Anilines rearrangement reactions

A similar reaction, the rearrangement of m-phenylenediamine was patented by Bayer (Figure 1) [6]. In this patent, a much higher conversion and a better selectivity than obtainable with aniline was reported. Two reaction mechanisms were proposed for the aniline rearrangement reaction [3,7]. In this contribution, we will discuss this interesting reaction and report on some studies on process variables and on the reaction mechanism. As a model compound, we used m-phenylenediamine because of the higher conversion and relatively milder reaction conditions required for its conversion into 2-amino-6-methylpyridine (a-amino-a -picoline). 

Nowhere, perhaps, is this phenomenon better illustrated than in the phenothiazine class. The earlier volume devoted a full chapter to the discussion of this important structural class, which was represented by both major tranquilizers and antihistamines. The lone phenothiazine below, flutiazin (130), in fact fails to show the activities characteristic of its class. Instead, the ring system is used as the aromatic nucleus for a nonsteroidal antiinflammatory agent. Preparation of 130 starts with formylation of the rather complex aniline 123. Reaction with alcoholic sodium hydroxide results in net overall transformation to the phenothiazine by the Smiles rearrangement. The sequence begins with formation of the anion on the amide nitrogen addition to the carbon bearing sulfur affords the corresponding transient spiro intermediate 126. Rearomatization... 

The rearrangement reaction continues to be of synthetic utility, often involved in industrial processes. Patent references (e.g. Reference 48) refer to the formation of 4-amino phenols. Often the reactant nitro compound is reduced (to the hydroxylamine) in an acid environment so that the two-stage reaction can be accomplished as a one-pot synthesis. 4-Amino phenol itself 45 can be made in high yield directly from nitrobenzene49 and the 4-methoxy aniline derivative 46 similarly from 2-methylnitrobenzene by hydrogenation in MeOH/H2S0450. 

Fisons PLC (UK) also had an early interest in the PPI area. Apparently, by having an early understanding of the chemical mechanism for the acid rearrangement reaction, they devised two novel ideas (a) to exchange the pyridine in omeprazole for an N-alkyl- and N,N-dialkyl-substituted aniline moiety and (b) to exchange the methylene as a connecting chain for a phenylene unit. At least one compound of this latter type, FPL 65372 [28] was quite active in early human testing, but no compound of this type ever reached the market (Fig. 2.14). 

Nitrosamine and para Nitroso Methyl Aniline.—The reaction with nitrous acid is characteristic of secondary amines and yields phenyl methyl nitrosamine, the nitroso group entering the amino radical. This, however, undergoes rearrangement with the transference of the nitroso group to the ring yielding a nitroso benzene compound. 

Diazo amino Compounds.—In the case of para primary di-amines and primary mono-amines such as aniline, the reaction does not take place in this way. It was found later, however, that primary monoamines did yield azo compounds by a molecular rearrangement of an intermediate diazo amino compound. 

Hofmann established a route to higher homologues of aromatic amines by intramolecular rearrangement of /V-alkylated anilines, a reaction that was of great theoretical and technical importance. In 1870, he reported the conversion of an acid amide into an amine, with loss of one carbon. In 1881, he discovered that when the degradation was carried out with sodium hypochlorite or hypobromite, the yields of primary amines were excellent. This is the Hofmann degradation, or reaction, that takes place via formation of isocyanate60. 

In an nmr study of the reaction of N,N-dimethylbenzylamine with benzyne, Lepley 98> observed a free radical intermediate (path 8) which is formed from the ylid and which rearranges to N-methyl-N-(a-phen-ethyl)aniline via a Stevens rearrangement. Prior to this report 8 ") radical intermediates had not been observed in the Stevens rearrangement but their presence had been suggested m>. This radical path must be considered in all reactions of nitrogen ylids for it may be the route by which many rearrangement reactions occur. 

In order to learn more about the reaction mechanism and the scope of the aniline rearrangement, additional substrates were tested. Experiments with toluidines (methylpyridines) showed a substantial isomerisation and disproportionation of the substrate (Table 4) due to the methyl-shift reaction on the highly acidic catalyst. Selectivities are low due to disproportionation reaction of the reactants and a large amount of di- and trimethylated reactants and several addition products were formed (which explains the missing 60% in the reaction of o-toluidine). 

The reaction of the benzopyranylnitrones (166) with sulfene also gave the benzopyranyl-1,2,5-benzoxathiazepines (167) in hi yields (Scheme 26) <93S468>. The dihydro-1,2,5-benzoxathiazepines (170) can also be prepared in about 50% yields through a novel rearrangement reaction of the unstable cycloadducts (169), formed initially by treatment of sulfene with 7V-benzilidene-2-hydroxy-anilines (168) <8icc97i>. 

Attack on the electrophilic C-2 may occur as in the 2-aminothiazoles series, which probably explains the rearrangements observed in acidic medium (121, 711, 712, 723, 724), in aqueous medium with NaOAc (725), or with aqueous NaHCOj (725) (Scheme 232). That the initial attack probably involves the C-2 atom is substantiated by the fact that this rearrangement occurs under extremely mild conditions for 2-iinino-3-substituted-5-nitro-4-thiazolines (725). As the whole mechanism proposed (see p. 92) is reversible, when imino derivatives are submitted to such rearrangement conditions the rearrangement is expected to occur faster if steric interaction between 3- and 4-substituents exists in the 2-imino isomer. Another reaction may occur in acidic medium phenylimino-2-bipheny]-3,4-4-thiazoline hydrolyzed with hydrochloric acid gives the corresponding 4-thiazoline-2-one and aniline (717). 

V-Alkylaniline and /V,/V-di alkyl aniline hydrochlorides can be rearranged to C-alkyl anilines by heating the salts to 200—300°C. In this reaction, known as the Hofmann-Martius rearrangement, the alkyl group preferentially migrates to the para position. If this position is occupied, the ortho position is alkylated. 

Primary aromatic amines (e.g., aniline) and secondary aliphatic-aromatic amines (e. g., 7V-methylaniline) usually form triazenes in coupling reactions with benzenedi-azonium salts. If the nucleophilicity of the aryl residue is increased by addition of substituents or fused rings, as in 3-methylaniline and 1- and 2-naphthylamine, aminoazo formation takes place (C-coupling). However, the possibility has also been noted that in aminoazo formation the initial attack of the diazonium ion may still be at the amine N-atom, but the aN-complex might rearrange too rapidly to allow its identification (Beranek and Vecera, 1970). 

The Sn2 reaction of quinazolinone 147 with phenylhydrazine was followed by rearrangement of the tautomerized intermediate 148 <00T7987>. The loss of both ammonia and aniline was followed by the addition of a second equivalent of phenylhydrazine to the resulting imine to produce quinazolinone hydrazone 149. Subsequent Fischer indolization of 149 followed by condensations with aldehydes led to 7-azarutacarpines. 

Initially, a reaction of A-acetoxy-A-butoxybenzamide 25c with A-methyl aniline 61 in butyl benzoate 63(R = Bu) and acetic acid. Close examination of these highly coloured reaction mixtures indicated the presence of crystals of A,A-dimethyl-A,A-diphenyltetrazene 65 (Scheme 11, R = Bu). The reaction is promoted by polar solvents as reactants are unchanged in pure acetonitrile. A crossover experiment using a mixture of /V- a ce t o x y - A-- b u t o x y - to 1 u a m i d e 26d and A-acetoxy-A-ethoxybenz-amide 25a afforded clean yields of butyl /Moluatc and ethyl benzoate thus pointing to an intramolecular rearrangement.41... 

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