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Synlett 2009(12): 1997-2001  
DOI: 10.1055/s-0029-1217532
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Synthesis of the First Thiazolidine-Condensed Five-, Six-, and Seven-Membered Heterocycles via Cyclization of Vinylogous N-Acyliminium Ions

Milovan Stojanovića, Rade Marković*a,b
a Center for Chemistry ICTM, P. O. Box 473, 11000 Belgrade, Serbia
b Faculty of Chemistry, University of Belgrade, Studentski trg 16, P. O. Box 158, 11001 Belgrade, Serbia
Fax: +381(11)2636061; e-Mail: markovic@chem.bg.ac.rs;
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Publikationsverlauf

Received 18 March 2009
Publikationsdatum:
01. Juli 2009 (online)

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Abstract

Synthesis of new thiazolidine-fused five-, six-, and seven-membered heterocycles through vinylogous N-acyliminium ion-cyclization sequence, involving positions 3 and 4 of the thiazolidine ring, is described. The formation of bicyclic products, arising by generally disfavored 5-endo-trig cyclization initiated by sulfur atom acting as a nucleophile, indicates the preparative value of this method.

Key words

neighboring-group effects - lactams - iminium ions - cyclization - fused-ring systems

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Typical Procedure for the Synthesis of ( Z )-Ethyl 2-(Tetrahydrothiazolo[4,3- b ][1,3]thiazin-6 (2 H )-ylidene)acetate (9f) The thioester 7f (50.5 mg, 0.17 mmol) was dissolved in dry EtOH (5 mL) and a solution of NaOEt (0.2 M in EtOH, 0.85 mL, 0.17 mmol) was added at r.t. with vigorous stirring. After hydrolysis to thiol, as evidenced by complete consumption of the reactant (ca. 15 min; TLC), the reaction mixture was cooled down to 0 ˚C. Twofold mass excess of NaBH4 (101 mg, 15-20 mmol equiv) was added, followed by 3 drops of 0.4 M HCl in EtOH. The addition of the same amount of acid was continued in regular 10 min intervals until the end of the reaction (45 min), when the reaction mixture was quenched with 1 M HCl in EtOH. The suspension was stirred for an additional 30 min at 0 ˚C, diluted with H2O, extracted with CHCl3, the organic phase separated, dried with Na2SO4, and the solvent evaporated under reduced pressure. Purification of a crude product by column chromatography (SiO2; PE-EtOAc solvent gradient 100:0 → 80:20) afforded the final product 9f as a white solid (27.4 mg, 66%); mp 108-109 ˚C. ¹H NMR (200 MHz, CDCl3): δ = 1.27 (3 H, t, J = 7.4 Hz, CH 3CH2), 1.65-2.05 (2 H, m, C3H2), 2.76-2.83 (1 H, m, C2H), 2.83 (1 H, dd, J 1 = 11.8 Hz, J 2 = 2.0 Hz, C8H), 3.12 (1 H, ddd, J 1 = 13.6 Hz, J 2 = 12.2 Hz, J 3 = 3.0 Hz, C2H), 3.27 (1 H, ddd, J 1 = 14.4 Hz, J 2 = 12.6 Hz, J 3 = 2.6 Hz, C4H), 3.39 (1 H, dd, J 1 = 11.8 Hz, J 2 = 7.2 Hz, C8H), 3.80-3.87 (1 H, m, C4H), 4.17 (2 H, q, J = 7.4 Hz), 5.05 (1 H, s, C6 ′H), 5.18 (1 H, dd, J 1 = 7.2 Hz, J 2 = 2.0, C8aH) ppm. ¹³C NMR (50.3 MHz, CDCl3): δ = 14.6 (CH3CH2), 22.0 (C3), 29.1 (C2), 33.0 (C8), 46.8 (C4), 59.3 (CH2CH3), 67.5 (C8a), 83.5 (C6 ′), 162.3 (C6), 168.9 (CO2) ppm. IR: 2977, 2951, 2925, 2897, 1662, 1531, 1459, 1427, 1335, 1276, 1226, 1205, 1177, 1144, 1102, 1043, 1003, 900, 809 cm-¹. HR MS (CI/TOF): m/z [M + H]+ calcd: 246.06170; found: 246.06176 ± 0.24 ppm.

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Analytical Data of (Z)-Ethyl 2-{7-Methyl-2H-thiazolo[4,3-b]thiazol-5 (3H,7H,7aH)-ylidene}acetate (9c)
Isolated in 37% yield as a mixture of trans- and cis-isomer in a 75:25 ratio.
Compound trans-9c: ¹H NMR (500 MHz, CDCl3): δ = 1.26 (3 H, t, J = 7.0 Hz, CH 3CH2), 1.49 (3 H, d, J = 6.5 Hz, CH 3CHS), 3.09-3.12 (1 H, m, CH2S), 3.15-3.20 (1 H, m, CH2S), 3.26-3.32 (1 H m, CH2N), 3.66 (1 H, dq, J 1 = 6.5 Hz, J 2 = 5.5 Hz, CHCH3S), 3.97 (1 H, ddd, J 1 = 9.0 Hz, J 2 = 6.0 Hz, J 3 = 3.0 Hz, CH2N) 4.16 (2 H, q, J = 7.0 Hz, CH 2CH3), 4.89 (1 H, d, J = 5.5 Hz, CHSN), 5.07 (1 H, s, = CH) ppm. ¹³C NMR (50.3 MHz, CDCl3): δ = 14.5 (CH3CH2), 20.1 (CH3CHS), 32.0 (CH2S), 45.1 (CHCH3S), 50.7 (CH2N), 59.4 (CH2CH3), 76.8 (CHSN), 84.4 (=CH), 163.76 (C=), 168.6 (CO2) ppm.
Compound cis-9c: ¹H NMR (500 MHz, CDCl3): δ = 1.27 (3 H, t, J = 7.0 Hz, CH 3CH2), 1.46 (3 H, d, J = 7.0 Hz, CH 3CHS), 3.05-3.09 (1 H, m, CH2S), 3.24-3.33 (1 H, m, CH2S), 3.29-3.41 (1 H, m, CH2N), 3.89 (1 H, dq, J 1 = 7.0 Hz, J 2 = 5.5 Hz, CHCH3S), 4.00 (1 H, ddd, J 1 = 9.2 Hz, J 2 = 5.8 Hz, J 3 = 3.2 Hz, CH2N) 4.16 (2 H, q, J = 7.0 Hz, CH2CH3), 5.10 (1 H, s, =CH), 5.28 (1 H, d, J = 5.5 Hz, CHSN) ppm. ¹³C NMR (50.3 MHz, CDCl3): δ = 14.5 (CH3CH2), 17.0 (CH3CHS), 31.0 (CH2S), 41.3 (CHCH3S), 51.0 (CH2N), 59.4 (CH2CH3), 76.8 (CHSN), 84.8 (=CH), 163.8 (C=), 168.6 ppm.