Arylation of Nitrogen Nucleophiles

Preparation of aromatic amines by the reaction of aryl halides with aliphatic and aromatic amines has been regarded as a difficult reaction. Recently a facile synthetic method for aromatic amines by amination of aryl halides has been discovered, and rapid progress has occurred in the Pd-catalyzed reaction of amines with aryl halides [1]. One simple example which shows the usefulness of the new method is cited here. The commercially important arylpiperazines 1 have been synthesized by intramoleular N-alkylation of aniline derivatives with N,N-di-(2-chloroethyl)amine (2), which is highly carcinogenic. Now the amines 3 can be prepared efficiently by coupling aryl iodides, bromides or chlorides with N-substituted piperidines. This example provides a big contribution to synthetic chemistry by the new Pd-catalyzed efficient preparative method for arylamines, which are usefial in medicinal and material chemistry. 

The first report on the Pd-catalyzed preparation of arylamines by the reaction of aryl bromides with A,N-diethylaminotributyltin (4) was given by Kosugi et al. in 1983. A poor result was obtained with aryl iodides. In this reaction, bulky P(o-To1)3 was used as the most suitable ligand [2]. 

The success of the new method is due to selection of bases which are stable under the reaction conditions and also the use of bulky phosphine ligands. Later, reductive elimination was fovmd to be crucial in the C—N bond formation, which is accelerated by bulky ligands. As bases, MN(TMS)2 (M = Li, Na, K) and r-BuONa give good results. Alkoxides such as MeONa, EtONa, and n-BuONa seem to be unsuitable, because oxidation of alcohols and reduction of aryl halides occur via facile jS-H elimination of the palladium alkoxide 5. 

Aryl iodides, bromides, chlorides, triflates and some tosylates are used for the arylamine synthesis. Secondary (dialkyl, alicyclic, alkyl-aryl, and diarylamines) and primary amines (alkyl and arylamines) participate in the reaction with different reactivity. In general, more basic and less bulky amines react faster. 

Generally aryl bromides are better substrates than aryl iodides. A disappointing result was obtained in the reaction of aryl iodides when IV-1 was used as a ligand. Satisfactory results were obtained by using IV-2, IV-12 and xantphos (IX-10). Reaction of o-iodoanisole 5c with morpholine using IX-10 provided 5d in 94% yield [6]. 

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Recently, Taillefer et al. reported an Fe/Cu cooperative catalysis in the assembly of N-aryl heterocycles by C—N bond formation [90]. Similarly, Wakharkar and coworkers described the N-arylation of various amines with aryl halides in the presence of Cu—Fe hydrotalcite [91]. Interestingly, Correa and Bolm developed a novel and promising ligand-assisted iron-catalyzed N-arylation of nitrogen nucleophiles without any Cu co-catalysts (Scheme 6.19) [92]. Differently substituted aryl iodides and bromides react with various amides and N-heterocycles. The new catalyst system consists of a mixture of inexpensive FeCl3 and N,N -dimethylethylenediamine (dmeda). Clearly, this research established a useful starting point for numerous future applications of iron-catalyzed arylation reactions. 

A formally related yet most likely Ullman type of arylation of nitrogen nucleophiles was reported most recently. A bimetallic catalytic system of Fe(acac)3—CuO was shown to be highly active in the simple arylation of a variety of N-heterocycles with aryl iodides and bromides in the presence of CsC03. Although a deeper mechanistic understanding awaits further investigations, the broad scope plus its operational simplicity make this procedure especially amenable to applications on an industrial scale (Scheme 7.6) [10]. 

Chouhan, G., Wang, D., and AJper, H. 2007. Magnetic nanoparticle-supported proline as a recyclable and recoverable ligand for the Cul catalyzed arylation of nitrogen nucleophiles. Chem. Commun. (45) 4809-4811. 

In addition to bromides and iodides, the reaction has been successfully extended to chlorides,163 triflates,164 and nonafluorobutanesulfonates (nonaflates).165 These reaction conditions permit substitution in both electron-poor and electron-rich aryl systems by a variety of nitrogen nucleophiles, including alkyl or aryl amines and heterocycles. These reactions proceed via a catalytic cycle involving Pd(0) and Pd(II) intermediates. 

A number of nitrogen nucleophiles can be arylated by triflates, and this methodology has found application, for example, in the synthesis of nonsteroidal selective glucocorticoid modulators [91]. However, triflates are not always practical due to their sensitivity toward moisture and strong nucleophiles such as NaOtBu, which is still the most often utilized base in aminations. Buchwald et al. [92] reported the efficient coupling of nonaflates as an appealing alternative to triflates (Scheme 13.30). 

The arylation of nitrogen-containing heterocycles, such as benzotriazole, with aryl iodides can be done only in anhydrous media under rather harsh conditions (DMSO, DBU, 120°C, Pd2(DBA)3-CHCl3) No reaction occurred in the presence of the water-soluble TPPMS ligand. However, the arylation can be accomplished with diaryliodonium salts in neat water under phosphine-less conditions and in the absence of copper salt promoter [88]. Both products of substitution are formed, as the anion of benzotriazole is an ambident nucleophile ... 

A variety of nitrogen nucleophiles have been utilized in Pd-catalyzed 77-alkenylation reactions. For example, Bolm has employed iV-alkenylation reactions for the preparation of iV-alkenyl sulfoximines (Eq. 18) [140], and Yudin has applied this method to the synthesis of W-alkenyl aziridines (Eq. 19) [141]. Analogous W-arylation reactions of sulfoximines and aziridines have also been developed [142, 143]. Movassaghi has effected W-alkenylation reactions between functionalized alkenyl triflates and several aromatic nitrogen heterocycles including indoles and pyrroles (Eq. 20) [144]. The use of p-chloroacrolein derivatives as substrates in iV-alkenylation reactions has also been illustrated [145, 146]. 

This chapter covers the C(aryl)-N bond formation via copper-catalyzed coupling of nitrogen nucleophiles (N-heterocycles, amines, anilines, amides, ammonia, azides, hydroxylamines, nitrite salts, phosphonic amides) with aryl hahdes. The C(aryl)-N bond formation as a result of the coupling between these nucleophiles and arylboronic acids (the Chan-Lam reaction) will be presented, too. 

In an update [57, 58], of a 2002 report [59], Buchwald et al. described a very competitive catalytic system based on the use of 1,2-diamine ligand Lll for the coupling of aryl bromides with a very wide range of nitrogen nucleophiles (Table 1, entry 8). 

Since a decade, impressive progressions have been accomplished for the copper-catalyzed formation of C(sp )-N bonds. Both Ullmann and Chan-Lam reactions have permitted the coupling of a wide array of nitrogen nucleophiles with aryl/vinyl halides and boronic acids, respectively. The simplicity of the ligands, when necessary, their commercial availability and the low cost of copper make these reactions very attractive compared to palladium cross coupling, though the latter are considered complementary one to another. 

The volume highlights in the first chapter, written by Lemen and Wolfe, the discovery and the development of original palladium-based catalysts for C(sp )-N bond formation via the coupling of nitrogen nucleophiles and aryl/alkenyl halides and pseudohalides. The authors also report various applications of these transformations to the synthesis of useful compounds, including biologically active molecules and materials. 

In a classic study in 1940, Crossley and coworkers demonstrated that the rates of nucleophilic substitution of the diazonio group of the arenediazonium ion in acidic aqueous solution were independent of the nucleophile concentration, and that these rates were identical with the rate of hydrolysis. Since that time it has therefore been accepted without question that these reactions proceed by a DN + AN mechanism, i.e., that they consist of a rate-determining irreversible dissociation of the diazonium ion into an aryl cation and nitrogen followed by rapid reactions of the cation with water or other nucleophiles present in solution (Scheme 8-6). 

Introduction of Other Nucleophiles Using Diazonium Ion Intermediates. Cyano and azido groups are also readily introduced via diazonium intermediates. The former involves a copper-catalyzed reaction analogous to the Sandmeyer reaction. Reaction of diazonium salts with azide ion gives adducts that smoothly decompose to nitrogen and the aryl azide.56... 

The addition-elimination mechanism has been used primarily for arylation of oxygen and nitrogen nucleophiles. There are not many successful examples of arylation of carbanions by this mechanism. A major limitation is the fact that aromatic nitro... 

Synthesis of quinolines by nucleophilic substitution of nitrogen atom in oxime derivatives was described by Narasaka and coworkers. /3-Aryl ketone oximes 297 in the presence of trifluoroacetic anhydride and 4-chloranil afforded quinolines 298 in 72-82% yield (equation 128). However, interaction of oxime 299 with 48% HBr at 105 °C proceeded with elimination of hydroxyimino group and gave 2,3-dimethoxynaphtho[l,2-fc]quinolizinium bromide (300) in 45% yield (equation 129). ... 

Due to their synthetic accessibility, phenoxazines of the type 8 are the best-known 1,4-oxazines whose 4-nitrogen has been reacted with electrophiles. The nucleophilicity of this nitrogen can be compared to that of diphenylamine, and numerous examples of alkylation and acylation have been reviewed already in early literature <1962HC(17)377>. This section therefore includes only examples of N-arylation of phenoxazines (Equation 3) that were not included in CHEC(1984) <1984CHEC(3)995>. 

A variety of methods exist for the formation of 1,2-thiazines via the construction of an S-N bond by nucleophilic attack of nitrogen onto a sulfur-bearing leaving group. For example, the reaction of aryl bromide 189 with potassium thiocyanate in the presence of copper(l) iodide and triethylamine affords benzothiazine 190, although in low yield and as a mixture with indoline by-product 191 (Equation 28) <2000JOC8152>. 

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