Metal-Free Denitrogenative C–C Couplings of Pyridotriazoles with Boronic Acids To Afford α-Secondary and α-Tertiary Pyridines

Abstract

Pyridotriazoles are utilized as robust building blocks to access α-secondary and α-tertiary pyridines via the development of a simple yet practically useful metal-free denitrogenative C−C crosscoupling with boronic acids. The reaction shows a high level of functional tolerance, broad substrate scope, and facile scalability. The synthetic potential of the method is demonstrated by the strurctural modification of a bioactive molecule and concise synthesis of pheniramine analogs.

Light-induced metal-free transformations of unactivated pyridotriazoles

“…Only 25% of the product was formed without K 2 CO 3 (entry 8), which points on the importance of the base for formation of the reactive triphenylboroxine arylating reagent 7 a . The control experiments indicated no reaction under 455 nm or 427 nm LED irradiating (entries 9 and 10) or under thermal conditions in the absence of light (entry 11) 11. Expectedly, the attempts on employment of pyridotriazoles 1c and 1d , which are transparent in 390 nm region under these reaction conditions failed.…”

Rhodium‐Catalyzed O−H Bond Insertion Reaction between H‐Phosphoryl Compounds and 2‐Pyridyl Carbenes Generated from Pyridotriazoles

“…However, the reaction of 4‐methyl pyridotriazole 1 d took place sluggishly, and produced 3 d in 47% yield after 48 h of heating (Table 2, entry 4). The low reactivity may be attributed to higher activation energy of the ring‐opening process towards diazo species, which has also been observed in the reaction with phenylboronic acid [14] . Notably, halogen atoms Br and Cl were tolerated, as exemplified by the generation of the products 3 f – 3 i in moderate to good yields (Table 2, entries 6–9).…”

“…[a] [a] Unless otherwise noted, a mixture of 1 a (0.2 mmol), 2 a (0.28 mmol) and [Rh 2 ] (1-5 mol%) was heated in dioxane (1 mL) This may be attributed to the high activation energy of the ring-chain equilibrium towards diazo species of these substrates. [14] With respect to H-phosphine oxide, H-posphine oxides 2 b and 2 c bearing electron-donating or electron-withdrawing groups both reacted smoothly to give 3 r and 3 s in high yields (Scheme 2). However, the 2-methylphenyl-substituted substrate 2 d did not give the expected product probably due to the steric effect of this substrate.…”

“…Pyridotriazoles 1 , a class of readily available and thermally stable azacycles, can be regarded as “masked” diazo compounds because they have ring‐chain equilibrium with the corresponding 2‐pyridyl diazo species 1’ in solution (Scheme 1b) [11,12] . Based on this unique property, a variety of denitrogenative transformations of pyridotriazoles have been recently developed, e. g., TM‐catalyzed transannulations with alkynes or nitriles, [13] thermally [14] or photo‐induced [15] C−C couplings with organoboronic acids, and C−H/N−H/Si−H bond insertion reactions and related cascade cyclizations [13a,15,16] . As an interest in developing new reactions towards organophosphorus chemicals, [17,18] we previously communicated the copper‐catalyzed reactions of pyridotriazoles with H‐phosphoryl compounds to afford a new synthesis of phosphorylated pyridines via the formation of C−P bonds, and the reaction produced a picolyl phosphinate in a low yield under aerobic conditions [17] .…”

Recent Advances in Denitrogenative Reactions of Pyridotriazoles

“…Shen and co-workers have developed a metal-, baseand additive-free synthesis of pyridine-containing molecules 111 via cross-coupling reactions of pyridotriazoles 109 with organoboronic acids 110 (Scheme 33). 28 A wide range of alkyl-, aryl-and heteroarylboronic acids as well as 3-unsubstituted and 3-alkyl-substituted pyridotriazoles 109 gave the products 111 in modest to excellent yields. Interestingly, 3-aryl-and 3-CO 2 Et-substituted pyridotriazoles 109 did not work in the reaction.…”