Development of the First Brønsted Acid Assisted Enantioselective Brønsted Acid Catalyzed Direct Mannich Reaction

Abstract

We here describe the development of the first enantioselective Brønsted acid assisted chiral Brønsted acid catalyzed direct Mannich reaction of acetophenone with various aldimines. The reaction proceeds in the presence of a chiral and an achiral Brønsted acid which simultaneously activate the ketone and aldimine to give the corresponding β-amino ketones with good enantioselectivities and without the necessity of enolate preformation.

Mannich reaction - organocatalysis - Brønsted acid - BINOL-phosphate - cooperative catalysis

References and Notes

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<A NAME="RG08307ST-12">12</A>

Other achiral acids tested gave inferior results with regard to both reactivity and selectivity.

<A NAME="RG08307ST-13">13</A>

No reaction was observed with N-benzyl, N-phenyl, N-(4-methoxyphenyl), N-Boc, N-CBz, N-Bz, N-benzhydryl derivatives.

<A NAME="RG08307ST-14">14</A>

General Procedure for Direct Mannich Reaction
In a typical experiment acetophenone 3 (2 equiv), aldimine 2, catalyst 1c (10 mol%) and AcOH (20 mol%) were suspended in Bu₂O in a screw-capped vial and the resulting mixture was allowed to stir at r.t. for 60 h. Purification of the crude product by column chromatography on silica gel afforded the corresponding product 4.
3-(4-Chlorophenylamino)-1,3-diphenylpropan-1-one (4a) The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as a colorless solid in 43% yield and 86% ee. The ee was determined by HPLC using Chiralcel OD-H column [n-hexane-i-PrOH (90:10), flow rate 0.6 mL/min; major enantiomer: t _R = 25.3 min; minor enantiomer: t _R = 28.2 min); mp 162 °C; [α]_D +31.0 (c 1.0, CH₂Cl₂). IR (KBR): 3373, 2924, 1666, 1507, 1489, 1286, 1003, 820, 703 cm^-1. ESI-HRMS: m/z calcd for C₂₁H₁₈NOClNa [M + Na]⁺: 358.0975; found: 358.0974. ¹H NMR (250 MHz, CDCl₃): δ = 3.25-3.49 (m, 2 H), 4.55 (br s, 1 H), 4.80-4.94 (m, 1 H), 6.34-6.45 (m, 2 H), 6.90-6.99 (m, 2 H), 7.11-7.29 (m, 4 H), 7.30-7.42 (m, 3 H), 7.43-7.54 (m, 1 H), 7.78-7.87 (m, 2 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 46.1, 54.9, 114.9, 122.4, 126.2, 128.1, 128.7, 128.8, 128.9, 133.4, 136.6, 142.4, 145.5, 198.1.
3-(4-Chlorophenylamino)-1-phenyl-3- p -tolylpropan-1-one (4b)
The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as a colorless solid in 40% yield and 63% ee. The ee was determined by HPLC using Chiralpak AD-H column [n-hexane-i-PrOH (80:20), flow rate 0.6 mL/min; major enantiomer: t _R = 18.8 min; minor enantiomer: t _R = 20.1 min]; mp 149-152 °C; [α]_D +21.4 (c 1.0, CH₂Cl₂). IR (KBr): 3449, 2843, 1595, 1492, 1250, 1095, 909, 776, 758, 536 cm^-1. ESI-HRMS: m/z calcd for C₂₂H₂₀NOClNa [M + Na]⁺: 372.1131; found: 372.1137. ¹H NMR (250 MHz, CDCl₃): δ = 2.23 (s, 3 H), 3.20-3.50 (m, 2 H), 4.50 (br s, 1 H), 4.76-4.91 (m, 1 H), 6.30-6.50 (m, 2 H), 6.89-6.98 (m, 2 H), 7.00-7.10 (m, 2 H), 7.15-7.26 (m, 2 H), 7.30-7.41 (m, 2 H), 7.42-7.54 (m, 1 H), 7.75-7.91 (m, 2 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.1, 46.3, 54.6, 114.9, 122.3, 126.2, 128.2, 128.7, 128.9, 129.6, 133.5, 136.6, 137.1, 139.4, 145.6, 198.2.
3-(4-Chlorophenylamino)-3-(4-chlorophenyl)-1-phenyl Propan-1-one (4c)
The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as a colorless solid in 53% yield and 64% ee. The ee was determined by HPLC using Chiralpak AD-H column [n-hexane-i-PrOH (80:20), flow rate 0.6 mL/min; major enantiomer: t _R = 21.7 min; minor enantiomer: t _R = 24.4 min]; mp 140 °C; [α]_D +22.8 (c 1.0, CH₂Cl₂). IR (KBr): 3386, 1671, 1597, 1508, 1289, 1095, 1015, 810, 684 cm^-1. ESI-HRMS: m/z calcd for C₂₁H₁₇NOCl₂Na [M + Na]⁺: 392.0585; found: 392.0590. ¹H NMR (250 MHz, CDCl₃): δ = 3.19-3.48 (m, 2 H), 4.55 (br s, 1 H), 4.84 (t, J = 6.5, 12.5 Hz, 1 H), 6.26-6.44 (m, 2 H), 6.82-7.04 (m, 2 H), 7.14-7.31 (m, 4 H), 7.32-7.41 (m, 2 H), 7.44-7.54 (m, 1 H), 7.73-7.90 (m, 2 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 46.0, 54.3, 115.0, 122.7, 127.7, 128.1, 128.8, 129.0, 129.0, 133.1, 133.7, 136.5, 141.0, 145.3, 197.8.
3-(4-Chlorophenylamino)-3-(2-fluorophenyl)-1-phenyl Propan-1-one (4d)
The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as a colorless solid in 51% yield and 65% ee. The ee was determined by HPLC using Chiralpak AD-H column [n-hexane-i-PrOH (80:20), flow rate 0.6 mL/min; major enantiomer: t _R = 38.3 min; minor enantiomer: t _R = 35.9 min]; mp 125-130 °C; [α]_D +20.2 (c 1.0, CH₂Cl₂). IR (KBr): 3368, 2924, 1666, 1597, 1488, 1286, 1220, 819, 757 cm^-1. ESI-HRMS: m/z calcd for C₂₁H₁₇NOClFNa [M + Na]⁺: 376.0880; found: 376.0872. ¹H NMR (250 MHz, CDCl₃): δ = 3.24-3.58 (m, 2 H), 4.66 (d, J = 4.5 Hz, 1 H), 5.04-5.21 (m, 1 H), 6.33-6.46 (m, 2 H), 6.89-7.04 (m, 4 H), 7.08-7.20 (m, 1 H), 7.28-7.41 (m, 3 H), 7.42-7.54 (m, 1 H), 7.80-7.90 (m, 2 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 44.2, 49.6, 114.8, 115.5, 115.8, 122.6, 124.5, 124.5, 128.2, 128.3, 128.4, 128.7, 128.8, 128.9, 129.0, 129.1, 133.6, 136.4, 145.2, 158.5, 162.4, 198.1.
3-(4-Chlorophenylamino)-1-phenyl-3- o -tolylpropan-1-one (4e)
The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as a colorless solid in 41% yield and 65% ee. The ee was determined by HPLC using Chiralcel OD-H column [n-hexane-i-PrOH (98:2), flow rate 0.6 mL/min; major enantiomer: t _R = 42.2 min; minor enantiomer: t _R = 55.4 min]; mp 149-153 °C; [α]_D +26.8 (c 1.0, CH₂Cl₂). IR (KBr): 3392, 2915, 1671, 1596, 1500, 1445, 1314, 1289, 1175, 1078, 818 cm^-1. ESI-HRMS: m/z calcd for C₂₂H₂₀NOClNa [M + Na]⁺: 372.1131; found: 372.1139. ¹H NMR (250 MHz, CDCl₃): δ = 2.25 (s, 3 H), 3.22-3.48 (m, 2 H), 4.49 (br s, 1 H), 4.82 (t, J = 6.8, 12.5 Hz, 1 H), 6.34-6.46 (m, 2 H), 6.90-7.02 (m, 2 H), 7.08-7.16 (m, 3 H), 7.30-7.54 (m, 3 H), 7.78-7.88 (m, 2 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.5, 46.3, 54.9, 114.9, 122.3, 123.3, 126.9, 128.2, 128.3, 128.7, 128.8, 128.9, 133.5, 136.6, 138.5, 142.5, 145.7, 198.2.
3-(4-Chlorophenylamino)-3-(2,5-dimethoxyphenyl)-1-phenylpropan-1-one (4f)
The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as a colorless solid in 45% yield and 65% ee. The ee was determined by HPLC using Chiralpak AD-H column [n-hexane-i-PrOH (80:20), flow rate 0.6 mL/min; major enantiomer: t _R = 23.6 min; minor enantiomer: t _R = 22.6 min]; mp 144-145 °C; [α]_D +19.6 (c 1.0, CH₂Cl₂). IR (KBr): 3413, 2929, 1684, 1599, 1496, 1280, 1221, 1092, 1045, 817 cm^-1. ESI-HRMS: m/z calcd for C₂₃H₂₂NO₃ClNa [M + Na]⁺: 418.1186; found: 418.1176. ¹H NMR (250 MHz, CDCl₃): δ = 3.03-3.21 (m, 1 H), 3.45-3.65 (m, 4 H), 3.83 (s, 3 H), 4.66 (br s, 1 H), 4.98-5.20 (m, 1 H), 6.27-6.42 (m, 2 H), 6.64 (dd, J = 3.3, 8.8 Hz, 1 H), 6.76 (d, J = 8.8 Hz, 1 H), 6.83-6.97 (m, 3 H), 7.30-7.53 (m, 3 H), 7.85-7.96 (m, 2 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 44.3, 50.8, 55.6, 55.8, 111.4, 112.3, 113.8, 114.8, 116.2, 122.1, 128.4, 128.6, 128.8, 129.1, 130.9, 133.3, 136.6, 145.6, 150.6, 153.9, 198.8.
3-(4-Chlorophenylamino)-1-phenyl-3-(thiophen-2-yl)-propan-1-one (4g)
The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as a yellowish solid in 39% yield and 65% ee. The ee was determined by HPLC using Chiralpak AD-H column [n-hexane-i-PrOH (80:20), flow rate 1.0 mL/min; major enantiomer: t _R = 15.5; minor enantiomer: t _R = 14.2]; mp 126-130 °C; [α]_D +10.9 (c 1.0, CH₂Cl₂). IR (KBr): 3399, 2925, 1667, 1598, 1503, 1286, 1217, 1088, 1001, 813 cm^-1. ESI-HRMS: m/z calcd for C₁₉H₁₆NOClSNa [M + Na]⁺: 364.0539; found: 364.0529. ¹H NMR (250 MHz, CDCl₃): δ = 3.50 (d, J = 5.0 Hz, 2 H), 4.49 (br s, 1 H), 5.15-5.30 (m, 1 H), 6.44-6.60 (m, 2 H), 6.81-6.87 (m, 1 H), 6.89-6.94 (m, 1 H), 6.96-7.05 (m, 2 H), 7.10 (m, 1 H), 7.34-7.44 (m, 2 H), 7.46-7.55 (m, 1 H), 7.77-7.92 (m, 2 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 45.9, 50.9, 115.2, 123.1, 124.0, 124.3, 126.9, 128.1, 128.7, 129.0, 133.5, 136.7, 145.2, 147.2, 197.6.
3-(4-Chlorophenylamino)-3-(4,6-dihydropyren-3-yl)-1-phenylpropan-1-one (4h)
The title compound was isolated by column chromatography (n-hexane-EtOAc, 10:1) as an orange-colored solid in 22% yield and 56% ee. The ee was determined by HPLC using Chiralpak AD-H column [n-hexane-i-PrOH (80:20), flow rate 0.6 mL/min; major enantiomer: t _R = 23.2 min; minor enantiomer: t _R = 28.2 min]; mp 65-69 °C; [α]_D +122.3 (c 1.0, CH₂Cl₂). IR (KBr): 3397, 2923, 1681, 1598, 1496, 1314, 1260, 1088, 848 cm^-1. ESI-HRMS: m/z calcd for C₃₁H₂₂NOClNa [M + Na]⁺: 482.1288; found: 482.1273. ¹H NMR (250 MHz, CDCl₃): δ = 3.41-3.72 (m, 2 H), 4.82 (br s, 1 H), 5.88-6.06 (m, 1 H), 6.30-6.50 (m, 2 H), 6.78-6.96 (m, 2 H), 7.26-7.38 (m, 2 H), 7.40-7.52 (m, 1 H), 7.76-7.86 (m, 2 H), 7.88-8.07 (m, 4 H), 8.08-8.20 (m, 4 H), 8.39 (d, J = 9.3 Hz, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 45.7, 51.2, 115.0, 121.4, 122.5, 123.4, 125.0, 125.2, 125.4, 125.5, 126.1, 127.3, 127.5, 127.5, 128.2, 128.4, 128.7, 128.9, 130.6, 131.4, 133.6, 135.4, 136.6, 145.6, 198.1.

<A NAME="RG08307ST-15">15</A> For a review on the concept of combined acids, see: Yamamoto H. Futatsugi K. Angew. Chem. Int. Ed.  2005,  44:  1924 ; Angew. Chem. 2005, 117, 1958