The Disappearing Director: The Case of Directed N‐Arylation via a Removable Hydroxyl Group

Abstract

A facile and broadly applicable method for the regiospecific N-arylation of benzotriazoles is reported. Copper-mediated reactions of diverse 1-hydroxy-1H-benzotriazoles with aryl boronic acids lead to 1-aryl-1H-benzotriazole 3-oxides. A N1-OH → N3 prototropy in the 1-hydroxy-1H-benzotriazoles is plausibly the underlying basis, where the tautomer is captured by the boronic acid, leading to C–N (not C–O) bond formation. Because the N–O bond in amine N-oxides and 1-hydroxy-1H-benzotriazoles can be easily reduced by diboron reagents such as (pinB)2 and B2(OH)4, exposure of the 1-aryl-1H-benzotriazole 3-oxides to B2(OH)4 then leads to facile reduction of the N–O bond resulting in diverse, regiospecifically-arylated benzotriazoles. Thus, the N-hydroxyl group in 1-hydroxy-1H-benzotriazoles acts as a disposable arylation director.

Base Modifications of Nucleosides via the Use of Peptide‐Coupling Agents, and Beyond

“…By contrast, the N ‐oxide 107 was observed in reaction mixtures. We did prove that this was the N ‐oxide by reducing it to the benzotriazolyl derivative 108 with B 2 (OH) 4 in MeCN, at 60 °C [44,74] …”

“…This work led to our later efforts on the use of diboron reactions for reduction of amine N-oxides, [42] the synthesis of benzotriazoles from 1hydroxybenzotriazoles, [43] and a regiospecific N-arylation of benzotriazoles. [44] In the context of this Account, as described later, (pinB) 2 was also central to the synthesis of diverse C6 benzotriazolyl nucleosides. In that later work we probed the mechanism for the formation of compound 10.…”

“…We did prove that this was the N-oxide by reducing it to the benzotriazolyl derivative 108 with B 2 (OH) 4 in MeCN, at 60 °C. [44,74] We then assessed the mechanism via which the O 4benzotriazolyl ether 98 may be formed. As with the purines, the reaction of precursor 97 with BOP and DBU in CD 3 CN was monitored by 31 P{ 1 H} NMR.…”

“…The potential tautomerism of 1-hydroxybenzotriazoles led us to hypothesize that the N-oxide form, even if very minor, could be trapped with aryl boronic acids in a Cu-catalyzed C-C bond-forming reaction. [44] Thus, an approach that combines easy synthesis of 1-hydroxybenzotriazoles, Cu-catalyzed Narylation, and facile reduction, would yield a new and facile regiospecific N-arylation of benzotriazoles. Synthesis of N-aryl As hypothesized, after some optimizations, we found that 1-hydroxybenzotriazoles could be arylated at the remote N3 atom (Scheme 35).…”

Copper-Promoted One-Pot Sandmeyer-Type Reaction for the Synthesis of N-Aryltriazoles

“…13 Ethyl 3-(1H-benzotriazole-1-yl)benzoate (3pd). 38 Yellow oil, 82.9 mg, 62% yield; 1 H NMR (600 MHz, Chloroform-d) δ = 8.48 (s, 1H), 8.19 (d, J = 7.9, 2H), 8.03 (d, J = 7.9, 1H), 7.83 (d, J = 6.3, 1H), 7.71 (t, J = 7.9, 1H), 7.61−7.57 (m, 1H), 7.47 (t, J = 7.4, 1H), 4.45 (q, J = 7.1, 2H), 1.43 (t, J = 7.1, 3H). 13 39 Yellow oil, 124.2 mg, 87% yield; 1 H NMR (600 MHz, Chloroform-d) δ = 8.16 (d, J = 8.4, 1H), 7.74 (d, J = 8.3, 1H), 7.57 (t, J = 7.6, 1H), 7.45 (t, J = 7.6, 1H), 6.99 (s, 2H), 3.94 (d, J = 6.9, 9H).…”