An Efficient Palladium-Catalyzed N-Alkylation of Amines Using Primary and Secondary Alcohols

Abstract

PdCl 2 in the presence of dppe or Xantphos(t-Bu) as the ligand is found to be an efficient catalyst for the N-alkylation of various primary and cyclic secondary amines using primary alcohols at 90−130 °C under neat conditions. Interestingly, good to excellent yields were achieved when more challenging secondary alcohols were used as alkylating agents at 130−150 °C. The reaction could be easily scaled up, as demonstrated for a 10 mmol scale achieving yields up to 90% with a TON of 900.

DFT Study on the Homogeneous Palladium-Catalyzed N-Alkylation of Amines with Alcohols

“…18,40 5 In the present study, the experimental PdCl 2 , dppe (1,2-Bis(diphenylphosphino)ethane), and LiOH are employed as the catalyst, the ligand, and the base, respectively, and the N-alkylation of PhNH 2 with PhCH 2 OH is selected as the model reaction (Eq 1). 24 Because PhNH 2 and PhCH 2 OH used in Seayad and co-workers' experiment are 2 and 6 mmol, respectively, PhCH 2 OH is treated as the solvent in the calculations.…”

“…23 However, this catalytic system is not active for aliphatic and secondary alcohols as the alkylating agents under relatively moderate experimental conditions. In 2013, a highly efficient and scalable homogeneous palladium catalytic system was developed by Seayad and co-workers for the N-alkylation of primary and cyclic secondary amines, and good to excellent yields (TON up to 900) were obtained when benzyl alcohol is used as the alkylating agent at 90-100 • C or when aliphatic and secondary alcohols are used as the alkylating agents at 130-150 • C. 24 On the basis of their experimental results and the similar Pd-catalyzed transformations, 25 Seayad and co-workers proposed a plausible catalytic cycle for the Pd-catalyzed N-alkylation of amines with alcohols. As shown in Scheme 1, the palladium alkoxide complex with a Cl − ligand, Pd(R 1 R 2 CHO)(dppe)Cl, was postulated as the catalytically active species, which could generate the carbonyl compound 3 Scheme 1: Seayad and Co-workers' Proposed Catalytic Cycle for the Pd-Catalyzed N-Alkylation of Amines with Alcohols 24 R 1 R 2 C=O and the Pd hydride PdH(dppe)Cl via the β -H elimination.…”

Ligand‐free Iron(II)‐Catalyzed N‐Alkylation of Hindered Secondary Arylamines with Non‐activated Secondary and Primary Alcohols via a Carbocationic Pathway

“…[2] The alkylation of amines with alcohols to produce higher amines is an attractive and ecofriendly alternative to conventional methods, such as Buchwald-Hartwig amination, [3] reductive amination of carbonyl compounds, [4] hydroamination of alkynes/ alkenes [5] and CÀH nitrogen insertion. Recently, precious transition metal catalysts such as Ru, [7] Pt, [8] Pd [9] and Ir [10] were shown to be highly effective for this strategy. Recently, precious transition metal catalysts such as Ru, [7] Pt, [8] Pd [9] and Ir [10] were shown to be highly effective for this strategy.…”

“…Noteworthy, highly abundant and bio-relevant homogeneous transition metal catalysts such as Fe, Co and Mn which were used in the mono alkylation of primary amines with primary as well as secondary alcohols. Nevertheless, N-alkylation of secondary arylamines with secondary benzyl alcohols is still a challenge due to the following reasons: (a) the larger size of secondary arylamines; they are generally considered more difficult coupling partners than primary anilines for N-arylation reactions, [18,19] (b) as an alkylating agent, secondary alcohols are less reactive substrates as compared to primary alcohols in borrowing hydrogen transfer strategy because of the difficulty in its in situ dehydrogenation to the corresponding ketones, [20,21] (c) the hydrogenation of the iminium or enamine intermediate is also challenging (Scheme 1b). Moreover, Saito group [15] reported Nalkylation of primary amines with primary benzyl alcohol using ligand assisted iron as a catalyst.…”

Insight into O2‐Promoted Base‐Catalyzed N‐Alkylation of Amines with Alcohols

“…Indeed, numerous other homogeneous catalysts such as those that contain palladium, [6] rhodium, [7] copper, [8] iron, [9] platinum, [10] and osmium [11] have also been developed, and several protocols are already utilized in the pharmaceutical industry. [12] The mechanism of these transition-metal-catalyzed N-alkylation reactions proceeds through a dehydrogenation/imination/ hydrogenation sequence.…”