Facile synthesis of 1-alkoxy-1H-benzo- and 7-azabenzotriazoles from peptide coupling agents, mechanistic studies, and synthetic applications

Abstract

Summary(1H-Benzo[d][1,2,3]triazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzo[d][1,2,3]triazol-1-yl 4-methylbenzenesulfonate (Bt-OTs), and 3H-[1,2,3]triazolo[4,5-b]pyridine-3-yl 4-methylbenzenesulfonate (At-OTs) are classically utilized in peptide synthesis for amide-bond formation. However, a previously undescribed reaction of these compounds with alcohols in the presence of a base, leads to 1-alkoxy-1H-benzo- (Bt-OR) and 7-azabenzotriazoles (At-OR). Although BOP undergoes reactions with alcohols to furnish 1-alkoxy-1H-benzotriazoles, Bt-OTs proved to be superior. Both, primary and secondary alcohols undergo reaction under generally mild reaction conditions. Correspondingly, 1-alkoxy-1H-7-azabenzotriazoles were synthesized from At-OTs. Mechanistically, there are three pathways by which these peptide-coupling agents can react with alcohols. From 31P{1H}, [18O]-labeling, and other chemical experiments, phosphonium and tosylate derivatives of alcohols seem to be intermediates. These then react with BtO− and AtO− produced in situ. In order to demonstrate broader utility, this novel reaction has been used to prepare a series of acyclic nucleoside-like compounds. Because BtO− is a nucleofuge, several Bt-OCH2Ar substrates have been evaluated in nucleophilic substitution reactions. Finally, the possible formation of Pd π–allyl complexes by departure of BtO− has been queried. Thus, alpha-allylation of three cyclic ketones was evaluated with 1-(cinnamyloxy)-1H-benzo[d][1,2,3]triazole, via in situ formation of pyrrolidine enamines and Pd catalysis.

Facile functionalization at the C4 position of pyrimidine nucleosides via amide group activation with (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and biological evaluations of the products

“…Although Cs 2 CO 3 was used previously, DBU was also effective and was used here, and good yields were obtained. In reactions with MeOH, allyl alcohol, and benzyl alcohol, 1-alkoxy-1 H -benzotriazoles 51 were observed to be byproducts (8–20%).…”

Diarylmethanes through an Unprecedented Palladium‐Catalyzed C−C Cross‐Coupling of 1‐(Aryl)methoxy‐1 H‐Benzotriazoles with Arylboronic Acids

“…One is an attempted decarboxylative Heck reaction of the benzoate ester of HOBt with styrene, which gave a 25 % yield of 1,2 and 1,1 Heck arylation products . The other is a Pd‐mediated α‐allylation of ketones using the cinnamyl ether of BtOH (PhCH=CHCH 2 OBt) . The latter indicated the plausible formation of π‐allyl Pd complexes, which led us to consider Pd‐mediated C−C bond‐forming reactions of 1‐(aryl)methoxy‐1 H ‐benzotriazoles.…”

“…We have investigated benzotriazole‐based peptide coupling agents for nucleoside functionalization and other synthetic applications . In this context, we showed that 1‐alkoxy‐1 H ‐benzotriazoles (RCH(R′)OBt) are formed readily in reactions of alcohols with 1 H ‐benzotriazol‐1‐yl‐4‐methylbenzenesulfonate (BtOTs) and (1 H ‐benzotriazol‐1‐yloxy)tris(dimethylaminophosphonium) hexafluorophosphate (BOP) . Herein, we disclose the previously unknown reactivity of 1‐(aryl)methoxy‐1 H ‐ benzotriazoles in which a benzylic benzotriazolyloxy group acts as a nucleofuge in Pd‐mediated C −C cross‐couplings (Scheme ).…”

Facile Modifications at the C4 Position of Pyrimidine Nucleosides via In Situ Amide Activation with 1H‐Benzotriazol‐1‐yloxy‐tris(dimethyl‐amino)phosphonium Hexafluorophosphate

“…The reactions conducted via this approach were complete in shorter reaction times and produced higher yields as compared to the results of the two‐step, one‐pot approach. Only amines and thiols were tested, and because alcohols are known to react with BOP in the presence of base to produce the corresponding benzotriazol‐1‐yl ethers, they were not tested (Lakshman et al., ). This was further supported by observations that in the reaction with alcohols, small amounts of benzotriazol‐1‐yl ethers were isolated in the two‐step, one‐pot approach.…”

“…As in Basic Protocol 1, several alkyl and aryl amines and thiols were tested as nucleophiles in Basic Protocol 2. However, alcohols were not tested in this protocol, as they tend to react with BOP, and lead to the formation of corresponding benzotriazolyl ethers (Lakshman et al., ).…”