Traceless Solid-Phase Synthesis of 2,4,5-Trisubstituted Thiazoles

Abstract

The solid-phase synthesis of trisubstituted thiazoles is described. The synthetic strategy involves the formation of a ­polymer-bound thiazole by reacting resin-bound cyanodithioimidocarbonic acid and α-bromoketone. The resin-bound thiazole was reacted with acyl chlorides or isocyanates. After oxidation-activation of a thioether linker to a sulfone linker, traceless cleavage was achieved with nucleophiles to give trisubstituted thiazoles.

Key words

thiazoles - traceless solid-phase synthesis - cyanodithioimidocarbonic acid

References

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15

A Typical Procedure for Preparing Compound 5.
Merrifield resin 1 (2.50 g, from Advanced ChemTech, loading 0.94 mmol/g) was treated with dipotassium cyano-dithioimidocarbonate (1.94 g, 10 mmol) in DMF (20 mL). The mixture was stirred at r.t. for 6 h, and then filtered and washed with H₂O, DMF, MeOH, and CH₂Cl₂ several times. The resin was dried under vacuum, and then treated with 5 mL of 2-bromoacetophenone (2 M) and 5 mL of Et₃N (2 M) in DMF, the resulting slurry was heating at 80 °C for 3 h to get resin 3 which was filtered and washed with H₂O, DMF, MeOH, and CH₂Cl₂ several times and dried at r.t. The dried resin 3 was then treated 6 mL of MCPBA (1 M) in CH₂Cl₂ to get resin 4 which was filtered and washed with DMF, MeOH, and CH₂Cl₂ several times. The resin 5 (each 250 mg) loaded into the Mettler-Toledo MiniBlock synthesizer. To each block was added dioxane (1 mL) and amine (0.5 mmol). The reaction was then shaken 12 h, filtered and concentrated under reduced pressure in a Genevac HT-4X. The residue was purified on a Biotage Quad 3⁺ using a flash 12 M column. Analytical data of 5a: [7b] ¹H NMR (500 MHz, CDCl₃): δ = 11.67 (s, 1 H), (m, 2 H), 7.40-7.45 (m, 3 H), 3.17-3.20 (m, 2 H), 1.65 (q, 2 H, m), 0.96 (t, 3 H, J = 7.4 Hz). LCMS: m/z = 262 [M + 1].

16

A Typical Procedure for Preparing Compound 7.
To a microwave reaction vessel was added dried resin 4 (1 g), isocyanate (5 mmol) and DMSO (3 mL). The reaction vessel was irradiated at 150 °C for 30 min (Emrys Creator from Personal Chemistry). The resin 6 (R² = NHCOR) was collected by filtration and washed with H₂O, DMF, MeOH, and CH₂Cl₂ several times and dried in a vacuum. Thiazolureas were prepared in the same manner from resin 6 (R² = NHCOR) as described in the preparation of 5 from resin 4.
Analytical data of 7a: ¹H NMR (500 MHz, CDCl₃): δ = 11.67 (br s, 1 H), 7.76-7.79 (m, 2 H), 7.66 (d, 2 H, J = 7.8 Hz), 7.43-7.47 (m, 3 H), 7.33 (dd, 2 H, J ₁ = 7.6 Hz, J ₂ = 8.3Hz), 7.06 (dd, 1 H, J ₁ = 7.4 Hz, J ₂ = 7.4 Hz), 5.88 (br s, 1 H), 3.22-3.28 (m, 2 H), 1.67-1.73 (m, 2 H), 1.00 (t, 3 H, J = 7.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 183.5, 162.1, 130.5, 141.8, 139.7, 130.5, 129.0, 128.4, 127.2, 123.0, 120.2, 47.5, 22.4, 11.4. LCMS: m/z = 403 [M + Na].
The resin 4 (250 mg) was treated with acyl chloride (2.5 mmol) and pyridine (2.5 mmol) in MeCN (1 mL) to yield 6 (R² = COR). After shaking for 6 h at r.t., the resin 6 (R² = COR) was collected by filtration and washed with H₂O, DMF, MeOH, and CH₂Cl₂ several times and dried in a vacuum. N-Acylthiazoles were prepared in the same manner from resin 6 (R² = COR) as described in the preparation of 5 from resin 4.
Analytical data of 7f: ¹H NMR (500 MHz, CDCl₃): δ = 12.93 (s, 1 H), 8.15 (d, 2 H, J = 7.2 Hz), 7.80-8.14 (m, 2 H), 7.49-7.57 (m, 6 H), 3.21-3.26 (m, 2 H), 1.70 (m, 2 H), 1.00 (t, 3 H, J = 7.4 Hz). ¹³C NMR (125 MHz, CDCl₃): δ = 186.7, 174.2, 164.0, 158.0, 140.9, 133.8, 132.5, 131.5, 128.9, 128.6, 128.0, 127.5, 102.7, 48.0, 22.1, 11.3. LCMS: m/z = 366 [M + 1].