The Reaction of 6-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one with Benzene-1,2-diamine: Synthesis and Chemistry of N-(2-Aminophenyl)-2-hydroxy-5-methylbenzimidoyl Cyanide

Abstract

(Z)-6-(4-Chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one, readily prepared from 4,5-dichloro-1,3,4-dithiazolium chloride and p-cresol, reacts with benzene-1,2-diamine to give N-(2-aminophenyl)-2-hydroxy-5-methylbenzimidoyl cyanide. The latter, in acidic media, cyclizes to give, depending on the reaction conditions, 2-methylbenzofuro[2,3-b]quinoxaline, 2-(1H-benzo[d]imidazol-2-yl)-4-methylphenol or 2-(3-aminoquinoxalin-2-yl)-4-methylphenol.

Key words

1,2,3-dithiazole - imidazole - quinoxaline - benzofuran - ionizing power - carboxylic acid - heterocycle - cyclization

• References and Notes

• 1 Appel R, Janssen H, Siray M, Knoch F. Chem. Ber. 1985; 118: 1632
• 2 Koutentis PA. Molecules 2005; 10: 346
• 3 Kim K. Phosphorus, Sulfur Silicon Relat. Elem. 1997; 120: 229
• 4 Kim K. Sulfur Rep. 1998; 21: 147
• 5 Konstantinova LS, Rakitin OA. Russ. Chem. Rev. 2008; 77: 521
• 6 Rakitin OA. ; In Comprehensive Heterocyclic Chemistry III. Vol. 6;. Zhdankin VV, Katritzky AR, Ramsden CA, Scriven EF. V, Taylor RJ. K. Elsevier; Oxford: 2008. Chap 6.01, 1-36
• 7 Konstantinova LS, Bol’shakov OI, Obruchnikova NV, Laborie H, Tanga A, Sopéna V, Lanneluc I, Picot L, Sablé S, Thiéry V, Rakitin OA. Bioorg. Med. Chem. Lett. 2009; 19: 136
• 8 Cottenceau G, Besson T, Gautier V, Rees CW, Pons A.-M. Bioorg. Med. Chem. Lett. 1996; 6: 529
• 9 Thiéry V, Rees CW, Besson T, Cottenceau G, Pons A.-M. Eur. J. Med. Chem. 1998; 33: 149
• 10 Besson T, Rees CW, Cottenceau G, Pons A.-M. Bioorg. Med. Chem. Lett. 1996; 6: 2343
• 11 Joseph RW, Antes DL, Osei-Gyimah P. US Pat 5,688,744, 1997
• 12 Moore JE. US Pat 4,119,722, 1977
• 13 Appel R, Janssen H, Haller I, Plempel M. DE Pat 2,848,221, 1980
• 14 Benting J, Dahmen P, Wachendorff-Neumann U, Hadano H, Vors J.-P. WO Pat 2012/045726, 2012
• 15 Mayer R, Foerster E, Matauschek B. DD Pat 212,387, 1984
• 16 Oppedisano F, Catto M, Koutentis PA, Nicolotti O, Pochini L, Koyioni M, Introcaso A, Michaelidou SS, Carotti A, Indiveri C. Toxicol. Appl. Pharmacol. 2012; 265: 93
• 17 Charalambous A, Koyioni M, Antoniades I, Pegeioti D, Eleftheriou I, Michaelidou SS, Amelichev SA, Konstantinova LS, Rakitin OA, Koutentis PA, Skourides PA. Med. Chem. Commun. 2015; 6: 935
• 18 Koyioni M, Manoli M, Manolis MJ, Koutentis PA. J. Org. Chem. 2014; 79: 4025
• 19 Koutentis PA, Koyioni M, Michaelidou SS. Org. Biomol. Chem. 2013; 11: 621
• 20 Kalogirou AS, Michaelidou SS, White AJ. P, Koutentis PA. Tetrahedron 2015; 71: 1799
• 21 Koyioni M, Manoli M, Koutentis PA. J. Org. Chem. 2014; 79: 9717
• 22 Kalogirou AS, Koutentis PA. Tetrahedron 2009; 65: 6850
• 23 Koutentis PA, Rees CW. J. Chem. Soc., Perkin Trans. 1 1998; 2505
• 24 Christoforou IC, Koutentis PA, Rees CW. J. Chem. Soc., Perkin Trans. 1 2002; 1236
• 25 Emayan K, English RF, Koutentis PA, Rees CW. J. Chem. Soc., Perkin Trans. 1 1997; 3345
• 26 Lee H.-S, Kim K. Tetrahedron Lett. 1998; 39: 5781
• 27 Popov VV, Bol’shakov OI, Konstantinova LS, Rakitin OA. Russ. Chem. Bull., Int. Ed. 2009; 58: 437
• 28 Kalogirou AS, Christoforou IC, Ioannidou HA, Manos MJ, Koutentis PA. RSC Adv. 2014; 4: 7735
• 29 Jeon M.-K, Kim K. J. Chem. Soc., Perkin Trans. 1 2000; 3107
• 30 Lee H.-S, Kim K. Tetrahedron Lett. 1998; 39: 6895
• 31 Letribot B, Delatouche R, Rouillard H, Bonnet A, Chérouvrier J.-R, Domon L, Besson T, Thiéry V. Molecules 2018; 23: 1390
• 32 To a stirred solution of (Z)-6-(4-chloro-5H-1,2,3-dithiazol-5-ylidene)-4-methylcyclohexa-2,4-dien-1-one (8; 20.0 mg, 0.082 mmol) and benzene-1,2-diamine (13.3 mg, 0.123 mmol) in dry DCM (5 mL) was added dry DBU (18.5 μL, 0.123 mmol, 1.5 equiv) in one portion. After complete consumption of the starting material (10 min, by TLC) the reaction mixture was poured onto a packed column of silica and purified by chromatography (n-hexane/DCM, 10:90) to give N-(2-aminophenyl)-2-hydroxy-5-methylbenzimidoyl cyanide (12; 14.4 mg, 70%) as bright-red needles; mp (hot stage): 151–153 °C (from cyclohexane); R_f 0.62 (DCM). Anal. Calcd (%) for C₁₅H₁₃N₃O: C, 71.70; H, 5.21; N, 16.72. Found: C, 71.61; H, 5.31; N, 16.54. UV: λ _max (DCM) = 229 (log ε 4.29), 245 (4.28), 261 (4.27), 291 (4.33), 412 inf (3.96), 450 nm (4.03). IR: 3483m, 3379m, 3034w (aryl C-H), 2924m and 2853w (alkyl C-H), 2222w (C≡N), 1628m, 1580m, 1537m, 1487s, 1458m, 1389m, 1317m, 1294m, 1275m, 1254m, 1231m, 1192m, 1157m, 1144m, 1099w, 1065w, 1034w, 1022m, 989m, 955w, 928m, 905m, 868m, 843m, 814m, 789m cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 12.25 (s, 1 H, OH), 7.67 (d, J = 1.0 Hz, 1 H, ArH), 7.30–7.25 (m, 2 H, ArH), 7.20 (dd, J = 8.0, 1.0 Hz, 1 H, ArH), 6.97 (d, J = 8.5 Hz, 1 H, ArH), 8.67–8.63 (m, 2 H, ArH), 2.37 (s, 3 H, CH₃). ¹³C NMR (125 MHz, CDCl₃): δ = 158.6 (s), 141.8 (s), 140.6 (s), 135.9 (d), 132.5 (s), 130.4 (d), 130.1 (d), 129.3 (s), 120.4 (d), 118.6 (d), 117.9 (d), 117.1 (s), 116.1 (d), 110.3 (s), 20.5 (q). MALDI-TOF MS: m/z (%) = 252 (100) [M + H]⁺, 225 (75).
• 33 General procedure: A solution of N-(2-aminophenyl)-2-hydroxy-5-methylbenzimidoyl cyanide (12; 30.0 mg, 0.12 mmol) in the appropriate carboxylic acid (3.0 mL) was stirred at the appropriate temperature (Table 1) until complete consumption of the starting material (indicated by TLC). After completion of the reaction, the mixture was poured onto crushed ice and neutralized by careful addition of aqueous NaHCO₃. The aqueous phase was extracted with DCM (4 × 20 mL) and the combined organic extracts were dried (Na₂SO₄), filtered and evaporated. The remaining residue was adsorbed onto silica and purified by chromatography to give the corresponding products.
• 34 Zamet J.-J, Haddadin MJ, Issidorides CH. J. Chem. Soc., Perkin Trans. 1 1974; 1687
• 35 Zaika LL, Joullié MM. J. Heterocycl. Chem. 1966; 3: 444
• 36 Gibson HW. Chem. Rev. 1969; 69: 673
• 37 Cope AC, Martin MM, McKervey MA. Q. Rev., Chem. Soc. 1966; 20: 119
• 38 Evans AG, Price A, Thomas JH. Trans. Faraday Soc. 1955; 51: 481
• 39 Bentley TW, Carter GE, Roberts K. J. Org. Chem. 1984; 49: 5183

For examples of reported biological activities of structurally similar compounds, see:
• 40a Adegboye AA, Khan KM, Salar U, Aboaba SA. Kanwal, Chigurupati S, Fatima I, Taha M, Wadood A, Mohammad JI, Khan H, Perveen S. Eur. J. Med. Chem. 2018; 150: 248
• 40b You L, Cho EJ, Leavitt J, Ma L.-C, Montelione GT, Anslyn EV, Krug RM, Ellington A, Robertus JD. Bioorg. Med. Chem. Lett. 2011; 21: 3007
• 40c Deady LW, Kaye AJ, Finlay GJ, Baguley BC, Denny WA. J. Med. Chem. 1997; 40: 2040