Deprotonative Metalation of Chloro‐ and Bromopyridines Using Amido‐Based Bimetallic Species and Regioselectivity‐Computed CH Acidity Relationships

Abstract

A series of chloro- and bromopyridines have been deprotometalated by using a range of 2,2,6,6-tetramethylpiperidino-based mixed lithium-metal combinations. Whereas lithium-zinc and lithium-cadmium bases afforded different mono- and diiodides after subsequent interception with iodine, complete regioselectivities were observed with the corresponding lithium-copper combination, as demonstrated by subsequent trapping with benzoyl chlorides. The obtained selectivities have been discussed in light of the CH acidities of the substrates, determined both in the gas phase and as a solution in THF by using the DFT B3LYP method.

A study on the BF3 directed lithiation of 3-chloro- and 3-bromopyridine

“…18 Also, the treatment of 1b with a mixture of ZnCl 2 $TMEDA and [(TMP)Li] provides a mixture of C-2 and C-4 substituted product. 19 Clearly, different methodologies afford different products depending upon the reaction conditions and the type of the reagents used. A survey of the literature reveals no report on the BF 3 -directed lithiation of 3-chloro-and 3-bromopyridine with LDA and lithium tetramethylpiperidide (LTMP) as the lithiating reagent.…”

Long-range Effect of Bromine in the Deprotonative Metalation of Aromatic Compounds

“…The regioselectivity corresponds to combined acidifying and congesting effects of the bromo groups. [27] A clean C(4) deprotonation of 2,6-dibromopyridine (19a) can be performed by using LiCl-activated hinTa ble 3. Substituent effects on the rates of benzyne formation from ortho-, meta-, and para-substituted bromobenzenes (k rel , relative to bromobenzene for which k rel = 1).…”

Scalable and Straightforward Synthesis of All Isomeric (Cyclo)alkylpiperidines

“…It was found that metalation of 20 with organozinc [49,50] or magnesium agents [51] occurred selectively at the C-2 position of the pyridine ring ( Table 6, Entry 1). It was found that metalation of 20 with organozinc [49,50] or magnesium agents [51] occurred selectively at the C-2 position of the pyridine ring ( Table 6, Entry 1).…”