1.3.4- Thiadiazole, 2-amino-, bromination

However, a 2-amino group does activate the ring towards electrophilic agents, since Bak et al. could prepare 2-amino-5-bromo-1,3,4-thiadiazole by bromination of 2-amino-l,3,4-thiadiazole in 40% hydrobromic acid. The product was not isolated but was diazotized in situ to give 2,5-dibromo-l,3,4-thiadiazole. 

Amino-l,2,5-thiadiazole is chlorinated or brominated at the 4-position at 20°C in acetic acid. 3-Methyl-l,2,5-thiadiazole can also be chlorinated in the 4-position (68AHC(9)107). Bromination of 2-amino-l,3,4-thiadiazole succeeds in the 5-position (65ACS2434). 

A variation using thioacylguanidines affords 5-substituted-3-amino-l,2,4-thiadiazoles. If an amidinothiourea is oxidized, 5-amino-l,2,4-thiadiazoles are obtained. A recent example of this type of synthesis has been reported the amidinothiourea 87 was oxidized to the 1,2,4-thiadiazolium salt 88 on treatment with bromine (Equation 25) <2003SC2053>. 

V-(Arylsulfonamidino)thioureas (108) afford the expected 5-amino-3-sulfonamido-l,2,4-thiadiazoles (109). The cyclization occurs almost quantitatively under the influence of bromine, but fails with hydrogen peroxide, which cleaves part of the starting material to sulfonylguanidine (110), and desulfurizes part to sulfonamidinourea (111).116. 

Guanidine cannot be thioacylated by O-alkylchlorothioformates (RO—CS—Cl) the action of dialkylthiocarbonates [(RO)2CS], however, yields unstable intermediates (130) which are cyclized by bromine to 5-alkoxy-3-amino-l,2,4-thiadiazoles (131) in low yield (14.5% when R = Et).92... 

The 1,2,5-thiadiazoles were relatively inert in electrophilic substitution reactions (see also Section 4.02.1.4). The parent ring does not react with bromine, either under irradiation or in the presence of iron(III) salts, nor does it enter the Friedel-Crafts or nitration reactions. Electrophilic deuteration has been effected in low yield under drastic conditions (250 °C in trideuterophosphoric acid). If the thiadiazole ring bears an activating group, e.g. amino or methyl, electrophilic substitution can be achieved <68AHC(9)107, 70RCR923). 

Due to the low electron density at the carbon atoms in 1,3,4-thiadiazole, such reactions as nitration, sulfonation, acetylation, halogenation, etc. normally do not take place. However, 2-amino-substituted 1,3,4-thiadiazoles (73a-i) react with bromine in acetic acid to give the 5-bromo derivatives (74a-i). Similarly, the thiadiazolines (75b) and (75d-f) yield the corresponding 5-bromo derivatives (76b) and (76d-f). The thiadiazoline (75a), however,... 

Reaction of an amino-substituted heterocyclic thiol such as 84 with acylating agents gives compounds 85, which are cyclized by POCl3 to form the respective imidazo[2,l- ][l,3,4]thiadiazoles 86 (Scheme 51) (for a review see <1998CHE1003>). Bromine oxidation of the cyclic thiourea 87 forms 2,3,5,6-tetrahydroimidazo[l,2- /][l,2,4]thiadia-zol-3-ones 88 (Scheme 52) <1973JPR539>. 

Goerdeler s general synthesis3 of 5-amino-1,2,4-thiadiazoles by the cyclization of N-thiocyanatoamidino compounds formed in situ has been further exploited.114-116 l-Amino-3-iminoisoindoleninium thiocyanates (144), which are accessible from o-dinitriles, can function as the amidine, and yield, by the usual simultaneous action of bromine and sodium methoxide,117 or of sodium hypobromite,118 3-substituted 5-amino-l,2,4-thiadiazoles (145). 

In a variation of this synthesis, the amidine is N-halogenated prior to its condensation with an isothiocyanate ester the resulting IV-haloimidoyl-thioureas (238) are readily cyclized to 239 by alkalis. By employing bromine in conjunction with methylene chloride-aqueous alkali as the reaction medium, the reaction may be performed in one operation. 3-Trichloromethyl-5-(substituted)amino-l,2,4-thiadiazoles have been produced by this method.187 The use of potassium ethyl xanthate similarly yields the 5-ethoxy analogs (240 e.g., R = CC13, R1 = Et) directly, with elimination of the elements of hydrogen sulfide.188... 

The structure of 2-anilino-5-phenylazo-1,3,4-thiadiazole (89 R = Ph) is established by its alternative synthesis from 2-amino-5-anilino-l,3,4-thiadiazole (90) and nitrosobenzene by the Mills reaction. Further examples of arylazo-thiadiazoles of this type (89) have been prepared by the oxidative cyclization of l-aryl-5-arylthiocarbamoylthiocarbonohydrazides (e.g. p-TolNHNH-CS-NHNH-CS-NHR, i.e. bithiourea derivatives), using bromine, hydrogen peroxide, or aqueous iron(iii) chloride as oxidizing agent. ... 

Type B Syntheses [NCN + CS].—l-Amino-3-imino-isoindoleninium thiocyanates (60), which are accessible from o-dinitriles (59), are convertible into 3-substituted 5-amino-1,2,4-thiadiazoles (61) by the simultaneous action of bromine and sodium methoxide. The reactants (60) thus play the role of the linear amidines in Goerdeler s synthesis, of which the present modification is a useful extension/ ... 

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