Synlett 2006(3): 0460-0462  
DOI: 10.1055/s-2006-926243
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Peter W. Sheldrake*, Mizio Matteucci, Edward McDonald*
Medicinal Chemistry Team, The Cancer Research UK Centre for Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Belmont, Sutton, Surrey SM2 5NG, UK
e-Mail: peter.sheldrake@icr.ac.uk; e-Mail: ted.mcdonald@icr.ac.uk.;
Further Information

Publication History

Received 8 November 2005
Publication Date:
06 February 2006 (online)

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.

    References and Notes

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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.

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.