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

Abstract

Regioselective halogen/metal exchange reactions were carried out on a series of 3-substituted- 1,2-dibromoarenes. Product mixtures were quenched with CO2 to form the corresponding benzoic acid analogs to facilitate HPLC and NMR analysis. Substitution at the 3-position could readily be assigned on the basis of 2D HMBC long-range correlations, while assignment at the 2-position was not as straightforward. The use of three-bond J(CH) coupling constant measurements, extracted from 1-D 1H coupled 13C experiments, were necessary to render unequivocal regio assignments.

Complete assignment of 1H- and 13C-NMR spectra of anthranilic acid and its hydroxy derivatives and salicylic acid and its amino derivatives

“…Furthermore, 13 C-H coupling constants of the investigated benzoic acids showed the following trends: (1) 3 J CH couplings are larger (6-12 Hz) than the 2 J CH couplings (0-4 Hz) and easier to discern (in the case of 3-HAA, C-4 displayed a three-bond coupling of 9 Hz to H-6, and a coupling constant of 1.5 Hz to H-5 through two bonds); (2) The magnitude of the 3 J CH couplings are directly proportional to the increased electronegativity of the substituent (in the case of AA, J(C-6-H-4) = 7.8 Hz, while in SA, J(C-6-H-4) increased to 8.4 Hz); (3) If a substituent is on the coupling pathway, the 3 J values decrease with increased electronegativity (in the case of 3-HAA, J(C-4-H-6) = 9.0 Hz, while in 5-HAA, J(C-4-H-6) decreased to 5.9 Hz). This is in agreement with other di-or tri-substituted aromatic systems (DiMichele et al, 2006, and references cited therein).…”

Efficient and Selective Synthesis of α,β‐Epoxy‐γ‐Butyrolactones from 2‐Peroxy‐1,4‐Dicarbonyl Compounds

“…Due to the known biological activities of iodinated benzyl alcohols in the literature and to our interest in the chemistry and application of 1,2,3‐triiodoarenes in synthesis and medicine, we felt intrigued in examining the reactivity of 1,2,3‐triiodoarenes using MIE reactions aiming toward to the synthesis of diiodinated benzyl alcohol derivatives. In spite of the number of reports on functionalization of dibromo‐ and tribromoarene derivatives using metal–bromine exchange reactions, 21‐24, 27, 35–38 polyiodoarene derivatives remain a challenging task. A few examples of 1,2‐dihaloarene functionalization have been reported.…”

“…33 Due to the relatively weak nature of the CI and CBr bonds,34 iodo‐bromoarenes are often used in this type of transformations. The regioselective metal–halogen exchange reaction of dibromo‐ and tribromoarene derivatives is well documented 21–24. 27, 35–38 Interestingly, there are only a few examples of metal–halogen exchange reactions with diiodoarenes and triiodoarenes 8.…”

Process Development of a Potent Bradykinin 1 Antagonist

“…A major challenge in the synthesis of A is the regioselective synthesis of the tetrasubstituted benzene ring. Instead of developing an electrophilic aromatic substitution, an alternative approach was explored: a previously reported regioselective halogen−metal exchange of 1,2-dibromobenzene derivatives − was investigated by trapping the metalated benzene derivative with a carbonyl compound such as dimethylformamide as outlined in Scheme . This synthetic route was evaluated and found to be more efficient and safer with respect to large-scale operations compared to the route shown in Scheme .…”