Halogen–lithium exchange between substituted dihalobenzenes and butyllithium: application to the regioselective synthesis of functionalized bromobenzaldehydes

Long‐Range Effects in the Metalation/Boronation of Functionalized 1,4‐Dihalobenzenes

“…This shows that the long-range inductive effect of fluorine is significantly stronger than that of oxygen, which is in line with the lithiation results of isomeric 1,2-dibromo-4-fluoro-5-methoxybenzene by means of Li/Br exchange. [21] For comparison, nBuLi/THF slowly deprotonates the parent 2-fluoroanisole ortho to the methoxy group, whereas a selective metalation ortho to fluorine requires a superbase such as nBuLi premixed with PMDTA or KOtBu. [22] The Impact of Buttressing Effects…”

“…All starting materials: 2,5-dihalophenols, 2,5-dibromoanisole, 2,5-dihalobenzaldehydes, 3,6-dibromo-2-fluorophenylboronic acid, and other important reagents including hexamethyldisilazane HN(SiMe 3 ) 2 , dimethyl sulfate, trimethyl orthoformate, diisopropylamine, n-butyllithium (10  solution in hexanes), triethyl and triisopropyl borates were received from Aldrich. 2,5-Difluoroanisole, [11] 2,5-dichloroanisole, [30] 1,4-dichloro-2-(dimethoxymethyl)benzene, [31] 1,4-dibromo-2-(dimeth-oxymethyl)benzene, [21] 1,4-dibromo-2-(dimethoxymethyl)-3-fluorobenzene [21] have been prepared according to literature procedures. The NMR chemical shifts are given relative to TMS using known chemical shifts of residual proton ( 1 H) or carbon ( 13 C) solvent resonances.…”

Halogen – metal exchange of 3‐substituted 1,2‐dibromoarenes: the use of long‐range JCH coupling constants to determine regiochemistry

“…In the course of our study of halogen/metal exchange reactions of 3-substituted 1,2-dibromoarenes with Grignard reagents, we found that isopropylmagnesiumchloride (iPrMgCl) 1 had a clear advantage over the more commonly used n-butyl lithium (nBuLi) 2,3 in providing high assay yield, thermal stability and site selectivity. A series of 3-substituted 1,2-dibromobenzene analogs were prepared to examine the effect of R-group substitution on regioselectivity in the transmetalation.…”

Selective Halogen-Lithium Exchange of 1,2-Dihaloarenes for Successive [2+4] Cycloadditions of Arynes and Isobenzofurans

“…The key to achieve this sequential process is search for a suitable aryne precursor to enable the selective halogen-lithium exchange [27][28][29][30]. Along these lines, we select 1,2-dihaloarenes as an aryne precursor and expect that controlling the reactivity of the halogen would be possible by taking advantage of the following two features: (1) utilization of the more electropositive halogen (type 1); or (2) tuning the reactivity of halogen by the adjacent halogen (type 2) as shown in Scheme 3.…”