Heterocyclic compounds aniline derivatives

Meerwein reactions can conveniently be used for syntheses of intermediates which can be cyclized to heterocyclic compounds, if an appropriate heteroatom substituent is present in the 2-position of the aniline derivative used for diazotization. For instance, Raucher and Koolpe (1983) described an elegant method for the synthesis of a variety of substituted indoles via the Meerwein arylation of vinyl acetate, vinyl bromide, or 2-acetoxy-l-alkenes with arenediazonium salts derived from 2-nitroani-line (Scheme 10-46). In the Meerwein reaction one obtains a mixture of the usual arylation/HCl-addition product (10.9) and the carbonyl compound 10.10, i. e., the product of hydrolysis of 10.9. For the subsequent reductive cyclization to the indole (10.11) the mixture of 10.9 and 10.10 can be treated with any of a variety of reducing agents, preferably Fe/HOAc. 

Phthalic anhydride condenses with the aniline derivative in the presence of zinc or aluminum chlorides to yield the intermediate benzoyl-benzoic acid, which subsequently reacts with l,3-bis-V,V-dimethylaniline in acetic anhydride to yield the phthalide. The above compound gives a violet-gray image when applied to a clay developer. Clearly this synthesis is also very flexible and variations in shades of color formers have been obtained by varying the aniline components and also by using phthalic anhydrides substituted, for example, by nitro groups or chlorine atoms. Such products have excellent properties as color formers and have been used commercially. Furthermore, this synthetic route is of great importance for the preparation of heterocyclic substituted phthalides, as will be seen later. 

Notes Used for allylic and benzylic brominations (Wohl-Zieeler Reaction). With moist DMSO the reagent is useful for bromohydrin formation, providing trans addition of bromine and water. Can brominate alpha to carbonyl in carbonyl (carboxyl)-containing compounds. With DMF useful for aromatic bromination of activated aromatic rings, such as phenols, aromatic ethers, aniline derivatives and activated heterocyclic compounds. For similar chemistry, see also NBA, N-Bromoacetamide. 

There have been several reports of the use of intramolecular displacements of nitro groups in the synthesis of heterocyclic compounds. Thus, reaction16 of the intermediate (2) with a strong base in DMF results in the substitution of a nitro group by the amide function to yield a dibenzothiazepinone derivative (3). Nucleophilic addition across the double bond of 2,4,6-trinitrostyrene may occur with thiophenol, aniline, and aliphatic amines. The adducts so formed with primary amines may undergo intramolecular substitution of an o-nitro group to give IV-substituted 4,6-dinitroindoles.17... 

Oxidative amination of aromatic amines which are less basic than aliphatic amines proceeds smoothly without protection of amines. The intramolecular reaction of aniline derivatives offers good synthetic methods for heterocycles. 2-Methylindole is obtained by 5-exo amination of 2-allylaniline [50]. As an application, A-methyl-2-methyl-3-siloxyindole 114 was prepared from A-methyl-2-(l-siloxyallyl)aniline 113. Without silyl protection, no reaction occurred [51]. If there is another olefinic bond in the same molecule, the aminopalladation product 116 of the amide 115 undergoes olefin insertion to give the tricyclic compound 117 [50]. 2,2-Dimethyl-1,2-dihydroquinoline (119) was obtained by 6-endo cyclization of 2-(3,3-dimethylallyl)aniline (118). 

Oxidative Couplings of Heterocyclic Hydrazones. This method has opened the way to the preparation of azo derivatives of diazo compounds unobtainable by other means, ie, heterocycHc compounds ia which the diazotizable amino group is conjugated with the heterocycHc nitrogen atom as ia 2- and 4-amiQopyridine, compounds which do not normally yield stable diazonium salts (38). The reaction occurs as illustrated by equation 7 for the iateraction of (A/-methylcarbostyryl)hydrazone [28219-37-6] and dimethyl aniline the overall process is oxidation. 

To get a complex set of substituents by direct derivatization of benzotriazole is not feasible. In such situations, it is better to have all the substituents in place first and later construct the heterocyclic ring. High reactivity of anilines and their well-developed chemistry makes them good stating materials. In an example shown in Scheme 215, acetanilide 1288 is nitrated to afford nitro derivative 1289 in 73% yield. Catalytic reduction of the nitro group provides methyl 4-acetylamino-3-amino-5-chloro-2-methoxybenzoate 1290 in 96% yield. Nitrosation of compound 1290 in diluted sulfuric acid leads to intermediate 1291, which without separation is heated to be converted to 7-chloro-4-methoxy-l//-benzotriazole-5-carboxylic acid 1292, isolated in 64% yield <2002CPB941>. 

Rearangement of furoxans leads to the formation of new heterocyclic systems derivatives of triazoles, diazoles, isoxazoles, and pyrimidinones. For example, on the basis of the experimental results using labeled compound 52-15N , the formation of 8-phenyltheophylline 53, the 1,3-dimethylalloxazines (54 n = 0, 1), and l,3,7,9-tetramethyl-l//,9//-pyrimido[5,4-g]-pteridine-2,4,6,8-tetraone 55 in the thermal reaction of the iV-oxide 52 with benzylamine, aniline, or piperidine and the generation of NO or NO-related species in the reaction with iV-acetylcysteamine were reasonably explained by... 

The structure of sulfonamides is shown for representative purposes. Among the several thousand compounds in existence, about 25-30 have found widespread use. Sulfanilamide itself is, by present-day standards, very inactive. It was the development of heterocyclic derivatives that produced the highly potent sulfathiazole (9.90). When a succinyl or phthalyl group is attached to the aniline nitrogen, the inactive acylanilide derivatives will not be absorbed from the intestinal tract. Slow deacylation by intestinal... 

Similarly, reclosure to a new heterocyclic system after ring opening is possible in benzo[c] derivatives (158) in these last compounds initial attack is always in the a-position adjacent to the benzene ring because of partial double bond fixation. By contrast, ring opening of an a(3-benzo derivative gives a phenol or aniline (159) in which the Z—C bond is not easily broken. 

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