Chlorination 1.2.5- thiadiazole

Other Accelerators. Amine isophthalate and thiazolidine thione, which are used as alternatives to thioureas for cross-linking polychloroprene (Neoprene) and other chlorine-containing polymers, are also used as accelerators. A few free amines are used as accelerators of sulfur vulcanization these have high molecular weight to minimize volatility and workplace exposure. Several amines and amine salts are used to speed up the dimercapto thiadiazole cure of chlorinated polyethylene and polyacrylates. Phosphonium salts are used as accelerators for the bisphenol cure of fluorocarbon mbbers. 

Dimercapto-l,3,4-thiadiazole derivatives, accelerated by amines, are used to cross-link chlorinated polyethylene. Polyisobutylene containing brominated i ra-methylstyrene cure functionahty can be cross-linked in polymer blends with dimercapto-1,3,4-thiadiazole derivatives accelerated with thiuram disulfides. Trithiocyanuric acid is suggested for use in polyacrylates containing a chlorine cure site and in epichlorohydrin mbbers. 

Amino-l,2,5-thiadiazole is chlorinated or brominated at the 4-position at 20°C in acetic acid. 3-Methyl-l,2,5-thiadiazole can also be chlorinated in the 4-position (68AHC(9)107). Bromination of 2-amino-l,3,4-thiadiazole succeeds in the 5-position (65ACS2434). 

Then, as described in U.S. Patent 2,55416, the 2-acetylamido-5-mercapto-1,3,4-thiadiazole is converted to the sulfonyl chloride by passing chlorine gas into a cooled (5°-10°C) solution in 33% acetic acid (66 parts to 4 parts of mercapto compound) used as a reaction medium. Chlorine treatment is continued for two hours. The crude product can be dried and purified by recrystallization from ethylene chloride. The pure compound is a white crystalline solid, MP l94°C,with decomposition, when heated rapidly. The crude damp sulfonyl chloride is converted to the sulfonamide by addition to a large excess of liquid ammonia. The product is purified by recrystallization from water. The pure compound is a white, crystalline solid, MP 259°C, with decomposition. The yield of sulfonamide was 85% of theory based on mercapto compound. 

As 1,2,5-thiadiazole analogues, potent HlV-1 reverse transcriptase inhibitors, some simple 1,2,5-oxadiazoles, compounds 4-6 (Fig. 9), have been synthesized using the traditional Wieland procedure as key for the heterocycle formation [121]. Such as thiadiazole parent compounds, derivative with chlorine atoms on the phenyl ring, i.e., 5, showed the best anti-viral activity. Selectivity index (ratio of cytotoxic concentration to effective concentration) ranked in the order of 5 > 6 > 4. The activity of Fz derivative 6 proved the N-oxide lack of relevance in the studied bioactivity. These products have been claimed in an invention patent [122]. On the other hand, compound 7 (Fig. 9) was evaluated for its nitric oxide (NO)-releasing property (see below) as modulator of the catalytic activity of HlV-1 reverse transcriptase. It was found that NO inhibited dose-dependently the enzyme activity, which is hkely due to oxidation of Cys residues [123]. 

Usually, N-sulfinyl compounds (59) behave as thionyl transfer reagents, similar to, but milder than, thionyl chloride. For example, o-diamines with A-sulfinylbenzeneamine (59 R = Ph) afford fused 1,2,5-thiadiazoles, as in Scheme 8a.77 The advantage of using Af-sulfinyl compounds, rather than thionyl chloride itself, is that concomitant chlorinations and oxidations are avoided. This is of particular importance in the synthesis of 2,1-benzisothia-zoles (Section V,B,6). Singerman s reagent, N-sulfinylmethanesulfonamide (60) is especially valuable 78 it was used very successfully in the synthesis of a series of benzobis(isothiazoles).79... 

The chlorine in 5-chloro-l,2,3-thiadiazole is displaced by methoxide ion <1974JHC343>. 

A modified reaction mechanism to the one suggested by Hurd and Mori is proposed for the preparation of some thieno[2,3- 7][l,2,3]thiadiazole derivatives in order to explain the formation of a chlorinated by-product <1998J(P1)853>. 

The most convenient method of preparing thio derivatives of 1,2,4-thiadiazoles is by a type E synthesis. Treating dipotassium cyanodithioiminocarbonate with chlorine gas affords 5-thio-substituted 1,2,4-thiadiazoles. Alternatively, treatment with sulfur followed by chlorine gas affords 3,5-bisthio-substituted 1,2,4-thiadiazoles <1996CHEC-II(4)307>. 

Phenyl-l,2,5-thiadiazole-3-carboxamide can be converted to the methyl 4-phenyl-l,2,4-thiadiazole-3-carboxylate with BF3-OEt2 in MeOH at reflux <2001H(55)75>. Alkyl substituents bearing a-chlorines can be dehalogenated with Pd/C-H2 in EtOH <1998JME4378>, or with Raney-Ni and H2 at atmospheric pressure in EtOH <1995USP5418240>. 

Treatment of ethenes 158 with trithiazyl trichloride afforded 1,2,5-thiadiazoles 159 in moderate to good yields (Equation 32 Table 10). The reaction, however, suffers from the possibility of chlorination at allylic or benzylic positions, in particular if excess trimer is used. 

JME538, 1997CH739>. The main thiadiazole product 185, however, suffered chlorination in the a-position. The isolation of 2-amino acrylonitrile 184 from the reaction mixture supported decomposition of the 2-oximino acetonitrile 183 furthermore, treatment of the pure acrylonitrile under typical reaction conditions gave exclusively ot-chloro-3-chloro-l,2,5-thiadiazole 185 (Scheme 27 Table 11). Mechanisms explaining the formation of both thiadiazoles were proposed <1998H(48)2111>. 

In a development on the reaction of monohaloalkyl aryl ketoximes with tetrasulfur tetranitride, the introduction of two halogens such as chlorine, bromine, or fluorine at the a-position of alkyl aryl ketoximes significantly improved the yields of thiadiazoles <1998J(P1)109>. The preferential displacement of chlorine over bromine or fluorine allowed the preparation of monobromo- and monofluoro-3-aryl-thiadiazoles 195 from a,a-chlorobromoalkyl- and a,a-chlorofluoro-alkyl aryl ketoximes 194 (Equation 41). 

Electrophilic substitution reactions on the carbon atoms of 1,3,4-thiadiazoles are rare due to the low electron density of ring carbons. G-Acylation can be accomplished via rearrangement of intermediate W-acylthiadiazolium salts while radical halogenation can give chlorinated or brominated 2-halo-5-substituted thiadiazoles. Examples can be found in CHEC(1984) <1984CHEC(6)545> and in Houben-Weyls Science of Synthesis <2004HOU(13)349>. 

However, there are some cases when an unpaired electron is localized not on the n, but on the o orbital of an anion-radical. Of course, in such a case, a simple molecular orbital consideration that is based on the n approach does not coincide with experimental data. Chlorobenzothiadiazole may serve as a representative example (Gul maliev et al. 1975). Although the thiadiazole ring is a weaker acceptor than the nitro group, the elimination of the chloride ion from the 5-chlorobenzothiadiazole anion-radical does not take place (Solodovnikov and Todres 1968). At the same time, the anion-radical of 7-chloroquinoline readily loses the chlorine anion (Fujinaga et al. 1968). Notably, 7-chloroquinoline is very close to 5-chlorobenzothiadiazole in the sense of structure and electrophilicity of the heterocycle. To explain the mentioned difference, calculations are needed to clearly take into account the o electron framework of the molecules compared. It would also be interesting to exploit the concept of an increased valency in the consideration of anion-radical electronic structures, especially of those anion-radicals that contain atoms (fragments) with available d orbitals. This concept is traditionally derived from valence-shell expansion through the use of d orbital, but it is also understandable in terms of simple (and cheaper for calculations) MO theory, without t(-orbital participation. For a comparative analysis refer the paper by ElSolhy et al. (2005). Solvation of intermediary states on the way to a final product should be involved in the calculations as well (Parker 1981). 

In the presence of FeCls and chlorine, ethylenediamine dihydrochloride formed 3,4-dichloro-l,2,5-thiadiazole (74%) (1989DDP271425). 

A mechanism for 1,2,5-thiadiazole formation was proposed in the 1960s (1967JOC2823) and seems to be reliable this includes the formation of the M-chlorodithio intermediate followed by chlorination of the nitrile function, ring closure, addition of the second molecule of sulfur monochloride and formation of the heteroaromatic 1,2,5-thiadiazole cycle (Scheme 18). 

Acetazolamide Acetazolamide is 5-acetamido-l,3,4-thiadiazole-2-sulfonamide (9.7.5). The synthesis of acetazolamide is based on the production of 2-amino-5-mercapto-l,3, 4-thiadiazole (9.7.2), which is synthesized by the reaction of ammonium thiocyanate and hydrazine, forming hydrazino-N,N -( ji-(thiourea) (9.7.1), which cycles into thiazole (9.7.2) upon reaction with phosgene. Acylation of (9.7.2) with acetic anhydride gives 2-acetylamino-5-mercapto-l,3,4-thiadiazol (9.7.3). The obtained product is chlorinated to give 2-acetylamino-5-mercapto-l,3,4-thiadiazol-5-sulfonylchloride (9.7.4), which is transformed into acetazolamide upon reaction with ammonia (9.7.5) [24,25]. 

Methazolamide Methazolamide, N-(4-methyl-2-sulfamoyl-l,3,4-thiadiazol-5-yliden) acetamide (21.2.3), is made by an intermediate product of acetazolamide synthesis— 2-acetylamino-5-mercapto-l,3,4-thadiazol (9.7.3). This is benzylated with benzylchloride at the mercapto group, forming 2-acetylamino-5-benzylthio-l,3,4-thiadiazole (21.2.1). Further methylation of the product with methyl iodide leads to the formation of N-(4-methyl-2-benzylthio-l,3,4-thiadiazol-5-yliden)acetamide (21.2.2). Oxidation and simultaneous chlorination of the resulting product with chlorine in an aqueous solution of acetic acid, and reacting the resulting chlorosulfonic derivative with ammonia gives (21.2.3) [5-7]. 

The extraordinary activation of the 5-CI3C group is further demonstrated by comparison of (68) with the thio analogues (69). The whole CI3C group of (68) is displaced by piperidine (Equation (15a)) <73CPB1641>, while under similar conditions only one chlorine atom is displaced in the thiadiazoles (69) (Equation (15b)) <86PS(26)151>. 

These are few clear examples of reactions involving nucleophilic attack at the 1,2,3-thiadiazole ring. The chlorine in 5-chloro-1,2,3-thiadiazole is displaced by methoxide ion <74JHC343> and there is evidence that the fragmentation of 4,5-diphenyl-l,2,3-thiadiazole resulting from reaction with butyl lithium is initiated by attack at sulfur <710PP163>. 

Reaction of chlorine with thio-l,2,4-thiadiazoles yields sulfonyl chlorides, sulfenyl chlorides, or chloro compounds, depending on the nature of the substrate and on the experimental conditions employed. Thus, treatment of (146) with one mole of chlorine yields the disulfide (147), whilst an excess of chlorine converts (147) into the sulfonyl chloride (148) and then further into the 3-chloro derivative (149) (Scheme 32) <82AHC(32)285>. 

The fusion of a second aromatic ring results in subtle changes in reactivity. Halogenation of naphtho[l,2-c]-l,2,5-thiadiazole (42) occurs either by 4,5-addition of chlorine (43a) or by 5,6-substitution (44) by bromine. This heterocyclic analog of phenanthrene behaves like phenanthrene in that it gave the 4,5-addition product (43b) when treated with Br2 in glacial acetic acid (Scheme... 

A greatly improved experimental procedure for the synthesis of thieno[2,3-d]-1,2,3-thiadiazole caiboxylates 68 was reported by Stanetty et al. and involved diazotisation of aminothiophene derivatives 67 <99JHC761>. In these systems, substituents could be introduced into the 5-position by nucleophilic displacement of a chlorine atom or by metallation of the unsubstituted compound (68 R = H) and subsequent electrophilic quenching <99JPR391>. 

Sulfur-linked substituents are usually prone to oxidation by halogens. In aqueous solution, chlorine converted 5-amino-3-benzylthio-1,2,4-thiadiazole successively into sulfoxide and sulfone, but in glacial acetic... 

The sulfur in alkylthio groups of 1,2,4-thiadiazoles may be oxidized successively to the sulfoxide and sulfone stage. Thus, 5-amino(or anilino)-3-alkylthio- 1,2,4-thiadiazoles (321 R = NH2 or PhNH)85,133 and 3-alkylthio-1,2,4-thiadiazoles (321 R = H),90 on treatment with one or two moles of monoperphthalic acid, yield the appropriate oxidation products (322 and 323). Hydrogen peroxide or chlorine may replace the less convenient per-acid as the oxidizing reagent.86 By careful... 

Mercapto-l,2,4-thiadiazoles are oxidized, by 2N nitric acid at 50-60°, by chromic acid mixture, chlorine, or potassium permanganate to the disulfides, which are reconvertible to the thiols by reduction with sodium amalgam and alcohol.71,72,91 168 Use of excess chlorine in aqueous acetic acid results in replacement of the mercapto group by the halogen.168... 

Bromination is usually performed with bromine in a suitable solvent, but in a few cases where this is ineffective (e.g., 415197b and 414143b), N-bromosuccinimide has been employed. In the case of 414, bromination was found to be successful only when R1 = Me. Chlorination of 410 has been achieved with sulfuryl chloride (Table III). Thiocyanations have been carried out either with bromine and ammonium thiocyanate307 or bromine and thiourea236,242,414 though the structures of the products (thiocyanates or isothiocyanates) have not been established with certainty. Kano242 showed that imidazo[2,1-6]-1,3,4-thiadiazole 411 undergoes bromination and thiocyanation preferentially at C-5 (position a, Scheme 18) when this position is free. C-5-substituted derivatives are brominated at C-6 (position b), but thiocyanation fails. Electrophilic substitution reactions in 1 //-pyrrolol 1,2-6]-s-triazole have also been studied.289 ... 

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