Regiocomplementary Cycloaddition Reactions of Boryl- and Silylbenzynes with 1,3-Dipoles: Selective Synthesis of Benzo-Fused Azole Derivatives

Abstract

Benzo-fused nitrogen-containing heterocycles are abundant in biologically active compounds. One of the most important methods for preparing such heterocycles is the (3 + 2) cycloaddition reaction of benzynes with 1,3-dipolar compounds. However, the reactions of unsymmetrically substituted benzynes generally show low selectivity and hence yield mixtures of two regioisomers. In this paper, we describe the synthesis of both regioisomers of multisubstituted benzo-fused azole derivatives such as benzotriazoles, 1H-indazoles, and benzo[d]isoxazoles through the regiocomplementary (3 + 2) cycloaddition reactions of 3-boryl- and 3-silylbenzynes with 1,3-dipoles. The improved generation of 3-borylbenzynes from new precursors was one of the most important results of this work, which produced the successful (3 + 2) cycloaddition reactions with exclusive and proximal selectivities. On the other hand, similar reactions of 3-silylbenzynes selectively afforded distal cycloadducts. Analysis of the reaction pathways of these amazing regioselectivities by density functional theory calculations revealed that the (3 + 2) cycloadditions of borylbenzynes are controlled by the electrostatic effect of the boryl group, while those of silylbenzynes are controlled mainly by the steric effect of the bulky silyl groups that produced electrostatically unfavorable adducts via anomalous transition states.

Iridium‐Catalyzed Intermolecular Azide–Alkyne Cycloaddition of Internal Thioalkynes under Mild Conditions

“…As a result, most intermolecular AACs of internal alkynes require high temperatures [8] and/or activated substrates, such as electrondeficient alkynes (e.g., haloalkynes) [9,10] or strained alkynes (e.g., cyclooctynes). [11] Mild and regioselective AACs of electron-rich internal alkynes are scarce. While the advent of ruthenium-based catalytic systems (RuAAC) has addressed the challenge to some extent, [12] additional robust catalytic systems complementary to CuAAC and RuAAC remain in high demand.…”

Microflow Fluorinations of Benzynes: Efficient Synthesis of Fluoroaromatic Compounds

“…In these cases, the reactive sites of the benzynes were completely controlled by the electron-withdrawing and electron-donating inductive effects of the C3-alkoxy and C3-boryl group, respectively. [68][69][70][71][72][73][74][75][76][77][78] The fluorination of 3-(tert-butyldimethylsilyl) benzyne 4f gave a mixture of meta-1f and ortho-1f in a 6.4 : 1 ratio under both batch and flow conditions (Entry 5). In this case, the regiochemistry is believed to be mainly controlled by the steric bulkiness of the C3-silyl group of 4f.…”

Synthesis of Distorted 1,8,13‐Trisilyl‐9‐hydroxytriptycenes by Triple Cycloaddition of Ynolates to 3‐Silylbenzynes

“…The regioselectivity of the addition of the ynolate and other nucleophiles to 3‐silylbenzyne can be elucidated by the steric effect rather than −I effect, according to Tokiwa and Akai . The sterically bulky nucleophiles tended to attack at C1, while C2 became electronically positive owing to its silicon substituent.…”

“…The regioselectivity of the addition of the ynolatea nd other nucleophiles to 3-silylbenzyne can be elucidated by the steric effect rather than ÀIe ffect, according to To kiwa and Akai. [19] The sterically bulky nucleophilest ended to attack at C1, while C2 became electronically positive owing to its silicon substituent. However, secondaryo rbitali nteractions and/or SiÀO( ynolate) interactions could not be dismissed because stronger driving forces should be ap rerequisite for producing these highly distorted products with high regioselectivity.…”