Synthesis of 2-Amino-5-arylthiazoles by Palladium-Catalyzed Arylation at the C5 Position with Aryl Iodides

Abstract

A new synthetic route to afford 2-amino-5-aryl thiazoles has been developed. The starting aminothiazole derivative can be arylated at position 5 with aryl iodides under palladium-catalyzed conditions. Mechanistic studies suggest a proton-abstraction pathway for this transformation.

Key words

palladium - catalysis - cross-coupling - heterocycles - Heck reaction

References and Notes

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• 22b

  See also ref. 14c,d, 15.

9

The Pd-coupling reaction with free 2-aminothiazole provided the corresponding amination product.

10

Lower yields were obtained with bidentate phosphine ligands, such as XantPhos (4,5-bis-diphenylphosphanyl-9,9-dimethyl-9H-xanthene, 64%), BINAP (60%) or DPPF [1,1′-bis(diphenylphosphino)ferrocene, 58%].

12

Typical Experimental Procedure
A 16 × 100 tube was charged with thiazole 2 (0.37 mmol), aryl iodide (0.55 mmol), Cs₂CO₃ (0.239 g, 0.73 mmol), Pd(OAc)₂ (0.004 g, 5 mol%, 0.02 mmol), ligand 7 (0.014 g, 10 mol%, 0.04 mmol) and DMF (2 mL, 0.2 M). The resulting mixture was stirred at 120 °C for 24 h under a nitrogen atmosphere. The mixture was then filtered through Celite and concentrated to dryness. The residue was purified first on silica gel (4:1 hexane-EtOAc) and then with an HLB cartridge [using NH₄HCO₃ (pH 10) and MeCN as eluents]. Next, the compound was dissolved in CH₂CH₂ (1 mL) and TFA in CH₂CH₂ (25%, 1 mL) was added. The corresponding solution was shaken on an arm shaker overnight. After that, the mixture was concentrated to dryness, dissolved in MeOH, passed through an SCX-2 cartridge; two volumes of MeOH and two volumes of NH₃-MeOH (2 N) were eluted. The NH₃-MeOH washings were concentrated to dryness to afford the desired compound.
2-Amino-5-phenylthiazole-4-carboxylic acid ethyl ester (4a): white solid (73 mg, 80%). ¹H NMR (300 MHz, CDCl₃): δ = 7.47-7.38 (m, 5 H), 5.48-5.39 (m, 2 H), 4.23 (q, J = 7.1 Hz, 2 H), 1.19 (t, J = 7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃): δ = 163.91, 160.92, 135.83, 134.10, 129.81, 129.02, 127.62, 126.99, 59.99, 13.02.