Alkylation of Amines with Alcohols

Mylroie et al. studied the optimal conditions for reductive alkylation of A-(4-ni-trophenyl)acetamide with ketones using Pt-C and sulfided Pt-C.49 In general, the sulfided catalyst was superior in the yield of the alkylated amines. There was no indication of either reduction of the ketone or saturation of the ring. With a higher loading of ketone (6 equiv) at 100°C and 6.9 MPa H2 in ethanol, excellent yields (98.5-99%) of the alkylated amines were obtained from the reaction of acetone (eq. 6.24), cyclohexanone, 2-pentanone, and 3-pentanone with A-(4-ni-trophenyl)acetamide. 

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The most widely used iridium catalyst for the V-alkylation of amines with alcohols is [Cp lrCl2]2, which was identified and developed by Fujita, Yamaguchi, and CO workers [94]. Aniline 111 has been selectively alkylated by a range of... 

Scheme 26 Alkylation of amines with alcohols by borrowing hydrogen...

Complexation of [Cp IrCl2]2 with iV-heterocyclic carbenes has led to complexes such as 25, developed by Peris and coworkers [107, 108], and 133, developed by Crabtree and coworkers [12]. Complex 24 is activated by the addition of silver triflate and is effective for the iV-alkylation of amines with alcohols and for the iV-alkylation of anilines with primary amines. Complex 25 has also been shown to couple benzyl alcohol 15 with a range of alcohols, including ethanol 134, to give ether products such as ether 135 (Scheme 31). Complex 133 was an active hydrogen transfer catalyst for the reduction of ketones and imines, using 2-propanol as the hydrogen source. It was also an effective catalyst for the iV-alkylation of amines... 

The development of versatile and efficient methods for the synthesis of amines has long been an active area of research, mainly because a wide variety of amines play important roles in many fields of organic chemistry. The N-alkylation of amines with alcohols represents an attractive method for synthesizing various amines because it does not generate any wasteful byproducts (H2O is the only stoichiometric coproduct). Although several catalytic systems for this process have been studied using transition-metal catalysts [53-57], most of these require a high reaction temperature (>150°C). 

The N-alkylation of amines with alcohols [63] can also be carried out with Ir catalysts through a similar domino sequence reaction. In this case, the aldehyde/ketone resulting from oxidation is condensed with an amine to the corresponding imine, which is hydrogenated to the alkylated amine [63]. By way of example, the reaction of benzyl alcohol with aniline in toluene afforded benzylaniline in a 88% isolated yield by using catalytic amounts of [ lr(/z-Cl)Cp Cl 2]/K2C03. 

Saidi O, Blacker AJ, Lamb GW et al (2010) Borrowing hydrogen in water and ionic liquids iridium-catalyzed alkylation of amines with alcohols. Org Process Res Dev 14(4) 1046-1049... 

Selective N-Alkylation of Amines with Alcohols over j Alumina... 

N-Alkylation. Gas-phase alkylation of amines with alcohols over y-alumina has been reported. 

In 2015, Xiao and co-workers reported an iridium complex (14)-catalyzed N-alkylation of amines with alcohols under mild conditions (100 °C) (Scheme 22) [113]. Anilines, heteroarylamines, A -alkyl-A(-arylamines, and sulfonamides could serve as A-nucleophiles. The same method can also be applied to amine-based N-... 

In 2014, Feringa, Barta and co-workers reported an IV-alkylation reaction of amines with aliphatic alcohols catalyzed by an iron cyclopentadienone complex 16 [130]. A catalytic cycle was proposed based on in situ NMR studies (Scheme 25). Complex 16 was first transformed to the active complex 17 by addition of oxidant MejNO. Complex 17 was then reduced to 18 by the alcohol. 16 and 18 acted as the catalysts to dehydrogenate the alcohol and hydrogenate the imine intermediates. In 2015, Zhao and co-workers realized an AgF-assisted amination of secondary alcohols using complex 16 as the catalyst [131]. In the same year. Wills and coworkers demonstrated a similar iron complex for A-alkylation of amines with alcohols [132]. 

Later in 2012, Corma, Sabater and co-workers reported a nano-Au/CeOa-catalyzed IV-alkylation of amines with alcohols [167]. In 2014, De Vos and coworkers reported a nano-Ag/Al203/Ga203-catalyzed amination of alcohols with a variety of aliphatic and aryl amines under mild conditions [168]. The catalyst remained active for at least three runs (1st, TOP = 1.01/h 3rd, 1.02/h). 

Scheme 34 Cp Iridium complex (33)-catalyzed iV-alkylation of amines with alcohols under air...

In 2011, Fujita, Yamaguchi and co-workers reported a water-soluble Cp Iridium complex (33)-catalyzed base-free A(-alkylation of amines with alcohols in water (Scheme 34) [183]. Since the catalyst is air-stable, the reactions could be readily carried out under air. Primary and secondary benzylamines, aliphatic amines, cyclic amines, anilines, as well as benzylic, aliphatic, secondary alcohols can be used to synthesize secondary and tertiary amines. Cyclic amines could also be achieved by A -alkylation of amines with diols. The authors also proposed a mechanism with hydrogen transfers from alcohols to form [Ir-H] complexes and finally to the product amines. 

In 2014, Xia and co-workers also reported a base-catalyzed solvent-free N-alkylation of amines with alcohols under air (Eq. 67) [205]. Both aromatic and aliphatic amines and alcohols are suitable substrates. In this method, alcohols are used in large excess amounts (10 equiv.) as both the reactant and solvent, and some reactions have to be heated at high temperatures up to 220 °C. The authors also observed the significant accelerating effects of both aldehyde and imine on the reaction, concluding that they are actual intermediates of the reaction. 

Balcells D, Crabtree RH, Eisenstein O et al (2008) Mechanism of homogeneous iridium-catalyzed alkylation of amines with alcohols from a DFT study. Organometallics 27(ll) 2529-2535... 

Fristrup P, Tursky M, Madsen R (2012) Mechanistic investigation of the iridium-catalysed alkylation of amines with alcohols. Org Biomol Chem 10(13) 2569-2577... 

Zhao G-M, Liu H-L, Huang X-R et al (2015) Mechanistic study on the Cp iridium-catalyzed JV-alkylation of amines with alcohols. RSC Adv 5(29) 22996-23008... 

Bartoszewicz A, Gonzalez Miera G, Martm-Matute B et al (2015) Mechanistic studies on the alkylation of amines with alcohols catalyzed by a bifunctional iridium complex. ACS Catal 5(6) 3704-3716... 

Enyong AB, Moasser B (2014) Ruthenium-catalyzed Al-alkylation of amines with alcohols under mild conditions using the borrowing hydrogen methodology. J Org Chem 79(16) 7553-7563... 

Zou Q, Wang C, Xiao J et al (2015) Alkylation of amines with alcohols and amines by a single catalyst under mild conditions. Chem-Eur J 21(27) 9656-9661... 

Yang H, Mao R, Cheng Get al (2014) An efficient homogeneous gold(l) catalyst for A-alkylation of amines with alcohols by hydrogen autotransfer. Tetrahedron 70(46) 8829-8835... 

Yan T, Feringa BL, Barta K (2014) Iron catalysed direct alkylation of amines with alcohols. Nat Commun 5 5602. doi 10.1038/ncomms6602... 

Zhang Y, Shi F, Deng Y et al (2011) Palladium catalyzed A-alkylation of amines with alcohols. Tetrahedron Lett 52(12) 1334-1338... 

He L, Cao Y, Fan KN et al (2010) Efficient and clean gold-catalyzed one-pot selective A-alkylation of amines with alcohols. Chem-Eur J 16(47) 13965-13969... 

Liu H, Chuah G-K, Jaenicke S (2012) A-alkylation of amines with alcohols over alumina-entrapped Ag catalysts using the borrowing hydrogen methodology. J Catal 292 130-137... 

K-1 Shimizu, Imaiida N, Kon K et al (2013) Heterogeneous Ni catalysts for N-alkylation of amines with alcohols. ACS Catal 3(5) 998-1005... 

Mehta A, Thaker A, Nandan SR et al (2014) Reinvestigating Raney nickel mediated selective alkylation of amines with alcohols via hydrogen autotransfer methodology. Appl Catal A Gen 478 241-251... 

K-I Shimizu, Shimura K, Nishimura M et al (2011) Silver cluster-promoted heterogeneous copper catalyst for iV-alkylation of amines with alcohols. RSC Adv 1(7) 1310-1317... 

Geukens 1, Vermoortele F, De Vos DE et al (2014) Ag nanoparticles on mixed Al203-Ga203 supports as catalysts for the iV-alkylation of amines with alcohols. Appl Catal A Gen 469 373-379... 

Gonzalez-Arellano C, Luque R, Gai PL et al (2010) Highly active and selective supported iron oxide nanoparticles in microwave-assisted N-alkylations of amines with alcohols. Green Chem 12(7) 1281 1287... 

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