Metalation of a 3,5-Dichloro-Tertiary Benzamide. An Unusual Regioselectivity Observation

Perturbative perspectives on the chemical reaction prediction problem

“…Lithiation at the para position, however, is experimentally observed. The current study reveals that the reactivity of b is in fact governed by electronic effects, rather than steric 71, effects.…”

“…As an example of a situation where the Fukui function is an appropriate measure, consider the lithiation of 3,5‐dichloro‐ N , N ‐diethyl carboamide (entry b in Table I) 71. The lithium atom is nominally neutral (although it is expected to have a slightly positive charge) and is a soft reagent.…”

The directing group wins over acidity: kinetically controlled regioselective lithiation for functionalization of 2-(2,4-dihalophenyl)-1,3-dithiane derivatives

“…5, 6 Also it has been demonstrated that the complexation of a directing group with lithium increases the kinetic acidity of the protons ortho to the directing group relative to other available protons. 13 They noticed that two moderately coordinating chloro groups decided the site of metalation over the strong carboxamide directing group. 8 Among the halogen directed lithiations, 9,10 reactions involving 1,3-dichloro and 1,3-difluoro benzene derivatives are interesting because of the ability of these systems to direct the lithiation at the 2 nd position.…”

Expedient Preparation of 4,6-Dihalo-3-arylisobenzofuran-1(3H)-ones from 3,5-Dihalo-N-ethylbenzamides

“…For example, compounds incorporating this moiety exhibit phytotoxicity, 1 selective inhibition of 11β-HSD1 for the treatment of metabolic syndrome, 2 MCH 1 receptor antagonism, 3 and serve as intermediates in the preparation of liquid crystals, fungicides, organo-tin antitumor compounds, insecticides, and quinolones possessing antibiotic activity. 4 While our previous studies have shown that 3,5-dichloro tertiary benzamides are metalated para to the carboxamide group, 5 we have found that use of secondary amides derived from 3,5-dihalobenzoic acids (1, X = Cl, F) result in exclusive ortho-metalation. In light of the paucity of methods available to prepare highly ring-functionalized derivatives of 3,5-dihalobenzoic acids, coupled with recent studies documenting the unique antitumor properties of benzolactones, 6 we now describe the application of the chelation-controlled directed ortho-metalation reaction in this series as a useful method for the preparation of 4,6-dihalo-3-arylisobenzofuran-1(3H)-ones.…”