Solvent Choice and Kinetic Isotope Effects (KIEs) Dramatically Alter Regioselectivity in the Directed ortho Metalation (DoM) of 1,5‐Dichloro‐2,4‐dimethoxybenzene

Abstract

The regioselective formation of the 6-lithio derivative of 1,5-dichloro-2,4-dimethoxybenzene (i.e., 12) by directed ortho metalation (DoM) with nBuLi in THF is described. Although literature reports suggest direct deprotonation at C6, a series of time-course and labelling studies has revealed that deprotonation rather occurs exclusively at C3 followed by isomerization of the anion to C6. By contrast, when DoM was performed in Et2 O, deprotonation again occurred selectively at C3, but now no isomerization occurs, and electrophilic capture produces the regioisomer of that produced in THF. In these labeling studies, it has been found that deuterium has an enormous kinetic isotope effect (KIE) that suppresses not only the original DoM reaction at C3 when deuterium is present there, but also suppresses isomerization to C6 when the label is at that site. Remarkably, this "protecting-group" role of the deuterium is unique to THF; in ether, full deprotonation of the deuterium at C3 was observed.

Large Isotope Effects in Organometallic Chemistry

“…The review is focused specifically on transition metal examples, although large KIEs have also been found in main group organometallic reactions, particularly with lithium. [26][27][28][29][30][31][32][33][34][35][36][37][38] By compiling and examining this body of data, we can better categorize and understand the causes and potential uses of large isotope effects in organometallic chemistry.…”

Solvent effects on the thermal isomerization of a rotary molecular motor

“…Pioneering work in the field was performed among others by Menshutkin, 3 Grunwald and Winstein, 4 Hammett and Deyrup, 5 and Hughes and Ingold, 6 but even after 150 years of extensive research, the nature of solvent effects remains elusive and its study of great importance. Recent examples include solvent effects in catalysis, 7 gelation, 8 regioselectivity in ortho-metalation, 9 radical reactions 10 and biomass conversion. 11 In unimolecular reactions, solvent effects are generally smaller but can comprise many different interactions.…”

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

“…It was established that, in the presence of electron-withdrawing directed metalation groups (DMGs) such as F, Cl, Br, CF 3 and CN, the inductive effect and, in the presence of an electron donating group such as OMe, NMe 2 , the coordination effect influence much the deprotonation during ortho-lithiation. 12 Bradley and co-workers have reported an interesting observation where the relative directing abilities of two different directing groups namely the 1,3-dichloro moiety against the stronger amide directing group for lithiation were evaluated (Scheme 1). 7 Development of new directing groups led to the discovery of unique synthetic methodologies.…”

“…11 Recently, Organ and co-workers reported a regioselective directed ortho-metalation (DoM) of 1,5-dichloro-2,4-dimethoxybenzene where the site of metalation depends on the nature of the solvent. 12 Bradley and co-workers have reported an interesting observation where the relative directing abilities of two different directing groups namely the 1,3-dichloro moiety against the stronger amide directing group for lithiation were evaluated (Scheme 1). 13 They noticed that two moderately coordinating chloro groups decided the site of metalation over the strong carboxamide directing group.…”