Heterocyclics thiadiazoles

The above examples illustrate reactions at an electron-deficient carbon atom. Other 1,1-bielectrophiles allow the direct introduction of a heteroatom into the resultant heterocycle. The most widely applicable and versatile methods for the synthesis of 1,2,5-thiadiazoles and 1,2,5-selenadiazole rely on this approach. 

Cyclotrithiazyl chloride is also a useful reagent in organic chemistry in the fusion of 1,2,5-thiadiazoles to quinones as well as the synthesis of (a) isothiazoles from 2,5-disubstituted furans and (b) bis-1,2,5-thiadiazoles from A-alkylpyrroles (Scheme 8.4). Alkenes and alkynes react readily with (NSC1)3 to give 1,2,5-thiadiazoles, while 1,4-diphenyl-1,3-butadiene gives a variety of heterocyclic products including a bis(l, 2,5-thiadiazole). ... 

Preparation of thiadiazoles via the Hurd-Mori cyclization has led to the synthesis of a variety of biologically active and functionally useful compounds. Discussion of reactions prior to 1998 on the preparation of thiadiazoles have been compiled in a review by Stanetty et al Recent syntheses of thiadiazoles as intermediates for useful transformations to other heterocycles have appeared. For example, the thiadiazole intermediate 36 was prepared from the hydrazone 35 and converted to benzofuran upon treatment with base. Similarly, the thiadiazole acid chloride 38 was converted to the hydrazine 39 which, upon base treatment, provided the pyrazolone, which can be sequentially alkylated in situ to provide the product 40. ... 

Papers dealing with this topic are exhaustively reviewed in Comprehensive Heterocyclic Chemistry I (84CHEC-I(6)235) and II (96CHEC-II(3)373). Nevertheless, little information is available on the 5-oxides. Recently, the heteroaromaticity of thiazole compared with isothiazole and thiadiazole 5,5-dioxide systems was studied (97MI1). Quantum-chemical calculations and X-ray studies were performed on 3,3 -di[l,3-thiazolidin-4-one] derivatives (95JCC(25)589) studied for their potential biological activity (97FA(52)43). 

Thiadiazole 5-oxides and 5,5-dioxides are the least studied among the four possible isomers of thiadiazole system. The main summary is in the first and the second editions of Comprehensive Heterocyclic Chemistry (84CHEC-I(6)447, 96CHEC-II(4)289). Apparently the 5-oxide and the 5,5-dioxide derivatives have not yet been reviewed. There are very few papers in the literature treating these derivatives, and most of these are regarding polycyclic systems. 

Acylation of thiosemicarbazide with propionyl chloride, interestingly, does not stop at the acylated product (124). Instead, this intermediate cyclizes to the thiadiazole, 125, under the reaction conditions. Hydrolysis then affords the heterocyclic amine, 126. Acylation by 88 followed by removal qf the acetyl group affords sulfaethidole (116) variation of thle acid chloride used in the preparation of the heterocycle leads to 117 and 118. 

The only heterocyclic seven-membered ring system with maximum unsaturation containing six heteroatoms is 1,3A4,5,2,4,6-trithiatriazepine (1). The methoxycarbonyl derivative 2 is a minor product (14%) of the complex reaction of tetrasulfur tetranitride with dimethyl acetylenedicarboxylatc in refluxing toluene, which gives mainly dimethyl l,2,5-thiadiazole-3,4-dicarboxylate (3, 67%) (see Houben-Wcyl, Vol. E8d, pl54ff which includes an experimental procedure). Two other products are the trithiadiazepine 4 (5%, see Section 4.4.1.1.1.) and the 1,2,4-thiadiazole derivative 5 (3%).385... 

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]. 

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

An ab initio theoretical study was conducted on 1,2,5-oxadiazole and 3-phenyl-l,2,5-oxadiazole to determine the molecular structures of these heterocyclic compounds. The rotational energy barrier between Ph ring and diazole nucleus was also evaluated. No considerable change of bond lengths inside the diazole nucleus was observed in the Ph-substituted heterocyclic compounds as compared to the oxadiazole and thiadiazole alone <2001MI215>. 

The 1,2,3-thiadiazole literature was extensively reviewed in CHEC(1984) <1984CHEC(6)447> and CHEC-II(1996) <1996CHEC-II(4)289>. It covered the literature up to 1996 and cited many excellent references to 1,2,3-thiadiazoles. A further review on the chemistry of 1,2,3-thiadiazoles, which gives a critical review of methods of synthesis and is accompanied by experimental procedures, appeared in Science of Synthesis <2004HOU(13)253>. Another review of 1,2,3-thiadiazoles also appeared in 2004 . An annual review of the chemistry of 1,2,3-thiadiazoles appears in Progress in Heterocyclic Chemistry (Chapter 5.5). This review covers the 1,2,3-thiadiazole literature up to 2006. 

Carbon-13 NMR is often a more useful tool than H NMR for the elucidation of heterocyclic structures in which there are few or no ring protons. For symmetrically substituted 1,2,3-thiadiazoles, the carbon adjacent to the nitrogen atom is expected to have a lower field chemical shift than the carbon atom adjacent to the sulfur atom, as exemplified in CHEC-II(1996) <1996CHEC-II(4)289>. Several examples that follow this rule are illustrated in Table 5. There is now a more extensive body of data available and it is possible to more accurately predict the chemical shift of ring carbons. In the case of monosubstituted 1,2,3-thiadiazoles, the substituted carbon usually has a lower field chemical shift than the unsubstituted carbon. 

Rings incorporating [4 +2] rt-electrons are aromatic according to the Hiickel definition and on this basis 1,2,3-thiadiazoles can be considered as aromatic. This is supported by 13C and 111 NMR chemical shifts. In 1990, the aromaticities of some five- and six-membered ring heterocycles including 1,2,3-thiadiazole were studied by computational methods and found to correlate well with their chemical natures <1990JPR885>. 

A new method for the synthesis of 1,2,3-thiadiazoles has been reported. The method starts with the thioanilide derivative 72, which is converted into the hydrazone 73. Oxidative heterocyclization by treatment with hydrogen peroxide gave exclusively the 1,2,3-thiadiazoline 74 (Scheme 8) <2003S2559>. 

Thiadiazolines are less stable compared to 1,2,4-thiadiazoles and this can be attributed to the loss of aromatic character. They are readily cleaved at the N-S bond under fairly mild conditions (H2S in pyridine) in some cases, the product from ring cleavage can recyclize to give new heterocyclic ring systems. The 3-imino-l,2,3-thiadiazoline 24 when reduced with H2S affords the two J-triazine derivatives 25 and 26 (Scheme 3) <1996CHEC-II(4)307>. 

A number of ring systems have been converted into 1,2,4-thiadiazole derivatives. The most common include 5-imino-1,2,4-dithiazolidines, isoxazoles, oxadiazoles, and 5-imino-l,2,3,4-thiatriazolines. In general, a ring-opening reaction is followed by rotation and ring closure, or the heterocyclic ring may act as a masked 1,3-dipole which reacts with a suitable dipolarophile. 

A novel class of cathepsin B inhibitors has been developed with a 1,2,4-thiadiazole heterocycle as the thiol-trapping pharmacophore. The most potent inhibitor is compound 128 <2003BML5529>. 

Dithiazolyl radical 228 photochemically and thermally disproportionates to afford the 1,2,5-thiadiazole 229 and the unstable 1,2,3-trithiole 230 (Equation 54) <2000JCD3365>. Thermolysis of perfluoro-l,3A4(i2,2,4-benzodithiadia-zine 231 affords complex mixtures of heterocycles including perfluoro-2,l,3-benzothiadiazole 232 and 7,8-difluoro-benzo[l,2- 3,4-f ]bis[l,2,5]thiadiazole 233 (Equation 55) <2005EJI4099>. 

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