Phenyl heterocycles

Schofield (80MI1) has provided a comprehensive review of aromatic nitration but with slight emphasis on phenyl heterocycles. There have also been extensive reviews of the methods and mechanisms of nitration... 

Nitrations of aromatic compounds represent one of the most important classes or organic reactions. However, although a lot of data has been collected in relation to simple substituted benzenes, and the reactions have been subjected to quantitative and theoretical studies, the nitration of phenyl heterocycles has been much less studied in a systematic way. This chapter has attempted to bring together as much information as possible on the topic through a manual search of Chemical Abstracts and recent literature. 

A fused benzene has little influence on the electronic effects of azinyl groups. This can be concluded by comparing the values of the inductive and mesomeric constants for the 2-quinolyl (ct, = 0.13, CTr = 0.01) and 2-pyridyl (0.10 and 0.01) groups, as well as for the 2-quinazolinyl (0.06 and 0.10) and 2-pyrimidinyl (0.05 and 0.10) groups determined under identical conditions (85MI4). A similar situation has been noted for the respective 4-substituted 2-quinazolinyl, and 4-substituted 2-pyrimidinyl groups. The values of these constants were determined from C spectra of the respective phenyl heterocycles (series 8) (Table XIV). 

Imai et al. [52-54] used the following highly phenylated heterocyclic systems as diamine monomers 2,5-bis(4-aminophenyl)-3,4-diphenylthiophene 35, 3,4-bis(4-amino-phenyl)-2,5-diphenylfuran 36, and 3,4-bis(4-aminophenyl)-2,5-diphenylpyrrole 37. 

Several chemistries introduced in the 1990s did not conform to the established structure-activity relationships (SARs) of previous chemistries like the diphenyl ethers and the 2,4-dihalo-5-substituted-phenyl heterocycles. Figure 3.13 shows the SARs of 2-fluoro-4-chloro-5-substituted-phenyl heterocycles [5, 64]. These newer developments impacted both the aromatic and the heterocyclic portion of N-phenyl heterocycles. 

Fig. 3.13. Structure-activity relationships of the two aromatic rings of 2,4,5-trisubstituted-phenyl heterocyclic systems.

Fig. 3.16. Benzoheterocycles resulting from linking aromatic positions 4 and 5 of phenyl heterocyclic Protox inhibitors.

Q = phenyl, heterocycle, substituted or unsubstituted alkyl, allyl, geranyl, farnesyl, glycidyl, acetonyl etc. 

The 2,6-dichloro-4-(trifluoromethyl)phenyl-heterocycle-4-(halo)alkylthio scaffold has been considered as the essential toxophore. The heterocyclic unit and the substituents at the 3- and 5-position on the heterocycle permit more variability and may serve as sites for prodrug attachment [76-79]. 

Very recently, Varalashmi et al. prepared a new class of diethyl(3,5-di-bromo-4-hydro3g henylamino)(substituted phenyl/heterocyclic)methylphos-phonates (52) by one-pot three-component Kabachnik-Fields reactions of 4-amino-2,6-dibromophenol (51), substituted heterocyclic/phenyl aldehydes (44) and diethylphosphite (2) using hydrated ceric chloride (5 mol%) under microwave irradiation in THF (Scheme 24). The reaction is rapid and highly efficient Moreover, the investigators evaluated in vitro... 

Rajasekhar et al. also synthesized a new class of diethyl a-aryl/2-thienyl-a-[2-(phenylthio)phenylamino]methylphosphonates (54) via a three-component Kabachnik-Fields reaction of 2-aminodiphenylsulfide (53), substituted phenyl/heterocyclic aldehydes (44), and diethyl-phosphate (2) in the presence of heterogeneous nano-silica-supported nano-BFs SiOa under solvent-free conditions under microwave irradiation (Scheme 25). The procedure has several advantages such as short reaction time, low loading of catalyst, good yields, and reusability of the heterogeneous silica-supported nano-catalyst. The title compounds were found to exhibit considerable in vitro antibacterial and antifungal activity. 

The nitration of phenylpyridines and related compounds has attracted attention for a long time, and measurements of isomer proportions have been made for several compounds of this type. Nitration occurs in the phenyl ring. For 2-phenylpyridine and 2-phenylpyridine i-oxide measurements of the dependence of rate of nitration upon acidity in 75-81 % sulphuric acid at 25 °C show that both compounds are nitrated as their cations (table 8.1). The isomer distribution did not depend significantly upon the acidity, and by comparison with the kinetic data for quinolinium ( 10.4.2) the partial rate factors illustrated below were obtained.They should be compared with those for the nitration of 2-nitrobiphenyl ( 10.1). The protonated heterocyclic groups are much... 

The general pattern of alkylation of 2-acylaininothiazoles parallels that of 2-aminothia2ole itself (see Section III.l). In neutral medium attack occurs on the ring nitrogen, and in alkaline medium a mixture of N-ring and N-amino alkylation takes place (40, 43, 161. 163). In acidic medium unusual behavior has been reported (477) 2-acetamido-4-substituted thiazoles react with acetic anhydride in the presence of sulfuric acid to yield 2-acetylimino-3-acetyl-4-phenyl-4-thiazolines (255) when R = Ph. but when R4 = Me or H no acetylation occurs (Scheme 151). The explanation rests perhaps in an acid-catalyzed heterocyclization with an acetylation on the open-chain compound (253), this compound being stabilized... 

The synthesis of 9H-benzo[2,l-e]thiazolo-[2,3-c]-as-triazine (401) was achieved by oxydative cyclization of 2-imino-3-(o-aminophenyl)-4-phenyl-4-thiazoline (718, 719). This latter reacts also with paraformaldehyde in hot toluene yielding 3-phenyl-9H.10H-benzo[l,2-/]thiazolo-[2,3-d][l,3,5]triazepine (402) (720). This heterocyclic sytem is also formed when carboxylic acids replace paraformaldehyde (Scheme 230) (721). 

The importance of the stabilization by the tt system of the heterocycle of the developing positive charge on the a carbon reaction center decreases in the order, 5-thiazolyl>4-thiazolyl phenyl >2-thiazolyl. 

The free-radical reactivity of thiazoles has been well studied with various radicals such as methyl, phenyl, substituted phenyl, cyclohexyl, and aromatic-heterocyclic, in nonpolar solvent or strong acids (180-182). 

For the sulfonamides, the best activity is found where R is heterocycHc, but it can also be isocycHc or acyl. For the sulfones, R can be phenylene or a heterocycle the parent dapsone, where R is phenyl, is the most active. 

Phenylthiazirine (40) can be isolated as an intermediate in the photolysis of 5-phenyl-1,2,3,4-thiatriazole and also from other five-membered ring heterocycles capable of losing stable fragments see Scheme 2 (81AHC(28)231). Photolysis of 5-phenylthiatriazole in the presence of cyclohexene yields cyclohexene episulfide (60CB2353) by trapping the sulfur atom. 

Sulfonation of 2- and 3-pyrazolin-5-ones occurs at position 4. Thus 3-methyl-1-phenyl-pyrazolin-5-one with 20% oleum at 10-15 °C yields the corresponding 4-sulfonic acid (304) (64HC(20)l). Higher temperatures cause sulfonation not only of the heterocycle but also of the phenyl group. Antipyrine treated with sulfuric acid and acetic anhydride yields (305). 

Another example of the analogy between pyrazole and chlorine is provided by the alkaline cleavage of l-(2,4-dinitrophenyl)pyrazoles. As occurs with l-chloro-2,4-dinitrobenzene, the phenyl substituent bond is broken with concomitant formation of 2,4-dinitrophenol and chlorine or pyrazole anions, respectively (66AHC(6)347). Heterocyclization of iV-arylpyrazoles involving a nitrene has already been discussed (Section 4.04.2.1.8(i)). Another example, related to the Pschorr reaction, is the photochemical cyclization of (515) to (516) (80CJC1880). An unusual transfer of chlorine to the side-chain of a pyrazole derivative was observed when the amine (517 X = H, Y = NH2) was diazotized in hydrochloric acid and subsequently treated with copper powder (72TL3637). The product (517 X = Cl, Y = H) was isolated. 

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