Preparation and Mechanistic Studies of 2‐Substituted Bisthiazolidines by Imine Exchange

Abstract

Bisthiazolidines (BTZ) are bicyclic compounds considered as penicillin analogs that inhibit the full range of Metallo‐β‐Lactamases (MBLs) and potentiate β‐lactam activity against resistant bacteria. Herein, we present a new methodology to prepare 2‐substituted bisthiazolidines by aldehyde exchange. Thirteen new bisthiazolidines were prepared using this methodology, with yields ranging from 31 to 75 %. The reaction is based on in situ imines formation, which are able to exchange side chains. The reaction intermediates were studied based on NMR experiments, and a key imine 1b‐II could be detected in the reaction mixture. Furthermore, a DFT computational analysis was performed to gain insights into the reaction mechanism, allowing us to unveil the different pathways and their activation barriers within the synthetic route. The results suggest that the most favorable route involve the formation of the thiazolidine 1b‐III by i) a N‐assisted N–C bond cleavage, and ii) a thiol‐mediated 5 endo‐trig cyclization followed by a C–N bond cleavage. In contrast with previously reported evidence, the imine metathesis was discarded as a plausible pathway. Finally, the reaction of 1b‐III with aldehyde 2a leads to bicycle 4a via the iminium ion 1b‐V.

Novel Kinetic Resolution of Thiazolo-Benzimidazolines Using MAO Enzymes

“…(3a,4-Dihydro-1H,3H-benzo [4,5]imidazo [1,2-c]thiazol-1yl)methanethiol (2a). Prepared starting from o-phenylenediamine (200 mg, 0.925 mmol) and purified with n-hexanes/ EtOAc 8:2 to give 2a (112 mg, 58%) as a colorless oil: 1 H NMR: δ 6.81 (m, 3H), 6.71 (dd, J = 6.1, 2.6 Hz, 1H), 5.35 (dd, J = 7.5, 5.4 Hz, 1H), 4.98 (dd, J = 8.9, 4.7 Hz, 1H), 4.18 (br, 1H), 3.16 (dd, J = 10.6, 5.4 Hz, 1H), 2.91 (ddd, J = 13.8, 8.9, 6.3 Hz, 1H), 2.83 (dd, J = 10.6, 7.5 Hz, 1H), 2.70 (ddd, J = 13.6, 10.6, 4.7 Hz, 1H), 1.90 (dd, J = 10.6, 6.3 Hz, 1H); 13 (6-Methyl-3a,4-dihydro-1H,3H-benzo [4,5]imidazo [1,2-c]thiazol-1-yl) Methanethiol (4-2c) and (7-Methyl-3a,4-dihydro-1H,3H-benzo [4,5]imidazo [1,2-c]thiazol-1-yl)-methanethiol (5-2c). Prepared starting from 4-methyl-ophenylenediamine (120 mg, 1 mmol) and purified with CH 2 Cl 2 /n-hexanes 1:1 to give a mixture of isomers 4-2c and 5-2c, 0.138 g, 58%, (7:3).…”

“…Prepared starting from 4-nitro-o-phenylenediamine (150 mg, 1 mmol) and purified with n-hexanes/EtOAc 8:2 to give a mixture of isomers 4-2e and 5-2e 0.223 g, 83%, (3:7). H NMR: δ 7.81 (dd, J = 8.5, 2.2 Hz, 1H), 7.58 (d, J = 2.2 Hz, 1H), 6.51 (d, J = 8.5 Hz, 1H), 5.62 (ddd, J = 6.7, 5.1, 1.5 Hz, 1H), 4.97 (dd, J = 8.5, 4.9 Hz, 1H), 4.92 (br, 1H), 3.28 (dd, J = 10.8, 5.2 Hz, 1H), 2.90 (m, 2H), 2.77 (ddd, J = 13.9, 10.2, 4.9 Hz, 1H), 1.87 (dd, J = 10.2, 6.9 Hz, 1H); 13 (6-Fluoro-3a,4-dihydro-1H,3H-benzo [4,5]imidazo [1,2-c]thiazol-1-yl)methanethiol (4-2f) and (7-Fluoro-3a,4-dihydro-1H,3H-benzo [4,5]imidazo [1,2-c]thiazol-1-yl)methanethiol (5-2f). Prepared starting from 4-fluoro-1,2phenylenediamine (126 mg, 1 mmol) and purified with nhexanes/EtOAc 8:2 to give a mixture of isomers 4-2f and 5-2f, 0.182 g, 75%, (7:3).…”

“…4-2g: 109.2 mg; 36%, white solid; mp 146−152 °C; 1 H NMR: δ 6.90 (dd, J = 8.1, 1.8 Hz, 1H), 6.75 (d, J = 1.8 Hz, 1H), 6.63 (d, J = 8.1 Hz, 1H), 5.37 (dd, J = 7.1, 5.4 Hz, 1H), 4.88 (dd, J = 8.9, 4.6 Hz, 1H), 4.26 (br, 1H), 3.17 (dd, J = 10.7, 5.3 Hz, 1H), 2.87 (ddd, J = 13.0, 8.5, 6.0 Hz, 1H), 2.82 (dd, J = 10.8, 7.2 Hz, 1H), 2.68 (ddd, J = 13.7, 10.5, 4.7 Hz, 1H), 1.87 (dd, J = 10.5, 6.4 Hz, 1H); 13 5-2g: 57.6 mg; 19%; white solid; mp 102−105 °C; 1 H NMR: δ 6.88 (m, 2H), 6.52 (m, 1H), 5.37 (dd, J = 7.5, 5.4 Hz, 1H), 4.89 (dd, J = 8.9, 4.6 Hz, 1H), 4.17 (br, 1H), 3.16 (dd, J = 10.7, 5.3 Hz, 1H), 2.88 (ddd, J = 14.1, 9.1, 6.6 Hz, 1H), 2.82 (dd, J = 10.7, 7.6 Hz, 1H), 2.69 (ddd, J = 13.8, 10.6, 4.6 Hz, 1H), 1.86 (dd, J = 10.5, 6.5 Hz, 1H); 13 C NMR: δ 142. 4, 137.5, 124.3, 113.7, 113.1, 112.5, 83.5, 71.2, 38.9, 33.7 Synthesis of S-(((1R,3aR)-3a,4-Dihydro-1H,3H-benzo [4,5]imidazo [1,2-c]thiazol-1-yl)methyl) 4-Chlorobenzothioate (7).…”

“…Similarly, in this work, we prepare new 1 H ,3 H -thiazolo­[3,4- a ]­benzimidazolines TBIM 2 starting from 1,2-diaminoanilines and dithiane, Figure . These heterocycles are obtained as a racemic mixture of the syn diastereomer as the main product, bearing both substituents on the same side of the bicycle plane …”

“…d, J = 8.5 Hz, 2H), 5.54 (t, J = 6.0 Hz, 1H), 4.99 (dd, J = 8.8, 4.6 Hz, 1H), 4.59 (br, 1H), 3.22 (dd, J = 10.6, 5.2 Hz, 1H), 2.90 (dt, J = 8.8, 7.0 Hz, 1H), 2.84 (dd, J = 10.6, 7.9 Hz, 1H), 2.75 (ddd, J = 14.0, 10.5, 4.6 Hz, 1H), 1.83 (dd, J = 10.5, 6.8 Hz, 1H);13 C NMR: δ 146.0, 142.6, 138.9, 119.5, 107.3, 105.0, 83.4, 69.4, 38.9, 33.4; IR (NaCl) ν: 1603, 1489, 1447, 1400, 1364, 1317, 1281, 1130, 1072, 858, 741 cm −1 ; HRMS (ESI)…”