Compounds with activated halogen groups

Appropriate active ingredients for non-persistent slimicides one finds above all among the compounds with activated halogen groups (III.7 and III.15). Other active ingredients belong to the carbamates (III.9 and III.3.4.10.1) and the heterocyclic N,S compounds (III. 13). It is also proposed to use glutaraldehyde (III.2.3) or 3,5-dimethyl-tetrahydro-2-thiono-thiadiazine (III.3.3.16). 

The halogenopurines react with many other nucleophiles including hydrazines, hydrox-ylamine and alkoxyamines, sulfonic acids and thiocyanates, and compounds with active methylene groups such as diethyl malonate furnish appropriate purine derivatives which offer valuable routes to alkyl and substituted alkyl derivatives. Also aryl groups have been substituted for halogen using aryllithiums (63N224). 

Compounds with activated halogen atoms, e.g., 7-chloro-4-nitrobenzo-furoxan (234), undergo displacement reactions with a variety of nucleophiles, including sulfides,300 443,444 amines,300,443,491 phenoxides,300 and others mentioned earlier.6 Sometimes rearrangements of the type discussed in Section V,C,4 occur, leading to products other than those of simple displacement.300,443 When 7-chloro-4-nitrobenzofuroxan is treated with an aryl-sulfinate, both substituents are replaced, and the 4,7-bisarylsulfonyl compound is formed. One of the arylsulfonyl groups is, in its turn, susceptible to replacement by other nucleophiles.444... 

The electrophilically active substances have as toxophoric constituent an electrophilic group which is responsible for the antimicrobial effect, because it enables these active substances to react with specific nucleophilic entities of the microbial cell (Paulus, 1993) Examples of this class are aldehydes [II, 2.], e.g. Glutaraldehyde, compounds with activated halogen atoms [II, 17.], e.g. Bronopol, and microbiocides with an activated S-N-bond [II, 15.], for example Isothiazolinones. Since Isothiazolinones represent a major class of bactericides for industrial preservation, much research has been performed in this area. 

Alkylation (R" = alkyl or substituted alkyl) is most satisfactorily accomplished with active halogen compounds such as allyl, benzyl, and propargyl halides, but a-halo ketones, esters, and nitriles can also be used.467,474 Treating l-(l-cyclohexenyl)pyrrolidine with allyl bromide in the presence of /V-ethyl-dicyclohexylamine as base leads to introduction of two allyl groups, i.e., formation of 2,6-diallylcyclohexanone.475 Arylation can be effected by, for example, l-chloro-2,4-dinitrobenzene (R" = 2,4-dinitrophenyl).476 A-Isobutyl-fl-butylamine477 and pyrrolidine478 have been recommended as amine components for C-alkylation by simple alkyl halides such as ethyl and methyl iodides. The following two examples are illustrative ... 

Acylation converts compounds with active hydrogen, for example, in the -SH into thioesters by reaction with carboxyl acids or their derivatives. The presence of a carbonyl group next to the halogenated carbon increases the ECD response. For thiols, using Af-methyl-bis(trifluoroacetamide) (MBTFA) is recommended. 

Alkyl groups are activating while halogens are deactivating toward electrophilic aromatic substitution. As such, the compound with two aUcyl groups will be the most activated toward electrophilic aromatic substitution, while the compound with two halogens will be the least activated ... 

It is possible to introduce sulfonic acid groups by alternative methods, but these ate Htde used in the dyes industry. However, one worth mentioning is sulfitation, because it provides an example of the introduction of a sulfonic acid group by nucleophilic substitution. The process involves treating an active halogen compound with sodium sulfite. This reaction is used in the purification of m-dinitrohen7ene. 

Direct chlorination of 3,6-dichloropyridazine with phosphorus pentachloride affords 3,4,5,6-tetrachloropyridazine. The halogen is usually introduced next to the activating oxo group. Thus, 1,3-disubstituted pyridazin-6(l//)-ones give the corresponding 5-chloro derivatives, frequently accompanied by 4,5-dichloro compounds as by-products on treatment with chlorine, phosphorus pentachloride or phosphoryl chloride-phosphorus pentachloride. 

Reaction of pyroc techol with epichlorohydrin in the presence of base affords the benzodioxan derivative, 136, (The reaction may well involve initial displacement of halogen by phenoxide followed by opening of the oxirane by the anion from the second phenolic group.) Treatment of the alcohol with thio-nyl chloride gives the corresponding chloro compound (137). Displacement of halogen by means of diethylamine affords piper-oxan (138), a compound with a-sympathetic blocking activity. 

Hydrazinopyridazines such as hydralazine have a venerable history as anti hypertensive agents. It is of note that this biological activity is maintained in the face of major modifications in the heterocyclic nucleus. The key intermediate keto ester in principle can be obtained by alkylation of the anion of pi peri done 44 with ethyl bromo-acetate. The cyclic acylhydrazone formed on reaction with hydrazine (46) is then oxidized to give the aromatized compound 47. The hydroxyl group is then transformed to chloro by treatment with phosphorus oxychloride (48). Displacement of halogen with hydrazine leads to the formation of endralazine (49). ... 

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