1,2,5 -Thiadiazoles, reaction with

The ring nitrogens react with electrophiles to afford either 1,3,4-thiadiazolium salts or l,3,4-thiadiazol-2(37/)-ones depending on the tautomerisability of the substituents at the C-2 or C-5 positions. While N-alkylation is the most common electrophilic reaction of 1,3,4-thiadiazoles, reactions with acyl and cyanogen halides as well as Mannich salts have also been reported. 

Reaction of a hydrazide (128) with phosgeneiminium chloride (115) led to the 2-dimethylamino-l,3,4-oxadiazole (129) in 90% yield (75AG(E)806). The 1,3,4-thiadiazole system was also obtained in an analogous reaction in which the dithioimidate (130) underwent reaction with the thiohydrazide (131). Depending on the nature of X in (131), the 2-substituent in the resultant 1,3,4-thiadiazole (132) may be varied (80ZC413). Although (130)... 

Thiadiazole, 2-methyl-5-pheny 1-reactions with butyllithium, 6, 563... 

They have been several recent investigations of the reactions of disulfur dichloride with other organic substrates. Rokach and co-workers37 have found that 2-aminoacetamides afford 2-substituted l,2,5-thiadiazol-3(2J7)-ones (33). This illustrates a frequent facet of such reactions the elision of the second sulfur atom. A similar reaction, with loss of a sulfur atom, occurs with 2-alkylaminophenyl acetamides.38... 

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>. 

Amidines and cyclic amidines are also converted into 1,2,4-thiadiazoles by reaction with isothiocyanates, imino-sulfenyl chlorides, di- and trichloromethyl sulfenyl chlorides, and carbon disulfide in the presence of sulfur. Ureas, thioureas, guanidines, carbodiimides, and cyanimides react with chlorocarbonylsulfenyl chloride to produce 1,2,4-thiadiazol-5-one derivatives in another example of a type B synthesis <1996CHEC-II(4)307>. 

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>. 

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). 

A-Alkylpyrroles undergo cycloaddition reactions with trithiazyl trichloride (NSC1)3 to afford, depending on the substituents R1, R2, and R3, thiadiazoles 216-218. The reactions are proposed to proceed by addition of the N-S(C1)-N fragment across the 2,3- and the 4,5-bonds of the A-alkylpyrrole, followed by a series of eliminations to give the observed products (Equation 49) <1997CC1493, 1997J(P 1)3189>. 

Tautomerism was reviewed quite extensively in CHEC(1984) <1984CHEC(6)545> and CHEC-II(1996) <1996CHEC-II(4)379>. The tautomeric ability of the 2-mercapto-5-methyl-l,3,4-thiadiazole 9 was studied by its reaction with the electrophilic Cl3 FnCSCl <2003JP01>. 2-Mercapto-5-methyl-l,3,4-thiadiazole 9 was considered to exist mainly as the thione tautomer however, electrophilic substitution occurred on the thiol (Scheme 1). 

The bromine atoms in 2,5-dibromo-l,3,4-thiadiazole 54 undergo a palladium-catalyzed Stille reaction with the organostannyl derivative 55 (Equation 7) <1998CEJ2211>. The thiadiazole 54 was co-polymerized with diethynyl benzene 56 (Equation 8) and diethynyl pyrrole in a Sonogashira cross-coupling reaction <2005MM4687>. 

Bistrifluoromethyl-l,3,4-thiadiazole 71 undergoes a Diels-Alder reaction with norbornadiene under high pressure to give the unstable cycloadduct 72 which rapidly loses dinitrogen forming the 1,3-dipolar intermediate 73. The [4+2] cycloaddition of the intermediate 73 with a second alkene affords product 74 in 29% yield (Scheme 5) <1997SL196>. 

The cycloaddition reactions of [(thioacyl)methylene]thiadiazoles 83 with dimethyl acetylenedicarboxylate (DMAD) under UV irradiation at room temperature gave the spiro[3/7-l,3,4-thiadiazoline-2,4 -477-thiopyrans] 84 in 50-60% yields (Equation 23) <2003EJ02480>. 

Acylation of l,3,4-thiadiazol-2-(3//)-ones is also possible although competitive reaction with the ring nitrogen atoms is often observed. This reaction has been reviewed in the Houben-Weyl Science of Synthesis <2004HOU(13)349>. 

The sulfide derivative of furocoumarin based natural products can be synthesized by treatment of a thiadiazole 107 with KO-f-Bu and an organohalide in an one-pot operation. This process presumably involves the generation of a phenolate 108 and is followed by an intramolecular proton shift and a rearrangement to give an alkynethiolate 109, which undergoes a sequence of intramolecular proton shift, cyclization and alkylation to lead to the furocoumarin product. The thiadiazole, in turn, can be prepared by reaction of the corresponding acetyl precursor with carbethoxyhydrazine, followed by treatment with thionyl chloride . 

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>. 

Iwakawa et al. studied the reaction of 3-acetonyl-5-cyano-l,2,4-thiadiazole 72 with a series of 4-substituted phenylhydrazine hydrochlorides. When electron-donating substituents were used (e.g., methyl and methoxy) in the phenyl ring of the hydrazine, the reaction proceeded via a Fischer-indole mechanism to give indoles 73 as the sole product. In contrast, reaction of 72 with phenylhydrazine and 4-chlorophenylhydrazine gave only small amounts of indole 72, but much higher yields of the pyrazole 74. The authors described in detail the respective reaction mechanisms... 

Kidwai and co-workers reported a series of insertion reactions of the thiadiazoles 87 with oxadiazoles 88 on a solid support using microwaves. This produced the triazoles 89 in much higher yield and in much shorter reaction times than conventional heating <00SC3031>. 

Mannich reaction of 2-cyloalkyl(heteroaryl)-6-aryl-imidazo[2,l-A][l,3,4]thiadiazoles 161 with formaldehyde in the presence of cyclic bases (piperidine and pyrrolidine), in methanol with a catalytic amount of acetic acid, gives the corresponding C-alkylated derivatives 172 (Equation 8) <2006BMC3069>. 

When compound 241 is refluxed with hydrazine hydrate, 2,6-dimethyl-imidazo[2,l- ][l,3,4]thiadiazole-5-carbohy-drazide 242 was isolated. This product, after reaction with the appropriate aldehydes, yields the corresponding... 

The reaction of 3-methyl-6-(4-chlorophenyl)[l,2,4]triazolo[3,4-7]-l,3,4-thiadiazole 319 with thioglycolic acid gives thiazolo[2,3-3]-.r-triazolo[3,4-7][l,2,3]thiadiazol-6(7//)-one 320 (Equation 56) <2002IJH167>. 

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