Enantioselective Direct Amination of α-Cyanoketones Catalyzed by Bifunctional Organocatalysts

Abstract

The catalytic enantioselective electrophilic α-amination promoted by chiral bifunctional organocatalysts is described. Treatment of α-cyanoketones with azodicarboxylates as electrophilic amination reagents under mild reaction conditions afforded the corresponding α-aminated α-cyanoketones with excellent enantiomeric excesses (87-99%).

electrophilic amination - asymmetric catalysis - bifunctional organocatalyst - α-cyanoketones

References and Notes

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<A NAME="RU06508ST-15">15</A>

Typical Procedure for the Preparation of Organocatalyst V
To a stirred solution of N-(1S,2S)-2-{(R)-3,5-dihydro-4H-dinaphth[2,1-c:1′,2′-e]azepin-4-yl}-cyclohexanamine (785 mg, 2 mmol) [¹4] in dry THF (10 mL) was added 3,5-bis(trifluoromethyl)phenyl isothiocyanate (542 mg, 2 mmol). After the reaction mixture was stirred for 48 h, the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography on silica gel (EtOAc-hexane, 1:5) gave the desired thiourea V (862 mg, 65%) as yellow solid; mp 151-152 ˚C; [α]_D ^²5 -349 (c 1.0, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 7.97-7.77 (m, 4 H), 7.62-7.38 (m, 5 H), 7.35-7.15 (m, 6 H), 6.72-6.15 (br s, 1 H), 4.16-3.66 (m, 3 H), 3.65-3.40 (m, 2 H), 2.73-2.53 (m, 1 H), 2.48-2.12 (br s, 1 H), 2.09-1.88 (m, 1 H), 1.87-1.67 (m, 3 H), 1.66-1.45 (m, 1 H), 1.44-1.21 (m, 2 H), 1.20-1.04 (m, 1 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 180.0, 135.09, 133.15, 132.19, 131.15, 130.89, 129.05, 128.33, 127.48, 127.34, 126.09, 125.89, 125.46, 123.07, 120.05, 117.58, 69.46, 52.30, 33.34, 28.54, 25.54, 25.35. ESI-HRMS: m/z calcd for C₃₇H₃₂F₆N₃S [M + H]⁺: 664.2221; found: 664.2212.

<A NAME="RU06508ST-16">16</A>

Typical Procedure for the Amination of 2-Cyano-1-indanone (1a)
To a stirred solution of 2-cyano-1-indanone (1a, 47.15 mg, 0.3 mmol) and catalyst V (1.99 mg, 0.003 mmol) in toluene (0.3 mL) was added dropwise the solution of tert-butyl azodicarboxylate (103.6 mg, 0.45 mmol) in 0.3 mL of toluene at -20 ˚C. Reaction mixture was stirred for 30 min at -20 ˚C. The mixture was concentrated and purified by flash chromatography (EtOAc-hexane, 1:4) to afford the 110.4 mg (95%) of α-aminated 2-cyano-1-indanone 3ad; [α]_D ^²¹
-22.5 (c 1.38, CHCl₃, 97% ee). ^¹H NMR (200 MHz, CDCl₃): δ = 7.90-7.86 (d, J = 8.0 Hz, 1 H), 7.82-7.70 (t, J = 8.1 Hz, 1 H), 7.56-7.43 (m, 2 H), 7.09-7.01 (s, 1 H), 4.07-3.87 (q, J = 10.0 Hz, 2 H), 1.62-1.22 (m, 18 H). ^¹³C NMR (50 MHz, CDCl₃): δ = 192.0, 155.5, 149.3, 136.9, 136.6, 132.2, 128.6, 126.5, 123.8, 115.6, 83.0, 82.6, 68.4, 40.0, 28.2, 27.8. ESI-MS: m/z (%) = 387 [M⁺], 356 (10), 332 (70), 275 (32), 232 (8), 213 (12), 188 (7.5), 158 (8). ESI-HRMS: m/z [M]⁺ calcd for C₂₀H₂₅N₃O₅: 387.1794; found: 387.1802. HPLC (hexane-i-PrOH, 8:2, 254 nm, 1.0 mL/min, Chiralpak AD column): t _R = 5.8 min (minor), t _R = 7.7 min (major).