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

• Published in: Chemistry : a European journal 2016-03, Vol.22 (13), p.4440-4446
• Main Authors: Lam, Bao Vy, Berhault, Yohann, Stiebing, Silvia, Fossey, Christine, Cailly, Thomas, Collot, Valérie, Fabis, Frédéric
• Format: Article
• Language: English
• Subjects: Alcohols; Aldehydes; Amides; Chemical Sciences; Chemical synthesis; Chemistry; Coupling; Cross coupling; Esters; Exchanging; Functional anatomy; Functional groups; Halogens; heterocycles; Iodine; Ketones; magnesium; metalation; Metals; Organic chemistry; regioselectivity; Scaffolds; Substitution reactions; synthetic methods
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.201504828

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. A selective magnesiation at position 3 of iodo‐2‐THP‐indazole isomers has been developed by using TMPMgCl⋅LiCl (TMP=2,2,6,6‐tetramethylpiperidyl). The obtained magnesiate can be trapped by different electrophiles. Further functionalizations of the iodine atom followed by N‐substitution led to highly functionalized indazoles through a unique route (see scheme; THP=tetrahydropyranyl).