Synthesis of 2-Cyanobenzothiazoles via Pd-Catalyzed/Cu-Assisted C-H Functionalization/Intramolecular C-S Bond Formation from N-Arylcyanothioformamides

Abstract

We report herein on a catalytic system involving palladium and copper to achieve the cyclization of N-arylcyanothioformamides and the synthesis of 2-cyanobenzothiazoles. The C-H functionalization/intramolecular C-S bond formation reaction was achieved in the presence of air, using 2.0 equiv of an inorganic additive (KI). In many cases, the reaction led to a sole product regioselectively obtained in good yields, allowing the synthesis of a wide range of substituted 2-cyanobenzothiazole derivatives, providing valuable building blocks for the design of more complex heterocyclic or molecular labeling systems.

Synthesis of Trifunctional Thiazole-Fused Anthranilonitrile and Anthranilic Acid Derivatives

“…Moreover, whatever the additive (KI or LiBr), the cyclization process is more efficient when the free aromatic amine and the attracting group (CO 2 Me or CN) present on the reactant are located at meta - and para -positions relative to the cyanothioformamide group, respectively (e.g., 3b and 3d ). According to the mechanism proposed in our previous study, 8 this can favor formation of the Cu(I) thioamidate and the intermediate palladacycle before reductive elimination and generation of the 2-cyanobenzothiazole ring.…”

“…3b and 3d). According the mechanism proposed in our previous study, 8 it can favour the formation of the Cu (I) thioamidate and the intermediate palladacycle before reductive elimination and generation of the 2-cyanobenzothiazole ring.…”

“…Paper / PSP / Special Topic Template for SYNTHESIS Thieme To achieve the envisioned synthesis of the target compounds it appeared necessary to first prepare the Narylcyanothioformamides 3a-d before achieving the fusion of the thiazole ring on the benzenic part (Figure 1). 8 Methyl 4-or 5amino-2-[di(tert-butoxycarbonyl)amino] benzoates (1a-d) were reacted with Appel salt (1.1 equiv) in the presence of pyridine (2.0 equiv) in dichloromethane (0.3 M), at room temperature. After 1h of stirring, trifluoroacetic acid (15.0 equiv) was added and the resulting mixture was stirred again overnight at room temperature to yield the N-deprotected methyl-2-amino-5-or 4-[(4-chloro-5H-1,2,3-dithiazol-5-ylidene) amino]benzoates (2a and 2b) in 95 % and 87% yields, respectively.…”

“…9,11 This disappointing result led us to optimize the reaction conditions and to test inorganic additives that previously allowed the synthesis of 2-cyanobenzothiazoles in yields close to those obtained with KI. 8 Table 2 reports our results with 2 equivalents of KBr, LiI and LiBr as additives. The quantities of the other reactants and solvent proportions remained unchanged (see Table 2, entries 2-4).…”

“…Recently, we described a Pd-catalyzed/Cu-assisted reaction to achieve the synthesis of 2-cyanobenzothiazoles via C–H functionalization/intramolecular C–S bond formation of N -arylcyanothioformamides derived from the corresponding N -arylimino-1,2,3-dithiazoles (see bottom part of Scheme 1 ). 8 The cyclization was efficiently achieved in the presence of air and 2 equivalents of an inorganic additive (KI). Under these conditions, cyanothioformanilides bearing halogen, alkyl or ether groups at positions C3 and C4 regioselectively provided the corresponding 5,6-disubstituted 2-cyanobenzothiazoles.…”