A One-Pot Synthesis of Disubstituted Thiazoles from Chalcone C–H Bonds, Elemental Sulfur, and Glycine Ethyl Ester

Abstract

A method for assembling chalcones, glycine ethyl ester hydrochloride, and elemental sulfur toward a synthesis of 4,5-disubstituted thiazoles is reported. The transformation presumably proceeds via a sequence of β-C–H amination, annulation, and dealkoxycarbonylation. This tactic represents a rare example of a method for obtaining such disubstituted thiazoles directly from chalcone C–H bonds.

Key words

C–H bond functionalization - enaminones - sulfur - thiazoles - annulation

Publication History

Received: 05 September 2021

Accepted after revision: 28 January 2022

Article published online:
21 February 2022

• References and Notes


For recent reviews, see:
• 1a Liu S, Deng G.-J, Huang H. Synlett 2021; 32: 142
• 1b Nguyen TB. Adv. Synth. Catal. 2020; 362: 3448
• 1c Sundaravelu N, Sangeetha S, Sekar G. Org. Biomol. Chem. 2021; 19: 1459
• 2a Wang X, Qiu X, Wei J, Liu J, Song S, Wang W, Jiao N. Org. Lett. 2018; 20: 2632
• 2b Zhang B, Liu D, Sun Y, Zhang Y, Feng J, Yu F. Org. Lett. 2021; 23: 3076
• 2c Xu Z, Huang H, Chen H, Deng G.-J. Org. Chem. Front. 2019; 6: 3060
• 2d Wu M, Jiang Y, An Z, Qi Z, Yan R. Adv. Synth. Catal. 2018; 360: 4236
• 2e Jiang J, Huang H, Deng G.-J. Green Chem. 2019; 21: 986
• 2f Wang K, Jia Z, Bai Y, Wang X, Hodgkiss SE, Chen L, Chong SY, Wang X, Yang H, Xu Y, Feng F, Ward JW, Cooper AI. J. Am. Chem. Soc. 2020; 142: 11131
• 2g Zhu X, Yang Y, Xiao G, Song J, Liang Y, Deng G. Chem. Commun. 2017; 53: 11917
• 2h Zhang J, Zhao X, Liu P, Sun P. J. Org. Chem. 2019; 84: 12596
• 2i Fu R.-G, Wang Y, Xia F, Zhang H.-L, Sun Y, Yang D.-W, Wang Y.-W, Yin P. J. Org. Chem. 2019; 84: 12237
• 2j Németh AG, Marlok BM, Domján A, Gao Q, Han X, Keserű GM, Ábrányi-Balogh P. Eur. J. Org. Chem. 2021; 3587
• 2k Ma X, Yu X, Huang H, Zhou Y, Song Q. Org. Lett. 2020; 22: 5284
• 2l Lin M, Wang Z, Fang H, Liu L, Yin H, Yan C.-H, Fu X. RSC Adv. 2016; 6: 10861

For recent discussions, see:
• 3a Gehrke S, Hollóczki O. Chem. Eur. J. 2020; 26: 10140
• 3b Pareek M, Reddi Y, Sunoj RB. Chem. Sci. 2021; 12: 7973
• 4a Gao Y, Wei L, Liu Y, Wan J.-P. Org. Biomol. Chem. 2017; 15: 4631
• 4b Gan L, Gao Y, Wei L, Wan J.-P. J. Org. Chem. 2019; 84: 1064
• 4c Nguyen KX, Pham PH, Nguyen TT, Yang C.-H, Pham HT. B, Nguyen TT, Wang H, Phan NT. S. Org. Lett. 2020; 22: 9751 ; See also refs 2b, 2d, 2i, and 2k.
• 5 See the Supporting Information for more details of the optimization toward the synthesis of enaminone 3aa and thiazole 4aa.
• 6 [2-(Benzyloxy)phenyl][4-(4-tolyl)-1,3-thiazol-5-yl]methanone (4ma); Typical Procedure An 8-mL vial equipped with a magnetic stirrer bar was charged with glycine ethyl ester hydrochloride 2a (0.3 mmol, 41.8 mg), Na₂CO₃ (0.33 mmol, 35 mg), and DMSO (0.5 mL), and the mixture was stirred at r.t. for 10 min. Elemental sulfur (0.5 mmol, 16 mg) and chalcone 1m (0.1 mmol, 31.4 mg) were added, and the mixture was heated to 40 ℃ for 12 h then cooled to r.t. Additional DMSO (0.5 mL) was added and the mixture was heated at 140 ℃ for 5 h. When the reaction was complete, the crude mixture was diluted with a mixture of H₂O and EtOAc. Extraction followed by drying (Na₂SO₄), filtration, and concentration afforded a crude product that was purified by column chromatography (silica gel, hexanes–EtOAc) to give a brown oil; yield: 24.5 mg (32%). ¹H NMR (500 MHz, CDCl₃): δ = 8.90 (s, 1 H), 7.50 (dd, J = 7.6, 1.7 Hz, 1 H), 7.33–7.26 (m, 6 H, overlapping with CHCl₃ signal), 7.11–7.05 (m, 2 H), 6.94 (dt, J = 7.4, 3.5 Hz, 3 H), 6.64 (d, J = 8.3 Hz, 1 H), 4.79 (s, 2 H), 2.28 (s, 3 H). ¹³C NMR (126 MHz, CDCl₃): δ = 188.6, 158.3, 156.5, 155.2, 138.7, 136.1, 134.4, 133.0, 130.62, 130.55, 129.4, 128.6, 128.4, 128.2, 127.8, 126.5, 120.7, 111.9, 69.8, 21.3. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₄H₂₀NO₂S⁺: 386.1209; found: 386.1223.