1.2.4- Thiadiazole ring opening

Thiadiazine from 1,3,4-thiadiazole ring via selective 1,3,4-thiadiazole ring opening... 

Regarding the reactivity of fluorinated 1,3,4-thiadiazoles, rare examples of peculiar reaction due to the presence of fluorinated moieties are reported in the literature, and all involve the thiadiazole ring-opening. Beside the above discussed obtaimnent of perfluorinated open-chain compound 160[62] the only example is related to the treatment 2-amino-5-trifluoromethyl-l,3,4-lhiadiazole 218 with an alcoholate, causing dimerization with opening of a thiadiazole ring and formation of 219 in 34 % yield (Schane 56) [106]. 

Benzylthio-6-phenylimidazo[2,l-b] [l,3,4]thiadiazole refluxed 50 hrs. with hydrazine hydrate in ethanol l-amino-2-mercapto-4-phenylimidazole (Y di%) refluxed 20 min. with [Pg.21]

Deacylations are known. C-Acyl groups in 1,3,4-thiadiazoles are cleaved by sodium ethoxide in ethanol (68AHC(9)165). Imidazole-2-carbaldehyde behaves similarly, yielding imidazole and ethyl formate this reaction involves an ylide intermediate. 3-Acylisoxazoles (405) are attacked by nucleophiles in a reaction which involves ring opening (79AHC(25)147). 

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>. 

The 1,2,3-thiadiazole 1 possesses three contiguous heteroatoms in a five-membered ring and exists as a remarkably stable neutral aromatic compound. It is isomeric with the ring-opened a-diazothioketone 2 (Equation 1) although there is evidence that it reacts through this intermediate, all structural methods, including X-ray diffraction, point to 1 as the structure for a 1,2,3-thiadiazole. 

A number of ring systems have been converted into 1,2,4-thiadiazole derivatives. The most common include 5-imino-1,2,4-dithiazolidines, isoxazoles, oxadiazoles, and 5-imino-l,2,3,4-thiatriazolines. In general, a ring-opening reaction is followed by rotation and ring closure, or the heterocyclic ring may act as a masked 1,3-dipole which reacts with a suitable dipolarophile. 

Treatment of the 2,5-dihydro-l,2,5-thiadiazole 1,1-dioxide 69 with/>-toluenesulfonic acid monohydrate affords the ring-opened phenylethyl sulfamide 70 (Equation 9) <2004BMC6249>. 

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>. 

Electron-deficient 1,2,3-triazoles 222 can be converted into 1,2,5-thiadiazoles 223 with trithiazyl trichloride (Equation 51). The triazoles were proposed to react by initial ring opening to their diazoimine tautomers <2001J(P1)662>. 

Heating of a solution of 5-ethyl-3-phenyl-l,3,4-thiadiazol-2(377)-imine 85 in aq. NaOH to 80°C for 5h gave the 5-ethyl-2,3-dihydro-2-phenyl-l/7-l,2,4-triazole-3-thione 86 via Dimroth rearrangement (Scheme 7) <2002HCA1883>. Nucleophilic attack of the hydroxide on the electrophilic C-5 resulted in ring opening and, after rotation around the C(2)-N(3) bond and subsequent recyclization, triazole thione 86 formed. 

Thiadiazoles (THDs) react with an excess of phenylethyl mercaptan at room temperature to produce the ring opening of the tricyclic derivatives <2005JOC6230, 2005JMC2266>, for THD 173 to give compound 174 in 65% yield (Equation 9). 

Ring opening of the tricyclic thiadiazoloquinazolone derivative 84 was described by Santagati et al. <1994PHA880> the transformation is shown in Scheme 10. When this compound was heated with sodium hydroxide in a mixture of ethanol and dioxane, the central pyrimidine ring underwent hydrolytic ring opening, and the substituted thiadiazole derivative 85 was formed. 

A reductive ring opening of a linearly fused thiadiazole derivative 92 was reported by Nawrocka and Stasko <1997PJC792>. Reaction of this compound with sodium borohydride in methanol under heating afforded the iV-aminoquinazolone-thione 93. 

Nucleophilic attack at sulfur is implicated in many reactions of 1,2,4-thiadiazoles <84CHEC-I(6)463> and in general soft nucleophiles attack at sulfur. For example, reaction of 3-hydroxy-5-phenyl-1,2,4-thiadiazole (23) with acetic anhydride in the presence of dbu at 130°C gives the thiazoles (31) and (32) <85JHC1497>. These products may be reasonably explained by the mechanism outlined in Scheme 9 in which the thiadiazole ring is opened by the acetic anhydride carbanion. There is some evidence that (32) may arise from attack of the carbanion on the A-acylated derivative (30a) (Scheme 9) <85JHC1497>. 

The treatment of thiurets (diimino-l,2,4-dithiazolidines, (297)) with aromatic amines results in ring opening to form thiocarbamylguanidines (298) and sulfur cyclization to 3,5-diamino-1,2,4-thiadiazole derivatives (299) can occur spontaneously or upon oxidation (Scheme 67) <84CHEC-1(6)463 >. 

The only synthesis of 1,2,4-thiadiazole (1) was reported by Goerdler et al. in 1955 and is illustrated in Scheme 76 <84CHEC-I(6)463>. Owing to the sensitivity of (1) to ring-opening reactions, it is not a suitable starting material for the preparation of other derivatives. 

The nucleophilic attack of organometallic species occurs with cleavage of the N—S bond and eventual formation of an a-diketone. This reaction has been shown to proceed through an unsym-metrical diimine (17) (Scheme 2) <90JHC1861>. The 4-unsubstituted series (18) can be functionalized in this way. The diimine product of ring opening (19) can add a nucleophile at carbon (20) and then be recyclized to a 3,4-disubstituted 1,2,5-thiadiazole (21) (Scheme 3) <86H1131>. 

In some cases, aliphatic thiocarbonyl (5)-methylides can be protonated by 2,5-dihydro-l,3,4-thiadiazoles, which are their precursors, to give a thioxonium ion (e.g., 56). Carbanion 57 undergoes a ring opening to thiolate 58, which subsequently combines with 56 to give (5,5)-acetal 59 (40,103) (Scheme 5.22). 

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