Alkylations 1,2,4-thiadiazole

Pyrazolin-5-one, 3-alkyl-( 1,2,4-thiadiazol-5-yl)-reactions, 6, 483 2-Pyrazolin-5-one, 3-amino-tautomerism, S, 215 2-Pyrazolin-5-one, 4,4-diazido-rearrangement, S, 720 2-Pyrazolin-5-one, 3-hydroxy-tautomerism, S, 215 2-Pyrazolin-5-one, 3-methyl-1-phenyl-reactions, S, 252... 

Figure 3 presents the reconstructed mass spectrum of the first discriminant function which separated the river and marine stations in the DiD2-map of Figure 1. The positive D-function describes the covariant mass peaks with higher intensities with respect to the zero point spectrum. All sample spectra with such characteristics will have positive score values. This spectrum is a representation of the characteristics of riverine material. The negative D-function spectrum in Figure 3 is indicative of the marine characteristics. The D spectrum shows a number of mass peaks indicative for carbohydrates, lignin and proteinaceous material (12). The mass peak m/z=86 and 100 are uncommon and a special characteristic of these fluvial samples. It can be speculated to be the molecular ion of (alkyl)thiadiazole (a metal binding pollutant), however a cyclic ketone, short chain alcohol or unsaturated acid are also possibilities. These mass peaks were chosen for further study because of their rare occurrence and their high discriminating power in the factor-discriminant analysis.

For both azole and benzazole rings the introduction of further heteroatoms into the ring affects the ease of quaternization. In series with the same number and orientation of heteroatoms, rate constants increase in the order X = 0requires stronger reagents and conditions methyl fluorosulfonate is sometimes used (78AHC(22)71). The 1-or 2-substituted 1,2,3-triazoles are difficult to alkylate, but methyl fluorosulfonate succeeds (7IACS2087). 

Thiadiazoles are quaternized to give 3- or mixtures of 2- and 3-alkyl quaternary salts. In 5-amino-1,2,4-thiadiazole, quaternization takes place at the 4-position (90) (64AHC(3il). 1-Substituted 1,2,4-triazoles are quaternized in the 4-position (91), and 4-substituted 1.2,4-triazoles are quaternized in the 1- or the 2-position (92) 64AHC(3)l). 

Thiadiazole with MeaO BF gives the diquaternary salt (95) diquaternary salts are also known in the 1,2,4-triazole series. 1,3-Disubstituted 1,2,4-triazolium salts can be further alkylated to diquaternary derivatives. 

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. ... 

Polarographic techniques have been used by Sturm and Hans to demonstrate that certain amino-thiadiazoles and -benzthiazoles exist in the amino form (cf. also references 62, 63). This method, which involves comparison of the polarographic rdeuction potentials of the potentially tautomeric substance with those of alkylated reference compounds, has not been applied often, but may well prove to be a means to obtain qualitative information quickly. There is a possibility that the method can be modified to yield quantitative data. ... 

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 ... 

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>. 

Thiadiazoles (57) are produced by the reaction of fV-substituted hydrazones (58 R1, R2 = alkyl, aryl, H R3 = acetyl, ester, tosylate, etc.) with thionyl chloride.67... 

Treated with thionyl chloride, hydrazones 490 (R1 = H, R2 = aryl) undergo cyclocondensation to thiadiazoles 506 whereas from aliphatic derivatives 490 (R1 = H, R2 = alkyl), mixtures of thiadiazoles 507 and 508 are formed... 

The base-catalyzed fragmentation of 4-alkyl-l,2,3-thiadiazoles is a useful method for the preparation of alkyne-1-thiolates <1996T3171>. These alkyne-l-thiolates can then react with carbon disulfide to afford l,3-dithiole-2-thiones. This strategy has been developed to give a synthesis of some novel tetrathiafulvene derivatives <1996T3171>. 

There are several examples of alkyl halides reacting with 1,2,3-thiadiazoles at nitrogen to yield either salts or mesoionic compounds <1996CHEC-II(4)289>. Similarly, with Meerwein s reagent, several substituted thiadiazoles yielded various 2- and 3-methylated 1,2,3-thiadiazoles (Scheme 4 Table 8) <1993JHC301>. The isomer ratios were determined by integrating the methyl singlets in the H NMR spectra and the compounds were further studied by 1SN NMR spectroscopy (Section 5.07.3.4). 

Diaryl-l,2,3-thiadiazoles and 1,2,3-benzothiadiazoles have been alkylated at N-3 with trimethylsilylmethyl trifluoromethanesulfonate and treatment of these salts with cesium fluoride generate new l,2,3-thiadiazol-3-ium-3-methanide 1,3-dipoles (see Section 5.07.8.1) <1999J(P1)1415>. 

Alkylation of 3,5-diaryl-l,2,4-thiadiazoles 22 with trimethylsilylmethyl triflate, in contrast to methyl iodide, occurs at N-2 to afford the salt 23 (Equation 5) and the quaternization at N-2 was confirmed by analysis of the 1SN NMR spectrum <1999J(P1)1709>. 

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>. 

The coupling of thioamides with a variety of oxidizing agents is a widely utilized method for the synthesis of 3,5-diaryl-l,2,4-thiadiazoles (see Section 5.08.9.2). This method is not suitable for alkyl derivatives. 3,5-Dialkyl derivatives can be more effectively prepared from a suitably substituted thioacylamidine (see Equation 22), and this method allows a range of unsymmetrical derivatives to be prepared. 

Addition reactions such as A-alkylation do not occur readily, and trimethylsilylmethylation of 3,4-diphenyl-l,2,5-thiadiazole 8 with trimethylsilylmethyl trifluoromethanesulfonate at 80°C occurred at N-2 < 1999J(P1) 1709>. The electron-rich 3-hydroxy-l,2,5-thiadiazole can be preferentially methylated on N-2 using trimethyl orthoacetate in toluene to afford the 2-methyl-l,2,5-thiadiazol-3-one in 69% yield <2002EJ01763>, although a mixture of 3-hydroxythiadiazole and neat trimethyl orthoacetate showed a 20 80 ratio of N- versus 0-alkylation products by H NMR. Treatment of 3-hydroxy-l,2,5-thiadiazole with /-butyl acetate under acid catalysis (Amberlyst 15) gave almost exclusively the A-alkylated compound <2002BMC2259>. 

Hydrolysis of amino-alkylamino-l,2,5-thiadiazole 1-oxides 55 with concentrated aqueous HC1 gave the amidines 56 (Equation 4) <2001JME1231>. The hydrolysis reactions of 2-alkyl-4-amino-2,3-dihydro-l, 2,5-thiadiazol-3-one 1,1-dioxides 57 in the range 24-73 °C in buffered aqueous solutions gave the corresponding 2-amino-2-[(iV-alkyl-substituted-sulfamoyl)imino]acetic acid salts 58 (Equation 5) <1998JP0489>. 

Phenyl-l,2,5-thiadiazole-3-carboxamide can be converted to the methyl 4-phenyl-l,2,4-thiadiazole-3-carboxylate with BF3-OEt2 in MeOH at reflux <2001H(55)75>. Alkyl substituents bearing a-chlorines can be dehalogenated with Pd/C-H2 in EtOH <1998JME4378>, or with Raney-Ni and H2 at atmospheric pressure in EtOH <1995USP5418240>. 

Hydroxythiadiazole and neat trimethyl orthoacetate showed a 20 80 ratio of N- versus O-alkylation products by H NMR <2002EJ01763>. The acidic hydroxyl group of thiadiazole 130 can be selectively protected as the benzyl ether 113 (Equation 22) <2004TL5441>. Nonhydrogenative debenzylation of the bisbenzyl thiadiazole 116 was achieved with boron tribromide to afford the bis-l,2,5-thiadiazole 131 (Equation 23) <2004TL5441>. 

O-Alkylation of 4-hydroxy-3-morpholino-l,2,5-thiadiazole 132 has been achieved with the chiral cyclic chloro-methyl sulfite 133 which subsequently suffers ring opening on treatment with simple alcohols <2001RCB436> or alkylamines <2002RJ0213> to afford the timolol analogues 134 with very little racemization (Scheme 20). This indicated an almost exclusive attack of the oxy anion on the exocyclic carbon atom and is a significant improvement on the previous oxirane method, which suffers from racemization. An alternative biocatalytic asymmetric synthesis of (A)- and (R)-timolol has also appeared <2004S1625>. 

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). 

The preparation of thiadiazoles 180 from 1-cyanoformamide 177 (2-nitrilo-acetimidic acid), or its alkyl esters 178, using disulfur dichloride under mild conditions was previously reviewed in CHEC(1984) and CHEC-II(1996). The synthesis of thiadiazoles from the thioesters 179, formed by the addition of alkylthiols to cyanogens, was more recently investigated (Equation 36) <1998JME379>. In several cases, the esters 178 or thioesters 179 prepared from cyanogen were not isolated but added directly to disulfur dichloride <1996W038431, 1998JME379>. 

The reaction between 2-oximino acetonitriles 183 and disulfur dichloride was used to prepare several 3-chloro-4-alkyl-l,2,5-thiadiazoles for muscarinic agonist studies <1995USP5418240, 1998H(48)2111, 1996EJM221,... 

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