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Synlett 2010(10): 1489-1492  
DOI: 10.1055/s-0029-1219946
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Enantioenriched Naphthoquinone Mannich Bases by Organocatalyzed Nucleophilic Additions to in situ Formed Imines

Muhammad Ayaza, Bernhard Westermann*a,b
a Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Weinberg 3, 06120 Halle/Saale, Germany
b Institute of Organic Chemistry, Martin-Luther-University Halle-Wittenberg, Kurt-Mothes-Str. 2, 06120 Halle/Saale, Germany
Fax: +49(345)55821309; e-Mail: Bernhard.Westermann@ipb-halle.de;
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Publication History

Received 4 February 2010
Publication Date:
25 May 2010 (online)

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Abstract

Organocatalytic nucleophilic addition of 2-hydroxylnaphthaquinone to imines is reported. This new route can be used to produce enantioenriched Mannich bases with excellent yields and moderate enantioselectivities.

Key words

organocatalysis - enantioselective Mannich reaction - 1,4-addition - α-amidosulfone - naphthoquinone

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Under the same set of conditions, an attempt to carry out the reaction with benzaldehyde-derived α-amidosulfone (Cbz protected) and 1 resulted in 90% yield, however, enantioselectivity of the product was only 22%.

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General Procedure for Addition of Hydroxynaphthoquinone to in situ Formed Imines In a 4 mL process vial α-amidosulfone (0.1 mmol),
2-hydroxy-1,4-naphthoquinone (1, 0.11 mmol), and catalyst (10 mol%) were dissolved in solvent (0.5 mL). The reaction was allowed to stir at r.t. (except where mentioned otherwise) for 24 h. Completion of the reaction was monitored by TLC after which the reaction mixture was directly subjected to column chromatography (CH2Cl2-MeOH = 99.5:0.5). The products were dissolved in freshly distilled THF (4-5 mL), and Et3N (1.1 equiv) was added. After stirring the reaction mixture at r.t. for 5 min, it was cooled to 0 ˚C and acetyl chloride (1.2 equiv) was added slowly. The reaction mixture was stirred at the same temperature for another 30 min after which the product was filtered and concentrated under reduced pressure. Purification of the product was done by column chromatog-raphy (n-hexane-EtOAc = 90:10). The ee values for all the products were determined by HPLC on a chiral stationary phase [Daicel Chiralpak AD-H, n-hexane-i-PrOH (80:20), flow rate = 1.0 mL/min, λ = 254 nm].
3-(1-{[(Benzyloxy)carbonyl]amino}hexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (5a) Yellow oil; yield 40.8 mg (91%); [α]D ²0 25.5 (c 0.38, CH2Cl2); ee 65%. ¹H NMR (300 MHz, CDCl3-d): δ = 0.86 (t, J = 6.60 Hz, 3 H), 1.20-1.46 (m, 5 H), 1.60-1.79 (m, 2 H), 1.80-1.97 (m, 1 H), 2.44 (s, 3 H), 4.96-5.20 (m, 3 H), 5.79 (d, J = 9.54 Hz, 1 H), 7.22-7.40 (m, 5 H), 7.66-7.79 (m, 2 H), 8.00-8.14 (m, 2 H). ¹³C NMR (75 MHz, CDCl3-d): δ = 13.9, 20.4, 22.4, 25.8, 31.3, 34.5, 47.8, 66.9, 126.7, 128.1, 128.5, 130.7, 132.0, 134.1, 134.3, 136.3, 136.5, 150.7, 155.8, 167.8, 177.9, 185.1. ESI-MS: m/z (%) = 472.5 (100) [M + Na]+. t R(major) = 8.7 min; t R(minor) = 14.9 min.
3-(1-{[(Benzyloxy)carbonyl]amino}ethyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (5b) Yellow oil; yield 36.2 mg (92%); [α]D ²0 10.8 (c 0.95, CH2Cl2); ee 42%. ¹H NMR (300 MHz, CDCl3-d): δ = 1.49 (d, J = 6.95 Hz, 3 H), 2.45 (s, 3 H), 4.86-5.36 (m, 3 H), 5.90 (d, J = 9.51 Hz, 1 H), 7.28-7.42 (m, 5 H), 7.67-7.83 (m, 2 H), 8.08 (m, 2 H). ¹³C NMR (75 MHz, CDCl3-d): δ = 20.4, 20.6, 43.6, 66.9, 126.7, 128.1, 128.5, 130.6, 132.0, 134.1, 134.4, 136.2, 137.1, 150.1, 155.5, 167.9, 178.1, 184.9. ESI-MS: m/z (%) = 416.4 (100) [M + Na]+. t R(major) = 10.9 min; t R(minor) = 12.9 min.
3-{1-[( tert -Butoxycarbonyl)amino]hexyl}-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (12) Yellow oil; yield 27.8 mg (67%); [α]D ²0 7.2 (c 0.41, CH2Cl2); ee 33%. ¹H NMR (300 MHz, CDCl3-d): δ = 0.84 (t, J = 6.80 Hz, 3 H), 1.36 (m, 6 H), 1.40 (s, 9 H), 1.36-1.40 (m, 2 H), 2.42 (s, 3 H), 5.05 (m, 1 H), 5.49 (d, J = 9.57 Hz, 1 H), 7.78 (m, 2 H), 8.08 (m, 2 H). ¹³C NMR (75 MHz, CDCl3-d): δ = 13.9, 20.4, 22.4, 25.8, 28.3, 30.5, 31.3, 34.8, 47.2, 79.6, 126.7, 130.7, 132.0, 134.0, 134.3, 137.0, 150.6, 155.2, 167.8, 178.1. ESI-MS: m/z (%) = 438.4 (100) [M + Na]+. t R(major) = 4.7 min; t R(minor) = 6.0 min.
3-(1-{[(4-Methylphenyl)sulfonyl]amino}hexyl)-1,4-dioxo-1,4-dihydronaphthalen-2-yl Acetate (13) Yellow oil; yield 41.7 mg (89%); [α]D ²0 -13.7 (c 0.34, CH2Cl2); ee -31%. ¹H NMR (300 MHz, CDCl3-d): δ = 0.82-0.92 (m, 3 H), 1.17-1.51 (m, 3 H), 1.55-1.68 (m, 4 H), 1.88 (dt, J = 9.17, 4.59 Hz, 1 H), 1.93 (s, 3 H), 2.43 (s, 3 H), 4.54 (d, J = 7.34 Hz, 1 H), 5.73 (br s, 1 H), 6.86 (d, J = 7.70 Hz, 2 H), 7.55 (d, J = 8.07 Hz, 2 H), 7.67-7.77 (m, 2 H), 7.83-7.91 (m, 1 H), 7.93-8.01 (m, 1 H). ¹³C NMR (75 MHz, CDCl3-d): δ = 13.9, 20.4, 20.9, 22.3, 25.5, 31.0, 34.8, 50.7, 126.4, 126.6, 127.5, 129.4, 130.3, 131.7, 134.2, 137.1, 143.3, 150.9, 167.5, 176.9. ESI-MS: m/z (%) = 492.3 (100) [M + Na]+. t R(major) = 11.9 min; t R(minor) = 16.3 min.