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Palladium-catalyzed Deoxygenative Amination Of Phenols

Arylamines serve as important structural units in pharmaceuticals, pigments and functional materials. They are also versatile intermediates in numerous transformations such as C-halo (the Sandmeyer and Schiemann reactions) or C-N (the Buchwald-Hartwig, the Chan-Lam, and the Ullmann reactions) bond formations.

Very recently, N-cyclohexyl anilines have been used as a ligand to promote dehydrogenative transformations, and as an antioxidant in food chemistry. To date, a series of elegant methods for the synthesis of N-cyclohexyl anilines have been developed, which can be divided into two categories: one involves the use of anilines as amino source, with coupling partners including arylboronic acids, phenols, anilines, cyclohexanones or cyclohexanols; and the other relates to the use of cyclohexylamines as precursors, with coupling partners covering various aryl sources such as haloarenes, phenol and its derivatives, arylboronic acids, and aryl Grignard reagents.

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However, most of these methods require the prefunctionalization, thereby decreasing the total reaction efficiency. Phenols are abundant and naturally occurring motifs in renewable lignocellulosic biomass and are important precursors of aryl or cyclohexyl groups. In 2015, our group developed a Pd-catalyzed reductive coupling of phenols with amines using sodium formate as a convenient hydrogen source to produce anilines or cyclohexylamines. Later, Taddei accomplished this transformation in a flow reactor.

In 2016, Beller reported a Pd-catalyzed deoxygenative coupling of phenols or aryl ethers to generate alkylated cyclohexylamines with Lewis acid Hf(OTf)4 as co-catalyst under molecular H2, and Fu’s group further investigated N-cyclohexylation of amines with phenols using Al2O3 supported palladium hydride (PdHx) catalyst.

The N-N bond cleavage of hydrazines has recently been utilized as a strategy for the formation of C-N bond through the transition-metal-catalyzed C-H bond functionalization. Indeed, it has earlier been documented that hydrazines served as a nitrogen source with carbonyl compounds to prepare amines via catalytically hydrogenative N-N cleavage. Yet to our knowledge, there seems to be no report regarding the synthesis of amines from phenols with hydrazine via the cleavage of C-O and N-N bonds.

In 2015, our group also reported a formal coupling of phenol with amines catalyzed by palladium to generate aniline products. In this paper, we present an efficient palladium-catalyzed direct deoxygenative coupling of phenols with hydrazine or hydroxylamine as nitrogen atom source via C-O bond and N-N/O bond cleavages, which can not only greatly improve the efficiency to synthesize the N-cyclohexyl aniline type substrates but also utilize biomass-derived phenols and common industrial starting materials or catalyst (hydrazine, hydroxyamine, Pd/C, sodium formate).

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For the scope of such a transformation, generally speaking, less hindered C-alkylated phenols such as cresols, the hydroxyl benzoates and hydroxyphenyl acetates and the aryl ethers which are more abundant structural units in biomass resources, for example, lignins, all proceeded smoothly under the standard conditions.

Mechanism studies suggest that this chemistry probably involves the sequential formations of various intermediates cyclohexanone or cyclohexanone, hydrazone or azine, and cyclohexylamine. This chemistry involves a complex sp2 C-O bond and N-N or N-O bond-cleavage process and enables access to a variety of N-substituted cyclohexyl anilines from lignin-derived phenols. Further deoxygenative transformations of biomass are underway in our lab.

This study, Palladium-Catalyzed Synthesis of N-Cyclohexyl Anilines from Phenols with Hydrazine or Hydroxylamine via N-N/O Cleavage was recently published by Jiang-Sheng Li, Zihang Qiu and Chao-Jun Li in the journal Advanced Synthesis & Catalysis.

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