Palladium-Catalyzed Nitromethylation of Aryl Halides: An Orthogonal Formylation Equivalent

Abstract

An efficient cross-coupling reaction of aryl halides and nitromethane was developed with the use of parallel microscale experimentation. The arylnitromethane products are precursors for numerous useful synthetic products. An efficient method for their direct conversion to the corresponding oximes and aldehydes in a one-pot operation has been discovered. The process exploits inexpensive nitromethane as a carbonyl equivalent, providing a mild and convenient formylation method that is compatible with many functional groups.

The Nitro to Carbonyl Conversion (Nef Reaction): New Perspectives for a Classical Transformation

“…[59] Cleavage of the obtained oximes to the parent arylaldehydes has been efficiently carriedo ut using SnCl 2 ·2 H 2 O/l-tartaric acid in ethanol-water. Thew hole process,N ef reactiona nd hydrolysis, was realized in ao ne-pot fashion with chemical yields ranging from 41% to 87%.…”

Minimizing the Amount of Nitromethane in Palladium-Catalyzed Cross-Coupling with Aryl Halides

“…20 70–71 °C); 1 H NMR (500 MHz, CDCl 3 ) δ 8.12 (d, J = 8.5 Hz, 2H), 7.54 (d, J = 8.2 Hz, 2H), 5.51 (s, 2H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).…”

“…20 Due to its weakly nucleophilic nature, nitromethane was employed as a solvent (0.1 M, 185 equiv) to optimize the yield. Nitromethane is often used as a polar organic solvent in small-scale processes and is stable at ambient temperature and pressure.…”

“…20 Specifically, the coupling of 4-bromoanisole ( 1a ) with nitromethane (2 equivalents) was examined while varying the ligand, base, and solvent. 27 Sufficient reactivity was observed at 70 °C, and several trends emerged.…”

“…It is especially noteworthy that acidic ketone 1d did not compete even though coupling of ketones, via the enols, have been reported in other systems 15,29,30 at the higher temperature used here compared to the initial report with nitromethane as solvent. 20 Bromoindole 1g also provided the nitromethylated heteroarene in high yield (entry 7). Notably, ortho -substitution does not inhibit the reactivity or yield, as determined with a variety of sterically hindered substrates (entries 5, 6, 12, and 13) including the very hindered 2-bromomesitylene 1f .…”