Highly Enantioselective and Regioselective Conjugate Addition of Nitromethane to 1,5-Diarylpenta-2,4-dien-1-ones Using Bifunctional Cinchona Organocatalysts

Abstract

A general and efficient asymmetric organocatalytic 1,4-Michael addition of nitromethane to 1,5-diarylpenta-2,4-dien-1-ones (cinnamylideneacetophenones) catalyzed by 9-thiourea-9-(deoxy)-epi-hydroquinine has been developed. The reactions afforded excellent enantioselectivities (up to 99%), high yields (up to 97%), and exclusive regioselectivity.

Key words

asymmetric catalysis - enantioselectivity - regioselectivity - ketones

References and Notes

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9

Further details on the single-crystal X-ray diffraction studies are given as Electronic Supporting Information. This compound crystallized as colorless prisms, in the orthorhombic P212121 space group with Z = 4.
Crystal Data for ( R )-5a
C₁₈H₁₇NO₃, M = 295.33, T = 150 (2) K, a = 5.59290 (10) Å, b = 11.9990 (3) Å, c = 23.0093 (5) Å, V = 1544.14 (6) Å^³, µ(MoKα) = 0.087 mm^-¹, D _c = 1.270 g cm^-³, crystal size of 0.14 × 0.12 × 0.10 mm^³. Of a total of 35216 reflections collected, 2411 were independent (R _int = 0.0233). Final R1 = 0.0360 [I > 2σ(I)] and wR2 = 0.0969 (all data). Data completeness to theta = 29.13˚, 99.8%. Data have been deposited at the Cambridge Crystallographic database: CCDC 739749

12

Synthesis of ( E , E )-1-(2-Aminophenyl)-5-phenylpenta-2,4-dien-1-one (4h)
Sodium hydride (265 mg, 11 mmol) was added to a solution of 2′-aminoacetophenone (675 mg, 5.0 mmol) in dry THF (15.5 mL), and the mixture was cooled to r.t. Cinnamaldehyde (792 mg, 6.0 mmol) in dry THF (20 mL) was added, and the reaction mixture was stirred for 12 h and then poured into a mixture of H₂O (20 mL) and ice (20 g) and acidified with HCl to pH ˜2. The solid obtained was filtered, taken up in CH₂Cl₂ and washed with H₂O. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography with a 1:1 mixture of light PE-CH₂Cl₂ as eluent. The residue was recrystallized from EtOH. Orange solid (573 mg, 46% yield); 113-114 ˚C. ^¹H NMR (300.13 MHz, CDCl₃): δ = 7.79 (dd, 1 H, ^³ J = 8.5 Hz, ⁴ J = 1.5 Hz, H-6′), 7.58-7.48 (m, 3 H, H-3, H-2′′,6′′), 7.40-7.25 (m, 4 H, H-3′′,5′′, H-4′, H-4′′), 7.18 (d, 1 H, ^³ J _trans  = 14.8 Hz, H-2), 7.08-6.94 (m, 2 H, H-4, H-5), 6.70-6.66 (m, 2 H, H-3′, H-5′), 6.31 (br s, 2 H, NH₂) ppm. ^¹³C NMR (125.77 MHz, CDCl₃): δ = 191.7 (C-1), 150.9 (C-2′), 143.0 (C-3), 140.7 (C-4), 136.3 (C-1′′), 134.2 (C-4′), 130.9 (C-6′), 129.0 (C-4′′), 128.8 (C-3′′,5′′), 127.2 (C-2′′,6′′, C-5), 126.5 (C-2), 119.1 (C-1′), 117.3 (C-5′), 115.9 (C-3′) ppm.

13

General Procedure for Enantioselective Addition of Nitromethane to Cinnamylideneacetophenones 4a-h: Synthesis of 5a-h
1,5-Diarylpenta-2,4-dien-1-ones 4a-h (0.128 mmol) and thiourea catalyst 2a (22.9 mg, 0.038 mmol) were dissolved in nitromethane (0.47 mL) under a nitrogen atmosphere. The mixture was stirred for 7 d at r.t. The resulting solution was evaporated and purified by column chromatography eluting with hexane-EtOAc (9:1). The purified material was crystallized to obtain compounds 5a-h.



Selected Data for ( R , E )-3-(Nitromethyl)-1,5-diphenylpent-4-en-1-one [( R )-5a]
White solid (36.7 mg, 97% yield); 105-107 ˚C (hexane-EtOAc). ^¹H NMR (300.13 MHz, CDCl₃): δ = 7.96 (d, 2 H, ^³ J = 7.5 Hz, H-2′,6′), 7.60 (t, 1 H, ^³ J = 7.5 Hz, H-4′), 7.48 (t, 2 H, ^³ J = 7.5 Hz, H-3′′,5′′), 7.34-7.21 (m, 5 H, H-2′′,6′′, H-3′′,5′′, H-4′′), 6.58 (d, 1 H, ^³ J _trans  = 15.9 Hz, H-5), 6.17 (dd, 1 H, ^³ J _trans  = 15.9 Hz, ^³ J = 8.6 Hz, H-4), 4.72 (ABX, 1 H, ^² J _AB = 12.2 Hz, ^³ J _AX = 5.9 Hz, H-1A′′′), 4.62 (ABX, 1 H, ^² J _AB = 12.2 Hz, ^³ J _BX = 7.4 Hz, H-1B′′′), 3.81-3.70 (m, 1 H, H-3), 3.30 (d, 2 H, ^³ J = 6.5 Hz, H-2) ppm. ^¹³C NMR (75.47 MHz, CDCl₃): δ = 197.0 (C-1), 136.5 (C-1′), 136.2 (C-1′′), 133.6 (C-4′), 133.4 (C-5), 128.8 (C-3′,5′), 128.6 (C-3′′,5′′), 128.1 (C-2′,6′), 128.0 (C-4′′), 126.5 (C-4), 126.4 (C-2′′,6′′), 78.8 (C-1′′′), 40.3 (C-2), 37.3 (C-3) ppm. HRMS (ESI⁺): m/z calcd for [C₁₈H₁₇NO₃ + H]⁺: 296.1281; found: 296.1279. Anal. Calcd for [C₁₈H₁₇NO₃ + H]⁺: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.17; H, 5.82; N, 4.79. HPLC (i-PrOH-hexane = 10:90, flow rate 0.7 mL/min, λ = 254 nm): t _R(minor) = 18.31 min; t _R(major) = 20.70 min (ee = 96%), after recrystallization (ee >99%).
Selected Data for ( R , E ) - 1-(4-Chlorophenyl)-3-(nitromethyl)-5-phenylpent-4-en-1-one [( R )-5f]
White solid (38.8 mg, 92% yield); 147-148 ˚C (hexane-EtOAc). ^¹H NMR (300.13 MHz, CDCl₃, 20 ˚C): δ = 7.89 (AA′BB ′, ^³ J _AB = 8.6, Hz, ⁴ J _{AA ′} = 2.4 Hz, ⁵ J _{AB ′} = 1.9 Hz, 2 H, H-2′,6′), 7.46 (AA′BB ′, ^³ J _AB = 8.6, Hz, ⁴ J _{BB ′} = 2.4 Hz, ⁵ J _{AB ′} = 1.9 Hz, 2 H, H-3′,5′), 7.32-7.24 (m, 5 H, H-3′′,5′′, H-2′′,6′′, H-4′′), 6.58 (d, ^³ J _trans  = 15.8 Hz, 1 H, H-5), 6.15 (dd, ^³ J _trans  = 15.8 Hz, ^³ J = 8.5 Hz, 1 H, H-4), 4.71 (ABX, ^² J _AB = 12.1 Hz, ^³ J _BX = 6.0 Hz, 1 H, H-1A′′′), 4.61 (ABX, ^² J _AB = 12.1 Hz, ^³ J _BX = 7.1 Hz, 1 H, H-1B′′′), 3.79-3.68 (m, 1 H, H-3), 3.30 (dd, ^² J = 17.7 Hz, ^³ J = 6.5 Hz, 1 H, H-2A), 3.24 (dd, ^² J = 17.7 Hz, ^³ J = 6.5 Hz, 1 H, H-2B) ppm. ^¹³C NMR (125.77 MHz, CDCl₃, 20 ˚C): δ = 195.8 (C-1), 140.1 (C-4′), 136.0 (C-1′′), 134.7 (C-1′), 133.6 (C-5), 129.4 (C-2′,6′), 129.1 (C-3′,5′), 128.6 (C-3′′,5′′), 128.0 (C-4′′), 126.4 (C-2′′,6′′), 126.2 (C-4), 78.8 (C-1′′′), 40.3 (C-2), 37.3 (C-3) ppm. HRMS (ESI⁺): m/z calcd for [C₁₈H₁₆ClNO₃ + Na]⁺: 352.0711; found: 352.0710. Anal. Calcd for [C₁₈H₁₆ClNO₃ + Na]⁺: C, 65.56; H, 4.89; N, 4.25. Found: C, 65.27; H, 4.92; N, 4.21. HPLC (i-PrOH-hexane = 10:90, flow rate 0.7 mL/min, λ = 254 nm): t _R(minor) = 24.31 min; t _R(major) = 28.95 min (ee = 94%), after recrystallization (ee > 99%).