N-Alkylation of Amines with Alcohols

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 carbonyl intermediate then reacts readily with a primary amine to afford an imine and water. A subsequent addition of the iridium hydride to the C=N double bond of the imine, followed by amide-alkoxide exchange, would then occur to release the product. 

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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. 

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

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, 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. 

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... 

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... 

RuH2(PPh3)4 is used as a dehydrogenation type oxidation catalyst for alcohols and aldehydes [66a,66b]. For example, the esterification of alcohol, lactone formation from diol, N-alkylation of amine with alcohol, and the condensation of aldehyde with alcohol. 

N-Alkylation of amines with alcohols is of interest for the atom-economical synthesis of pharmaceutically relevant moleeules. The postulated general mechanism goes through dehydrogenation of the primary alcohol, formation of an imine, and hydrogenation of the latter to regenerate the catalytic species (Scheme 8.14). 

A mesoporous SBA-15-supported pyrimidine-substituted NHC-Ir " complex 132 was successfully applied to the N-alkylation of amines with alcohols. 

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

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 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. 

Scheme 8.14 Proposed mechanism for the iridium-catalysed N-alkylation of amines with primary alcohols.

Sulfonamide iV-alkylation with alcohols is an important transformation due to the abundance of the sulfonamide moiety in drugs. Traditional sulfonamide synthesis involves the reaction of a sulfonyl chloride with a primary or secondary amine. However, these methods require the use of unstable sulfonyl chlorides and generate stoichiometric salt waste. In contrast, the N-alkylation of sulfonamides with alcohols presents a convenient alternative that utilises stable starting materials and produces water as the... 

Aldehydes and ketones react with aniline derivatives in the presence of hydrogen and a catalyst to yield N-alkylanilines (Fache et al., 1996 Freifelder, 1971). N-Alkylation of aliphatic amines under microwave irradiation is a well-documented process (Caddick, 1995 Loupy et al., 1998 Varma, 1999 Lidstrom et al., 2001 Wathey et al., 2002). Jiang et al. (1996) reported the N-alkylation of anilines with alcohols over Raney nickel under microwave irradiation. More recently, Khadilkar and Jaizinghani (1999) carried out the direct monobenzylation of aniline with ben-zylchloride on alumina supported potassium carbonate. They reported a fast and efficient metal-free method for the N-alkylation of anilines under microwave irradiation. Romera et al. (2004) reported potassium iodide catalyzed monoalkylation of anilines, where they obtained 54-98% yield. 

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... 

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. 

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... 

The more challenging asymmetric iV-alkylation reactions of amines with alcohols was also developed in recent years. In 2009, by employing an Ir-catalyzed N-heterocyclization reaction as the key step, Trudell and co-workers first achieved the enantioselective total synthesis of both enantiomers of noranabasamine with >30 % overall yields and >80 % ee (Eq. 53) [175]. 

Binuclear complexes with bridging trimethyltriazoldiylidene ligands were also used in TH and p-alkylation reactions. Thus, complexes 124 and 125 were applied for TH of ketones and imines in KOH/i-PrOH (Figure 13.14). The reductions of ketones and N-ben lidene anilines were complete within 1 h. Related 126 and 127 ruthenium complexes were investigated as catalysts in the p-alkylation of secondary alcohols with primary alcohols. Such catalytic systems were very selective and more active than the previously reported catalysts. Cationic Ru" complexes 128 with a picolyl-functionalized NHC catalyzed the N-alkylation of amines under mild conditions. Ru" complexes 129, with benzimidazol-2-ylidene, gave excellent yields of <99% for the alkylation of various amines using benzylic and aliphatic alcohols at 130 C under solvent free conditions. ... 

The N-alkylation of secondary amines was also examined under the same catalytic conditions. Reactions of N-methylaniline and N-methylbenzylamine with benzyl alcohol gave the corresponding tertiary amines in good yields (Scheme 5.20). 

Table 5.10 N-Alkylation of primary amines with various primary and secondary alcohols catalyzed by [Cp lrCl2]2 (1)- ...

In the synthesis of analogues of calicheamicin 71 and esperamicin Ajb, Moutel and Prandi employed the glycosyla-tion of a nitrone with a trichloroacetimidate as a key step - /3-N-O glycosidic bond formation. Preparation of the nitrone begins with the alkylation of the known alcohol 69 <1992CC1494> with 1,4-dibromobutane in the presence of sodium hydride. Subsequent aminoalkylation, amine protection with 9-fluorenylmethoxycarbonyl (Fmoc), and reduction with NaBHsCN were followed by nitrone 70 formation with 4-methoxybenzaldehyde (Scheme 8) <2001J(P1)305>. 

Sulfonamides of primary amines are readily deprotonated (pAia 9-11) and can thus be N-alkylated or N-arylated. Because of their high nucleophilicity and low basicity, deprotonated sulfonamides also react smoothly with less reactive electrophiles, such as n-alkyl bromides [136] (Table 8.9). Sulfonamides can also be N-alkylated with aliphatic alcohols under Mitsunobu conditions. Suitable solvents for the N-alkylation of sulfonamides on polystyrene by Mitsunobu reaction are DCM, toluene, and THF. 

The Mitsunobu reaction is usually only suitable for the alkylation of negatively charged nucleophiles rather than for the alkylation of amines, and only a few examples of such reactions (mainly intramolecular N-alkylations or N-benzylations) have been reported (Entry 15, Table 10.2). Halides, however, are very efficiently alkylated under Mitsunobu conditions, and it has been found that the treatment of resin-bound ammonium iodides with benzylic alcohols, a phosphine, and an azodicarboxylate leads to clean benzylation of the amine (Entry 9, Table 10.3). Unfortunately, alkylations with aliphatic alcohols do not proceed under these conditions. The latter can, however, also be used to alkylate resin-bound aliphatic amines when (cyanomethyl)-phosphonium iodides [R3P-CH2CN+][r] are used as coupling reagents [62]. These reagents convert aliphatic alcohols into alkyl iodides, which then alkylate the amine (Entry 10, Table 10.3). 

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