1.3.4- Thiadiazoles basicity

Direct electrophilic silylation of thiadiazole 321 with bromotrimethylsilane (TMSBr) under basic conditions provides easy access to C-silyl thiadiazole 322, which can serve as a synthetic equivalent of an organometallic intermediate or a silyl-protected azole <06S 1279>. 

Ring protons of 1,2,3-thiadiazoles are known to undergo rapid deuterium exchange under basic conditions. It has been reported that even weak bases such as phenolate can extract the proton at the 5-position of 4-phenyl-l,2,3-thiadiazole <1999J(P1)1473>. 

Oxidative cyclization of dithiobiuret under basic conditions provides bis(5-amino-l,2,4-thiadiazolyl)-3,3 -disulfide 92 via oxidative dimerization of the intermediate 5-amino-3-mercapto-l,2,4-thiadiazole 91. However, alkylation of disulfide 91 under basic conditions gives the thioalkyl-l,2,4-thiadiazole 93 (Scheme 9) <2003H(60)1401>. 

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>. 

Methyl-4-phenyl-l,2,5-thiadiazole 1,1-dioxide 21 suffers proton abstraction in basic nonaqueous media to give a resonance stabilized anion 43, neutralization of which using anhydrous TFA gives the orange tautomer 4-methylene-3-phenyl-l,2,5-thiadiazoline 1,1-dioxide 44 (Scheme 3) <2001JP0217>. The tautomeric equilibrium is practically displaced toward 21 in acetonitrile and toward 44 in DMF. 

The relatively high aromaticity of the parent 1,2,5-thiadiazole renders it good thermal stability (stable up to 220 °C) despite this, 3,4-diphenyl-l,2,5-thiadiazole 8 suffers slow photochemical degradation to give benzonitrile and sulfur. The low basicity of 1,2,5-thiadiazole indicates a relatively high electron density in the Jt-orbital and corresponding low electron density of the nitrogen lone pairs. Addition reactions such as Walkylation do not occur readily. A-Oxidation is... 

Ring protons of 1,2,3-thiadiazoles are known to undergo rapid deuterium exchange under basic conditions, yet to date there have been no published estimates or experiments to determine the pA of these protons. Few attempts have even been made to metalate and alkylate this heterocycle. One study <85S945> found that metalation of 5-phenyl-1,2,3-thiadiazole (25) with methyllithium gives 4-lithio-5-phenyl-l,2,3-thiadiazole, which is stable and reacts with aldehydes and ketones in high yields (Equation (11)). Also, treatment of 4-phenyl-1,2,3-thiadiazole with lithium diisopropylamide, in the presence of TMS-Cl, affords 4-phenyl-5-trimethylsilyl-1,2,3-thiadiazole. 

Amino-1,2,4-thiadiazoles yield monoacylated derivatives of type (115) under the usual conditions, whereas 3-amino-1,2,4-thiadiazoles give both monoacyl and diacyl derivatives ((116) and (117), respectively) <84CHEC-I(6)463>. Treatment of 3-amino- and 5-amino-1,2,4-thiadiazoles with sulfonyl halides under basic conditions generally leads to low yields of sulfonamides. By... 

Amidines are converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, iminosulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur <82AHC(32)285> for example, 5-mercapto-3-methyl-l,2,4-thiadiazole (205) is obtained by the treatment of acetamidine with carbon disulfide and sulfur under basic conditions (Equation (29)) <85JAP85255783>. A useful method for the synthesis of 5-chloro-l, 2,4-thiadiazole (206) (R = 6-methyl-2-pyridyl) involves the reaction of amidines with trichloromethylsulfenyl chloride (Equation (30)) <91JAP9183590>. 

Thiadiazole is a planar, thermally stable, and weakly basic aromatic ring system. Aromatic forms of the 1,2,5-thiadiazole nucleus are generally stable to concentrated mineral acids and are only slightly sensitive to base. Base-catalyzed deuterium exchange of the ring protons can be effected... 

Addition of nucleophiles to the cyano group of cyanothiadiazole under basic conditions takes place with unusual ease <88AG(E)434,94ACS372). Hydrolysis to the amide, for example, can be effected at 0°C in the presence of a catalytic amount of sodium hydroxide or basic ion-exchange resin. At reflux temperature, hydrazine and monosubstituted hydrazines convert 3,4-dicyano-l,2,5-thia-diazole into the l,2,5-thiadiazole[3,4-. The base-catalyzed addition of acetone to cyanothiadiazole forms an enamino ketone, used as a key intermediate for the synthesis of a number of heterocyclic ring systems, e.g. isothiazole, isoxazole, pyrazole, pyrimidine, and thiazole <77H(6)1985>. 

Unsubstituted thiadiazole is unstable under basic conditions, and will decompose. 2-Amino-thiadiazole derivatives (45) react with amines to yield triazolinethiones (46). 2-Amino-5-halo-thia-diazole reacts with hydrazine to give a mixture of (47) and (48). 2,5-Dihalo and 2,5-dithio-thiadiazoles yield only (48) under the same conditions. Even a weaker nucleophile such as aniline... 

New PVC membrane sensors for Cd(II) ions based on 2-(3, 4 -dihydroxyphenylazo-l )-l,3,4-thiadiazole [376] and 3-(2, 4 -dihydroxyphenylazo-l )-l,2,4-triazol [377] were prepared. Their basic analytical parameters were established. 

A mathematical analysis of all four isomeric thiadiazoles by the simple molecular orbital method has provided molecular diagrams of the free base and conjugate acid of each thiadiazole, with electron densities, bond orders, and free valencies. On this basis, predictions have been made concerning the reactivities of the six non-equivalent carbon atoms, the basicities of the nitrogen atoms, and the delocalization energies in these molecules. The 5-position in free 1,2,4-thiadiazole should possess maximum reactivity in nucleophilic substitution reactions. The treatment also accounts for the order of the polarographic half-wave potentials and the position of the absorption maxima in the ultraviolet region of the spectra of 1,2,4- and 1,3,4-thiadiazoles.4... 

In 1954, Goerdeler6 introduced a general synthesis of 1,2,4-thia-diazoles from amidines. This versatile method has since been widely extended and has made a great variety of 1,2,4-thiadiazole derivatives readily accessible. Basically, an amidine is converted into its i T-thio-cyanato derivative, which cyclizes spontaneously to the 5-amino-1,2,4-thiadiazole. 

Thiadiazole forms easily hydrolyzed salts with mineral acids, a methiodide, and 1 1 addition compounds with silver nitrate and mercuric and cobaltous chlorides.5 Its weakly basic properties are shared by its homologs14,22 which form salts and adducts similarly. 

Anilino-3-hydroxy-l,2,4-thiadiazole dissolves in dilute alkalis and is reprecipitated by dilute acid it is, however, appreciably soluble in more concentrated acids (e.g. 3A-hydrochloric acid), possibly due to the influence of the basic portion of the heterocylic nucleus.130... 

Hydroxy-5-methylamino-l,2-4-thiadiazole is sufficiently basic to yield a picrate, as are the 3-alkoxy homologs.180... 

The corresponding ethylation proceeds in lower yields, and may be suppressed entirely by the presence of substituents elsewhere in the nucleus (e.g. 192 R = Ph).171 The attempted introduction of higher alkyl, allyl, and benzyl residues also failed.171 The derivative (204) obtained with phenacyl bromide is readily ring-closed to the diheterocycle 205.171 Diphenyl- and triphenyl-methyl halides, on the other hand, alkylate 5-amino-1,2,4-thiadiazoles in the exocyclic amino group,171 as shown by the lower basicity of the resulting products (e.g. 202). 

A comparison of the dissociation constants shows that 5-amino-3-dialkylamino-l,2,4-thiadiazoles are only slightly more basic than the 3-alkyl-5-amino analogs. The low basicity of these compounds suggests that they exist, like the 5-monoamino analogs (see Section III,D, 1), as enamineB rather than as the more basic tautomeric ketimines.81,87 The prevalence of the 3-enamine form in 3-amino-5-anilino-1,2,4-thiadiazoles is supported by ultraviolet absorption data.122... 

Di-S-ethers of 3,5-dimercapto-l,2,4-thiadiazole are generally very stable and can be steam-distilled. The weakly basic diethyl ether is dealkylated by alcoholic potassium hydrogen sulfide, but resists attack by alcoholic ammonia at 200°. Hydrogen chloride under pressure causes complete degradation.144... 

The ionization constants of a number of 1,2,4-thiadiazoles have been determined potentiometrically87,88 or by Hammett s method205 based on the measurement of ultraviolet absorption spectra in media of different hydrogen ion concentration.126 The results are given in Table VTI. 2- and 4-Aminopyrimidine differ in their basicities (pA ... 

Thiocarbonyl ylides are both nucleophilic and basic compounds (40,41,86). For example, adamantanethione (5)-methylide (52) is able to deprotonate its precursor, the corresponding 2,5-dihydro-1,3,4-thiadiazole, and a 1 1 adduct is formed in a multistep reaction (40,86). Thioxonium ion (56) (Scheme 5.22) was proposed as a reactive intermediate. On the other hand, thiofenchone (S)-methylide (48) is not able to deprotonate its precursor but instead undergoes electrocyclization to give a mixture of diastereoisomeric thiiranes (41,87,88). The addition of a trace of acetic acid changes the reaction course remarkably, and instead of an electrocyclization product, the new isomer 51 was isolated (41,87) (Scheme 5.18). The formation of 51 is the result of a Wagner-Meerwein rearrangement of thioxonium ion 49. 

The oxidation of thiazoles by peroxy acids leads to the corresponding A-oxides. Peracetic, MCPBA, permaleic, and trifluoroperacetic acid have been employed for this reaction. Chemical yields range from 4% to 50%, the more basic thiazoles producing higher yields. Thus, thiazole, 2,4-dimethyl- and 4,5-dimethylthiazoles, and 2-phenylthiazole can be oxidized in moderate to good yields. However, neither 4-chloro-2-phenylthiazole nor 5-chloro-2-phenylthiazole could be oxidized. 3-Oxides were also obtained by oxidation of 1,2,3-thiadiazoles and 5-phenylthiatriazole (121—>122) (75T1783). 

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