Alkylation of anilines

Mono- and di-A-methylation of aniline are important reactions for the synthesis of intermediates in fine chemicals manufacture. Aniline methylation by methanol 

To investigate the methylation of aniline by methanol on basic zeolite CsOH/ Cs,NaY, the CF MAS NMR technique was combined with SF protocols (242 ). In the first period, these protocols allowed the observation of adsorbate complexes formed on solid catalysts under steady-state conditions. In subsequent periods, an identification of adsorbates acting as intermediates of the further reaction was carried out. 

The left-hand side of Figs 28a-c shows C CF MAS NMR spectra which were recorded during the conversion of pure C-enriched methanol on zeolite CsOH/ Cs,NaY under CF conditions at reaction temperatures of 473—523 K (242). As was observed previously (234-236), the conversion of methanol (49 ppm) on the basic zeolite catalysts caused the formation of surface formate species, leading to a C MAS NMR signal at 166 ppm. Upon cessation of the methanol flow at the reaction 

Mono- and di-A-methylation of aniline are important reactions for the synthesis 

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Another category Ic indole synthesis involves cyclization of a-anilino aldehydes or ketones under the influence of protonic or Lewis acids. This corresponds to retro.synthetic path d in Scheme 4.1. Considerable work on such reactions was done in the early 1960s by Julia and co-workers. The most successful examples involved alkylation of anilines with y-haloacetoacetic esters or amides. For example, heating IV-substituted anilines with ethyl 4-bromoacetoacetate followed by cyclization w ith ZnClj gave indole-3-acetate esterfi]. Additional examples are given in Table 4.3. 

Shape selective catalysts, such as ZeoHtes of the H-ZSM-5 type, are capable of directing alkyl groups preferentially to the para position (18). The ratio of the catalyst to the substrate also plays a role ia controlling the regiochemistry of the alkylations. For example, selective alkylation of anilines at the para position is achieved usiag alkylatiag ageats and AlCl ia equimolar ratio (19). 

Catalytic alkylation of aniline with diethyl ether, in the presence of mixed metal oxide catalysts, preferably titanium dioxide in combination with molybdenum oxide and/or ferric oxide, gives 63% V/-alkylation and 12% ring alkylation (14). 

V-Phenyl glycine [103-01 -5] the key intermediate for indigo, may be manufactured by alkylation of aniline with chloroacetic acid, but it is much more economical, even though three in situ stages are required, to use formaldehyde as the alkylating agent. 

This procedure illustrates a general method for the ortho-alkylation of anilines.4 It can be uttttzcd ftJT both anilines and mono-A7-substitu ted... 

Finally we must address the difference in rate between the in situ alkylation of aniline at the end of nitrobenzene hydrogenation and that found for the direct reaction between aniline and 1-hexanol. One significant difference between the systems is the presence of water. Two moles of water are produced for every mole of nitrobenzene converted so the final water concentration will be in excess of the aniline concentration. In the direct reaction no water was present. Water is a known poison for a range of catalytic reactions [8-11] and we have shown in our own laboratories that water will reduce the rate of nitrobenzene hydrogenation [12], Therefore it is likely that the deactivation of the aniline reaction after nitrobenzene hydrogenation is due to inhibition by water. 

Facile N -alkylation of anilines with alcohols in the presence of Raney nickel proved the high efficiency of the catalyst, which is a highly absorptive material for micro-... 

Mono-W-alkylation of anilines under soliddiquid two-phase conditions... 

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 general scheme is sufficiently flexible to permit the interchange of the order of some of the steps. Thus alkylation of aniline thioether (30-3) with 3-chloro-l-diethylaminopropane leads to the intermediate (31-1). Ring closure as above by nucleophilic aromatic displacement leads to the antipsychotic dmg chlorproethazine (31-2) [32]. 

Recently, a novel reaction mechanism was proposed for the alkylation of aniline with methanol on acidic zeolite HY (243). By SF MAS NMR spectroscopy, the formation and decomposition of N, AA-trimethylanilinium ions on the working catalyst were observed. Figure 29 shows the MAS NMR spectra recorded under CF conditions during methylation of aniline by methanol at reaction temperatures of 473-523 K. In these experiments, a mixture of aniline and C-enrichcd methanol (WjF — 40gh/mol) in a molar ratio of 1 2 was injected into the MAS NMR rotor... 

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

Stilbene compounds 4 were prepared according to Figure 2. N V-Dialkyl anilines 2 were synthesized by direct alkylation of aniline. 

Simple Af-alkyl- and Af,Af-dialkylanilines are readily prepared commercially by the alkylation of aniline with the appropriate alcohol. For example, N-methylaniline is prepared by heating a mixture of aniline hydrochloride (55 parts) and methanol (16 parts) at 120 °C in an autoclave. For N,N-dimethylaniline, aniline and methanol are mixed in the proportion 80 78, 8 parts of concentrated sulphuric acid are added and the mixture heated in an... 

N-Alkylation of aniline by alcohols. The Ru(II) complex catalyzes the alkylation of aniline by alcohols. If the reaction is prolonged, dialkylation is observed. Alkylation with allylic alcohols results in 2,3-dialkylquinolines (equation I).1... 

During the same year, both an acid-catalyzed [60] and a TiCl4-catalyzed [61] ortho-alkylation of anilines with styrene were published, but offering only a very low selectivity. The reaction of anisole and styrene catalyzed by Mo(CO)6 [62] afforded the corresponding branched diaryl product with a comparable yield and selectivity as shown by our protocol. Furthermore, Michelet and coworkers successfully employed substituted styrenes in a gold-catalyzed tandem Friedel-Crafts-type addition-carbocyclization reaction [63]. 

In the alkylation of aniline to diethylaniline by heating aniline and ethyl alcohol, sulfuric acid cannot be used because it will form ether consequently, hydrochloric acid is employed, but these conditions are so corrosive that the steel used to resist the pressure must be fitted with replaceable enameled liners. 

A series of pyrrolidines was conveniently prepared in a microwave-assisted double alkylation of aniline derivatives with alkyl dihalides in water in the presence of K2CO3 as a base (Scheme 1) [12,13]. Although the reaction mixture could be regarded as a multi-phase system, as neither reactant was soluble in the mildly basic aqueous medium, the microwave-assisted reaction proceeded readily without the use of phase-transfer reagents. The amount of side-reactions such as hydrolysis of bromides to alcohols in an alkaline reaction medium was substantially suppressed compared to the conventional thermal conditions. The reaction conditions were sufficiently mild to tolerate a variety of functional groups in anilines such as hydroxyls, ketones and esters. Alkyl bromides and tosylates were equally efficient as alkylating agents. Notably, isolation and purification comprised simply of phase separations (filtration or decantation) of the desired product from the aqueous media. 

A novel double alkylation of aniline derivatives by alkyl dihalides occurred in mildly basic aqueous media upon microwave irradiation and afforded a series of N-aryl azacycloalkanes (Scheme 22) [89]. 

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