For alkylation of amines

The reagent is recommended as the base for alkylation of amines and for dehydro-halogenation (see Ethyidiisopropylamine). It has been used as proton acceptor in the reaction of carboxylic acids with phenacyl bromide in acetone to form the phenacyl esters. Unlike triethylamine, usually used for this purpose, the hydrochloride of the reagent is soluble in acetone and other water-miscible solvents. In the presence of ethyldicyclohexylamine, dimethyl and diethyl sulfate convert carboxylic acids into their esters in high yield. The commercially available hindered amine tris(2-hydroxypropyl)amine, [CH3CH(OH)CH2]sN, Eastman s 1,1, 1-nitrilotri-2-propanol, can be used but is somewhat less satisfactory. 

A similar mechanism has been proposed for the alkylation of amines by p-nitrocumyl chloride. 

Coe et al. reported an efficient modification for the preparation of /-substituted indole analogs for biology screening in good yield. The intermediate P-nitrostyrene 44, prepared from the condensation of 43 with DMFDMA, underwent methanolysis and reduction to provide the aniline acetal intermediate 45. Alkylation of amine 45 was carried out employing standard conditions of reductive alkylation to provide A-alkyl analogs represented by 46. The indole 47 was generated by formation of the oxonium ion (from 46) under acidic conditions, followed by cyclization, accompanied by loss of methanol. 

Hydroxyalkyl sulphoxides 515 can be dehydrated either by treatment with phosphoric acid (equation 315) or by the alkylation with Mel in the presence of an excess of sodium hydride611 (equation 316). For other dehydration reactions see References 475 and 505 (Section IV.A.2.d). For elimination of amines see References 164 and 529 (Section IV.A.2.e). 

Amides are weakly nucleophilic and react only slowly with alkyl halides. The anions of amides are substantially more reactive. The classical Gabriel procedure for synthesis of amines from phthalimide is illustrative.58... 

The formation of resin-bound tert.-alkyl carbamates for anchoring of amines was recently described [209a]... 

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... 

HZ Sommer, HI Lipp, LL Jackson. Alkylation of amines. A general exhaustive alkylation method for the synthesis of quaternary ammonium compounds, (effects of hindrance) J Org Chem 36, 824, 1971. 

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... 

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 phosphate method has not been synthetically useful for alkylation of anilines of low basicity such as -nitro- or p-trifluoroaniline. Only monoalkylation occurs in introducing branched-chain alkyl groups such as isopropyl. Use of this method for alkylation of aliphatic amines has not been reported. 

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 [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 previous sections have dealt primarily with reactions in which the new carbon-carbon bond is formed by an SN2 reaction between the nucleophilic carbanions and the alkylating reagent. Another important method for alkylation of carbon involves the addition of a nucleophilic carbon species to an electrophilic multiple bond. The electrophilic reaction partner is typically an a,/i-unsaturated ketone, aldehyde, or ester, but other electron-withdrawing substituents such as nitro, cyano, or sulfonyl also activate carbon-carbon double and triple bonds to nucleophilic attack. The reaction is called conjugate addition or the Michael reaction. Other kinds of nucleophiles such as amines, alkoxides, and sulfide anions also react similarly, but we will focus on the carbon-carbon bondforming reactions. 

These new, uncharged amine bases are strong enough (pXa of 4 in acetonitrile is 42.62) to deprotonate esters or lactones, where they can even be used with advantage over the more conventional bases like LDA or metal hcxamethyldisilazanides. For example, the alkylation of dimethyl isopropylidene tartrate with n-alkyl iodide is not possible with the latter bases but can be achieved with phosphazene-base P4-t-Bu or phosphazene-base P4-t-Oct24. With phos-phazene-base P4- -Bu the yield of 8 is 41 % with 28 % of recovered starting material 6, whereas with phosphazene-base P4-i-Oct the yield of 8 is 71 % with only 9% of 6 left unreacted. (For alkylations of 6 with other more active electrophiles see later.)... 

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). 

Long-chain alkyl chlorides can be used lor the synthesis of various amines, while benzyl chloride is used for production of quaternary ammonium compounds. Alkyl chlorides are used for the formation of organometallics, including the Grignard reagents as well as for alkylation of aromatics. One of the important reactions or phosgene is with diamines for production of diisocyunates (polyurethanes). 

The increasing industrial demand for alkylated aromatic amines initiated research to develop heterogeneous catalytic process for the alkylation of aniline and alkyl anilines. 

Gives /V-alkylamides good only for alkenes (or alcohols) that form relatively stable carbonium ions useful for preparation of amines with tert-alkyl groups by hydrolysis of amides (Section 24-3B). 

Note that these group rate constants and substituent group factors should be used only for homologs of the compounds from which these factors were derived (Kwok and Atkinson, 1995 Koch et al., 1996). For example, the group rate constants k, N, k>NH and k N,l2 and the substituent factors F(-NH2), F(>NH) and F(>N-) are appropriate only for alkyl-substituted amines and not for amines containing halogen or other hetero-atoms (in particular, see Koch et al., 1996). For the phosphorothioamidates (with ->P(=S)N< structures) and... 

The most conspicuous property of aliphatic amines, apart from their fishy smell, is their high basicity, which usually precludes N-alkylations under acidic reaction conditions (last reaction, Scheme 6.3). Hence, alkylation of amines with tertiary alkyl groups is not usually possible without the use of highly stabilized carbocations which can be formed under basic reaction conditions. Rare exceptions are N-alkyla-tions of amines via radicals (Scheme 4.2), copper-catalyzed propargylations (Scheme 6.3), and the addition of amines to some Michael acceptors and allyl palladium or iridium complexes. Better strategies for the preparation of tert-alkylamines include the addition of Grignard reagents to ketone-derived imines [13] or the reduction of tert-alkyl nitro compounds. 

The reduction of nitroso compounds in the presence of ketones can be used for the reductive alkylation of amines ... 

---