Heterocycles 1-anilines

A number of heterocyclic aniline derivatives afforded moderate to good yields of the diarylamines. Among the reported systems were amino-indazole,106,106a aminobenzodioxole,107 and aminobenzodioxanne.98,108 In the latter series, good to excellent yields were obtained with the primary aniline, but modest yields were observed after monoalkylation of the amino group (Equation (81)). 

Esters Benzyl benzoate 10 Amines and Heterocyclics Aniline 3... 

Finally, Somei reported the use of a Sandmeyer bromination to access variably substituted indole heterocycles. Anilinic compounds 46 and 47 were efficiently diazotized and brominated to provide the tribromides 48 and 49 in 81% and 78% yields, respectively. 

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. 

Aminofurans substituted with electron-withdrawing groups e.g. NO2) are known and 3-amino-2-methylfuran is a relatively stable amine which can be acylated and diazotized. 2-Amino-3-acetylfurans are converted into 3-cyano-2-methylpyrroles on treatment with aqueous ammonia. This transformation is a further illustration of the relative instability of the amino derivatives of five-membered ring heterocycles compared with anilines (Scheme 67) (781003821). 

Because of the structural requirements of the bielectrophile, fully aromatized heterocycles are usually not readily available by this procedure. The dithiocarbamate (159) reacted with oxalyl chloride to give the substituted thiazolidine-4,5-dione (160) (see Chapter 4.19), and the same reagent reacted with iV-alkylbenzamidine (161) at 100-140 °C to give the 1 -alkyl-2-phenylimidazole-4,5-dione (162) (see Chapter 4.08). Iminochlorides of oxalic acid also react with iV,iV-disubstituted thioureas in this case the 2-dialkylaminothiazolidine-2,4-dione bis-imides are obtained. Thiobenzamide generally forms linear adducts, but 2-thiazolines will form under suitable conditions (70TL3781). Phenyliminooxalic acid dichloride, prepared from oxalic acid, phosphorus pentachloride and aniline in benzene, likewise yielded thiazolidine derivatives on reaction with thioureas (71KGS471). 

Polyfluorinated a-diketones react with 1,2-diainino compounds, such as ortlio-phenylenediamine, to give 2,3-substituted quinoxalmes [103] Furthermore, the carboxyl function of trifluoropyruvates offers an additional electrophilic center. Cyclic products are obtained with binucleophiles [13, 104] With aliphatic or aromatic 1,2-diamines, six-memhered heterocycles are formed Anilines and phenols undergo C-alkylation with trifluoropyruvates in the ortho position followed by ring closure to form y-lactams and y-lactones [11, 13, 52, 53, 54] (equation 23). 

Nearly every substitution of the aromatic ring has been tolerated for the cyclization step using thermal conditions, while acid-promoted conditions limited the functionality utilized. Substituents included halogens, esters, nitriles, nitro, thio-ethers, tertiary amines, alkyl, ethers, acetates, ketals, and amides. Primary and secondary amines are not well tolerated and poor yield resulted in the cyclization containing a free phenol. The Gould-Jacobs reaction has been applied to heterocycles attached and fused to the aniline. 

As previously described, the Gould-Jacobs reaction has been applied to heterocycles fused to anilines, and to some amino-substituted heterocycles. Selectivity of N- and C-cyclization of 2-aminopyridino-methylene malonates has been mentioned (51 and 56). The normal mode of cyclization of 2-aminopyridino-methylene malonates is on the nitrogen to form a pyridopyrimidine. If an electron-donating group (EDG) is in the 6-... 

CaveU and Chapman made the interesting observation that a difference exists between the orbital involved in the quatemization of aromatic nitrogen heterocycles and aromatic amines, which appears not to have been considered by later workers. The lone pair which exists in an sp orbital of the aniline nitrogen must conjugate, as shown by so many properties, with the aromatic ring and on protonation or quatemization sp hybridization occurs with a presumed loss of mesomerism, whereas in pyridine the nitrogen atom remains sp hybridized in the base whether it is protonated or quaternized. Similarly, in a saturated compound, the nitrogen atom is sp hybridized in the base and salt forms. 

Synthesis of heterocycles by ring closure of orr/io-substituted r-anilines 96AHC(65)1. 

The isosteric relationship of benzene and thiophene has often led medicinal chemists to substitute the sulfur containing heterocycle for benzene drugs in biologically active molecules. That this relationship has some foundation in fact is attested by the observation that the resulting analogs often possess full biologic activity. Alkylation of the diamine, 71 (obtained from aniline and the chloroethylamine), with 2-chloromethylthiophene affords the antihistamine methaphenylene (72) The correspond-... 

Physostigmine (36) is actually a complex fused heterocycle iMther than a simple derivative of aniline. The drug is men-... 

The relative inaccessibility of physostigmine led to molecular dissection studies to define the parts of the molecule necessary for activity. A surprisingly simple derivative of m-hydroxy-aniline, neostigmine (40), proved to have the same activity as the complex heterocyclic molecule. In addition, this drug has found use as a cholinsterase inhibitor in pathologic conditions such as myasthenia gravis, marked by insufficient muscle tone. Reaction of m-dimethylaminophenol (37) witn pnosgene affords tne... 

Cleavage of the heterocycle is observed when oxepin reacts with l-chloro-4-nitrosobenzene to give 4-chloro-AL(6-oxohexa-2,4-dienylidene)aniline iV-oxide (6) in 62% yield.215... 

The base of the aniline derivative has zero charge, and therefore H0 has to be used in 2-aminothiazole the heterocyclic nitrogen is protonated first and at much lower acidities than is the amino group (see Sec. 3.2). The protonation of the amino group of a cationic species therefore has to be treated using the H+ function (Rochester, 1970). 

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. 

Finally, Katritzky et al.sii have measured first-order rate coefficients for deuteration of pyrimidines by deuterated sulphuric acid (Table 152), and all pD and —D0 values given in the Table refer, as in the earlier work, to a temperature of 20 °C. For 2-aminopyrimidine, reaction clearly occurs on the free base and comparison of the data with the earlier work on anilines and by making a number of assumptions, conjugate acid at higher acidities is apparent and this follows the previously established pattern. This work yielded a value of 0.55 for [Pg.236]

The scope and mechanism of the isomerization of arylamines to methyl-substituted aromatic heterocycles have been studied. Aniline, toluidines, naphthylamines and m-phenylenediamine all gave the corresponding ortho-methyl-substituted aza-aromatics when exposed to high NHj pressure and elevated temperature in the presence of acid catalysts, e.g., zeolites. The yiel of pyridines formed by this process range from low to moderate <95JC(155)268>. 

The availability of aniline has made possible a direct study of the reactions of aniline with humic and fulvic acids (Thom et al. 1996), and the detection of resonances attributed to anilinoquinone, imines, and N-heterocyclic compounds are fully consistent with reactions involving quinone and ketone groups. 

The first examples utilising A-heterocyclic carbenes as ligands in the Buchwald-Hartwig amination involved the in situ formation of the catalyst from the corresponding imidazolium salt and a Pd(0) source. Nolan reported IPr-HCl/PdjCdbalj as a catalytic system for the amination of aryl chlorides in excellent yields, using different types of amines, anilines, and also imines or indoles [142,143] (Scheme 6.46). Hartwig showed later that in some cases the reactions could be performed at room temperature and without anhydrous conditions even for aryl chlorides [ 144]. This was later shown for the less challenging bromides and iodides [145,146]. 

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. 

The imidazole ring system provides the nucleus for two diuretic agents with structures unusual for that activity. Reaction of the N-cyanoaniline 140 (obtainable from the aniline (139) and cyanogen bromide) with N-methylchloroacetamide leads to the heterocycle 142. The sequence can be rationalized by... 

Pyrrole is thus referred to as a n-excessive heterocycle and behaves rather like a reactive benzene derivative, e.g. aniline (p. 153), undergoing very ready electrophilic attack. This may be complicated by the fact that in strongly acid solution protonation (69) is forced even on the weakly basic pyrrole (it takes place on the 2-carbon atom rather than on N, cf. p. 73) ... 

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