Homoleptic Zincate‐Promoted Room‐Temperature Halogen–Metal Exchange of Bromopyridines

Abstract

Homoleptic lithium tri- and tetraalkyl zincates were reacted with a set of bromopyridines. Efficient and chemoselective bromine-metal exchanges were realized at room temperature with a substoichiometric amount of nBu(4)ZnLi(2)·TMEDA reagent (1/3 equiv; TMEDA=N,N,N',N'-tetramethylethylenediamine). This reactivity contrasted with that of tBu(4)ZnLi(2)·TMEDA, which was inefficient below one equivalent. DFT calculations allowed us to rationalize the formation of N···Li stabilized polypyridyl zincates in the reaction. The one-pot difunctionalization of dibromopyridines was also realized using the reagent stoichiometrically. The direct creation of C-Zn bonds in bromopyridines enabled us to perform efficient Negishi-type cross-couplings.

Recent Advances of the Halogen–Zinc Exchange Reaction

“…These methodologies were extended to N‐heterocycles (Scheme ) . The more reactive zincate n Bu 4 ZnLi 2 ⋅TMEDA ( 60 ) is used to convert various bromo‐pyridines and ‐quinolines ( 61 – 64 ) to the corresponding lithium zincates.…”

“…[15] These methodologies were extended to N-heterocycles (Scheme 9). [16] The more reactive zincate nBu 4 ZnLi 2 ·TMEDA (60) is used to convert various bromo-pyridines and -quinolines (61-64)t ot he corresponding lithium zincates.A fter quenching with iodine, diphenyl disulfide or 5-bromopyrimidine in the presence of ap alladium catalyst, the functionalized pyridines 65-68 are obtained in 40-75 %y ield. [16] Remarkably,t he halogen-zinc exchange is performed in toluene and substoichiometric exchange reagent (0.33 equiv) is used, demonstrating that three of the four alkyl groups participate in this exchange reaction.…”

“…[16] Remarkably,t he halogen-zinc exchange is performed in toluene and substoichiometric exchange reagent (0.33 equiv) is used, demonstrating that three of the four alkyl groups participate in this exchange reaction. [16] Additionally,z incate reagents are used for the generation of benzynes, which subsequently undergo facile Diels-Alder cycloaddition reactions. [17] Also, zincates may participate in oxovanadium(V)-induced cross-coupling reactions.…”

Review. Regioselective Functionalization of Pyridines using a Directed Metalation or a Halogen/Metal Exchange

“…The use of 0.3 equivalents of the reagent may be sufficient for the exchange. Thus, the treatment of 6-bromo-2-methoxypyridine (73) with tBu 4 ZnLi 2 ·TMEDA provides the desired 2,6-functionalized products in satisfactory yields after reaction with various electrophiles (Scheme 18) [60].…”

Cheap and Easy Synthesis of Highly Functionalized (Het)aryl Iodides via the Aromatic Finkelstein Reaction

“…The disadvantage of this strategy, however, is the possible formation of various side products which usually requires the reaction to be performed at very low temperatures. 2 Instead of various types of butyllithium solutions, lithium alkyl zincates can also be used to perform a bromine-lithium exchange at room temperature; 3 but, also in this case, only compounds which are stable under these strongly basic conditions can be used. Furthermore, alkyl zincates are not commercially available and have to be freshly prepared beforehand.…”