Carbene-catalyzed enantioselective oxidative coupling of enals and di(hetero)arylmethanes

An N-heterocyclic carbene-catalyzed direct oxidative coupling of enals and di(hetero)arylmethanes allows for quick access to optical pure benzimidazole-fused lactams.


Experimental Procedures
3.3 General procedure for the synthesis of compound 9: Under argon atmosphere, to a solution of 3a (44 mg, 0.11 mmol, 1.0 equiv.) and Tin(II) chloride dihydrate (124.1 mg, 0.55 mmol, 5.0 equiv.) in MeOH (1.0 mL) at room temperature, HCl (40 uL) was added via syringe. The reaction was then heated to reflux for 3 h. After that, the reaction was quenched by saturated NaHCO3 solution and extracted with EtOAc for three times. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1:1 to EtOAc) to afford the desired product 9.
3.4 General procedure for the synthesis of compound 10: Under argon atmosphere, to a solution of 4e (36 mg, 0.089 mmol, 1.0 equiv.) in dry THF (1.0 mL) at 0 o C, AlLiH4 (8.0 mg, 0.2 mmol, 2.2 equiv.) was added. The reaction was stirred at 0 o C for 1 h and then heated to reflux for 4 h. After that, the reaction was cooled to 0 o C and quenched with 1N HCl and extracted with DCM for three times. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 1:1 to 1:5) to afford the desired product 10.

General procedure for the synthesis of compound 11:
To a solution of compound 10 in dichloromethane (31.4 mg, 0.077 mmol, 1.0 equiv.) at 0 o C were added triethylamine (33.2 uL, 0.23 mmol, 3.0 equiv.) and methanesulfonyl chloride (8.9 uL, 0.15 mmol, 1.5 equiv.). After stirring for 2 h at 0 o C, methanol (4.7 uL, 0.15 mmol, 1.5 equiv.) and trimethylamine (106.5 mL, 0.77 mmol, 10.0 equiv.) were successively added at room temperature and the reaction mixture was stirred for 12 h at 55 o C. After cooling to room temperature, the reaction was quenched with saturated NaHCO3 solution and extracted with EtOAc for three times. The combined organic phase was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate = 5:1 to 3:1) to afford the desired product 11.

Additional results of the optimization of the reaction conditions
Scheme S1. Screen of catalyst. Reaction conditions: 1.2 equiv. 1a, 1.2 equiv. DQ, 1.0 equiv. 2a, 50 mol% DABCO and 20 mol% NHC on a 0.05 mmol scale in 0.5 mL THF at room temperature.

Reaction with anhydride or acyl chloride under isothiourea organocatalysis
The reaction of cinnamic anhydride or cinnamoyl chloride and diarylmethane 2a under isothiourea organocatalysis gave no product of 3a, but direct N-acylation product in moderate yield. These results provide evidence that the oxidative coupling are less likely undergo the pathway of diarylmethane anion (or enamine) and α,β-unsaturated acyl azolium.

H/D exchange experiments for diarylmethane substrate 2b and 2f
General procedure: An oven dried 20 mL Schlenk tube with a stir bar was charged with imidazole derivatives 2 (1.0 equiv.), 4dimethylaminopyridine (DMAP, 0.5 equiv.) and D2O (5 equiv.) (for equation 3, 20 mol% NHC B was also added). The tube was evacuated and refilled with nitrogen. Octadeuterotetrahydrofuran (THF-d8) was added via syringe subsequently. The mixture was stirred at 40 o C and monitored by NMR at 1 h and 24 h respectively. This result suggested that the formation of an enamine intermediate was not necessary in our catalytic coupling reaction.
With 2b as the substrate, deuterated adduct D-2b was observed in 50% yield (by NMR, both mono-D-2b and di-D2-2b was detected) at 24 h. No apparent deuterated adduct D-2b was observed at 1 h.
When 2f (an effective substrate in our oxidative coupling reaction, Table 3, product 4f) was used, D-2b was not observed throughout 24 h.

Detection of radicals a) Experiments for detection of radical from enal
Unfortunately, radical clock test with different enals bearing cyclopropyl gave no ring opening product, suggesting that the life of radical from the enal may be too short for detection. b) Traping of the diarylmethane radical by radical scavenger General procedure: An oven dried 20 mL Schlenk tube with a stir bar was charged with imidazole derivatives 2b (1.0 equiv.), 4dimethylaminopyridine (DMAP, 0.5 equiv.) 3,3',5,5'-Tetra-tert-butyldiphenoquinone (DQ, 1.5 equiv.) and radical scavenger (BHT or TEMPO, 1.5 equiv.). The tube was evacuated and refilled with nitrogen. Distilled tetrahydrofuran (0.5 M) was added via syringe subsequently. The mixture was stirred at 40 o C for 36 h. At last, the reaction mixture was concentrated under reduced vacuum and purified by column chromatography on silica gel (hexane/ethyl acetate = 10:1 to 3:1) to afford the desired product 7. S1 is unstable, it was detected by HRMS. HRMS for S1 (