Accessing Heteroannular Benzoxazole and Benzimidazole Scaffolds via Carbodiimides Using Azide–Isocyanide Cross-Coupling as Catalyzed by Mesoionic Singlet Palladium Carbene Complexes Derived from a Phenothiazine Moiety

Abstract

The coupling of aryl and aliphatic azides with isocyanides yielding carbodiimides (8–17) were efficiently catalyzed by well-defined structurally characterized trans-(MIC)PdI2(L) [MIC = 1-CH2Ph-3-Me-4-(CH2N(C6H4)2S)-1,2,3-triazol-5-ylidene, L = NC5H5 (4), MesNC (5)], trans-(MIC)2PdI2 (6), and cis-(MIC)Pd(PPh3)I2 (7) type palladium complexes, which incidentally mark the first instances of the use of mesoionic singlet palladium carbene complexes for the said application. As observed from the product yields, the catalytic activity varied in the order 4 > 5 ∼ 6 > 7 for these complexes. A detailed mechanistic studies indicated that the catalysis proceeded via a palladium(0) (4a–7 a) species. Using a representative palladium precatalyst (4), the azide–isocyanide coupling was successfully extended to synthesizing two different bioactive heteroannular benzoxazole (18–22) and benzimidazole (23–27) derivatives, thereby broadening the scope of the catalytic application.

Assessment of Sulfur Impurities in GMP-Grade Diisopropylcarbodiimide and Their Impact on Coupling Reagent-Induced Side Reactions in Peptide Synthesis

“…Importantly, prompted by this study, efficient means of suppressing the H–CN formation by reaction engineering H–CN scavenging and/or solvent engineering as well as by replacing DIC with TBEC , have been developed. Overall, DIC is nowadays recognized as a universally used CR for ABF (Figure a), and while carbodiimides can be synthesized by a wide variety of methods, , a part of the broad appeal of using DIC in particular is that industrially it is manufactured in a highly scalable and cost-efficient manner by condensation of isopropylamine and i Pr-NCS, which also stems from isopropylamine, followed by a facile dehydrosulfurization of the resulting DITU to furnish the CR (Figure b) . With regards to using DIC in peptide synthesis, we have recently reported that this CR contains a varying amount of sulfur, and that the main S-containing impurity is the thiourea DITU, an intermediate in the route of synthesis (RoS) of DIC .…”

Elevating 1-tert-Butyl-3-ethylcarbodiimide (TBEC) as a Reagent for Sustainable Peptide Synthesis: Quality Assessment and Minimizing Racemization, Precipitation, and Radical-Induced Side Reactions by TBEC/Oxyma Couplings in an Environmentally Sensible Solvent

“…From the standpoint of cost and sustainability, CDIs are particularly attractive due to the simplicity of their RoS from bulk chemicals, facilitating an affordable supply of CDIs on an industrial scale. Specifically, despite the various approaches for the synthesis of CDIs in the literature, , industrially, CDIs are manufactured practically exclusively by the condensation of an amine with an isothiocyanate followed by dehydrosulfurization (Figure a) . In fact, as isothiocyanates are also made from amines by a reaction with CS 2 , the entire synthesis of CDIs can be accomplished in a practical and atom-efficient manner starting from one or two amines.…”