N-alkylation of amines

The [Cp IrCl2]/K2C03 system serves as an efficient catalyst for the N-alkylation of amines 106 with alcohols 107 (Equation 10.25) [48]. Alternatively, [IrCl(cod)]2 

The iridium-catalyzed reaction of primary amines with diols gave cyclic amines. The reaction of amine 109 with diol 110 in the presence of [Cp lrCl2]/NaHC03 catalyst gave heterocyclization product 111 (Equation 10.26) [50]. 

Intramolecular cycUzation of amino alcohols 112 took place with [Cp IrCl2]/ K2CO3 to give indoles 113 (Equation 10.27) [51]. 

Furthermore, the N-alkylation of 2-aminobenzyl alcohol 114 with ketones 115 in the presence of [IrCl(cod)]2 and KOH gave quinoline derivatives 116 (Equation 10.28) [52]. The reaction may be initiated by the formation of ketimine from 114 and 115, and the ketimine thus formed is oxidized by Ir catalyst and the 114 which serves as a hydrogen acceptor giving the corresponding aldehyde, which is eventually converted into quinoline 116 through intramolecular aldol-type condensation. 

Another type of N-alkylation was achieved by the [IrCl(cod)]2-catalyzed reductive alkylation of secondary amine with aldehyde and silane (Equation 10.29) [53], For example, the treatment of dibutylamine 117 with butyraldehyde 118 and EtsSiH 119 (a 1 1 1 molar ratio amine, aldehyde and silane) or polymethyUiydrosiloxane (PMHS) in 1,4-dioxane at 75 °C under the influence of a catalytic amount of [lrCl(cod)]2, gave tributylamine 120. 

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In addition, there are a few examples of heterogeneous nonaqueous sonochemistry, in both liquid-liquid and liquid-solid systems. Two recent reports have utilized ultrasonic agitation in place of or along with phase transfer catalysis for the preparation of dichlorocarbene from aqueous NaOH/CHCl3 (166), and for N-alkylation of amines with alkyl halides (167). Along the same lines, several papers have appeared in which... 

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. 

Torchy, S. and Barbry, D., N-alkylation of amines under microwave irradiation modified Eschweiler-Clarke reaction, /. Chem. Res. (S), 2001, 292-293. 

Salvatore, R. N. Nagle, A. S. Jung, K. W. Cesium effect high chemoselectivity in direct N-alkylation of amines./. Org. Chem. 2002, 67, 674-683. 

Aqueous N-Alkylation of Amines Using Alkyl Halides ... 

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

We have shown that N-alkylation of amines by aleohols in the gas-phase over y-alumina is possible for a wide range of amines (aliphatic or aromatic) and alcohols (from methanol to hexanol). We have also proved that ethers can be used as alkylating agents. This last point is of practical interest because separation of the polar amine from the non-polar ether solvent is easier than from the polar alcohol. Above all, we have clearly demonstrated that chirality is compatible with gas-phase conditions and thus proposed a selective new method for mono-N-alkyla-tion and, in particular, for methylation of chiral amines. This opens new perspectives for gas-phase heterogeneous catalysis. 

Tab. 4.14. Solvent-free N-alkylation of amines I and II by n-alkyl halides.

Reductive amination, a suitable method for N-alkylation of amines, can be carried out using methanolic pyridine-borane under conventional conditions at room temperature for 3-16 h (95JOC5995). Under MWI, alkylation of hexahydroazepine 432 with paraformaldehyde and formic acid gave 70% of A -methylhexahydroazepine 433 after 4min of irradiation (Scheme 85) (01JCR(S)292). Similarly, A -alkyl and A -cycloalkylhydroazepines 434 and 435 were obtained in 28-81% yields. 

Martin-Matute and coworkers described Cp Ir(III) complexes having hydroxyl-, ether-, and alkoxide-functionahzed NHC ligands, and their application in the N-alkylation of amines with primary and secondary alcohob [66]. In particular, the hydroxyl-functionalized complex dbplayed excellent catalytic outcomes, a broad substrate scope, and allowed amines to be alkylated with alcohob at temperatures as low as 50 °C. Indeed, thb hydroxyl-functionalized complex b one of the best catalysts known to date. The authors proposed a metal-ligand bifunctional mechanism for the iV-alkylation of amines with alcohob using this complex, which involves the formation of alcohol/alkoxide intermediates. Complex 38 (Figure 10.10) proved to be excellent for the A/,N -dialkylation of p-, m-, and 0-phenylenediamine with primary alcohob. The authors observed that the dimetal-lic compound 38 performs better than the monoiridium one, suggesting that a cooperative effect between the two metab may be at play [94]. 

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-... 

Some iV-alkylation reactions catalyzed by other noble metal catalysts have also been reported. In 2011, Gusev and co-workers reported an Osmium complex-catalyzed N-alkylation of amines at 200 °C with a low catalyst loading (0.1 mol%) [122]. In 2014, Zhu and co-workers disclosed a [ReH7(PCy3)2]-catalyzed amination of alcohols with anilines under CO atmosphere (Eq. 29) [123]. The authors proposed that coordination of CO with Re might lead to decomposition of ReH7(PCy3)2 to a rhenium carbonyl complex, which was believed to be the active... 

In 2010, Luque and co-workers were the first to report a microwave-assisted N-alkylation of amines with benzylic alcohols catalyzed by nano-Fe-HMS (HMS, hexagonal mesoporous silica) (Eq. 52) [170]. The authors found that base may be crucial in deprotonation/dehydrogenation of the alcohols. 

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. 

Cano R, Ramon DJ, Yus M (2011) Impregnated ruthenium on magnetite as a recyclable catalyst for the N-alkylation of amines, sulfonamides, sulfinamides, and nitroarenes using alcohols as electrophiles by a hydrogen autotransfer process. J Org Chem 76(14) 5547-5557... 

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... 

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