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Synlett 2008(16): 2433-2436  
DOI: 10.1055/s-2008-1078206
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

David Orain*, Anne-Catherine Blumstein, Engin Tasdelen, Samuel Haessig
Global Discovery Chemistry-Neuroscience, Novartis Institute for Biomedical Research, WKL-122.2.43, 4002 Basel, Switzerland
Fax: +41(61)6962455; e-Mail: david.orain@novartis.com;
Further Information

Publication History

Received 21 April 2008
Publication Date:
22 August 2008 (online)

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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

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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+].