1.2.5- Thiadiazolo derivative

Treatment of the 2,3-unsubstituted pyrrole 1124 and indoles 1127 with 1 equiv of 1,3,5-trichloro-lA, 3A , 5A , 2,4,6-trithiatriazine 1125 in refluxing carbon tetrachloride under nitrogen gives the 2,3-fused 1,2,5-thiadiazolo derivatives 1126 and 1128 (Equations 256 and 257) <1997J(P1)2695>. 

Rees has begun a series of investigations into the reaction of variously substituted pyrroles and indoles with trithiazyl trichloride (34) as a route to bisheterocycles <97CC1493>. In the simplest manifestation of this process, reaction of 34 with 2,3-unsubstituted pyrrole 35 in hot CCI4 gives the 2,3-fused 1,2,5-thiadiazolo derivative 36 <97JCS(P1)2695>. 

The 8-amino-7-nitrosopyrimido[2,l-fe][l,3]thiazine (352 R = Me, OH) was reduced to the diamino derivative (398) with Pd/C, H2, or sodium hydrosulfite. In the latter reaction, the sulfamic acid (350 R = Me, OH) and the thiadiazolo derivative (399) were also obtained as by-products... 

Under similar conditions, as in the case of 5-amino-2,l,3-benzothiadiazole, and starting from 6-amino-l,2,3-benzothiadiazole 72, the l,2,3-thiadiazolo[5, 4-/ quinoline derivatives 73 resulted (Scheme 28) and were tested for antibacterial properties (74JAP(K)1). 

When treated with 4-dimethylaminobenzaldehyde, diazonium salts, or phthalic anhydride, these salts produced the corresponding styryl or azamethine dyes derived from l,2,3-thiadiazolo[4,5-/] or [5,4-/]quinolines. The Xmax of azamethine... 

Reaction of pyridinium thiocyanatoacetamides (106) with a strong base (e.g potassium t-butoxide) in ethanol gave mesoionic Af-[2-(l,3,4-thiadiazolo[3,2-a]pyridino)]acetamidates (107) or (108) whose structures were confirmed by the X-ray analysis of (107 R = Me). Possible mechanisms for the formation of the mesoionic derivatives were discussed <96BCJ1769>. 

This type of method has been used to prepare l,2,4-thiadiazolo[2,3- ]pyridine derivatives. The oxidative hetero-cyclization is exemplified by the formation of compound 86 from thioacetamide 85 using nitrosobenzene (Equation 24) <2004S2975>. 

The reaction of /V-alkylamino[ 1,2,4]thiadiazolo[2,3- ]benzimidazoles 217 with arylmethyl bromides gives the iV-alkylated derivatives 218 (unreported yields) (Equation 22) <1998BMCL505>. 

Boron substituents in the [l,3,2]diazaborolo[l,5- ]pyridine derivative 109 were studied. This compound was obtained via reduction of its precursor 108 with sodium amalgam (Scheme 27). The bromide attached to the boron atom was further displaced with various halide, hydride, sulfur, and carbon nucleophiles <2001JCD378>. [l,2,5]thiadiazolo[2,3- ]pyridine derivative 110 was deprotected (R = Cbz to R=H) by classical hydrogenolysis <2002AGE3866>. 

Transformations of various 2-bromo-substituted derivatives of [l,3,4]thiadiazolo[3,2-tf]pyrimidines are shown in Scheme 27. Thus, reaction of 218 with dimethylamine gave 219 in medium yield <2005JHC1105>, treatment of 220 with mercaptans afforded 221 in good yield <1999IZV1154>, whereas reaction of 222 with hetarylamines and hetarylmercaptanes yielded 223 <1993IZV1954, 1994KGS560>. 

An Iranian group described the synthesis of some [l,3,4]thiadiazolo[2,3-c][l,2,4]triazinones 88 <2002PS2399> and in the course of the synthetic pathway the dihydro derivative 87 was first obtained. These authors found that microwave irradiation of 87 on montmorillonite in the presence of nitrobenzene allowed to accomplish the final oxidative step and yielded the fully conjugated end-product in good yields (50-62%). The reaction as proceeding was interpreted by electron transfer to 89 caused by the microwave irradiation followed by the formation of the intermediate radical 90. 

Scheme 44 also shows two further synthetic routes to [l,3,4]thiadiazolo[2,3-c][l,2,4]triazinones. Reaction of the 3-mercapto- or 3-methylsulfanyltriazinone 221 (R1 = H or R1 = Me) with a set of isothiocyanates was reported to give the 2-amino-substituted fused ring system 222 in medium to good yield (36-84%) <1997JHC1351>. Derivative 223 was described to undergo cyclization to a fused thiadiazole 224 by treatment with carbon disulfide in the presence of potassium hydroxide in ethanol <2001PHA376>. 

A Chinese research team found <1997PS299> that derivative 21 of the new [l,3,4]thiadiazolo[3,2-f][l,3,5,2,]thia-diazaphosphorine ring system undergoes spontaneous oxidation on air, as shown in Scheme 5. Thus, storage of the dichloromethane solution of 21 for 48 h at room temperature results in formation of a mixture of 22 and 23. 

A special rearrangement in the 1,2,4-thiadiazole series concerns the 2-phenylamino-l,2,4-thiadiazolo [2,3,-a]pyridinium salts (275 R = H, Me), which are obtained by oxidation of N-(2-pyridyl)thioureas (Scheme 45). In the case of the unsubstituted derivative (275 R = H X = Br), neutralization with sodium acetate in ethanol produces directly benzothiazole 277... 

Azirines are dimerized under various conditions to dihydropyrazines or their dehydrogenated products, namely pyrazines (Section 8.03.9.5). Quinoxalines are oxidized with potassium permanganate to afford 2,3-pyrazinedicarboxylic acids, and pteridines are hydrolyzed to give 3-amino-2-pyrazinecarboxylic acid derivatives. Condensation of 3,4-diamino-l,2,5-thiadiazole 176 with a-diketones produces l,2,5-thiadiazolo[3,4- Jpyrazines 177, which are reduced to provide 2,3-diaminopyrazines 178 (Scheme 51) <1997JCM250>. 

Oakley and co-workers reported the transformation of l,2,5-thiadiazolo[3,4-/ ]pyrazines into tricyclic rings 55 and 57. Titanocene 55 was prepared by reaction of 5,6-dithiol derivative 54 with Cp2TiCl2 under basic conditions (Scheme 37) <1998JA352>, and 6-amino-5-thiol 56 was condensed with sulfur monochloride to give the 1,2,3-dithiazolidine derivative 57 in excellent yield (Scheme 38) <1999JA969>. 

The novel derivative 56 (m.p. 127-128 °C) has been prepared in high yield by reaction of the 1,2,5-thiadiazole 55 with thionyl chloride (Scheme 3) <2000JHC1269>. The intermediate 55 is made by alkaline hydrolysis of 4,6-dimethyl[l,2,5]thiadiazolo[3,4-,7 pyrimidine-5,7(4//,6//)-dione 54 <2000JHC1269>. 

Two modifications of the well-known benzothiazole preparation have been employed to prepare unusual heteropoly cycles. Konig et al.ils treated l-thiocarbamoyl-l,2,3,4-tetrahydroquinoline (236) with bromine in chloroform to give the thiazolo[3,4,5-J,i]quinoline derivative 237. In a process which requires disruption of the resonance stabilization of the pyridine ring, Harris416 reported that treatment of l-(2-pyridyl)-2-thiourcas with sulfuryl chloride or with bromine gives the hydrohalide salts of 2-imino-2//-[l,2,4]thiadiazolo[2,3-a]pyridines (238). 

A combination EIMS and X-ray study of [l,2,4]triazolo[l,2-b]- and [l,3,4]thiadiazolo[3,4-i>]phthalazines was undertaken [95JHC283], and X-ray crystal structure determinations of 5-(2-chlorobenzyl)-6-methyl-3(2W)-pyridazinone [95AX(C)1834], and on 6-benzyloxy-7,8-dihydro-8-phenyl-3-trifluoromethyl-r-triazolo[4,3-i>]pyridazine and its 5,6-dihydro-6-one derivative [95AX(C)1829] have been performed. Structures of some pharmacologically-active pyridazines previously reported as arylidene-4,5-dihydropyridazines need to be revised to those of aromatic pyridazine tautomers 6-8 based on a combination H NMR nOe and X-ray study [95AJC1601],... 

Ab initio molecular orbital calculations on these systems have been confined to the 1,2,3-triazolo[4,5-d]pyrimidines (7), the so-called 8-azapurines , and references to this subject may be found in the previously mentioned review <86AHC(39)ii7>. In 1989, quantum mechanical perturbation methods have been used to study the activity of 8-azapurine nucleoside antibiotics in transcription processes <89Mi 7i3-oi>. The l,2,3-thiadiazolo[5,4-d]pyrimidine derivative (51), a rearrangement product of 8-aza-6-thioinosine, has been used in a molecular modeling study of the antitumor activity of sugar derivatives of pyrimidopyrimidines <89PNA(86)8242>. 

In Scheme 8, the 3-hydrazinopyrazolo[3,4-< ][l,2,4]triazine (103) has been used as a template for the build up of the pyrazolotetrazolotriazine (105) and a series of pyrazolotriazolotriazines (104a-d) <84JHC1565>. The hydrazine derivative is produced by nucleophilic displacement of the thiol (see Section 7.13.9). The 5,6-diamino[l,2,5]thiadiazolo[3,4-i]pyrazine (106) reacts with thionyl chloride to produce the tricyclic conjugated mesomeric betaine (107) (Equation (6)). 

The 4,7-dinitro-4,5,6,7-tetrahydro[l,2,5]oxadiazolo[3,4-6]pyrazine (67) has been tested as an explosive <85USP4539405>. The o-quinonoid nature of the [l,2,5]thiadiazolo[3,4-d]pyridazines results in their 4,7-diaryl derivatives being used as fluorescent yellow-red dyes for organic polymers... 

TCNQ derivatives fused with 1,2,5-thiadiazolo and pyrazino units (4,9-bis(dicyanomethylene)-l,2,5-thiadiazolo[3,4- ]quinoxalines) undergo reversible four-stage one-electron reductions, as determined by cyclic voltammetry <92H(33)337 . 

Disubstituted and unsubstituted l,2,5-thiadiazolo[3,4- ]quinoxaline-4,9-diones (110) have been prepared in good yield by condensation of 5,6-diaminobenzo[c][l,2,5]thiadiazole with a-dicarbonyl reagents (Equation (62)) <92H(33)337>. These quinones were then converted into 1,2,5-thiadiazolo-, pyrazino-fused TCNQ analogues by condensation with malononitrile in the presence of TiCl4 in dry pyridine. The x-ray crystal structure determination of the product derived from compound (110 R1 = R2 = H) has been accomplished. 

With one nitrogen and one oxygen or sulfur as azole 1,2-locants, ortho-fused derivatives are classified as isoxazolo- and isothiazolo-azines with the same heteroelements as azole 1,3-locants the fused derivatives are classified as oxazolo- and thiazolo-azines. With two nitrogens the compounds are oxadiazolo- or thiadiazolo-azines which are subdivided further according to the relative locations of the azole heteroatoms. This approach can also be extended to fused oxatriazole and thiatriazole. These systems, however, are omitted from this discussion since little work has hitherto been reported. 

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