Synthesis of 2-Arylbenzothiazol-5-amines from N,N-Dialkyl-3-nitroanilines

Abstract

We report a simple method for coupling of N,N-dialkyl-3-nitroarenes, elemental sulfur, and activated sp³ C–H bonds in 2-methylazaarenes or arylacetic acids to afford derivatives of 2-arylbenzothiazol-5-amines. Only DABCO base was required, and many heterocycles such as imidazoles, oxazoles, quinolines, and thiophenes were compatible with the reaction conditions. Our approach offers a simple route to useful substituted thiazol-5-amines from commercially available nitroarenes.

Key words - dialkylnitroanilines - sulfur - benzothiazolamines - heterocycles - multicomponent reaction

Publication History

Received: 14 July 2020

Accepted after revision: 14 August 2020

Article published online:
09 September 2020

• References and Notes

• 1a Ono N. The Nitro Group in Organic Synthesis . Wiley-VCH; New York: 2001
• 1b Mąkosza M, Wojciechowski K. Chem. Rev. 2004; 104: 2631

For selected examples, see:
• 2a Gui J, Pan C.-M, Jin Y, Qin T, Lo JC, Lee BJ, Spergel SH, Mertzman ME, Pitts WJ, La Cruz TE, Schmidt MA, Darvatkar N, Natarajan SR, Baran PS. Science 2015; 348: 886
• 2b Shevlin M, Guan X, Driver TG. ACS Catal. 2017; 7: 5518
• 2c Song H, Yang Z, Tung C.-H, Wang W. ACS Catal. 2020; 10: 276
• 2d Cheung CW, Ma J.-A, Hu X. J. Am. Chem. Soc. 2018; 140: 6789
• 2e Rauser M, Eckert R, Gerbershagen M, Niggemann M. Angew. Chem. Int. Ed. 2019; 58: 6713
• 3a Cadogan JI. G, Cameron-Wood M, Mackie RK, Searle RJ. G. J. Chem. Soc. 1965; 4831
• 3b Nykaza TV, Cooper JC, Li G, Mahieu N, Ramirez A, Luzung MR, Radosevich AT. J. Am. Chem. Soc. 2018; 140: 15200
• 3c Nykaza TV, Li G, Yang J, Luzung MR, Radosevich AT. Angew. Chem. Int. Ed. 2020; 59: 4505
• 4a Sapountzis I, Knochel P. J. Am. Chem. Soc. 2002; 124: 9390
• 4b Gao H, Xu Q.-L, Yousufuddin M, Ess DH, Kürti L. Angew. Chem. Int. Ed. 2014; 53: 2701

For reviews on the use of elemental sulfur in organic synthesis, see:
• 5a Nguyen TB. Adv. Synth. Catal. 2017; 359: 1066
• 5b Liu H, Jiang X. Chem. Asian J. 2013; 8: 2546

For selected examples, see:
• 6a Nguyen TB, Retailleau P. Org. Lett. 2017; 19: 4858
• 6b Guntreddi T, Vanjari R, Singh KN. Org. Lett. 2015; 17: 976
• 7a Do NT, Tran KM, Phan HT, To TA, Nguyen TT, Phan NT. S. Org. Biomol. Chem. 2019; 17: 8987
• 7b Ho TH, Le HH. K, To TA, Nguyen TT, Phan NT. S. Bull. Chem. Soc. Jpn. 2020; 93: 783
• 7c Nguyen TB, Ermolenko L, Al-Mourabit A. Org. Lett. 2013; 15: 4218
• 8 Xing Q, Ma Y, Xie H, Xiao F, Zhang F, Deng G.-J. J. Org. Chem. 2019; 84: 1238
• 9a Patrick DA, Gillespie JR, McQueen J, Hulverson MA, Ranade RM, Creason SA, Herbst ZM, Gelb MH, Buckner FS, Tidwell RR. J. Med. Chem. 2017; 60: 957
• 9b Haile PA, Casillas LN, Votta BJ, Wang GZ, Charnley AK, Dong X, Bury MJ, Romano JJ, Mehlmann JF, King BW, Erhard KF, Hanning CR, Lipshutz DB, Desai BM, Capriotti CA, Schaeffer MC, Berger SB, Mahajan MK, Reilly MA, Nagilla R, Rivera EJ, Sun HH, Kenna JK, Beal AM, Ouellette MT, Kelly M, Stemp G, Convery MA, Vossenkämper A, MacDonald TT, Gough PJ, Bertin J, Marquis RW. J. Med. Chem. 2019; 62: 6482

For a review of drugs containing sulfur-containing functionalities, see:
• 9c Feng M, Tang B, Liang SH, Jiang X. Curr. Top. Med. Chem. (Sharjah, United Arab Emirates) 2016; 16: 1200
• 10 N,N-Dimethyl-2-(6-methylpyridin-2-yl)-1,3-benzothiazol-5-amine (3ab); Typical Procedure An 8 mL screw-cap vial was charged with nitroaniline 1a (0.5 mmol, 83.0 mg), 2,6-dimethylpyridine (2b; 1.0 mmol, 107.0 mg), elemental sulfur (1 mmol, 32 mg), and DABCO (0.375 mmol, 42 mg). The vial was capped, flushed with a strong flow of argon for 5 min, and placed in a preheated bath at 120 °C for 16 h. The mixture was then cooled to r.t. and H₂O (3 mL) was added. The organic components were then extracted into EtOAc (3 × 5 mL). The combined organic extracts were dried (Na₂SO₄), filtered, concentrated in vacuo, and purified by column chromatography [silica gel, hexanes–EtOAc (gradient 20:1 to 3:1)] to give an orange solid; yield: 113.5 mg (84%); mp 127–130 °C; R_f = 0.37 (hexanes–EtOAc, 3:1). ¹H NMR (500 MHz, DMSO-d ₆): d = 8.07 (d, J = 7.5 Hz, 1 H), 7.91–7.85 (m, 2 H), 7.41 (d, J = 7.5 Hz, 1 H), 7.30 (s, 1 H), 7.04 (d, J = 8.5 Hz, 1 H), 2.99 (s, 6 H), 2.57 (s, 3 H). ¹³C NMR (126 MHz, DMSO-d ₆): d = 169.2, 158.4, 155.6, 150.1, 150.0, 137.8, 125.2, 123.2, 122.1, 117.2, 113.7, 105.0, 40.6, 23.9. HRMS (ESI+): m/z [M + H]⁺ calcd for C₁₅H₁₆N₃S⁺: 270.1059; found: 270.1061.
• 11a Emsley J, Griffiths DW, Jayne GJ. J. J. Chem. Soc., Perkin Trans. 1 1979; 228
• 11b Chivers T, Elder PJ. W. Chem. Soc. Rev. 2013; 42: 5996
• 11c Wang M, Dai Z, Jiang X. Nat. Commun. 2019; 10: 2661
• 11d Tan W, Wei J, Jiang X. Org. Lett. 2017; 19: 2166
• 11e Wang M, Fan Q, Jiang X. Org. Lett. 2016; 18: 5756