Transition-metal-free visible light-promoted photoredox oxidative dehydrogenative cyclization: expeditious approach to 1,2,4-thiadiazoles

A novel visible-light-catalyzed oxidative N-S bond formation for the synthesis of 3,5-disubstituted 1,2,4-thiadiazoles has been developed. This protocol features a metal-free approach, green oxidant, room temperature process, broad substrate scope, good functional group tolerance, excellent yields and a one-pot reaction without the isolation of the intermediates


Results and Discussion
We initiated our studies by choosing N-(phenylcarbamothioyl)benzimidamide (1a) as a model substrate in the presence of 0.5 mol % of fac-Ir(bpy)3 in CH3OH at room temperature under air atmosphere.After 8 h of irradiation with a 18 W blue LED light, the desired dehydrogenative cyclization product 2a was obtained in 63% yield (Table 1, entry 1).Encouraged by this promising result, we next surveyed a range of photocatalysts under the same conditions (Table 1, entries 2-7).We found that the Ru(bpy)3Cl2 photocatalyst can slightly improve the efficiency for generation of 2a (71%, Table 1, entry 2).To develop a metal-free protocol, we then examined various organic dyes including eosin Y, methylene blue, rose bengal, 3DPAFIN (1,3-dicyano-2,4,5,6tetrakis(diphenylamino)benzene), and Rhodamine 6G (Table 1, entries 3-7).These results showed that the organic photocatalyst rhodamine 6G provided the best result (87%, Table 1, entry 7).We then screened the reaction in various solvents such as CH3CN, DMF, CH2Cl2, CH3CH2OH, and 1,4-dioxane (Table 1, entries 8-12).Interestingly, we found that these solvents can promote this reaction in good yield and that CH3OH was found to be the best choice.The reaction time was examined and the yield did not improve (88%, Table 1, entry 13).The amount of the photocatlayst was also investigated, and it was found that 0.5 mol % catalyst loading was sufficient to furnish the product in excellent yields (Table 1, entries 14 and 15).Performing the reaction under oxygen atmosphere did not improve the product yield (Table 1, entry 16).Control experiments showed that the presence of the photocatalyst, air, and the light source is necessary for this transformation to proceed (Table 1, entries 17-19).Finally, we attempted to carry out the nucleophilic addition and oxidative cyclization in a one-pot fashion.To our delight, the desired product 2a was also obtained in similar yield when the imidoyl thiourea 1a was formed in a preceding step from an aryl isocyanate in the same reaction vessel without isolation and under the optimal reaction conditions (Table 1, entry 20).With the optimal conditions (Table 1, entry 7) in hand, we next probed the scope and generality of this intramolecular oxidative S-N bond formation approach to a variety of 3-substituted-5-amino-1,2,4-thiadiazoles in a one-pot fashion and the results are summarized in Scheme 2. First, we investigated the scope of the R substituent on aryl isothiocyanates.Various electron-donating and -withdrawing substituents including p-Me, p-OMe, p-F, p-Cl, p-Br, p-I, m-Me, and m-Cl, were well-tolerated, affording the corresponding 1,2,4thiadiazoles in good to excellent yields (2a-2i).Meanwhile, the o-methyl substituted isothiocyanates 1j had little influence on the reaction and afforded the desired product 2j in 73% yield.Next, we investigated the scope of the R substituent on phenyl amidines.A range of substrates bearing electron-donating or electron-withdrawing group-substituted aromatic rings all underwent the oxidative dehydrogenative cyclization smoothly and gave the desired products in very good yields (2k-2m).Moreover, both various substituted amidines and isothiocyanates could provide the desired products in 77% and 74% yield (2o and 2p), respectively.Furthermore, alkyl isothiocyanates such as isopropyl isothiocyanate were compatible with the optimized conditions as well, affording the desired products 2q-2s in excellent yields.Interestingly, alkyl amidines such as cyclopropyl and methyl amidine reacted smoothly, affording the desired products 2t-x in very high yields.

Conclusions
In conclusion, we have developed a metal-free, visible-light induced organophotoredox-catalyzed dehydrogenative cyclization protocol for the intramolecular N-S bond formation using rhodamine 6G as a photocatalyst under aerobic reaction conditions.A broad range of 3-substituted 5-amino-1,2,4-thiadiazole derivatives are conveniently synthesized in good to excellent yields with good functional group tolerance, Further investigation for other heterocyclic syntheses based on this photocatalytic protocol is underway in in our laboratory.

Experimental Section
General procedure for 3,5-disubstituted 1,2,4-thiadiazoles 2. In an oven-dried single-necked bottle (10 mL) equipped with a stir bar, amidine hydrochloride (0.2 mmol), isothiocyanate 2 (0.2 mmol), NEt3 (0.4 mmol), and CH3OH (2 mL) were added and stirred at room temperature until the conversion was completed as indicated by TLC.Then, rhodamine 6G (0.5 mol %) was added, the reaction mixture was open to the air and stirred at room temperature under the irradiation of a 18 W LED lamp for 8 h.After completion of the reaction, the resulting mixture was extracted with EtOAc and the organic phase was then removed under vacuum.The residue was purified by flash column chromatography using a mixture of petroleum ether and ethyl acetate as eluent to give the desired products 2.
Compounds 2a-x are known compounds and their spectral data are in agreement with those reported in the literature (see also the Supplementary Material file)

Table 1 .
Screening of optimal reaction conditions a,b,c