Decarboxylative Bromination of Sterically Hindered Carboxylic Acids with Hypervalent Iodine(III) Reagents

Abstract

Sterically hindered three-dimensional (3D) alkyl halides are promising precursors for various reactions; however, they are difficult to synthesize via conventional reactions. We present an efficient and practical method for decarboxylative bromination of sterically hindered 3D aliphatic carboxylic acids using commercially available (diacetoxyiodo)benzene and potassium bromide, one of the most stable and cheapest bromine sources in nature. The present method features a metal-free/Br 2 -free system, mild reaction conditions, one-pot operation under air at room temperature, wide functional group compatibility, and gram-scale synthetic capability. This highly efficient reaction cleanly converts a broad range of carboxylic acids, the most inexpensive and readily available sources of highly strained/naturally occurring/drug-related scaffolds, into the corresponding alkyl bromides in good to high yields.

On the potential intermediacy of PhIBr2 as a brominating agent

“…The 2020 report from Miyamoto and Uchiyama shows mass spectral evidence of the presence of PhIBr 2 as [PhIBr 2 -ONa] − in solutions generated from PIDA and 1 equivalent of [NBu 4 ][Br] in CH 2 Cl 2 . 32 The origin of the –ONa unit was not described. We repeated this work in CD 2 Cl 2 and obtained the same mass spectral data.…”

“…31 However in 2020, Miyamoto and Uchiyama presented mass spectral evidence for the presence of a species containing [PhIBr 2 -ONa] − from the reaction of PIDA with [NBu 4 ][Br] as evidence for the formation of PhIBr 2 . 32 Evans reported the mixed PhI(OAc)(Cl) species was an observable compound by 1 H NMR spectroscopy, 26 and PhI(OAc)(Cl) has been determined to have desirable properties over PhICl 2 in some applications. 23 Importantly, Evans highlighted differences in chlorination and bromination reactions, both in terms of their relative rates of reaction and their substrate selectivity, which is indicative of different reaction mechanisms.…”

Decarboxylative Halogenation of Organic Compounds

“… 160 α,α,α-Trifluorotoluene was also found to be a useful solvent for the bromodecarboxylation. 186 In some cases, iodinated products were isolated during the bromodecarboxylation reaction, arising from the abstraction of an iodine atom from the iodobenzene. 160 Usually, the use of inert atmosphere and dry solvents is not required, although in many protocols the reaction was performed under nitrogen and in a dry solvent.…”

“…For the bromodecarboxylation reaction, dibromomethane was employed, to avoid the bromination of benzene as the predominant process . α,α,α-Trifluorotoluene was also found to be a useful solvent for the bromodecarboxylation . In some cases, iodinated products were isolated during the bromodecarboxylation reaction, arising from the abstraction of an iodine atom from the iodobenzene .…”

Visible-Light-Induced Catalytic Selective Halogenation with Photocatalyst

“…Another decarboxylative bromination of carboxylic acids using potassium bromide was reported by Uchiyama and co-workers in 2020 [ 42 ]. In this protocol, a series of sterically hindered primary, secondary, and tertiary carboxylic acids, bearing different structures such as acyclic, cyclic, caged, and bridgehead, were treated with potassium bromide in the presence of (diacetoxyiodo)benzene as a photocatalyst in CH 2 Cl 2 or PhCF 3 under irradiation of a ceiling fluorescent light at room temperature to generate the corresponding products without rearrangement or fragmentation ( Scheme 35 ).…”