Domino Hydrogenation–Reductive Amination of Phenols, a Simple Process To Access Substituted Cyclohexylamines

Abstract

Phenols can be efficiently reduced by sodium formate and Pd/C as the catalyst in water and in the presence of amines to give the corresponding cyclohexylamines. This reaction works at rt for 12 h or at 60 °C under microwave dielectric heating for 20 min. With the exception of aniline, primary, secondary amines, amino alcohols, and even amino acids can be used as nucleophiles. The reductive process is based on a sustainable hydrogen source and a catalyst that can be efficiently recovered and reused. The protocol was developed into a continuous-flow production of cyclohexylamines in gram scale achieving very efficient preliminary results (TON 32.7 and TOF 5.45 h(-1)).

Pd/C Catalysis under Microwave Dielectric Heating

“…Substituted phenols are reduced to cyclohexanones that are coupled in situ with different amines to yield, under the reductive condition, the corresponding substituted cyclohexylamines (Scheme 27). This protocol was also developed in continuous-flow for the production of cyclohexylamines in Gram scale (TON 32.7 and TOF 5.45 h −1 ) [77]. Pd/C has also been used for dehalogenation of aromatic compounds in the presence of deuterated formates inside a domestic MW oven.…”

Continuous‐Flow Palladium‐Catalyzed Synthesis of Cyclohexanones from Phenols using Sodium Formate as a Safe Hydrogen Source

“…To define milder and more energy efficient one-step processes, the use of selectiveh omogeneous and heterogeneous catalysts hasb een investigated in the liquid phase and has resulted in many successful examples mainly based on single or mixed Pd, [3] Pt, [4] Ru, [5] Rh, [6] andN i [7] catalysts on different supports. [13] Following our interest in developing sustainable protocols based on the use of safe media, heterogeneous catalysis, [16] and the applicationo fflow technology, [17] we report herein our approacht owardst he definition of ac ontinuous-flow protocol by using commerciallya vailableP d/C for the catalyzed selective transfer hydrogenation of phenol to cyclohexanone in water by using sodium formate as ah ydrogen source.In ap reliminaryo ptimization study in batch, we investigated the best reaction conditions suitable for transfer to af low pro-Scheme1.Reactionsteps in at ypical phenol hydrogenation process. The chemical strategy to reduce phenol selectively is based on controlling the desorption of cyclohexanone from the catalyst surface beforef urther hydrogenation leads to cyclohexanol.…”

“…[8] Considering the commonly proposed mechanism for the hydrogenation of phenol on supported palladiumc atalysts, reductiono ccurs on the phenolate ion adsorbed on the support in proximity of the metal particles, which are responsible for the activation of hydrogen. [13] Following our interest in developing sustainable protocols based on the use of safe media, heterogeneous catalysis, [16] and the applicationo fflow technology, [17] we report herein our approacht owardst he definition of ac ontinuous-flow protocol by using commerciallya vailableP d/C for the catalyzed selective transfer hydrogenation of phenol to cyclohexanone in water by using sodium formate as ah ydrogen source. [9] The use of formic acid derivativesa sahydrogen sourcei n combination with ap alladium catalyst is ap romising, safe, and sustainable alternative to classic methods.…”

Palladium‐Catalyzed Synthesis of N‐Cyclohexyl Anilines from Phenols with Hydrazine or Hydroxylamine via N‐N/O Cleavage

“…[1] They are also versatile intermediates in numerous transformations [2] such as C-halo (the Sandmeyer and Schiemann reactions) or CÀN (the Buchwald-Hartwig, the Chan-Lam and the Ullmann reactions) bond formations. [4] To date, a series of elegant methods for the synthesis of N-cyclohexyl anilines have been developed, which can be divided into two categories (Scheme 1, a): one involves the use of anilines as amino sources, [5] with coupling partners including arylboronic acids, [6] phenols, [7] anilines, [8] cyclohexanones [9] or cyclohexanols; [10] and the other relates to the use of cyclohexylamines as precursors, with coupling partners covering various aryl sources such as haloarenes, [11] phenols [12] and their derivatives, [13] arylboronic acids [6] and aryl Grignard reagents. [4] To date, a series of elegant methods for the synthesis of N-cyclohexyl anilines have been developed, which can be divided into two categories (Scheme 1, a): one involves the use of anilines as amino sources, [5] with coupling partners including arylboronic acids, [6] phenols, [7] anilines, [8] cyclohexanones [9] or cyclohexanols; [10] and the other relates to the use of cyclohexylamines as precursors, with coupling partners covering various aryl sources such as haloarenes, [11] phenols [12] and their derivatives, [13] arylboronic acids [6] and aryl Grignard reagents.…”

“…Phenols are abundant and naturally occurring motifs in renewable lignocellulosic biomass, and are important precursors of aryl or cyclohexyl groups (Scheme 1, b). [8] 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 H 2 , [16] and Fu's group further investigated N-cyclohexylation of amines with phenols using Al 2 O 3 supported palladium hydride (PdH x ) catalyst. [7,12] Later, Taddei accomplished this transformation in a flow reactor.…”