1,2,5-Thiadiazole ketones

A detailed study of the synthesis of thiadiazole ketones via the reaction of 3-chlorocarbonyl-l,2,5-thiadiazoles with dialkylcadmium reagents was reported. In each case the ketone was obtained in only low yield, the major product being a tertiary carbinol or a tertiary carbinol dehydration product. These products stemmed from the reaction of the desired ketone with a second equivalent of the cadmium reagent. Thus, the 1,2,5-thiadiazole ketones are among the very few... 

High-speed synthesis of thiadiazoles has been recently completed on a solid support system using a catch and release technology to provide novel thiadiazoles. The solid-supported sulfonylhydrazine reacts with ketones to provide the solid phase hydrazones (catch) and formation of the thiadiazole with subsequent release of the... 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles from a-methylene ketones developed in 1955 is, even today, the method of choice for a number of 1,2,3-thia-diazole derivatives. Both the mechanism and the regiochemistry have been extensively studied, but since the isolation of the intermediate by Hurd and Mori (84CHEC-I(6)460), there has been no further work supporting the formation of this intermediate or its conversion into the aromatization product. In 1995 Kobori and coworkers published the isolation of several 1,2,3-thiadiazolin-1-oxides 186, finally demonstrating their participation in the formation of 1,2,3-thiadiazoles. Substituents R and R play an important role in the isolation of 1,2,3-thiadiazolin-1-oxide (95H(41)2413). 

Reaction of the pyridine-2-thiol (109) with ketones and with triethyl orthoformate has led to A(5-acetals (112) and 1,3,4-thiadiazoles (110) which on methylation and subsequent ring opening gave two new pyridine derivatives (113) and (111) <96JPR516>. 

On reaction of N-thioformylphenylhydrazine 1533 with aldehydes such as benz-aldehyde (or ketones such as acetophenone) in the presence of TCS 14 in benzene 2,3-dihydro-l,3,4-thiadiazoles such as 1535 are formed in high yields via 1534 [65, 66] (Scheme 9.36). 

One study found that metalation of 5-phenyl-l,2,3-thiadiazole 43 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) <1985S945>. 

A parallel synthesis of 1,2,3-thiadiazoles employing a catch-and-release strategy has been reported using the Hurd-Mori reaction. A polymer-bound tosyl hydrazide resin reacted with a-methylene ketones to afford a range of sulfonyl hydrazones. Treatment of these sulfonyl hydrazones with thionyl chloride causes 1,2,3-thiadiazole formation and cleavage of the resin in one step <1999JOC1049>. 

The Hurd-Mori synthesis of 1,2,3-thiadiazoles s the most widely used method. The availability of aldehydes and ketones which can then be converted into their corresponding hydrazones and the high yields obtained on treatment of these hydrazones with thionyl chloride mean that this method should always be considered as the first choice. 

Aroylformamido-4-aryl-l,2,5-thiadiazoles 156 can also be prepared from aryl dibromomethyl ketones 155 on treatment with tetrasulfur tetranitride at 115 °C (Equation 31) <1995J(P1)253>. These reactions are, however, complex, and the 1,2,4-thiadiazole 157 is often produced as a minor product. 

No mechanistic discussion was offered and the proposed conversion of 1,2,5-thiadiazole 156 into 1,2,4-thiadiazole 157 with MCPBA <1995J(P1)253> was incorrect, the error caused by incompletely purified 1,2,5-thiadiazole <1999JHC515>. In contrast, monohalogenated methyl aryl ketones gave 1,2,4-thiadiazoles 157 with tetrasulfur tetranitride in chlorobenzene at 110-115 °C <1992JHC1433>. 

Bakulev et al. reported the synthesis of 5//-[l,2,3]triazolo[5,l-i>] [l,3,4]thiadiazines starting from 5-N-nitrosylamino-l,2,3-thiadiazole 68. Reduction of 68 with SnCh and 1A/HC1 and then subsequent reaction with a ketone gave the imine 69. Treatment of 69 with thionyl chloride at -80 °C led to the formation of the isolable triazolothiazine 70 which on further reaction with thionyl chloride at room temperature gave the corresponding chloro derivative 71 <00MC19>. 

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>. 

Thioamides 176 react photochemically with 2,3-dimethyl-2-butene in the absence of oxygen to give ketones (equation 116)172. In the absence of oxygen, the photoproducts of 176 include nitriles, 1,2,4-thiadiazole and isothiazoline (equation 117). 

The a-halo ketone has also been prepared in situ (NBS, benzoyl peroxide, light) [89IJC(B)500]. Similarly, imidazo[2,l-b][l,3,4]thiadiazoles are accessible from 2-amino-l,3,4-thiadiazoles and acetophenones in the presence of hydroxy(tosyloxy)iodobenzene (HTIB). This latter method has been proposed as more convenient and versatile than the reaction of 2-amino-1,3,4-thiadizoles with a-halo ketones [94IJC(B)686, 94JCR(S)38, 94MI5],... 

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. 

Although introduced over 40 years ago, Hurd and Mori s synthesis of 1,2,3-thiadiazoles remains the most widely used for the synthesis of 1,2,3-thiadiazoles. The simplicity of the method has contributed to its popularity. A variety of ketones and aldehydes have been converted into their corresponding hydrazones (tosyl and acyl), and thioamides have been converted into thio-carbazonate esters. The carbonyl derivatives are then treated with thionyl chloride to yield 1,2,3-thiadiazoles in high yields. When one is faced with the task of synthesizing new 1,2,3-thiadiazoles, Hurd and Mori s method should always receive attention. 

Diaroyl and 3,5-diacyl-1,2,4-thiadiazoles (98) can be hydrolyzed with NaOH giving 3-mono-substituted ketones (99) (Equation (14)) <92JHC1433>. 

Hydroxy-1,2,4-thiadiazoles are generally distinctly acidic. 3-Ethyl-5-hydroxy-1,2,4-thiadiazole, for example, is more acidic than nitrophenol and 4-hydroxypyrimidine, but less so than 2,4-dinitrophenol. 3-Hydroxy-1,2,4-thiadiazoles fail to afford ketonic derivatives and give red to purple colors with iron(III) chloride, indicating their phenolic nature <65AHC(5)119>. Their IR spectra in... 

Reaction of tetrasulfur tetranitride with aryl and alkyl bromomethyl ketones (288) in refluxing chlorobenzene gives 3,5-diaroyl and 3,5-diacyl-l,2,4-thiadiazoles (98) in yields of 17-60% (Equation (44)) <92JHC1433>. 

The acid chlorides have served as useful synthetic intermediates leading to ketones via the malonic acid synthesis and Friedel rafts reaction, thiadiazole acetic acid derivatives, and halo ketones via the Arndt Eistert synthesis and carbinols by hydride reduction <68AHC(9)107>. The dialkylcadmium conversion of acid chlorides into ketones fails in the 1,2,5-thiadiazole series. The major product is either a tertiary carbinol or the corresponding dehydration product, by virtue of the high reactivity of the intermediate ketone. 

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>. 

Silyl-substituted diazoketones 29 cycloadd with aryl isocyanates to form 1,2,3-triazoles 194 (252) (Scheme 8.44). This reaction, which resembles the formation of 5-hydroxy-l,2,3-triazoles 190 in Scheme 8.43, has no analogy with other diazocarbonyl compounds. The beneficial effect of the silyl group in 29 can be seen from the fact that related diazomethyl-ketones do not react with phenyl isocyanate at 70 °C (252). Although the exact mechanistic details are unknown, one can speculate that the 2-siloxy-1-diazo-1-alkene isomer 30 [rather than 29 (see Section 8.1)] is involved in the cycloaddition step. With acyl isocyanates, diazoketones 29 cycloadd to give 5-acylamino-l,2,3-thiadiazoles 195 by addition across the C=S bond (252), in analogy with the behavior of diazomethyl-ketones and diazoacetates (5). 

Hydroxy-l,2,4-thiadiazoles possess phenolic character they give red to purple colors with ferric chloride, and fail to afford ketonic derivatives.130,178 They resist the action of hot alkaline sodium plumbite.130 The 3-alkoxy homologs are neither alkali soluble nor give colors with ferric chloride.130... 

III,D, 1). In spite of this, differences in the spectra of 5-anilino-3-hydroxy- and 3-alkoxy-5-anilino-l,2,4-thiadiazoles suggest that ketonic tautomers of the hydroxy compound contribute to the resultant absorption curve. Similar observations are made with 3-hydroxy-5-phenyl-l,2,4-thiadiazole.122 The spectra of 4-methylpyrimid-2-one and 2-methoxy-4-methylpyrimidine led to similar conclusions.170... 

Thiadiazolyl-5-hydrazines show the expected reducing action towards ammoniacal silver nitrate, and yield ketonic derivatives.176 3-Methylthio-5- (to -phenylhydrazino)-l,2,4-thiadiazole (290) is oxidized by yellow mercuric oxide in ethanol to the azo compound 291.198... 

Diazo ketones are converted by amines into 1,2,3-triazoles and by hydrogen sulfide into 1,2,3-thiadiazoles (371 — 372 Z = NR, S). The intramolecular cyclization of suitable precursors is a most useful method for the preparation of the 1,2,3-triazole ring, including (V-amino- and (V-imino-triazoles and triazole N-oxides. 

Reaction of N -phenylthioformhydrazine (73) with ketones in the presence of trimethylsilyl chloride at room temperature gave 2,2-disubstituted-2,3-dihydro-3-phenyl-l,3,4-thiadiazoles (74) in good yield, except with benzophenone and a,P-unsaturated ketones. O-Trimethylsilyl... 

The IR spectrum in Nujol of l,2,4-thiadiazolidine-3,5-dithione indicates that the dithione structure (18a) predominates. However, the dithione can be readily dialkylated on sulfur. Thus, treatment with 2,3-dichloropropene in aqueous sodium hydroxide forms (208 Scheme 73) (65AHC(5)119). The disulfenamide (209) condenses with aldehydes and ketones to give the corresponding imines (210) and (211 Scheme 74) (74ZOB2553). 5-Mercapto-3-methyl-thio-l,2,4-thiadiazole (212) reacts with di- -butyltin chloride in THF to give di-n-butyltin derivative (213 Scheme 75) (72USP3634442). 

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