One-Pot, Three-Step Copper-Catalyzed Five-/Four-Component Reaction Constructs Polysubstituted Oxa(Thia)zolidin-2-imines

Abstract

A novel one-pot synthesis of polysubstituted oxa(thia)zolidin-2-imines has been developed. It employs A³-coupling of aldehyde and amine with alkyne to form propargyl amine, which on (thio)amidation with iso(thio)cyanate produces N-propargyl(thio)urea, and a cyclization reaction. A 5-exo-dig iodocyclization of N-propargylurea constructs 5-iodomethyleneoxazolidin-2-imine, while cycloisomerization of the thio analogue provides 5-methylenethiazolidin-2-imine. In this process, CuI catalysis has been found to be crucial, and the cyclization occurs through oxygen/sulfur (not nitrogen) nucleophilic attack to alkyne.

Key words

multicomponent reaction - one-pot - cyclization - copper - heterocycles

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• 17 Representative Experimental Procedure for the Synthesis of (E,Z)-N,N′-Dibenzyl-4-(4′-chlorophenyl)-5-(1′,1′-iodophenylmethylene)oxazolidin-2-imine (Compound 1, Scheme 2) To a magnetically stirred solution of 4-chlorobenzaldehyde (140 mg, 1.0 mmol) and benzylamine (107 mg, 1 mmol) in anhyd 1,4-dioxane (2.5 mL) were added phenylacetylene (224 mg, 2.2 mmol) and CuI (30 mol%) under nitrogen. The reaction mixture was heated at 80 °C for 5 h (monitored by TLC). To the resultant mixture was added benzyl isocyanate (0.12 mL, 1.0 mmol). The mixture was stirred at 80 °C for 2 h (monitored by TLC). Then I₂ (506 mg, 2 mmol) and Na₂CO₃ (315 mg, 3 mmol) were added, and the reaction was continued at 80 °C for further 3 h (monitored by TLC). The resultant mixture was extracted with EtOAc. The combined organic solution was washed with H₂O, dried over anhyd Na₂SO₄, filtered, and concentrated under vacuum. The column chromatographic purification of crude mass on silica gel (100–200 mesh) eluting with EtOAc–PE provided (E,Z)-N,N′-dibenzyl-4-(4′-chlorophenyl)-5-(1′,1′-iodophenyl-methylene)oxazolidin-2-imine (301 mg, 51% yield); brown viscous liquid. MS (APCI): m/z = 591 [M(³⁵Cl) + H]⁺. ¹H NMR (600 MHz, CDCl₃): δ = 3.50 (d, J = 15.3 Hz, 1 H), 4.51 (d, J = 14.7 Hz, 1 H), 4.49 (d, J = 14.7 Hz, 1 H), 4.99 (d, J = 15.3 Hz, 1 H), 5.10 (s, 1 H), 7.16–7.37 (m, 17 H) 7.45 (d, J = 7.1 Hz, 2 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 46.00, 49.94, 65.97, 74.81, 126.44, 127.40, 127.82, 128.09, 128.21, 128.31, 128.74, 129.13, 129.67, 130.34, 134.43, 134.54, 134.80, 135.63, 137.55, 141.26, 148.15, 150.89 ppm. IR (KBr): ν_max = 2932, 2853, 2369, 2335, 1712, 1645, 691 cm^–1. HRMS: m/z calcd for C₃₀H₂₄ClIN₂O: 591.0702 [M(³⁵Cl) + H]⁺; found: 591.0685. All reactions (Scheme 2) were carried out following the representative procedure. Representative Experimental Procedure for the Synthesis of (Z,Z)-N,N′-Dibenzyl-5-benzylidene-4-phenylthiazolidin-2-imine (Compound 12, Scheme 3) To a magnetically stirred solution of benzaldehyde (106 mg, 1.0 mmol) and benzyl amine (107 mg, 1 mmol) in anhyd 1,4-dioxane (2.5 mL) were added phenylacetylene (224 mg, 2.2 mmol) and CuI (30 mol%) under nitrogen. The mixture was heated at 80 °C for 5 h (monitored by TLC). Benzyl isothiocyanate (0.14 mL, 1.0 mmol) was then added. The reaction was continued at 80 °C till completion (3 h, monitored by TLC). The resultant mixture was extracted with EtOAc. The combined organic solution was washed with H₂O, dried over anhyd Na₂SO₄, filtered, and concentrated under vacuum. The column chromatographic purification of crude mass on silica gel (100–200 mesh) eluting with EtOAc–PE provided (Z,Z)-N,N′-dibenzyl-5-benzylidene-4-phenylthiazolidin-2-imine (250 mg, 56% yield); light yellow solid; mp 106–109 °C. MS (APCI): m/z = 447 [M + H]⁺. ¹H NMR (600 MHz, CDCl₃): δ = 3.66 (d, J = 15.1 Hz, 1 H), 4.67 (d, J = 15.2 Hz, 1 H), 4.64 (d, J = 15.2 Hz, 1 H), 5.23 (d, J = 1.7 Hz, 1 H), 5.42 (d, J = 15.1 Hz, 1 H), 6.21 (d, J = 1.7 Hz, 1 H), 7.17–7.42 (m, 20 H) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 47.31, 58.18, 70.05, 122.29, 126.50, 127.05, 127.31, 127.34, 127.56, 128.02, 128.26, 128.47, 128.47, 128.48, 128.55, 129.01, 133.82, 136.01, 136.96, 140.27, 141.04, 155.81 ppm. IR (KBr): ν_max = 3032, 2919, 1751, 1645, 1619, 695 cm^–1. HRMS: m/z calcd for C₃₀H₂₆N₂S: 447.1897 [M + H]⁺; found: 447.1902. All reactions (Scheme 3) were carried out following the representative procedure: When 3,4-dihydroisoquinoline or 6,7-dimethoxy-3,4-dihydroisoquinoline was used as imine equivalent (Schemes 2 and 3), the reactions were done by using 10 mol% of CuI (in place of 30 mol%) keeping all other conditions the same.
• 18 Complete crystallographic X-ray data can be obtained free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge Crystallographic Data Centre (CCDC), 12 Union Road, Cambridge CB2 1EZ, UK; fax: [phone]; email: [e-mail]]. CCDC 879707 contains the supplementary crystallographic data for Compound 8, Scheme 2. CCDC 857504 contains the supplementary crystallographic data for Compound 17, Scheme 3.