Iodoindazoles with Selective Magnesiation at Position 3: A Route to Highly Functionalized Indazoles

Abstract

A unique route to highly functionalized indazoles is described. A regioselective magnesiation at position 3 of 4-, 5-, 6- and 7-iodo-2-THP-indazoles (THP=tetrahydropyranyl) has been developed using TMPMgCl⋅LiCl (TMP=2,2,6,6-tetramethylpiperidyl). The obtained magnesiate can be trapped by different electrophiles to introduce a wide range of functional groups including halogens, thioalkyls, alcohols, aldehydes, ketones, amides, or esters at position 3. Once this position is functionalized, the iodine atoms can be further reacted through metal-halogen exchange or cross-coupling strategies. Finally, N-substitution reactions allow the synthesis of a variety of highly functionalized indazoles giving access to these valuable scaffolds through a simple and unique route.

Thiofunctionalization of Electron‐Rich Heteroarenes through Magnesiation and Trapping with Octasulfur

“…13 C NMR (100 MHz, Chloroform‐d) δ 138.7, 134.9, 132.9, 130.1, 127.3, 112.2, 85.5, 84.6, 67.5, 29.4, 25.1, 22.5. Data consistent with literature values [32] …”

“…Our study began by reacting several N ‐THP nitrogen containing heterocycles 1 a – g with TMPMgCl ⋅ LiCl, using conditions previously described for iodoindazoles, [32] followed by trapping of the magnesiate with S 8 and 1‐iodopropane (Scheme 2). In a first attempt, N ‐THP‐pyrazole 1 a was metalated under inert atmosphere with 1.5 equiv.…”

Suzuki-Type Cross-Coupling Reaction of Unprotected 3-Iodoindazoles with Pinacol Vinyl Boronate: An Expeditive C-3 Vinylation of Indazoles under Microwave Irradiation

“…In this sense, some reports have used cross-coupling reactions to functionalize the indazole ring as an attractive alternative to cyclization reactions. The most notable works in this area have been performed by Collot et al [ 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. In one of such works, the authors report the synthesis of a C-3 methyl acrylate-substituted indazole ring through a Heck cross-coupling reaction in order to easily obtain azatryptamines [ 18 ].…”

A Predictive Model Towards Site‐Selective Metalations of Functionalized Heterocycles, Arenes, Olefins, and Alkanes using TMPZnCl⋅LiCl

“…A protected indole bearing an aldehyde functional group 3 a was deprotonated in the predicted position (p K a (H1)=29.5, 25 °C, 0.5 h), which led to the desired organozinc 4 a in about 90 % yield . Other indole derivatives, such as pyrazolo[1,5‐ a ]pyridine ( 3 b ), or indazole 3 c were also predicted correctly (p K a (H1)=31.1–32.4), producing zinc organometallics 4 b , c in 80–90 % yield. Also, the p K a values of various purine derivatives ( 3 d – f ) were analyzed, where deprotonation took place in the predicted C8 position within a small p K a range of p K a (H1)=28.2–29.5.…”