Reductive Molybdenum‐Catalyzed Direct Amination of Boronic Acids with Nitro Compounds

Abstract

The synthesis of aromatic amines is of utmost importance in a wide range of chemical contexts. We report a direct amination of boronic acids with nitro compounds to yield (hetero)aryl amines. The novel combination of a dioxomolybdenum(VI) catalyst and triphenylphosphine as inexpensive reductant has revealed to be decisive to achieve this new C−N coupling. Our methodology has proven to be scalable, air and moisture tolerant, highly chemoselective and engages both aliphatic and aromatic nitro compounds. Moreover, this general and step‐economical synthesis of aromatic secondary amines showcases orthogonality to other aromatic amine syntheses as it tolerates aryl halides and carbonyl compounds.

P(III)/P(V)-Catalyzed Methylamination of Arylboronic Acids and Esters: Reductive C–N Coupling with Nitromethane as a Methylamine Surrogate

“…[8][9][10][11] At present, reductive N-functionalization of H 3 C-NO 2 is limited to two isolated examples: Niggemann has reported reductive N-benzylation of nitromethane mediated by stoichiometric B 2 pin 2 in the presence of excess BnZnBr, 12 and Suarez-Pantiga and Sanz have reported a triphenylphosphine-mediated reductive N-phenylation of nitromethane catalyzed by an oxomolybdenum(VI) compound under microwave irradiation. 13 We report here a general catalytic method for the methylamination of arylboronic acids and esters with H 3 C-NO 2 by reductive C-N coupling driven by P III /P V =O redox cycling (Figure 1B). These results expand the scope of reductive C-N coupling, generalize the use of H 3 C-NO 2 as a methylamine surrogate in reductive cross coupling, and provide a unique pathway for introducing stable isotopes ( 15 N, 13 C, 2 H) widely-used for metabolic tracing.…”

“…13 We report here a general catalytic method for the methylamination of arylboronic acids and esters with H 3 C-NO 2 by reductive C-N coupling driven by P III /P V =O redox cycling (Figure 1B). These results expand the scope of reductive C-N coupling, generalize the use of H 3 C-NO 2 as a methylamine surrogate in reductive cross coupling, and provide a unique pathway for introducing stable isotopes ( 15 N, 13 C, 2 H) widely-used for metabolic tracing. 14 Prior work has established P III /P V =O catalysis [15][16][17] as a viable approach to reductive Nfunctionalization of nitroarene (Ar-NO 2 ) substrates, [18][19][20] but the translation of this technique to reductive N-functionalization of H 3 C-NO 2 requires that the desired C-N coupling sequence (Figure 1B) outcompete numerous unproductive but well-known decomposition pathways, both for H 3 C-NO 2 (e.g.…”

“…Also, the orthogonal reactivity to the nitro group with respect to other nitrogen-containing functional groups permits selective aryl methylamination even in the presence of free −NH 2 groups ( 16) without explicit protection. Carbonyl functionalities such esters (13) and ketones (17,19) that might be susceptible to acylation or condensation reaction with H 3 C-NH 2 are retained when H 3 C-NO 2 is used as a surrogate. Furthermore, substrates with other functional groups including benzyloxy (7), tetrahydropyranyl ether ( 14), thiomethyl (15), and trifluoromethyl (18) groups all yielded the corresponding N-methylaniline products in good yields.…”

“…As illustrated in Figure 2B, a suite of isotopically labeled N-methylaniline products 5b-5d are accessible with programmed labeling as dictated by the initial isotopic composition of the nitromethane isotopologue (viz. 2 H 3 C-NO 2 (2b), H 3 13 C-NO 2 (2c), H 3 C-15 NO 2 (2d)). The relative ease with which the isotopologues of nitromethane are accessed make this an attractive approach to potentially valuable stable isotope labeled compounds.…”

Exploring Homogeneous Conditions for Mild Buchwald-Hartwig Amination in Batch and Flow

“…Our group recently reported the adaptation of the BASF Basel process 8 to allow continuous flow acylation, arylation, alkylation to be reliably performed without concerns of clogging, regardless of the choice of solvent or concentration, by mediating them with bases that form ionic liquid conjugate acids upon protonation. 9 These simple substitution reactions are among the most frequently run in the pharmaceutical industry, 10 and are thus particularly important to be able to conduct in automated synthesis platforms. Cross-coupling reactions are no less important, and their use in complex molecule synthesis continues to grow.…”