A Novel, One-Pot, Three-Component Synthesis of 5H-[1,3]Thiazolo[3,2-a]pyrimidine Derivatives

Abstract

A novel synthesis of highly functionalized 5H-[1,3]thi­azolo[3,2-a]pyrimidines is described via a one-pot, three-component addition reaction between isocyanides, dialkyl acetylene-dicarboxylates and ethyl 2-oxo-2-(1,3-thiazol-2-ylamino)acetates in good yields.

5H-[1,3]thiazolo[3,2-a]pyrimidines - three-component reaction - isocyanides - cyclizations - heterocycles

References and Notes

1a Bagley MC. Dale JW. Bower J. Chem. Commun.  2002,  1682 

1b Mont N. Teixidó J. Borrell JI. Kappe CO. Tetrahedron Lett.  2003,  44:  5385 

1c Simon C. Constantieux T. Rodriguez J. Eur. J. Org. Chem.  2004,  4957 

1d Cui SL. Lin XF. Wang YG. J. Org. Chem.  2005,  70:  2866 

1e Huang YJ. Yang FY. Zhu CJ. J. Am. Chem. Soc.  2005,  127:  16386 

1f Ramón DJ. Yus M. Angew. Chem. Int. Ed.  2005,  44:  1602 

1g Dömling A. Chem. Rev.  2006,  106:  17 

1h Dömling A. Ugi I. Angew. Chem. Int. Ed.  2000,  39:  3168 

2 Tozkoparan B. Ertan M. Kelicen P. Demirdamar R. Farmaco  1999,  30:  588 

3 Jeanneau-Nicolle E. Benoit-Guyod M. Namil A. Leclerc G. Eur. J. Med. Chem.  1992,  27:  115 

4 Sayed HH. Shamroukh AH. Rashad AE. Acta Pharm.  2006,  56:  231 

5 Coburn RA. Glennon RA. J. Pharm. Sci.  1973,  62:  1785 

6 Nobe K. Miyatake M. Nobe H. Sakai Y. Takashima J. Momose K. Brit. J. Pharmacol.  2004,  143:  166 

7 Balkan A. Uma S. Ertan M. Wiegrebe W. Pharmazie  1992,  47:  687 

8 Wichmann J. Adam G. Kolczewski S. Mutel V. Woltering T. Bioorg. Med. Chem. Lett.  1999,  9:  1573 

9 Proudfoot JR. Expert Opin. Ther. Pat.  1998,  8:  971 

10a Elokhina VN. Nakhmanovich AS. Stepanova ZV. Lopyrev VA. Bannikova OB. Struchkov YT. Shishkin OV. Russ. Chem. Bull.  1996,  45:  2189 

10b Sherif SM. Youssef MM. Mobarak KM. Abdel-Fattah A.-SM. Tetrahedron  1993,  49:  9561 

10c Liu YS. Huang WY. J. Chem. Soc., Perkin Trans. 1  1997,  981 

10d Katritzky AR. Rogers JW. Witek RM. Nair SK. ARKIVOC  2004,  (viii):  52 

10e Ye FC. Chen BC. Huang X. Synthesis  1989,  317 

10f Landreau C. Deniaud D. Reliquet A. Meslin JC. Synthesis  2001,  2015 

10g Hurst DT. Beaumont C. Jones DTE. Kingsley DA. Patridge JD. Rutherford TJ. Aust. J. Chem.  1988,  41:  1209 

10h Liebscher J. Hassoun A. Synthesis  1988,  816 

11

Procedure for the Preparation of Dimethyl 7-[Cyclo-hexyl(2-ethoxy-2-oxoacetyl)amino]-5 H -[1,3]thiazolo[3,2- a ]pyrimidine-5,6-dicarboxylate ( 4a): To a magnetically stirred solution of ethyl 2-oxo-2-(1,3-thiazol-2-yl-amino)acetate (0.200 g, 1 mmol) and dimethyl acetylene-dicarboxylate (0.142 g, 1 mmol) in anhyd CH₂Cl₂ (6 mL) was added dropwise a solution of cyclohexyl isocyanide (0.109 g, 1 mmol) in anhyd CH₂Cl₂ (2 mL) at 25 °C over 10 min. The reaction mixture was then stirred for 24 h. The solvent was removed and the residue was purified by column chromatography using n-hexane-EtOAc (1:2) as eluent. The solvent was removed and the product was obtained. Yield: 0.41 g (90%); yellow crystals. IR (KBr): 1744, 1725, 1680, 1657 (C=O), 1535, 1483, 1414, 1340, 1223, 1193, 1121 cm^-1. ¹H NMR (500.1 MHz, CDCl₃): δ = 1.06-2.02 [t, J = 7.0 Hz, 3 H, OCH₂CH ₃; m, 10 H, CH(CH ₂)₅], 3.68, 3.69 (2 × s, 6 H, 2 × OMe), 4.05-4.25 [2 × dq, ABX₃ system, ² J = 10.6 Hz, ³ J = 7.0 Hz, 2 H, OCH _A H _BCH₃; m, 1 H, NCH(CH₂)₅], 5.92 (s, 1 H, NCH), 6.61 (d, J = 4.6 Hz, 1 H, CH), 6.84 (d, J = 4.6 Hz, 1 H, CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 13.78 (OCH₂ CH₃), 25.54, 26.04, 26.05, 28.63, 31.67 (5 × CH₂), 51.83, 52.90 (2 × OMe), 56.78, 57.72 (2 × NCH), 61.60 (OCH₂), 90.77 (NC=C), 107.90, 126.89 (2 × CH), 152.19, 161.38, 162.16, 165.07, 166.88, 168.23 (2 × C, 4 × C=O). MS: m/z (%) = 451 (<1) [M⁺], 432 (6), 374 (58), 318 (100), 244 (51), 216 (24), 199 (16), 172 (14), 145 (12), 78 (20), 57 (10). Anal. Calcd for C₂₀H₂₅N₃O₇S (451.50): C, 53.20; H, 5.58; N, 9.31. Found: C, 53.0; H, 5.7; N, 9.2. Di- tert -butyl 7-[Cyclo-hexyl(2-ethoxy-2-oxo-acetyl)amino]-3-methyl-5 H -[1,3]thiazolo[3,2- a ]pyrimi-dine-5,6-dicarboxylate (4f): yield: 0.46 g (84%); yellow crystals. IR (KBr): 1745, 1738, 1674, 1661 (C=O), 1556, 1489, 1416, 1391, 1354, 1317, 1225, 1153, 1097 cm^-1. ¹H NMR (300.1 MHz, CDCl₃): δ = 1.09-2.03 [t, J = 7.1 Hz, 3 H, OCH₂CH ₃; 2 × s, 18 H, 2 × t-Bu; m, 10 H, CH(CH ₂)₅], 2.19 (s, 3 H, Me), 4.05-4.25 [m, 2 H, OCH _AH_BCH₃, CH(CH₂)₅], 4.33 (dq, AB system, ² J = 10.5 Hz, ³ J = 7.1 Hz, 1 H, OCH_A H _BCH₃), 5.83 (s, 1 H, NCH), 6.16 (s, 1 H, CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.68, 13.88 (Me, OCH₂ CH₃), 25.66, 25.88, 26.08 (3 × CH₂), 27.91, 28.23 [2 × C(CH₃)₃], 28.60, 32.15 (2 × CH₂), 55.16, 55.69 (2 × NCH), 61.90 (OCH₂CH₃), 81.56, 83.45 [2 × OC(CH₃)₃], 94.51 (N₂C=C), 101.41 (CH), 135.51 (C), 150.22, 161.01, 162.21, 164.37, 166.89, 167.07 (2 × C, 4 × C=O). MS: m/z (%) = 549 (<1) [M⁺], 448 (50), 392 (51), 310 (21), 279 (14), 236 (51), 211 (52), 192 (13), 167 (34), 149 (100), 113 (10), 83 (22), 57 (26). Anal. Calcd for C₂₇H₃₉N₃O₇S (549.69): C, 59.00; H, 7.15; N, 7.64. Found: C, 58.8; H, 7.4; N, 7.5. Dimethyl 7-[ tert -Butyl(2-ethoxy-2-oxoacethyl)amino]-5 H -[1,3]thi-azolo[3,2- a ]pyrimidine-5,6-dicarboxylate (4g): yield: 0.36 g (85%); yellow crystals. IR (KBr): 1740, 1664 (C=O), 1483, 1367, 1329, 1232, 1200, 1086, 1013 cm^-1. ¹H NMR (300.1 MHz, CDCl₃): δ = 1.24 (t, J = 7.2 Hz, 3 H, OCH₂CH ₃), 1.50 [s, 9 H, t-Bu], 3.72, 3.76 (2 × s, 6 H, 2 × OMe), 4.10, 4.21 (2 × dq, ABX₃ system, ² J = 10.5 Hz, ³ J = 7.2 Hz, 2 H, OCH _A H _BCH₃), 5.95 (s, 1 H, NCH), 6.61 (d, J = 4.6 Hz, 1 H, CH), 6.86 (d, J = 4.6 Hz, 1 H, CH). ¹³C NMR (75.5 MHz, CDCl₃): δ = 13.85 (OCH₂ CH₃), 28.08 [C(CH₃)₃], 51.80, 53.04 (2 × OMe), 57.91 (NCH), 60.56 [C(CH₃)₃], 61.40 (OCH₂), 95.14 (N₂C=C), 107.81, 126.82 (2 × CH), 151.56, 161.33, 162.19, 165.07, 166.47, 168.23 (2 × C, 4 × C=O). MS: m/z (%) = 425 (6) [M⁺], 366 (20), 310 (100), 296 (13), 264 (9), 250 (8), 236 (95), 211 (18), 176 (14), 167 (15), 149 (34), 57 (13). Anal. Calcd for C₁₈H₂₃N₃O₇S (425.46): C, 50.81; H, 5.45; N, 9.88. Found: C, 50.6; H, 5.6; N, 9.7. Diethyl 7-[ tert -Butyl(2-ethoxy-2-acetyl)amino]-3-methyl-5 H -[1,3]thiazolo[3,2- a ]pyr-imidine-5,6-dicarboxylate (4j): yield: 0.42 g (90%); yellow crystals. IR (KBr): 1738, 1685, 1663 (C=O), 1556, 1403, 1360, 1329, 1221, 1200, 1097, 1022 cm^-1. ¹H NMR (500.1 MHZ, CDCl₃): δ = 1.21, 1.24, 1.32 (3 × t, J = 7.1 Hz, 9 H, 3 × OCH₂CH ₃), 1.49 [s, 9 H, t-Bu], 2.18 (d, ⁴ J = 1.1 Hz, 3 H, Me), 4.02-4.33 (m, 6 H, 3 × OCH ₂CH₃), 5.94 (s, 1 H, NCH), 6.16 (br q, ⁴ J = 1.1 Hz, 1 H, CH). ¹³C NMR (125.8 MHz, CDCl₃): δ = 13.73, 13.84, 13.95, 14.29 (Me, 3 × OCH₂ CH₃), 28.21 [C(CH₃)₃], 55.45 (NCH), 60.56 [C(CH₃)₃], 61.13, 61.30, 62.25 (3 × OCH₂CH₃), 95.14 (N₂C=C), 101.95 (CH), 135.20 (C), 150.17, 161.30, 162.10, 164.90, 167.24, 168.03 (2 × C, 4 × C=O). MS: m/z (%) = 467 (3) [M⁺], 394 (29), 338 (100), 264 (29), 236 (31), 192 (11), 167 (12), 149 (28), 57 (10). Anal. Calcd for C₂₁H₂₉N₃O₇S (467.54): C, 53.95; H, 6.25; N, 8.99. Found: C, 53.9; H, 6.4; N, 8.9.

12

Selected X-ray Crystallographic Data for Compound 4a: C₂₀H₂₅N₃O₇S, monoclinic, space group = P21/n, a = 8.7880(9) Å, b = 20.488(2) Å, c = 12.2861(12) Å, β = 99.901(1)°, V = 2179.1(4) ų, T = 295(2) K, Z = 4, D _calcd = 1.376 g cm^-3, µ(Mo-K_α) = 0.195 mm^-1, 16164 reflections measured, 4061 unique reflections (R _int = 0.032), 3284 observed reflections, final R ₁ = 0.050, ωR ₂ = 0.128 and for all data R ₁ = 0.062. CCDC 640870 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

13a Nair V. Vinod AU. Nair JS. Sreekanth AR. Rath NP. Tetrahedron Lett.  2000,  41:  6675 

13b Nair V. Deepthi A. Tetrahedron Lett.  2006,  47:  2037 

14 Walborsky HM. Periasamy MP. In The Chemistry of Functional Groups, Supplement C   Patai S. Rappoport Z. Wiley; New York: 1983.  Chap. 20. p.835-837  

15 Ugi I. Angew. Chem., Int. Ed. Engl.  1982,  21:  810 

16 Ugi I. Isonitrile Chemistry   Academic Press; London: 1971.