Condensed 1,2,5-Thiadiazoles

Thiazolo[2,3-c][l,2,4]thiadiazoles.—The condensation of a-amino-N-heterocycles with chlorocarbonylsulphenyl chloride (chlorothioformyl chloride, ClCOSCl) can give rise to either a 3,4- or a 2,3-fused 1,2,4-thiadiazolone (see Vol. 3, p. 684). The former reaction occurs when 2-aminothiazole or 2-amino-A -thiazoline is condensed with this reagent in chloroform, affording thiazolo[2,3-c][l,2,4]-thiadiazol-3-one (79) or the 5,6-dihydro-analogue, the structure of which has been confirmed by X-ray analysis. For another synthesis of this class see above.  

The use of 2-amino-(and 4-amino-2,6-dimethyl-)pyrimidine in this reaction similarly afforded l,2,4-thiadiazolo[4,3-fl]pyrimidin-3-one (80) (34%) and 5,7-dimethyl-l,2,4-thiadiazolo[4,3-c]pyrimidin-3-one (81) (39%), respectively. Very dilute ethanolic hydrochloric acid cleaves the thiadiazole ring of (81), yielding ethyl 2,6-dimethylpyrimidin-4-yl carbamate. Possible mechanisms of the reactions have been discussed.  

Members of the imidazo[2,l-b]- (203), sym-triazolo[3,4-b]- (204), and thiazolo[2,3-b]-l,3,4-thiadiazole (205) ring systems have been produced by variations of conventional syntheses. 

Golgolab, I. Lalezari, and L. Hosseini-Gohari, J. Heterocyclic Chem., 1973, 10, 387. 

The general synthesis of l,3 4-thiadiazolo[3,2-a]pyrimidines from 2-amino-l,3 4-thiadiazoles has been varied by the use of 2,3-dichloroacryl-oyl chloride the intermediate (206) is cyclized thermally to the final product (207) in 35% yield. A similar route [to (208)] is the condensation of 2-amino-l,3 4-thiadiazoles with the appropriate 3-diketones. 

In the opposite approach, 7-methyl-5H-l,3,4-thiadiazolo[3,2-a]pyrimidin-5-one (210) is formed from the N-aminopyrimidinone (209) by successive formylation and cyclization with phosphorus oxychloride.  

Anhydro-8-ethyI-5-hydroxythiadiazolo[3,2-a]pyrimidinium-7-one hydroxide (211) and homologues are meso-ionic members of this ring system that are accessible in good yield by the condensation of 2-amino-1,3,4-thia-diazoles and bis-(2,4,6-trichlorophenyI)malonate esters.  

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A new thiophene-based monomer bearing a condensed pyridine group (84) was synthesized to obtain a low-gap polymer but the maximum absorption of the polymer was found at a high energy (560 nm, 2.2 eV) [336]. A real lowering of the gap was obtained from a condensed thiadiazole unit (85) with maximum polymer absorption at 934 nm (1.3 eV) [337]. Recently by further insertion of a pyrazine ring (86) the maximum absorption has been increased to 990 nm (1.25 eV) and the threshold of absorption lowered to 0.3 eV [338] so... 

Thiadiazolo[5,4-6]indoles.— Arenesulphonyl azides react vigorously with indoline-2-thione in pyridine to afford a product that has been formulated as the condensed thiadiazole (34), arising presumably via the intermediate (33). The bis-(indoline) (35), formed as a by-product, becomes the main product with 1-methyl-indoline-2-thione, in accord with the suggested mechanism. ... 

Selenous acid produces the corresponding selenadiazole (191 X = Se). The condensed thiadiazole (191 X = S) is resistant to oxidation, but is reconverted into (190) (90%) by reduction with lithium aluminium hydride. The spectral properties (n.m.r., u.v.) and half-wave potentials of the compounds (191 X = S or Se) point to coplanarity of the phenyl substituent with the bicyclic heteronucleus. ... 

The chemistry of 1,2,5-thiadiazole systems (RC)2N2S has been extensively investigated. " In addition to the condensation reactions of sulfur halides with 1,2-diaminobenzenes, this ring system is obtained in high yields by the reaction of S4N4 with acetylenes (Section 5.2.6). For example, the reaction of S4N4 with diphenylacetylene produces 3,4-diphenyl-1,2,5-thiadiazole in 87% yield. 

The first A/ -oxides of the 1,2,4-thiadiazole ring system have been reported and were prepared by condensation of benzamidoximes (86) with 4,5-dichloro-l,2,3-dithiazohum chloride (87). A -labelling showed the compounds to be 4-oxides (88) and a mechanism was proposed for their formation. Alkyl amidoximes and arylamidoximes with electron-withdrawing substituents did not give A/ -oxides, but only the dithiazolone (89) and the dithiazolthione (90) <96CC1273>. 

Condensation of the thiadiazolium salt 192 with />-toluidine yielded 5-imino-2,5-dihydro-l,2,4-thiadiazole hydrochloride 195. This in turn was converted into a variety of 2,3-dihydro-6aA4-thiapolyheterapentalenes 197 in nearly quantitative yields upon addition of heterocumulenes 196 (see Scheme 23) <2003HAC95>. 

Amino-l,3,4-thiadiazol-2-yl)-l,2,5-oxadiazole-3-amine 175 was formed with a yield of more than 75% in a condensation of 3-amino 4-cyano-l,2,5-oxadiazole 174 with thiosemicarbazide in trifluoroacetic acid (Equation 30)... 

Condensations of 5-methyl-substituted 1,2,4-thiadiazoles with aromatic aldehydes lead to 5-styrylthiadiazoles. With carboxylic acid esters, ethoxalyl derivatives are formed, and isoamyl nitrite produces the corresponding oximes <1982AHC285>. These reactions are restricted exclusively to the 5-methyl-substituted 1,2,4-thiadiazoles reflecting the greater reactivity of substituents in the 5-position compared to the 3-position in 1,2,4-thiadiazoles. 

In this method, the 1,2-N-S bond and the 2,3-N-C bond are formed. This is a useful method for the preparation of 3-hydroxy- or 3-amino-5-substituted-l,2,4-thiadiazoles starting from either an ethoxycarbonyl or a cyano thioimino-carbonate. Thus the condensation reaction of the ethoxycarbonyl thioiminocarbonate 100 with chloramine at low temperatures affords 3-hydroxy-5-substituted-l,2,4-thiadiazoles 100 (Equation 28) <2004HOU277>. 

In another variation of a type E synthesis, thioamides or thioureas condense with /V,/V-dimcthylacylamide dimethyl acetal to give imino compounds which react with amino-transfer reagents like hydroxylamine-O-sulfonic acid and mesitylsulfonyloxyamine (MSH) to give 3,5-substituted-l,2,4-thiadiazoles in excellent yields <1996CHEC-II(4)307>. There have been no new reports of type E syntheses since the publication of CHEC-II(1996). 

Table 3 The net charges and condensed Fukui functions for 1,2,5-thiadiazole 1 with C2v symmetry <1997JMT67>...

Large macrocyclic phthalocyanines can be obtained from the condensation reactions of 2,5-diamino-l,3,4-thiadiazole <2006SC1801,2006MI837,20010L2153>. Diaminothiadiazole reacts with 5- z/-butyl-l,3-diiminoisoindoline in 2-ethoxy-ethanol at 135 °C for 24 h to give macrocycles 107 and 108 in 54% and 15% yields, respectively <20010L2153>. 

Condensation reactions of TV-substituted thioureas in dimethyl sulfoxide or methanol in the presence of DMSO-H+-X produce 1,2,4-thiadiazole derivatives (Scheme 64).150 151... 

The mechanism of formation of various 1,2,4-thiadiazoles by self condensation of aromatic thioamides and of TV-substituted thioureas was studied by Forlani et al. Typically, condensations were performed in the presence of DMSO and an acid such as hydrochloric acid <00JHC63>. 

The stepwise condensation of 2-amino-5-ethyl-l,3,4-thiadiazole 83 with a mixture of salicylic aldehyde and acetylacetone in ethanol in a reagent mixture of 1 1 1 gave compound 84 in 36% yield <99RJOC624>. 

Condensation of 3-amino-5-(l,2,3,4-tetrahydrocarbazol-9-ylmethyl)-l,3,4-thiadizole with chloroacetic acid affords compound 339 that on treatment with phosphoryl chloride cyclizes to 2-( 1,2,3,4-tetrahy drocarbazol-9-ylmethyl)-imidazo[2,l- ][l,3,4]thiadiazole-5-(67/)-one 340 (Equation 62) < 1998IJH231 >. 

Imidazo[2,l-/][[l,3,4]thiadiazoles 161 (Figure 33), containing practically planar and rigid heteroaromatic systems with two condensed heterocycles, which have different Tt-conjugation, have been identified as useful fragments for liquid crystal molecules <2002MI6>. 

The condensation of 4-amino-5-thiol-4//-[ 1.2,4 tri azoles 83 with aldehydes (or ketone) in the presence of an acid catalyst affords 3,6-disubstituted-5,6-dihydro[l,2,4]triazolo[3,4-A [l,3,4] thiadiazoles 87 (Equation 22) <1988MI102, 1990IJB176, 1990H(31)2147, 1991RRC619, 1992IJB167, 1998PS41, 1998IJB498>. 

Compound 155, analogous to structure 153, was prepared by a piperidine-mediated condensation of the 1,3,4-thiadiazole 154 with malononitrile (Equation 17) <1995PS51>. 

Condensed derivatives are also known. Treatment of 2-amino-l,3,4-thiadiazoles with 2,3-dichloro-l,4-naphthoquinone or 6-chloroquinoline-5,8-dione yields 102 and 103, respectively (82H333, 91JIC529). 

Condensation of the 5-methyl group in (80) (R = Me, Et, Ph, SMe) with aromatic aldehydes leads to 5-styrylthiadiazoles (79). The action of carboxylic acid esters gives ethoxalyl derivatives (81) and that of isoamyl nitrite produces the oxime (82) (Scheme 20) <82AHC(32)285>. These reactions are restricted exclusively to the 5-methyl group in (80) (R = Me), reflecting the greater reactivity of substituents in the 5-position compared to the 3-position in 1,2,4-thiadiazoles. This point is further illustrated when (80) (R = Me) is selectively converted into the carboxylic acid (83) on treatment with n-butyllithium and carbon dioxide (Scheme 20) <84CHEC-I(6)463). 

The condensation of 5-amino-3-methyl-l,2,4-thiadiazole (118) with aliphatic or aromatic nitriles yields 1 1 adducts, which are, according to their H NMR spectra, equilibrium mixtures of (119) and (120) (Scheme 28) <82AHC(32)285>. These adducts are produced by a bond switch at the n-hypervalent sulfur in (121). X-ray analysis of the adduct formed from the reaction of (118) with chloroacetonitrile showed the adduct to exist as (122) in the crystals <81AX(B)185>. Further examples of this type of bond switch at rc-hypervalent sulfur are observed in the reaction of 5-imino-1,2,4-thiadiazolines with various electrophilic reagents (Section 4.08.6.1). 

The condensation reaction of cyclic amidines with trichloromethylsulfenyl chloride yields sul-fenamides, which afford 5-arylimino-l,2,4-thiadiazolines on treatment with aromatic amines <84CHEC-I(6)463>. An example of this type of reaction starting from 2-amino-4-arylthiazoles (271) affords 3/f-thiazolo[2,3-c]-l,2,4-thiadiazoles (272), via the sulfenamide (270) (Scheme 60) <88IJC(B)501>. 

Acetyl thiadiazole also displays enhanced reactivity in both the carbonyl and the methyl groups and enters the aldol condensation, the Mannich reaction, cyanoethylation reaction, the Willgerodt... 

Aminothiadiazole (88 R = CF3) condenses with 5-fluoro-2-methylbenzoxazin-4-one in refluxing pyridine to give 5-fluoro-2-methyl-3-(2-trifluoromethyl-l,3,4-thiadiazol-5-yl)-4(3//)-quinazolinone in about 60% yield (Equation (4)) <92JHC749>. 

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