A Novel Intramolecular Palladium-Mediated Cyclization for the Synthesis of Substituted 2-(Aryl- or Benzylamino)-4H-1,3-Benzothiazines

Abstract

Synthesis of 2-aryl/benzylamino 4H-1,3-benzothiazine derivatives was achieved via an unprecedented intramolecular palladium cyclization for creating a sulfur-aryl bond.

Key words

palladium - sulfur - heterocycles - ring closure - catalysis

References and Notes

• 2 Sathunuru R. Zhang H. Rees CW. Biehl E. Heterocycles  2005,  65:  1615 
• 3a Reaction on thiopurine: He H. Llauger L. Rosen N. Chiosis G. J. Org. Chem.  2004,  69:  3230 
• 3b Reaction on thioimidazole and thiobenzothiazole: Schopfer U. Schlapbach A. Tetrahedron  2001,  57:  3069 
• 4 Takagi K. Iwachido T. Hayam N. Chem. Lett.  1987,  839 
• 5a Takagi K. Chem. Lett.  1986,  265 
• 5b Takagi K. Chem. Lett.  1990,  2205 
• 7 Klatsmanyi-Gabor P. Meisel T. Erdey L. Acta Chim. Acad. Sci. Hung.  1964,  40:  99 

1

Current address: Actelion Pharmaceuticals Ltd, Gewerbestrasse 16, 4123 Allschwil, Switzerland.

6

Synthesis of 2a
To a mixture of 1-(2-iodobenzyl)-3-phenylthiourea (1a′, 500 mg, 1.4 mmol) and Et₃N (0.38 mL, 2 equiv) in dioxane (20 mL), Ph₃P (158 mg, 0.1 equiv), and Pd(PPh₃)₄ (36 mg, 0.1 equiv) were added under argon. The resulting mixture was refluxed for 40 min. The solvent was removed in vacuo, and the crude was partitioned between EtOAc and sat. NaHCO₃ soln. The organic phase was separated, washed with sat. NH₄Cl, dried over Na₂SO₄, and concentrated in vacuo to afford a crude brown oil (520 mg). The crude material was purified by flash chromatography on SiO₂ using hexanes-EtOAc (100:0 to 60:40) as solvent system. From the purification, 2 (220 mg, 67.4% yield) was isolated as a light yellow oil. ^¹H NMR (400 MHz, CDCl₃): δ = 7.00-7.50 (m, 9 H), 4.52 (s, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 152.6, 149.2, 134.6, 131.7, 129.7, 128.1, 127.7, 127.6, 127.4, 123.7, 120.6, 53.1. IR (solution in CH₂Cl₂): 3418, 3054, 1638, 1590, 1518, 1498, 1437, 1311, 1252, 1031, 1025 cm^-¹. HRMS: m/z calcd for C₁₄H₁₂N₂S: 241.07940 [M + H⁺]; found : 241.07935 [M + H⁺].

8

A 40 mL clear vial, screw top hole cap with PTFE/silicone septa form SUPELCO (ref 27180).

9

Synthesis of 8
In a screw-capped vial, to a suspension of 1-benzyl-3-(2-iodobenzyl)-thiourea (7, 945 mg, 2.5 mmol) and DBU (0.76 mL, 2 equiv) in dioxane (5 mL), dppf (141 mg, 0.1 equiv), and Pd(OAc)₂ (57 mg, 0.1 equiv) were added under argon. The resulting mixture was stirred at 80 ˚C for 2 h. The solvent was removed in vacuo, and the crude material was purified by flash chromatography on SiO₂ using hexanes-EtOAc (70:30) as solvent system. The fractions containing the product were concentrated in vacuo to afford 570 mg of a light yellow solid. This solid was sonicated in hexanes and the resulting precipitate was filtered off, washed with hexanes, and after high-vacuum drying, 8 (452 mg, 71.9% yield) was isolated as a white powder. ^¹H NMR (400 MHz, DMSO-d ₆): δ = 7.41 (br m, 1 H, NH), 7.15-7.36 (m, 9 H), 4.36 (d, J = 4.8, 2 H), 4.27 (s, 2 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 154.9, 139.0, 135.5, 131.8, 129.3, 128.6, 128.2, 127.8, 127.6, 127.5, 127.4, 54.3, 48.3. IR (solution in CH₂Cl₂): 3427, 3034, 1633, 1483, 1468, 1251, 1205, 1192, 1129, 1066 cm^-¹. HRMS: m/z calcd for C₁₅H₁₄N₂S: 255.09505 [M + H⁺]; found: 255.09503 [M + H⁺].