Facile Generation of a Library of 5-Aryl-2-arylsulfonyl-1,3-thiazoles

Abstract

Treatment of N,N-diformylaminomethyl aryl ketones with phosphorus pentasulfide/triethylamine in chloroform gives 5-arylthiazoles directly in good yield. The 5-aryl-1,3-thiazole core has been successfully functionalised at the 2-position to yield, over two steps, a large array of 5-aryl-2-arylsulfonyl-1,3-thiazoles in a ­parallel fashion.

heterocycles - 1,3-thiazole - lithiation - phosphorus ­pentasulfide

References and Notes

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5 Bold G. Fässler A. Capraro H.-G. Cozens R. Klimmait T. Lazdins J. Mestan J. Poncioni B. Rösel J. Stover D. Tintelnot-Blomley M. Acemoglu F. Beck W. Boss E. Eschbach M. Hürlimann T. Masso E. Roussel S. Ucci-Stoll K. Wyss D. Lang M. J. Med. Chem.  1998,  41:  3387 

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11

General Procedure for the Preparation of Thiazoles 3.
The bisformamide derivative (1 mmol) was dissolved in CHCl₃ (5 mL). Then, Et₃N (0.28 mL, 0.20 g, 2 equiv) was added to the stirred mixture, followed by phosphorus pentasulfide (0.44 g, 2 mmol, 2 equiv). The mixture was stirred at 60 °C for the appropriate time (typically 45-60 min). After cooling to r.t., H₂O (3 mL) was added and the mixture stirred for 1 h. CH₂Cl₂ (15 mL) was then added and layers separated. The organic layer was washed with H₂O and brine, dried (Na₂SO₄ or MgSO₄) and the solvent removed in vacuo. The crude product was purified by flash chromatography [silica; Et₂O-PE (60-80) mixtures as eluant] or on silica preparative TLC plates.

12

We were also able to convert 6 into the thiazole 7 by the same method in 67% yield (Scheme [2] ).

Scheme 2

13

Spectroscopic data of 3 (Ar¹ = 4-MeOC₆H₄): ¹H NMR (250 MHz, CDCl₃): δ = 3.84 (s, 3 H), 7.50 (m, 2 H), 6.94 (m, 2 H), 7.98 (s, 1 H), 8.70 (s, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 55.53, 114.7, 123.8, 128.4, 138.2, 139.4, 151.4, 160.0.

14

Spectroscopic data of 3 (Ar¹ = 2-furyl): ¹H NMR (250 MHz, CDCl₃): δ = 6.46 (dd, J = 3.5, 1.8 Hz, 1 H), 6.57 (dd, J = 3.5, 0.6 Hz, 1 H), 7.45 (dd, J = 1.8, 0.6 Hz, 1 H), 8.05 (s, 1 H), 8.71 (s, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 107.6, 111.94, 129.2, 138.7, 142.8, 146.4, 151.4.

15

Spectroscopic data of 4 (Ar¹ = 3-NO₂C₆H₄, Ar² = 3-BrC₆H₄): ¹H NMR (250 MHz, CDCl₃): δ = 7.33 (m, 1 H), 7.52-7.68 (m, 3 H), 7.72-7.87 (m, 2 H), 7.97 (s, 1 H), 8.12-8.22 (m, 1 H), 8.28 (m, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 121.3, 123.0, 123.6, 130.32, 130.36, 131.3, 132.3, 132.7, 133.1, 133.4, 136.3, 138.4, 140.4, 148.85, 148.86.

16

Spectroscopic data of 4 (Ar¹ = 4-MeC₆H₄, Ar² = Ph): ¹H NMR (250 MHz, CDCl₃): δ = 2.35 (s, 3 H), 7.11-7.23 (m, 2 H), 7.29-7.51 (m, 5 H), 7.65 (m, 2 H), 7.82 (s, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.3, 126.5, 128.2, 129.5, 129.8, 132.2, 133.6, 138.3, 138.5, 141.2, 164.2.

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18 Cronje S. Raubenheimer HG. Spies HSC. Esterhuysen C. Schmidbaur H. Schier A. Kruger GJ. J. Chem. Soc., Dalton Trans.  2003,  14:  2859 

19

MP-carbonate resin (loading: 3.14 mmol/g) was purchased from Argonaut Technologies.

20

General Procedure for the Oxidation of Thioethers 4 to Sulfones 5.
To a solution of the thioether (1 equiv, 0.2 M) in CH₂Cl₂, dry MCPBA (5 or 10 equiv) was added. The resulting mixture was stirred for 3 h at 40 °C (recommended for sterically hindered thioethers) or 6 h at r.t. To the mixture diluted with CH₂Cl₂ (35 mL/mmol of thioether), MP-carbonate resin was added (4 equiv relative to the amount of peracid used) and stirred for 2 h. The resin was filtered off and washed twice with CH₂Cl₂. The solvent was removed in vacuo to give the expected sulfones in pure form. In a few cases, crude sulfones required further purification by preparative TLC (silica; Et₂O-PE (60-80) 7:3 as eluant).

21

Sulfones derived from 5-furylsubstituted thiazoles could not be isolated, probably due to side reactions affecting the furan ring under the acidic conditions used for the oxidation step.

22

Spectroscopic data of 5 (Ar¹ = 4-MeOC₆H₄, Ar² = 4-MeC₆H₄): ¹H NMR (250 MHz, CDCl₃): δ = 2.43 (s, 3 H), 3.84 (s, 3 H), 6.89-7.01 (m, 2 H), 7.31-7.42 (m, 2 H), 7.43-7.53 (m, 2 H), 7.91-8.10 (m, 3 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.8, 55.6, 115.0, 122.2, 128.7, 130.2, 136.2, 139.5, 145.6, 146.9, 161.0, 164.2.

23

Spectroscopic data of 5 (Ar¹ = 2-thienyl, Ar² = 2-MeC₆H₄): ¹H NMR (250 MHz, CDCl₃): δ = 2.65 (s, 3 H), 7.01 (dd, J = 5.0, 3.7 Hz, 1 H), 7.18-7.52 (m, 5 H), 7.84 (s, 1 H), 8.16 (m, 1 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 20.9, 127.0, 127.7, 127.9, 128.6, 130.6, 131.1, 133.1, 134.7, 137.2, 139.6, 139.9, 140.2, 164.7.