1.3.4- Thiadiazoles reactivity

Thieno[2,3-d]-1,2,3-thiadiazoles Thieno[2,3-d]-1,2,3-triazoles Thieno[3,2-d]-1,2,3-thiadiazoles Reactivity of Nonconjugated Ring Systems... 

In the 1,2,4-thiadiazole ring the electron density at the 5-position is markedly lower than at the 3-position, and this affects substituent reactions. 5-Halogeno derivatives, for example, approach the reactivity of 4-halogenopyrimidines. The 1,2,4-oxadiazole ring shows a similar difference between the 3- and 5-positions. 

Thiirenes have been isolated in argon matrices at 8 K by photolysis of 1,2,3-thiadiazoles or vinylene trithiocarbonates (Scheme 151) (80PAC1623, 8UA486). They are highly reactive and decompose to thioketenes and alkynes (Scheme 22). Electron withdrawing substituents stabilize thiirenes somewhat, but no known thiirene is stable at room temperature unlike the relatively stable thiirene 1-oxides and thiirene 1,1-dioxides. 

Ethyl iodide and 5-amino-2-methyl-l,3,4-thiadiazole react at 110° to give the N-3 salt (78 R = Me, R = NH2, R" = Et), as shown by the presence of the very reactive methyl group this salt is also used to prepare cyanine dyes. The slow quatemization at the ring-nitrogen atom furthest from the amino group is consistent with the reactions observed in other ring systems. As would be e pected, 5-alkylthio-2-methyl-l,3,4-thiadiazoles form salts at the N-3 (78 R = Me, R - S-alkyl).i ... 

Heteroaromatic sulfur compounds do form sulfoxides and sulfones, but these derivatives have their own special reactivity. Francesca Clerici (Milan, Italy) has now provided an up-to-date survey of the preparation and properties of the S-oxides of thiazoles and thiadiazoles, collecting literature scattered in many publications. 

It is the combination of exceptional reactivity and reasonable stability, either as a solid or in solution, that makes PTAD such an ideal dienophile. However, PTAD is decomposed to N2, CO and phenyl isocyanate by the action of UV light.61 The cyclic ADC compounds (6-23) all undergo the Diels-Alder reaction, although with the exception of phthalazine-l,4-dione (13, R = H), they have been used only occasionally. l,3,4-Thiadiazole-2,5-dione (11) is of comparable reactivity to PTAD,38 but like the other cyclic compounds (6-23) has the slight disadvantage in that it has to be generated in situ. 

The photochemical reactivity of 1,2,3-thiadiazoles has been utilized in the formation of cross-linked polymers <1996CHEC-II(4)289>. No new developments in this area have been reported since the publication of CHEC-II(1996). 

The 5-position of the nonprotonated 1,2,4-thiadiazole system was calculated to be the most reactive in nucleophilic substitution reactions using a simple molecular orbital method <1984CHEC(6)463>. 

The 5-position in 1,2,4-thiadiazoles is the most reactive in nucleophilic substitution reactions. For example, halogens may be displaced by a variety of nucleophiles <1984CHEC(6)463> however, halogens in the 3-position are inert toward most nucleophilic reagents. 

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. 

The enhanced reactivity of 5-halogeno-l,2,4-thiadiazoles over 3-halogeno-l,2,4-thiadiazoles has been mentioned before (see Section 5.08.7.1). Nucleophilic substitution at this center is a common route to other 1,2,4-thiadiazoles, including 5-hydroxy, alkoxy, mercapto, alkylthio, amino, sulfonamido, hydrazino, hydroxylamino, and azido derivatives. Halogens in the 3-position of 1,2,4-thiadiazoles are inert toward most nucleophilic reagents, but displacement of the 3-halogen atom can be achieved by reaction with sodium alkoxide in the appropriate alcohol <1996CHEC-II(4)307>. 

Type G syntheses are typified by the 1,3-dipolar cycloaddition reactions of nitrile sulfides with nitriles. Nitrile sulfides are reactive 1,3-dipoles and they are prepared as intermediates by the thermolysis of 5-substituted-l,3,4-oxathiazol-2-ones 102. The use of nitriles as dipolarophiles has resulted in a general method for the synthesis of 3,5-disubstituted-l,2,4-thiadiazoles 103 (Scheme 11). The thermolysis is performed at 190°C with an excess of the nitrile. The yields are moderate, but are satisfactory when aromatic nitrile sulfides interact with electrophilic nitriles. A common side reaction results from the decomposition of the nitrile sulfide to give a nitrile and sulfur. This nitrile then reacts with the nitrile sulfide to yield symmetrical 1,2,4-thiadiazoles <2004HOU277>. Excellent yields have been obtained when tosyl cyanide has been used as the acceptor molecule <1993JHC357>. 

The transformation of 1,2,4-thiadiazoles bearing a reactive substituent such as amino or halogen group in the 5-position is the most useful method for the synthesis of 5-substituted 1,2,4-thiadiazole derivatives. The latter compounds can be reacted with nucleophiles to afford a wide range of derivatives this is not the case for 3-halogen-substituted compounds. 

A local frontier orbital (LFO) study involving the variational method to analytically find appropriate combinations of valence atomic orbitals giving the maximum and minimum energies of the occupied and unoccupied LFOs, respectively, was employed to find the acidities of the conjugate cation of 1,2,5-thiadiazole 1 <1997PCA5593>. A later study adopted a projected reactive orbital (PRO) approach, which describes local reactivity better than frontier orbital theory in high-symmetry systems to predict the basicity of 1,2,5-thiadiazole 1 <2005PCA7642>. 

A difference in reactivity was observed between the phenanthro[9,10-r]- and acenaphtho[l,2-c]-l,2,5-thiadiazole 1,1-dioxides 51 and 53 when treated with thiourea. The acenaphtho derivative 53 gave the expected addition product however, the phenanthro thiadiazole 51 was reduced to the thiadiazoline 1,1-dioxide 52 (Equation 2) <2004JP01091>. The difference in reactivity was attributed to the enhanced resonance stability offered by the phenanthrene group. 

An extensive coverage of the reactivity of substituents attached to the 1,2,5-thiadiazole ring carbon atoms exists in both CFIEC(1984) and CFIEC-II(1996). Recent developments are described in this section. 

Chlorophenyl)-4-phenyl-l,2,5-thiadiazole 128 was prepared from 3-trifluoromethylsulfonyloxy-4-phenyl-1,2,5-thiadiazole 127 by palladium-catalyzed cross-coupling reaction with the tributyl(4-chlorophenyl)stannane (Equation 20) <1996H(43)2435>. The addition of lithium chloride improves the yield. The 3-chloro- and 3-bromo-l,2,5-thiadiazole derivatives were also reactive, but only the bromo compound gave the product in comparable yield (see Section 5.09.7.6). 

These reactions were proposed to proceed via electrophilic attack on the enol by the SN reagents at N followed by cyclization either via a second enol as in compound 151 or by cyclization onto the more reactive carbonyl <1997J(P1)2831>. Unsymmetrical 1,3-diketones can give a mixture of regioisomers if both carbonyls have similar reactivities however, aroylacetones react regiospecifically to afford only the 3-aroyl-4-alkyl-l,2,5-thiadiazoles 154 (R = Me). 

A formally antiaromatic 1,4-dihydropyrazinothiadiazole has been prepared and characterized by single crystal X-ray spectroscopy. The antiaromatic character of which has been supported computationally using NICS measurements <20070L1073>. CHIH-DFT computational studies on acenaphtho[l,2-f]-l,2,5-thiadiazole 1,1-dioxide led to simulations of its infrared (IR) and ultraviolate (LJV) spectra, the dipole moment and polarizability <2007JMT373>. 4,6-Dinitrobenzothiadiazole was determined to have an electrophilic reactivity of —8.40 which corresponds to a pK z° of 7.86 for Meisenheimer complexation with water and is close to the demarcation boundary (E = —8.5) between super-and normal-electrophiles and between reactive dienophiles and inert partners in Diels-Alder adduct formation <20070BC1744>. 

The chemical reactivity of 1,3,4-thiadiazole 1 was predicted using DFT by calculating the net atomic charges and the Fukui functions /+,/ , and f° (Table 2). 

Few examples on the reactivity of substituents attached to ring atoms are available. The desilylation of the 1,3,4-thia-diazolium salt 124 by CsF gave the unstable 1,3-dipole 125 which was trapped with N-substituted maleimides to afford exclusively the < . 

The reactivity of 5-amidinoisothiazoles (221) was explored to demonstrate the equilibrium 221 222 (Scheme 37). However, on reacting with nitriles or imidates, 5-amino compounds 220 (R = Me, Ph) give directly the rearranged thiadiazoles 222. The equilibrium between the two heterocycles (in different solvents at room temperature) is not observed, and this result is attributed to the greater stability of the 1,2,4-thiadiazole... 

The 1,2,3-thiadiazole salt (22) when heated in pyridine affords a reactive intermediate that dimerizes with the extrusion of sulfur (Scheme 4) <86JPR741>. 

Little is known about the reactivity of nonconjugated 1,2,3-thiadiazoles since few of these compounds are known (Section 4.07.1.3). 

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