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.

thiazoles - traceless solid-phase synthesis - cyanodithioimidocarbonic acid

References

1a Nicolaou KC. Hanko R. Hatwig W. Handbook of Combinatorial Chemistry   Wiley-VCH; Washington: 2002. 

1b Dolle RE. J. Comb. Chem.  2003,  6:  693 

2a Boyle PH. In Comprehensive Heterocyclic Chemistry   2nd ed., Vol. 3:  Katritzky AR. Rees CW. Scriven EFV. Elsevier; New York: 1996.  p.373 

2b Lewis JR. Nat. Prod. Rep.  1999,  16:  389 

3a Goff D. Fernandez J. Tetrahedron Lett.  1999,  40:  423 

3b Kazzouli SE. Berteina-Raboin S. Mouaddib A. Guillaumet G. Tetrahedron Lett.  2002,  43:  3193 

3c Stieber F. Mazitschek R. Soric N. Giannis A. Waldmann H. Angew. Chem. Int. Ed.  2002,  41:  4757 

3d Katrizky AR. Cai X. Rogovoy BV. J. Comb. Chem.  2003,  5:  392 

4 Chen L, Ding Q, Gillespie P, Kim K, Lovey AJ, Mccomas WW, Mullin JG, and Perrotta A. inventors; PCT Int. Appl.  WO02057261. 

5 Bowler AN, and Hansen BF. inventors; PCT Int. Appl.  WO03011843. 

6a Gompper R. Gang M. Saygin F. Tetrahedron Lett.  1966,  7:  1885 

6b Gewald K. Blauschimit P. Mayer R. J. Prakt. Chem.  1967,  35:  97 

7a Rajasekharan KN. Nair KP. Jenardanan GC. Synthesis  1986,  353 

7b Binu R. Thomas KK. Jenardannan GC. Rajasekharan KN. Org. Prep. Proced. Int.  1998,  30:  93 

7c Romero-Ortega M. Aviles A. Raymundo C. Fuentes A. Gomez RM. Plata A. J. Org. Chem.  2000,  65:  7244 

7d Masquelin T. Obrecht D. Tetrahedron  2001,  57:  153 

7e Baer R. Masquelin T. J. Comb. Chem.  2001,  3:  16 

8a Yamanaka H. Ohba S. Sakamoto T. Heterocycles  1990,  31:  1115 

8b Konno S. Masaki A. Mataichi S. Hiroshi Y. Yakugaku Zasshi  1990,  110:  105 

9 Timmons RJ. Wittenbrook LS. J. Org. Chem.  1967,  32:  1566 

10 Hwang JY. Choi H.-S. Lee D.-H. Yoo S.-e. Gong Y.-D. J. Comb. Chem.  2005,  7:  136 

11 Vernin G. Siv C. Metzger J. J. Heterocycl. Chem.  1978,  15:  1361 

12a Walchshofer N. Minjat M. Tinland B. Jaussaud P. Petavy AF. Paris J. Eur. J. Med. Chem.  1986,  59 

12b Yamamoto K, Kondoh K, Horiuchi K, Matsui Y, and Nagamine M. inventors; Eur. Pat. Appl. EP  761658. 

13a Lidstrom P. Tierney J. Wathey B. Westman J. Tetrahedron  2001,  57:  9225 

13b Larhed M. Moberg C. Hallberg A. Acc. Chem. Res.  2002,  35:  717 

13c Lew A. Krutzik PO. Hart ME. Chamberin R. J. Comb. Chem.  2002,  4:  95 

13d Lee IY. Lee JY. Gong Y.-D. Synthesis  2005,  DOI: 10.1055/5-2005-872099 

14a Hirai K. Sugimoto H. Ishiba T. J. Org. Chem.  1980,  45:  253 

14b Wamhoff H. Berressem R. Herrmann S. Synthesis  1993,  107 

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].