Heterocycles brominated

Amides capable of complexing with bromine (e.g., carboxamides, urea, HMPA) are known to increase yields in the bromination of methyl alkyl ketones (84BAU418), and there may be applications of this in heterocyclic bromination. 

Heterocyclic Bromination. Pyridines with electron-donating groups undergo regioselective bromination with NBS under mild acidic conditions as shown by the conversion of 10 into 11 (eq 37).i ... 

A white solid, m.p. 178 C. Primarily of interest as a brominaling agent which will replace activated hydrogen atoms in benzylic or allylic positions, and also those on a carbon atom a to a carbonyl group. Activating influences can produce nuclear substitution in a benzene ring and certain heterocyclic compounds also used in the oxidation of secondary alcohols to ketones. 

The reaction is applicable to the preparation of amines from amides of aliphatic aromatic, aryl-aliphatic and heterocyclic acids. A further example is given in Section IV,170 in connexion with the preparation of anthranilic acid from phthal-imide. It may be mentioned that for aliphatic monoamides containing more than eight carbon atoms aqueous alkaline hypohalite gives poor yields of the amines. Good results are obtained by treatment of the amide (C > 8) in methanol with sodium methoxide and bromine, followed by hydrolysis of the resulting N-alkyl methyl carbamate ... 

In the section dealing with electrophilic attack at carbon some results on indazole homocyclic reactivity were presented nitration at position 5 (Section 4.04.2.1.4(ii)), sulfon-ation at position 7 (Section 4.04.2.1.4(iii)) and bromination at positions 5 and 7 (Section 4.04.2.1.4(v)). The orientation depends on the nature (cationic, neutral or anionic) of the indazole. Protonation, for instance, deactivates the heterocycle and directs the attack towards the fused benzene ring. A careful study of the nitration of indazoles at positions 2, 3, 5 or 7 has been published by Habraken (7UOC3084) who described the synthesis of several dinitroindazoles (5,7 5,6 3,5 3,6 3,4 3,7). The kinetics of the nitration of indazole to form the 5-nitro derivative have been determined (72JCS(P2)632). The rate profile at acidities below 90% sulfuric acid shows that the reaction involves the conjugate acid of indazole. 

As demonstrated above, nitro derivatives of five-membered heterocycles have found extensive use as antiinfective agents. It is therefore of interest that the nitro derivative of a substituted thiazole was at one time used as an antitrichomonal agent. Bro-mination of 2-aminothiazole (136) (obtained from condensation of thiourea with chloroacetaldehyde) gives the 4-bromo derivative (138) this is then acetylated to 139. Treatment of 139 with nitric acid leads to an interesting displacement of bromine by a nitro group to afford aminitrazole (140)... 

The finding that the anthelmintic thiazoloimidazole levamisole showed immunoregulatory activity spurred further investigation of this heterocyclic system. Synthesis of a highly modified analogue starts by displacement of bromine in keto ester 149 by sulfur in substituted benzimidazole 148. Cyclization of the product (150), leads initially to the carbinol 151. Removal of the ester group by saponification in base followed by acid-catalyzed dehydration of the carbinol affords the immune regulator tilomisole (152) [28]. 

Since thiophene derivatives, heterocyclic aromatic compounds, are sensitive toward electrophilic substitution reactions, the bromination of these compounds generally gives a mixture of mono-, di-, and other poly-substituted bromination products (ref. 19). However, we have recently found that BTMA Br3 is a useful... 

The N-bromination of amides with bromine and alkali has been extensively researched as the first step of the Hofmann degradation. However, it is difficult to isolate the N-bromoamides because of their subsequent reaction to produce amines, which proceeds very readily under excessive alkaline conditions. Now, the reaction of amides with a stoichiometric amount of BTMA Br3 and sodium hydroxide in ice-water gave N-bromoamides in fairly good yields. Our method can be applied to various types of aliphatic, aromatic, and heterocyclic amides (Fig. 31) (ref. 39). 

The selection of appropriate polymeric bromine reagent according to the polymeric structure (step of crosslinking, porosity, step of dilution with styrene, granulation, type of heterocyclic ring incorporated, numbers of N) is very important. From production point of view the use of polymeric reagents reduces the costs for solvents and working hours. 

However, intramolecular O-alkylation can be performed under particular conditions leading to of annelation of a seven-membered heterocycle. Japanese researchers (170) prepared the corresponding seven-membered cyclic nitronates (50a-c) in good yields by the reaction of triethylamine with brominated aryl ketones (49a-c) containing the nitromethyl group in the ortho position. 

Fused heterocyclic systems derived from 3-mercapto-l,2,4-triazole can be obtained by heterocyclization of 4-allyl-l,2,4-triazole-3-thione derivatives by treatment with halogens or mineral acids <1996T791>. Compounds 342 react with bromine yielding thiazolium halides 28 in good yield (Equation 64) <2000RJOC1033>. 

In addition to benzenoid diazo components, diazotised heterocyclic amines in which the amino group is attached to a nitrogen- or sulphur-containing ring figure prominently in the preparation of disperse dyes [87,88], since these can produce marked bathochromic shifts. The most commonly used of these are the 6-substituted 2-aminobenzothiazoles, prepared by the reaction of a suitable arylamine with bromine and potassium thiocyanate (Scheme 4.31). Intermediates of this type, such as the 6-nitro derivative (4.79), are the source of red dyes, as in Cl Disperse Red 145 (4.80). It has been found that dichloroacetic acid is an effective solvent for the diazotisation of 2-amino-6-nitrobenzothiazole [89]. Subsequent coupling reactions can be carried out in the same solvent system. Monoazo disperse dyes have also been synthesised from other isomeric nitro derivatives of 2-aminobenzothiazole [90]. Various dichloronitro derivatives of this amine can be used to generate reddish blue dyes for polyester [91]. 

---