Regioselective zincation of indazoles using TMP2Zn and Negishi cross-coupling with aryl and heteroaryl iodides

Abstract

The metalation of various SEM-protected functionalized indazoles with TMP 2 Zn provides 3-zincated indazoles which undergo palladium-catalyzed Negishi cross-couplings in good yields.

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

“…However, in the case of direct metalation at position 3 of 1‐substituted indazoles, ring‐opening issues remain a strong limitation . Recently, two methods in the literature describing the selective functionalization of substituted indazoles at position 3 using direct metalation reactions have attracted our attention . First, Yu reported the selective 3‐arylation of 1‐methyl or 1‐THP indazoles by palladium‐catalyzed C−H activation (Figure A) .…”

“…Second, using TMP 2 Zn as a base, Knochel was able to selectively deprotonate diversely substituted N‐protected indazoles at position 3. Therefore, the obtained organozinc intermediates were further transmetalated with palladium and used in a Negishi cross‐coupling reaction or with copper and reacted with acyl chlorides or allylbromides to give 3‐arylated, ‐acylated or ‐alkylated indazoles, respectively (Figure B) …”

“…[36,37] Recently,t wo methods in the literature describing the selectivef unctionalization of substituted indazoles at position 3u sing direct metalation reactionsh ave attractedo ur attention. [38,39] First, Yu reported the selective3 -arylation of 1-methyl or 1-THP indazoles by palladium-catalyzed CÀHa ctivation( Figure 1A). [38] Although this strategy allows the use of substituted indazoles in position4 ,5 ,6 ,a nd 7, it remainsr estricted to functionalizationw ith aromatic groups.…”

“…Second, using TMP 2 Zn as abase, Knochel wasable to selectively deprotonate diversely substituted N-protected indazoles at position3 .T herefore,t he obtained organozinc intermediates were further transmetalated with palladium and used in aN egishi cross-couplingr eaction or with coppera nd reactedw ith acyl chlorides or allylbromides to give 3-arylated, -acylated or -alkylated indazoles, respectively ( Figure 1B). [39] Ta king into account these latter results, we were interested in extending the scope of thesem etalation strategiest of urther functionalize position3a nd promote higher molecular diversity in the other positions ( Figure 2). For this purpose, in this work, we decided to investigate the selectivem etalation of iodo-N-THP-indazoles followed by electrophilic trapping.…”

Metal‐Free Regioselective Dual C‐H Functionalization in a Cascade Fashion: Access to Isocryptolepine Alkaloid Analogues

“…Despite, lithiation or magnesiation have been reported which involve haloindazoles and drastic conditions; moreover these reactions are demanding owing to the facile fragmentation of these heterocycles leading to aminonitriles . Furthermore, zincated indazoles have been employed in traditional transition metal‐catalyzed cross‐coupling reaction to provide C3‐functionalized indazoles …”