Ruthenium Catalyzed N‐Alkylation of Cyclic Amines with Primary Alcohols

Abstract

A robust alcohol amination protocol using common saturated amines and primary alcohols as starting materials is described. The reactions are catalyzed by combination of dichloro(p-cymene)ruthenium(II) dimer precatalyst with triphenylphosphine ligand, with the excess alcohol substrate or toluene [a] Dr.amines. An important secondary goal was to minimize the waste produced in the purification of the products, i.e., simple removal of catalyst complex and purification of products without the need of chromatographic separation. Here, we describe a robust triphenylphosphine ligated dichloro(p-cymene)ruthenium(II) dimer catalyzed methodology for alkylation of cyclic amines with primary alcohols, while simultaneously minimizing the necessary purification operations. Results and DiscussionThe N-alkylation of morpholine with 1-butanol, illustrated in Scheme 2, was selected as a model reaction, based on the good availability of the reactants. This allowed the reactions to be performed at close to one gram scale in the preliminary screening, carried out in stainless steel reactors at elevated pressure and temperature. Scheme 2. N-Alkylation of morpholine with 1-butanol using dichloro(p-cymene)ruthenium(II) dimer precatalyst in combination with phosphine ligands.Based on prior art, [16][17][18]20] a selection of phosphine ligands illustrated in Figure 2 were tested. Results from the ligand screening are summarized in Table 1. As expected, the bidentate ligands DPPF, DPPB and DPEphos in combination with dichloro(p-cymene)ruthenium(II) dimer provided good results even at 0.13 mol-% catalyst loading within 21 hours (Table 1, Entries 4, 15 and 17). Tridentate Triphos ligand provided acceptable results in the same reaction setting (Table 1, Entry 21). Also, a number of monodentate ligands, cataCXium®PCy, triphenylphosphine (Ph 3 P) and methoxy derivatized triphenylphosphines were investigated. All monodentate ligands resulted in relatively poor GC-based yields for N-butyl morpholine, or in no reaction at all. In cases of bidentate ligands, having excess of ligand to ruthenium center (above 1:1 ratio) had minimal to no benefits with respect to the overall yield of N-butyl Figure 2. Ligands used in the reaction screening.

Titanium-Mediated Reduction of Carboxamides to Amines with Borane–Ammonia

“…13 C NMR (101 MHz, CDCl 3 ) δ 56.9, 50.2, 37.9, 31.7, 31.4, 30.1, 27.0, 26.6, 26.0, 22.5, 14.0. The compound characterization is in accordance with previous reports [ 50 ].…”

Recent advances in C/N-alkylation with alcohols through hydride transfer strategies

“…Leino and coworkers developed a synthetic method in 2020 to yield cyclic tertiary amines via alkylation of cyclic amines with primary alcohols through a hydrogen shuttle mechanism 59 catalyzed by a bidentate phosphine ligated Ru( ii ) complex, which is generated in situ from a dichloro( p -cymene)ruthenium( ii ) dimer as a precatalyst. Under a high-pressure argon atmosphere (10 bar), bidentate and tridentate phosphine ligands in combination with the precatalyst exhibited better conversion efficiency relative to simple monodentate ligands such as PPh 3 , but at normal pressure, the yields were similar.…”

“…Leino and coworkers developed a synthetic method in 2020 to yield cyclic tertiary amines via alkylation of cyclic amines with primary alcohols through a hydrogen shuttle mechanism 59 catalyzed by a bidentate phosphine ligated Ru(II) complex, which is generated in situ from a dichloro( p-cymene) ruthenium(II) dimer as a precatalyst. Under a high-pressure argon atmosphere (10 bar), bidentate and tridentate phos-…”

A sustainable strategic approach for N-alkylation of amines with activation of alcohols triggered via a hydrogen auto-transfer reaction using a Pd(ii) complex: evidence for metal–ligand cooperativity

“…[52][53][54] A number of catalysts based on transition metals 41,42,[55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71] have been developed and utilized for the N-alkylation of amines with alcohols as coupling partners. Nonetheless, research on the design and development of palladium based catalysts, mainly homogeneous catalysts for N-alkylation reactions, is scarcer than that of Ru [72][73][74][75][76][77][78][79][80][81][82][83] and Irbased [84][85][86][87][88][89][90] catalysts (Fig. 2).…”