In the footsteps of Victor Grignard: The simple LiCl‐mediated insertion of magnesium into aryl chlorides and bromides at moderate temperatures leads to functionalized organomagnesium reagents (see scheme). An unprecedented range of functional groups may be present in the substrates (e.g. CN, CO2R, OTs, OBoc; Ts=p‐toluenesulfonyl, Boc=tert‐butylcarbonyloxy).

The presence of LiCl considerably facilitates the insertion of magnesium into various aromatic and heterocyclic bromides. Several functional groups, such as -OBoc, -OTs, -Cl, -F, -CF(3), -OMe, -NMe(2), and -N(2)NR(2), are well tolerated. The presence of a cyano group leads in some cases to competitive reduction of the organic halide to the corresponding ArH compound. The presence of sensitive groups such as methyl or ethyl ester is tolerated upon in situ trapping of the intermediate magnesium reagent with ZnCl(2). This method can also be applied to the preparation of functionalized benzylic zinc reagents from benzylic chlorides. In the case of di- or tribromoaryl derivatives, directing groups such as -OPiv, -OTs, -N(2)NR(2), or -OAc orient the zinc insertion (Zn/LiCl) to the ortho-position, while the reaction with Mg/LiCl or Mg/LiCl/ZnCl(2) leads to regioselective insertion into the para-carbon-bromine bond. Large-scale experiments (20-100 mmol) for all of the metalation procedures are described.

Benzylic zinc chlorides bearing various functional groups are smoothly prepared by the direct insertion of magnesium into benzylic chlorides in the presence of LiCl and ZnCl(2).

Alkyl bromides bearing various functional groups are smoothly converted to functionalized alkylzinc reagents by the direct insertion of magnesium in the presence of LiCl and ZnCl(2).

A full functionalization of all four positions of the thiophene ring was achieved. Starting from readily available 2,5-dichlorothiophene, successive magnesiations of the 3- and 4-positions using TMPMgCl x LiCl furnish, after trapping with various electrophiles, 3,4-difunctionalized dichlorothiophenes. Subsequent dechlorination and metalation or magnesium insertion into the C-Cl bond provides fully functionalized thiophenes in high yields. An application to the synthesis of a thiophene analogue of Atorvastatin (Lipitor) is reported.