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Synlett 2004(9): 1569-1572  
DOI: 10.1055/s-2004-829067
LETTER
© Georg Thieme Verlag Stuttgart · New York

Reversal of Regioselectivity of Nitrone 1,3-Dipolar Cycloadditions by Lewis Acids

Branislav Dugoviča, Lubor Fišera*a, Christian Hametnerb
a Department of Organic Chemistry, Slovak University of Technology, 812 37 Bratislava, Slovak Republic
e-Mail: lubor.fisera@stuba.sk;
b Institute of Applied Synthetic Chemistry, University of Technology, 1060 Vienna, Austria
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Publication History

Received 31 March 2004
Publication Date:
01 July 2004 (online)

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Abstract

The regio- and stereoselectivity of cycloaddition of N-benzyl-2-benzyloxyethylideneamine N-oxide (1) with 3-acroyl-1,3-oxazolidin-2-one (2) in dichloromethane at room temperature depends upon the nature of the Lewis acid. Addition of Lewis acid reverses the regioselectivity of the cycloaddition. The sterically controlled isoxazolidine-5-oxazolidinones 3a,b are produced as the major products in the absence of Lewis acid, while the electronically controlled isoxazolidine-4-oxazolidinones 4a,b are given as dominant products in the Ti(Oi-Pr)2Cl2 complex-catalyzed reactions. The reactions with other Lewis acids such as BF3, ZnBr2 and Mg(ClO4)2 gave both regioisomeric pairs of the diastereoisomers favouring 4-substituted regioisomers.

Key words

dipolar cycloadditions - nitrones - isoxazolidines - Lewis acid

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Typical Experimental Procedure for Lewis Acid Mediated Cycloaddition: The reaction was carried out under argon atmosphere. To a stirred suspension of Lewis acid in CH2Cl2 (5 mL) the alkene 2 (0.4 mmol) was added at r.t. and the mixture was stirred for 15 min. The nitrone 1 (0.4 mmol) was then added in one portion. The appropriate amounts of Lewis acid and reaction time are listed in Table [1] and Table [2] . The mixture was stirred until complete conversion of nitrone 1 (monitored by TLC). The reaction was quenched with a sat. NH4Cl solution, extracted with CH2Cl2, the combined organic layers were washed with brine, dried over Na2SO4, filtered through a layer of Celite® and the solvent was removed by rotary evaporation. The yellow oil thus obtained was purified by flash chromatography (silica gel, hexanes-EtOAc 6:4). Yields of isolated mixtures of cycloadducts are given in Table [1] and Table [2] .

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trans -3-(2-Benzyl-3-benzyloxymethyl-isoxazolidine-4-carbonyl)-oxazolidin-2-one ( 4a): Yellowish oil. 1H NMR (400 MHz, CDCl3): δ = 7.55-7.24 (m, 10 H, H-Ph), 4.50 (s, 2 H, OCH2Ph), 4.47 (ddd, 1 H, J = 8.7 Hz, J = 5.4 Hz, J = 5.3 Hz, H-4), 4.43-4.27 (m, 3 H, H-5′′, 5a), 4.19 (d, 1 H, J = 13.2 Hz, NCH2Ph), 4.12 (d, 1 H, J = 13.4 Hz, NCH2Ph), 4.09 (dd, 1 H, J = 8.7 Hz, J = 5.6 Hz, H-5b), 4.06-3.94 (m, 2 H, H-4′′), 3.88-3.83 (m, 1 H, H-3), 3.57 (dd, 1 H, J 1 ′ a,b = 9.6 Hz, J 1 ′ a,3 = 6.2 Hz, H-1′a), 3.52 (dd, 1 H, J 1 ′ a,b = 9.6 Hz, J 1 ′ b,3 = 7.3 Hz, H-1′b). 13C NMR (100 MHz, CDCl3): δ = 172.0 (CO), 153.3 [OC(O)N], 137.9, 137.1, 129.1, 128.3, 127.6, 127.6, 127.3 (12 C, C-Ph), 73.2 (OCH2Ph), 71.3 (C-1′), 69.2 (C-5), 66.9 (C-3), 62.0 (C-5′′), 60.9 (NCH2Ph), 51.4 (C-4), 42.7 (C-4′′). cis -3-(2-Benzyl-3-benzyloxymethyl-isoxazolidine-4-carbonyl)-oxazolidin-2-one ( 4b): Yellowish oil. 1H NMR (400 MHz, CDCl3): δ = 7.45-7.27 (m, 10 H, H-Ph), 4.85 (ddd, 1 H, J 4,5b = 9.4 Hz, J 4,5a = 7.9 Hz, J 3,4 = 7.6 Hz, H-4), 4.55 (dd, 1 H, J 5a,b = 8.2 Hz, J 4.5a = 7.9 Hz, H-5a), 4.41 (d, 1 H, J = 11.1 Hz, OCH2Ph), 4.30 (dd, 1 H, J 4,5b = 9.1 Hz, J 5a,b = 8.2 Hz, H-5b), 4.20 (d, 1 H, J = 11.1 Hz, OCH2Ph), 4.15-4.10 (m, 1 H, H-3), 4.12 (d, 1 H, J = 12.6 Hz, NCH2Ph), 4.06 (ddd, 1 H, J 4 ′′ a,5 ′′ a = 9.4 Hz, J 5 ′′ a,b = 8.5 Hz, J 4 ′′ b,5 ′′ a = 7.6 Hz, H-5′′a), 3.90 (d, 1 H, J = 12.6 Hz, NCH2Ph), 3.68 (ddd, 1 H, J 4 ′′ a,b = 10.5 Hz, J 4 ′′ a,5 ′′ a = 9.4 Hz, J 4 ′′ a,5 ′′ b = 5.8 Hz, H-4′′a), 3.64-3.54 (m, 2 H, H-1′), 3.49 (ddd, 1 H, J 4 ′′ b,5 ′′ b = 9.6 Hz, J 5 ′′ a,b = 8.5 Hz, J 4 ′′ a,5 ′′ b = 5.8 Hz, H-5′′b), 3.19 (ddd, 1 H, J 4 ′′ a,b = 10.5 Hz, J 4 ′′ b,5 ′′ b = 9.6 Hz, J 4 ′′ b,5 ′′ a = 7.6 Hz, H-4′′b). 13C NMR (100 MHz, CDCl3): δ = 170.0 (CO), 153.5 [OC(O)N], 138.0, 136.4, 129.2, 128.4, 128.2, 127.5, 127.5, 127.4 (12 C, C-Ph), 72.7 (OCH2Ph), 70.2 (C-1′), 67.4 (C-5), 64.8 (C-3), 61.6 (C-5′′), 60.6 (NCH2Ph), 47.5 (C-4), 42.3 (C-4′′).

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trans -(2-Benzyl-3-benzyloxymethyl-isoxazolidin-5-yl)-methanol ( 6a): Colourless oil. 1H NMR (400 MHz, CDCl3): δ = 7.43-7.27 (m, 10 H, H-Ph); 4.56 (s, 2 H, OCH2Ph), 4.29 (d, 1 H, J = 14.0 Hz, NCH2Ph), 4.21-4.14 (m, 1 H, H-5), 4.00 (d, 1 H, J = 14.0 Hz, NCH2Ph), 3.74 (dd, 1 H, J 1 ′′ a,b = 12.0 Hz, J 1 ′′ a,5 = 2.9 Hz, H-1′′a), 3.60 (dd, 1 H, J 1 ′ a,b = 9.6 Hz, J 1 ′ a,3 = 6.7 Hz, H-1′a), 3.57 (dd, 1 H, J 1 ′ a,b = 9.6 Hz, J 1 ′ b,3 = 5.6 Hz, H-1′b), 3.54 (dd, 1 H, J 1 ′′ a,b = 12.0 Hz, J 1 ′′ b,5 = 5.0 Hz, H-1′′b), 3.30-3.23 (m, 1 H, H-3), 2.26 (ddd, 1 H, J 4a,b = 12.3 Hz, J = 8.2 Hz, J = 7.0 Hz, H-4a), 2.20 (br s, 1 H, OH), 2.11 (ddd, 1 H, J 4a,b = 12.3 Hz, J = 8.2 Hz, J = 6.7 Hz, H-4b). 13C NMR (100 MHz, CDCl3): δ = 137.9, 137.3, 129.1, 128.4, 128.2, 127.6, 127.6, 127.2 (12 C, C-Ph), 77.3 (C-5), 73.3 (OCH2Ph), 71.3 (C-1′), 64.4 (C-3), 63.6 (C-1′′), 61.9 (NCH2Ph), 33.7 (C-4). cis -(2-Benzyl-3-benzyloxymethyl-isoxazolidin-5-yl)-methanol ( 6b): Yellowish oil. 1H NMR (400 MHz, CDCl3): δ = 7.41-7.28 (m, 10 H, H-Ph), 4.57, 4.53 (2 × d, 2 H, J = 12.0 Hz, OCH2Ph), 4.36-4.30 (m, 1 H, H-5), 4.22, 3.97 (2 × d, 2 × 1 H, J = 13.7 Hz, NCH2Ph), 3.75 (dd, 1 H, J 1 ′′ a,b = 11.7 Hz, J 1 ′′ a,5 = 2.6 Hz, H-1′′a), 3.63 (dd, 1 H, J 1 ′ a,b = 9.6 Hz, J 1 ′ a,3 = 7.3 Hz, H-1′a), 3.59 (dd, 1 H, J 1 ′′ a,b = 11.7 Hz, J 1 ′′ b,5 = 4.7 Hz, H-1′′b), 3.56 (dd, 1 H, J 1 ′ a,b = 9.6 Hz, J 1 ′ b,3 = 5.3 Hz, H-1′b), 3.35-3.28 (m, 1 H, H-3), 2.62 (br s, 1 H, OH), 2.53 (ddd, 1 H, J 4a,b = 12.6 Hz, J 4a,3 = J 4a,5 = 8.5 Hz, H-4a), 1.99 (ddd, 1 H, J 4a,b = 12.6 Hz, J = 6.4 Hz, J = 6.1 Hz, H-4b). 13C NMR (100 MHz, CDCl3): δ = 137.9, 137.3, 128.8, 128.4, 128.3, 127.7, 127.6, 127.2 (12 C, C-Ph), 76.6 (C-5), 73.3 (OCH2Ph), 71.8 (C-1′), 64.8 (C-3), 64.7 (C-1′′), 61.4 (NCH2Ph), 33.5 (C-4).