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.

Key words

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 
• 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. 

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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.

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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.