Highly Enantioselective Michael
Addition of Malonates to Nitroolefins Catalyzed by Chiral
Bifunctional Tertiary Amine-Thioureas Based on Saccharides

Xiao-Juan Li; Kun Liu; Hai Ma; Jing Nie; Jun-An Ma

doi:10.1055/s-0028-1087370

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Synlett 2008(20): 3242-3246
DOI: 10.1055/s-0028-1087370

LETTER

Highly Enantioselective Michael Addition of Malonates to Nitroolefins Catalyzed by Chiral Bifunctional Tertiary Amine-Thioureas Based on Saccharides

Xiao-Juan Li, Kun Liu, Hai Ma, Jing Nie, Jun-An Ma*
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(022)27403475; e-Mail: majun_an68@tju.edu.cn;

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Publication History

Received 14 June 2008
Publication Date:
26 November 2008 (online)

Abstract
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Abstract

A series of saccharide-derived bifunctional tertiary amine-thioureas for the asymmetric Michael addition reaction have been designed and synthesized. The addition products between malonates and various nitroolefins were obtained in high yields (up to 99%) and excellent enantioselectivities (up to 99% ee).

Key words

asymmetric catalysis - Michael addition - nitroolefins - bifunctional thiourea - saccharides

Supporting Information

References and Notes

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15

A Typical Procedure for the Preparation of Organocatalyst
To a solution of 1, 2-cyclohexyldiamine (3.6 mmol) in CH₂Cl₂ (20 mL) was added the corresponding saccharide-derived isothiocyanates 1 (3 mmol). The mixture was stirred at r.t. for 3-24 h (TLC) and concentrated. The resulting residue was purified by flash column chromatography with the eluent (EtOAc-Et₃N, 100:1) to give the crude solid. The crude solid was dissolved in a minimal amount of CH₂Cl₂ and slowly precipitated from solution by the addition of PE at 0 ˚C. Filtration afforded the desired thiourea products 2.
Compound 2c: yield 55%; mp 90-92 ˚C; [α]_D ^²0 -0.5 (c 1.0, CH₂Cl₂). ^¹H NMR (500 MHz, CDCl₃): δ = 0.94-1.26 (m,
5 H, cyclohexane-H), 1.66-1.88 (m, 3 H, cyclohexane-H), 1.99 (s, 3 H, COCH₃), 2.01 (s, 3 H, COCH₃), 2.03 (s, 3 H, COCH₃), 2.05 (s, 3 H, COCH₃), 2.24 (s, 6 H, 2 NCH₃), 2.32 (m, 1 H, NCH), 3.45 (m, 1 H, NCH), 3.81-3.84 (m, 1 H, pyranose-H), 4.09-4.12 (m, 1 H, pyranose-H), 4.27-4.31 (m, 1 H, pyranose-H), 4.93-4.97 (t, 1 H, CH₂), 5.05-5.09 (t, 1 H, CH₂), 5.29-5.33 (m, 2 H, pyranose-H), 5.58-5.60 (br,
1 H, NH), 6.20 (br, 1 H, NH). ^¹³C NMR (125 MHz, CDCl₃): δ = 170.85, 170.81, 170.07, 169.85, 83.30, 73.41, 73.5, 73.16, 71.22, 68.50, 61.88, 56.76, 40.46, 32.86, 24.96, 24.58, 22.76, 20.96, 20.94, 20.82, 20.81. IR (KBr): 3352, 2936, 1753, 1542, 1377, 1225, 1035, 910, 758, 601cm^-¹. ESI-MS: m/z = 532.26 [M⁺ + 1].
Compound 2d: yield 50%; mp 83-86 ˚C; [α]_D ^²0 +4.0 (c 1.0, CH₂Cl₂). ^¹H NMR (500 MHz, CDCl₃): δ = 1.03-1.30 (m,
4 H, cyclohexane-H), 1.62-1.91 (m, 4 H, cyclohexane-H), 1.99 (s, 3 H, COCH₃), 2.01 (s, 3 H, COCH₃), 2.03 (s, 3 H, COCH₃), 2.05 (s, 3 H, COCH₃), 2.24 (s, 6 H, 2 NCH₃), 2.33 (m, 1 H, NCH), 3.45 (m, 1 H, NCH), 3.81-3.84 (m, 1 H, pyranose-H), 4.09-4.12 (m, 1 H, pyranose-H), 4.27-4.32 (m, 1 H, pyranose-H), 4.91-4.99 (t, 1 H, CH₂), 5.04-5.09 (t, 1 H, CH₂), 5.30-5.33 (m, 2 H, pyranose-H), 5.58-5.60 (br,
1 H, NH), 6.20 (br, 1 H NH). ^¹³C NMR (125 MHz, CDCl₃): δ = 170.86, 170.81, 170.07, 169.86, 83.30, 73.42, 73.16, 71.22, 68.50, 61.88, 56.76, 40.46, 32.86, 24.98, 24.58, 20.96, 20.94, 20.82, 20.81. IR (KBr): 3352, 2939, 1755, 1545, 1378, 1231, 1038, 907, 755, 602 cm^-¹. ESI-MS: m/z = 532.25 [M⁺ + 1].
Comound 2e: yield 30%; mp 94-97 ˚C; [α]_D ^²0 +63.0 (c 1.0, CH₂Cl₂). ^¹H NMR (500 MHz, CDCl₃): δ = 1.15-1.29 (m,
5 H, cyclohexane-H), 1.64-1.84 (m, 3 H, cyclohexane-H), 1.96-2.01 (s, 12 H, 4 COCH₃), 2.01-2.04 (s, 3 H, COCH₃), 2.04-2.07 (s, 3 H, COCH₃), 2.07-2.10 (s, 3 H, COCH₃), 2.19 (s, 6 H, 2 NCH₃), 2.24-2.38 (br, 1 H, NCH), 2.41-2.92 (br, 1 H, NCH), 3.76-3.82 (d, 1 H, OCH₂, J = 7.0 Hz), 3.84-3.89 (d, 1 H, OCH₂, J = 10.5 Hz), 3.98-4.04 (d, 2 H, OCH₂, J = 8.0 Hz), 4.04-4.10 (m, 1 H, pyranose-H), 4.16-4.27 (m, 3 H, pyranose-H), 4.42-4.46 (d, 1 H, pyranose-H, J = 12.5 Hz), 4.74-4.82 (m, 2 H, pyranose-H), 5.00-5.07 (m, 1 H, pyranose-H), 5.28-5.42 (m, 2 H, pyranose-H). ^¹³C NMR (125 MHz, DMSO): δ = 171.00, 170.86, 170.72, 170.60, 170.04, 169.95, 169.65, 95.60, 82.72, 75.51, 73.77, 72.54, 71.86, 70.19, 69.44, 68.62, 68.13, 62.80, 61.55, 60.60, 56.70, 40.34, 32.76, 29.86, 29.53, 25.06, 24.57, 21.25, 21.08, 21.03, 20.89, 20.82, 20.80, 14.39. IR (KBr): 3354, 2938, 1757, 1542, 1372, 1226, 1046, 940, 906, 754, 601
cm^-¹. ESI-MS: m/z = 820.22 [M⁺ + 1].
Compound 2f: yield 24%; mp 92-94 ˚C; [α]_D ^²0 +14.1 (c 1.0, CH₂Cl₂). ^¹H NMR (500 MHz, CDCl₃): δ = 0.97-1.28 (m,
5 H, cyclohexane-H), 1.54-1.87 (m, 3 H, cyclohexane-H), 1.88-2.25 (m, 27 H, 7 CH₃, 2 NCH₃), 2.34-2.51 (m, 1 H, NCH), 3.64-3.71 (m, 1 H, pyranose-H), 3.72-3.89 (m, 2 H, pyranose-H), 4.00-4.17 (m, 4 H, OCH₂), 4.27-4.48 (m, 2 H, pyranose-H), 4.72-4.87 (m, 1 H, pyranose-H), 4.87-4.93 (m, 1 H, pyranose-H), 5.02-5.09 (m, 1 H, pyranose-H), 5.12-5.27 (m, 1 H, pyranose-H), 5.27-5.31 (m, 1 H, pyranose-H), 5.42-5.65 (br, 1 H, NH). ^¹³C NMR (125 MHz, DMSO): δ = 170.97, 170.65, 170.54, 170.34, 170.26, 169.29, 169.11, 100.99, 90.16, 74.00, 73.10, 72.34, 71.19, 70.81, 70.77, 69.29, 69.16, 66.89, 66.83, 61.01, 52.66, 40.15, 34.08, 25.44, 24.80, 24.55., 21.04, 21.02, 20.86, 20.83, 20.81, 20.70, 14.38; IR (KBr): 3357, 2938, 1757, 1542, 1372, 1225, 1046, 940, 906, 754, 602 cm^-¹. ESI-MS: m/z = 820.19 [M⁺ + 1].
Compound 2g: yield 38%; mp 158-160 ˚C; [α]_D ^²0 +57.9 (c 1.0, CH₂Cl₂). ^¹H NMR (500 MHz, CDCl₃): δ = 0.75-0.88 (t, 12 H, CH₃), 0.89-1.72 (m, 8 H, cyclohexane-H), 1.72-2.38 (m, 20 H), 3.78-3.88 (m, 1 H, pyranose-H), 3.97-4.11 (m,
1 H, pyranose-H), 4.31-4.44 (m, 1 H, pyranose-H), 4.89-5.12 (m, 2 H, CH₂), 5.25-5.37 (m, 1 H, pyranose-H), 5.66-5.83 (m, 1 H, NH), 6.08-6.23 (m, 1 H, pyranose-H), 6.33-6.61 (m, 1 H, NH). ^¹³C NMR (125 MHz, CDCl₃): δ = 183.17, 171.38, 170.92, 170.04, 169.89, 82.83, 73.37, 73.14, 70.72, 68.63, 63.84, 61.84, 58.91, 55.05, 32.48, 26.80, 25.85, 24.65, 23.09, 21.36, 20.99, 20.95, 20.83, 20.79. IR (KBr): 3371, 2951, 1751, 1511, 1369, 1232, 1038, 909, 759, 594 cm^-¹. ESI-MS: m/z = 616.4 [M⁺ + 1].
Compound 2h: yield 35%; [α]_D ^²0 +23.3 (c 1.0, CH₂Cl₂). ^¹H NMR (500 MHz, CDCl₃): δ = 0.79-0.87 (t, 6 H, CH₃), 0.87-1.20 (m, 8 H, CH₂), 1.20-1.35 (7 H, cyclohexane-H), 1.63-1.84 (m, 3 H, cyclohexane-H), 1.94-2.08 (q, 12 H, COCH₃), 2.15-2.45 (m, 4 H, NCH₂), 3.30-3.65 (m, 1 H, NH), 3.72-4.34 (m, 3 H, pyranose-H), 4.90-5.71 (m, 4 H, pyranose-H), 6.35-6.60 (m, 1 H, NH). ^¹³C NMR (125 MHz, CDCl₃): δ = 183.16, 171.59, 170.83, 170.0, 169.81, 90.11, 82.81, 73.35, 73.04, 71.08, 68.61, 63.63, 62.09, 55.53, 49.55, 32.79, 31.41, 25.75, 24.68, 23.64, 20.91, 20.90, 20.83, 20.78, 14.28. IR (KBr): 3362, 2933, 1758, 1543, 1377, 1232, 1039, 912, 751, 610 cm^-¹. ESI-MS: m/z = 616.5 [M⁺ + 1].

Supplementary Material

Supporting Information