Novel 4- and 7-Sulfonylated 2-Substituted Benzoxazoles

Abstract

The efficient synthesis of sulfonylated benzoxazoles at positions C4 or C7 is reported. The condensation reactions involve original anilide acetal reagents which, upon acid catalysis, allow an easy cyclization reaction with the sulfonylated o-aminophenol partners. This method circumvents the classical use of orthoesters which drawback is the limited access to aromatic reagents.

Key words

acetals - condensation - cyclization - heterocycles - substituents effects

References and Notes

• 1a Reynolds MB. DeLuca MR. Kerwin SM. Bioorg. Chem.  1999,  27:  326 
• 1b Tipparaju S. Joyasamal S. Pieroni M. Kaiser M. Brun R. Kozikowski AP. J. Med. Chem.  2008,  51:  7344 
• 2a Do H.-Q. Daugulis O. J. Am. Chem. Soc.  2007,  129:  12404 
• 2b Kantam ML. Venkanna GT. Kumar KBS. Balasubrahmanyam V. Bhargava S. Synlett  2009,  1753 
• 2c Kumar D. Rudrawar S. Chakraborti AK. Aust. J. Chem.  2008,  61:  881 
• 3a Huxley A. Synlett  2006,  2658 
• 3b Kumar R. Selvam C. Kaur G. Chakraborti AK. Synlett  2005,  1401 
• 4 Sardarian AR. Shahsavari-Fard Z. Synlett  2008,  1391 
• 5 Chang J. Zhao K. Pan S. Tetrahedron Lett.  2002,  43:  951 
• 6a Bonnamour J. Bolm C. Org. Lett.  2008,  10:  2665 
• 6b Ueda S. Nagasawa H. J. Org. Chem.  2009,  74:  4272 
• 7a Wang BB. Maghami N. Goodlin VL. Smith PJ. Bioorg. Med. Chem. Lett.  2004,  14:  3221 
• 7b McKee ML. Kerwin S. Bioorg. Med. Chem.  2008,  16:  1775 
• 8 Tian Y. Chen CI. Yang CC. Young AC. Jang SH. Chen WC. Jen AK.-Y. Chem. Mater.  2008,  20:  1977 
• 9 Crocetti L. Maresca A. Temperini C. Hall RA. Scozzafava A. Mühlschlegel FA. Supuran CT. Bioorg. Med. Chem. Lett.  2009,  19:  1371 
• 10a Zonta C. DeLucchi O. Volpicelli R. Cotarca L. Top. Curr. Chem.  2007,  275:  131 
• 10b Brett AD, Rabinowitz M, Rosen MD, and Woods CR. inventors;  WO2008124524. 
• 11a Bruyneel F. Enaud E. Billottet L. Vanhulle S. Marchand-Brynaert J. Eur. J. Org. Chem.  2008,  72 
• 11b Bruyneel F. Payen O. Rescigno A. Tinant B. Marchand-Brynaert J. Chem. Eur. J.  2009,  8283 
• 12a So Y.-H. Heeschen JP. J. Org. Chem.  1997,  62:  3552 
• 12b Khajavi MS. Mohammadi AA. J. Chem. Res., Synop.  2002,  136 
• 13 Wrobel J. Rogers J. Green D. Kao K. Synth. Commun.  2002,  32:  2695 
• 14 DeWolfe RH. Carboxylic Ortho Acid Derivatives   Academic Press; New York: 1970. 
• 15 Breslow R. Pandey PS. J. Org. Chem.  1980,  45:  741 
• 16 McClelland RA. Patel G. Lam P. J. Org. Chem.  1981,  46:  1011 
• 19 Dipakranjan M. Synth. Commun.  1986,  16:  331 
• 20 Huang S.-T. Hsei I.-J. Chen C. Bioorg. Med. Chem.  2006,  14:  6106 
• 21a Abou-Zied OK. Chem. Phys.  2007,  337:  1 
• 21b Mazzitelli CL. Rodriguez M. Kerwin SM. Brodbelt JS. J. Am. Soc. Mass Spectrom.  2008,  19:  209 
• 22 Shank RP. Smith-Wintowsky VL. Maryanoff BE.
  J. Enzyme Inhib. Med. Chem.  2007,  23:  271 
• 23 Bruyneel F. D’Auria L. Payen O. Courtoy PJ. Marchand-Brynaert J. ChemBioChem  2010,  11:  1451 

17

Synthesis of Benzanilide Acetals - General Procedure Benzanilide (1 equiv, 10 mmol) and (m)ethyl trifluoro-methanesulfonate (1.2 equiv)were stirred in dry CH₂Cl₂ (6 mL) overnight. Dry Et₂O (40 mL) was added at 0 ˚C, and the mixture was left 1 h until all the imidatonium salt had precipitated. This salt was separated from the solvent, dissolved into CH₂Cl₂ (6 mL) and added dropwise over a period of 30 min to a cooled (0 ˚C) stirred solution of NaOEt freshly made by addition of Na (0.5 g) to EtOH (20 mL). The solvents were removed by rotary evaporation and hexane (40 mL) was added. This dissolved the crude anilide acetal, and the excess of salt was filtered off. Evaporation gave the crude acetal.
Cyclization into Benzoxazole - General Procedure Sulfonylated aminophenols (1 equiv, 1 mmol) and orthoester (3 equiv) or benzanilide acetal (3 equiv) were added to dioxane (3 mL), and the mixture was heated at 60 ˚C overnight. The crude reaction mixture was filtered directly, and the residual solid was triturated twice with CH₂Cl₂ and filtered again. The filtered solutions were pooled together and concentrated under vacuum. The residue was either recrystallized in a mixture of CH₂Cl₂-EtOH (8:2 v/v) or purified by column chromatography (silica gel, cyclohexane-EtOAc).

18

Spectroscopic Data for Selected Compounds
2-(2′-Methoxyphenyl)benzoxazole-4-sulfonic Acid (6a) White solid. Yield 70%. Mp <225 ˚C (slow decomp.). IR: 2923, 2352, 1647, 1548, 1419, 1240, 1105, 1049, 750 cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 3.90 (s, 3 H, OCH₃), 7.23 (ddd, 1 H, J = 0.8, 2.6 Hz, 8.3 Hz, H_{3 ′}), 7.37 (br t, 1 H, J = 7.9 Hz, H_{5 ′}), 7.56 (br t, 1 H, J = 8.0 Hz, H₆), 7.68 (dd, 1 H, J = 1.0, 7.8 Hz, H₇), 7.71 (m, 1 H, H_{4 ′}), 7.77 (dd, 1 H, J = 1.0, 8.2 Hz, H_{6 ′}), 7.82 (dd, 1 H, J = 1.0, 7.8 Hz, H₅). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 56.3 (OCH₃), 112.2 (C_{3 ′}), 112.6 (C₇), 119.0 (C_{5 ′}), 120.6 (C_{1 ′}), 123.6 (C_{4 ′}), 125.2 (C_{6 ′}), 128.7 (C₅), 131.4 (C₆), 138.6 (C₄), 140.3 (C₉), 151.4 (C₈), 160.5 (C₂), 162.4 (C_{2 ′}). ESI-MS: m/z (%) = 304.13 (100) [M - H]^-, 289.07 (25), 198.05 (10). ESI-HRMS: m/z [M - H]^- calcd for C₁₄H₁₀NO₅S: 304.0280; found: 304.0267. 2-(2′-Benzyloxyphenyl)benzoxazole-4-sulfonic Acid (6c)
Yellow powder. Yield 60%. Mp 180-185 ˚C. IR: 2923, 1549, 1450, 1419, 1249, 1197, 1051, 752 cm^-¹. ^¹H NMR (300 MHz, CD₃OD/CDCl₃): δ = 5.21 (s, 2 H, CH₂Ph), 6.64 (d, 1 H, J = 7.4 Hz, H_{3 ′}), 6.74 (t, 1 H, J = 7.4 Hz, H_{5 ′}), 6.90-7.05 (m, 6 H, Ph and H_{4 ′}), 7.29 (t, 1 H, J = 7.8 Hz, H₆), 7.39 (d, 1 H, J = 7.9 Hz, H₇), 7.55 (d, 1 H, J = 7.4 Hz, H_{6 ′}), 7.75 (d, 1 H, J = 7.7 Hz, H₅). ^¹³C NMR (75 MHz, CD₃OD/CDCl₃): δ = 72.2 (CH₂Ph), 112.8 (C_{3 ′}), 115.6 (C₇), 115.7 (C_{1 ′}), 121.8 (C_{5 ′}), 123.2 (C_{4 ′}), 125.1 (C_{6 ′}), 127.7 (Ph), 127.8 (Ph), 128.1 (Ph), 130.5 (C₅), 133.1 (C₆), 135.1 (C₄), 136.3 (C₉), 150.0 (C₈), 155.7 (C₂), 162.6 (C_{2 ′}). ESI-MS: m/z (%) = 380.07 (95) [M - H]^-, 289.36 (100). ESI-HRMS: m/z [M - H]^- calcd for C₂₀H₁₄NO₅S: 380.0588; found: 380.0593.
2-(2′-Methoxyphenyl)benzoxazole-7-sulfonic Acid (7a) Red solid. Yield 65%. Mp <210 ˚C (slow decomp.). IR: 2923, 1602, 1552, 1480, 1419, 1220, 1199, 817, 794 cm^-¹. ^¹H NMR (300 MHz, DMSO-d ₆): δ = 3.89 (s, 3 H, OCH₃), 7.24 (dd, 1 H, J = 2.5, 7.9 Hz, H_{3 ′}), 7.35 (t, 1 H, J = 7.8 Hz, H_{4 ′}), 7.55-7.62 (m, 2 H, H₅ and H_{5 ′}), 7.69 (m, 1 H, H_{6 ′}), 7.78 (m, 2 H, H₆ and H₄). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 56.3 (OCH₃), 112.9 (C_{3 ′}), 118.8 (C₉), 121.2 (C_{5 ′}), 124.4 (C_{4 ′}), 124.9 (C₄ and C_{6 ′}), 128.5 (C₆), 131.5 (C₅), 133.1 (C_{1 ′}), 143.0 (C₇), 146.7 (C₈), 160.5 (C₂), 163.1 (C_{2 ′}). ESI-MS: m/z (%) = 304.17 (100) [M - H]^-, 289.30 (70), 261.36 (30). ESI-HRMS: m/z [M - H]^- calcd for C₁₄H₁₀NO₅S: 304.0280; found: 304.0269.
2-(2′-Hydroxyphenyl)benzoxazole-4-sulfonic Acid (9) Brown solid. Yield 95%. Mp 197-200 ˚C. IR: 3174, 2921, 1631, 1548, 1454, 1421, 1247, 1054, 746 cm^-¹. ^¹H NMR (300 MHz, CD₃OD): δ = 7.02-7.07 (m, 2 H, H_{3 ′} and H_{4 ′}), 7.41-7.48 (m, 3 H, H₆, H_{5 ′}, OH), 7.81 (d, 1 H, J = 8.2 Hz, H₇), 7.87 (d, 1 H, J = 7.7 Hz, H_{6 ′}), 8.06 (d, 1 H, J = 7.9 Hz, H₅). ^¹³C NMR (75 MHz, CD₃OD): δ = 112.8 (C_{3 ′}), 115.3 (C₇), 119.9 (C_{5 ′}), 125.8 (C_{1 ′}), 127.3 (C_{4 ′}), 130.0 (C_{6 ′}), 133.8 (C₅), 136.5 (C₆), 137.8 (C₄), 139.3 (C₉), 152.5 (C₈ and C₂), 166.0 (C_{2 ′}). ESI-MS: m/z (%) = 289.87 (100) [M - H]^-. ESI-HRMS: m/z [M - H]^- calcd for C₁₃H₈NO₅S: 290.0234; found: 290.0123.
2-(2′-Methoxyphenyl)benzoxazole-4-sulfonamide (10) White powder. Yield 90%. Mp <210 ˚C (slow decomp.). IR: 2918, 1544, 1423, 1328, 1251, 1157, 1139, 754 cm^-¹. ^¹H NMR (300 M Hz, DMSO-d ₆): δ = 3.91 (s, 3 H, OCH₃), 7.27 (ddd, 1 H, J = 0.8, 2.6, 8.3 Hz, H_{3 ′}), 7.55-7.60 (m, 4 H, SO₂NH₂, H₇ and H_{4 ′}), 7.79-7.85 (m, 2 H, H_{5 ′} and H₆), 7.91 (dd, 1 H, J = 1.2, 6.6 Hz, H_{6 ′}), 8.07 (dd, 1 H, J = 0.8, 8.2 Hz, H₅). ^¹³C NMR (75 MHz, DMSO-d ₆): δ = 55.9 (OCH₃), 113.0 (C_{3 ′}), 115.2 (C₇), 119.2 (C_{5 ′}), 120.7 (C_{1 ′}), 122.9 (C_{4 ′}), 125.5 (C_{6 ′}), 127.4 (C₅), 131.0 (C₆), 134.7 (C₄), 138.0 (C₉), 151.3 (C₈), 160.1 (C₂), 163.8 (C_{2 ′}). ESI-MS: m/z (%) = 304.90 (100) [M + H]⁺, 242.09 (20). HRMS (CI): m/z [M + H]⁺ calcd for C₁₄H₁₂N₂O₄S: 305.05960; found: 305.05976.