product 3aa
in 13% yield with 91% ee [Table 1, entry 4]. Further screening of cinchona alkaloids identified quinidine C5
as a suitable catalyst to afford 3aa in 30% yield with 90% ee [Table 1, entries 5-7]. To our delight, systematic
screening studies including the effect of solvents [Table 1, entries 8-13], concentration [Table 1,
entries 14-18], reaction temperature [Table 1, entries 19-22], the molar ratio of reactants and temperature [
Table 1, entries 23-27] revealed that quinidine C5 enabled the formation of 3aa in 95% yield with 89% ee in
CH Cl (0.1 mL) at 35 °C after 96 h [Table 1, entry 27].
2
2
With the optimal conditions in hand, we then investigated the substrate scope. The scope of 2-(4H-benzo[d]
[1,3]oxazin-4-yl)acrylates 1 was firstly examined by the C5-catalyzed reaction of methyl 2-
[phenyl(tosylimino)methyl]acrylate 2a [Scheme 3]. Notably, all the probed 2-(4H-benzo[d][1,3]oxazin-4-
yl)acrylates could react smoothly to afford the corresponding products in high yields with asymmetric
induction. In detail, the reaction of ethyl 2-(2-phenyl-4H-benzo[d][1,3]oxazin-4-yl)acrylate 1b (R = Et)
1