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

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.

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

References and Notes

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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, C_{6 ′}H), 5.18 (1 H, dd, J ₁ = 7.2 Hz, J ₂ = 2.0, C_8aH) 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 (C_8a), 83.5 (C_{6 ′}), 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.

<A NAME="RG06909ST-16">16</A>

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.

For recent examples of the 5-endo-trig mode ring-closing reaction, see:

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