A one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH4I

The electrochemical preparation of 2-aminothiazoles has been achieved by the reaction of active methylene ketones with thioureas assisted by ᴅʟ-alanine using NH4I as a redox mediator. The electrochemical protocol proceeds in an undivided cell equipped with graphite plate electrodes under constant current conditions. Various active methylene ketones, including β-keto ester, β-keto amide, β-keto nitrile, β-keto sulfone and 1,3-diketones, can be converted to the corresponding 2-aminothiazoles. Mechanistically, the in situ generated α-iodoketone was proposed to be the key active species.

[26], 1,3-dichloro-5,5-dimethylhydantoin [27], HBr or HI, DMSO [28] etc. (Scheme 1b). Alternatively, the oxidation of α-C-H of active methylene ketones generate α-carbon-centered radicals, thus providing another way to obtain thiazoles. Recently, Sun et al. reported a tert-butyl hydroperoxide/azodiisobutyronitrile-mediated synthesis of 2-aminothiazoles from active methylene ketones and thiourea via an oxidative cyclization initiated by a radical process and a following condensation reaction (Scheme 1c) [29]. Although these methods are practical, most of these strategies require stoichiometric or excess amounts of halogenating reagents or oxidants, which are toxic, hazardous and would lead to a large quantity of waste. Considering the importance of thiazoles in synthetic and medicinal chemistry, the development of greener and more atom economic processes for the thiazole synthesis has become increasingly necessary with growing awareness of environmental constraints.
Organic electrosynthesis has been recognized as a green, modern, and safe technique, since electrons can be used as an alternative for oxidants or reductants [30][31][32][33][34][35][36][37][38]. During our continuous interests in halide-mediated indirect electrolysis [39][40][41][42], we have achieved the in situ generation of α-iodocarbonyl ketones from constant current electrolysis (CCE) of ketones in the presence of iodide ions. It is worth noting that we have also reported an electrochemical method for the synthesis of 2-aminothiazoles via the one-pot direct α-C-H functionalization of ketones with thioureas [42]. However, the reported method only tolerates aromatic and aliphatic ketones; the active methylene ketones were not suitable. Given that amino acids have been reported to work as green organocatalysts for the synthesis of 2-aminothiazole heterocycles [43,44]. We herein report a ᴅʟ-alanine-assisted one-pot electrochemical synthesis of 2-aminothiazoles from active methylene ketones and thioureas mediated by NH 4 I (Scheme 1d). This electrochemical method features external-oxidant-free conditions and avoids the prefunctionalization of the substrates.

Results and Discussion
To demonstrate the feasibility of our idea, ethyl acetoacetate (1a) and thiourea (2a) were chosen as model substrates for the optimization of reaction conditions. Based on our previous studies on the halide-mediated α-C-H functionalization of carbonyl compounds [32][33][34][35], graphite was chosen as the working electrode rather than exploring other options. As shown in Table 1, when the electrolysis of 1a with 2a was performed in aqueous DMSO at a constant current of 5 mA/cm 2 using NH 4 I as the mediator, LiClO 4 as electrolyte and asparagine as additive in an undivided cell, the desired product 3a was isolated in 51% after passing 6 F/mol of charge (Table 1, entry 1). The yield of 3a decreased obviously when the ratio of 1a to 2a changed from 2:1 to 1:1 or 1:2 (Table 1, entries 2 and 3). Subsequent solvent screening disclosed that aqueous DMSO was the optimal solvent and lower yields were obtained in other solvents, such as aqueous DMF, aqueous MeCN or aqueous EtOH (Table 1, entries 4-6). Owing to the tedious workup process in using a large amount of DMSO as solvent, we decided to increase the proportion of H 2 O and disclosed that the yield of 3a improved from 52% to 61% when the ratio of DMSO to H 2 O changed from 2:1 to 1:14 (Table 1, entry 7). When the . It was observed that the additive plays an important role, among which ᴅʟ-alanine was proved to be the best, although asparagine, ʟ-phenylalanine, ʟ-aspartic acid and ʟ-allysine also gave comparable yields of 3a (Table 1, entries 9-12). It is interesting to note that 3a was achieved in higher yields (75%) when the temperature decreased from 70 °C to 30 °C (Table 1, entry 14). The effect of current density was also examined. It was found that a slightly lower yield of 3a was produced when 4 mA/cm 2 ( branched alkyl acetoacetates including methyl, ethyl, tert-butyl, and amyl reacted smoothly with thiourea 2a under the optimized conditions, giving the corresponding products in 30-80% yields (3a-d). In addition, allyl and benzyl acetoacetate were also suitable substrates to give the desired 2-aminothiazoles 3e and 3f in 78% and 52% yields, respectively. β-ketoesters containing ethyl, n-propyl, isopropyl, n-butyl, tert-butyl and cyclohexyl moieties were also compatible with the optimized conditions, providing the corresponding 2-aminothiazoles in 24% to 65% yields (3g-l).
Different N-substituted thioureas were also screened for the electrochemical reactions. N-methylthiourea and N-(2-phenylethyl)thiourea reacted smoothly with ethyl acetoacetate 1a under the optimized conditions, providing the corresponding 2-aminothiazoles, 3bb and 3cc, in 77% and 44% yields, respectively. It is regretful that thioacetamide is not the best suitable partner due to its low reactivity under the optimized conditions.
To demonstrate the practicability of the reaction, a scale-up reaction of ethyl acetoacetate (1a, 28 mmol, 3.64 g) and thiourea (2a,14 mmol, 1.05 g) was carried out under the optimized conditions to give 3a in 50% yield (Scheme 3).
In order to better understand the iodide-mediated reaction mechanism and to determine the possible active intermediates involved, several control experiments were carried out. As shown in Scheme 4, when molecular iodine was employed as oxidant, the desired product 3a was obtained in a 67% yield under otherwise identical conditions (Scheme 4a), but without passing electricity. Therefore, the in situ-generated I 2 was one of the active species. Further investigation revealed that the condensation of ethyl 2-iodo-3-oxobutanoate (4a) with thiourea Scheme 5: The proposed mechanism for the one-pot electrochemical synthesis of 2-aminothiazoles mediated by NH 4 I.
Therefore, the in situ-generated ethyl 2-iodo-3-oxobutanoate (4a) should be a key intermediate for this tandem reaction.
On the basis of the above mechanistic studies and the previous works on iodide-mediated electrochemical transformation [37][38][39][40], a possible mechanism for this electrochemical reaction was proposed (Scheme 5). It is well known that amino acid can act as a bi-functional organocatalyst due to the existence of both Lewis base (NH 2 ) and Brønsted acidic (COOH) sites. In the suggested mechanism, the carboxy group may polarize the carbonyl group of the active methylene ketone and the amino group as a Lewis base serves the formation of enolate to produce α-iodo ketone with the molecular I 2 produced by anodic oxidation. Subsequently, the nucleophilic substitution between intermediate 4 and thiourea tautomer gives α-sulfur substituted ketone 5. Intermediate 5 undergoes intramolecular nucleophilic addition to the carbonyl group and followed by dehydration to give the heterocyclic product 3. At the cathode, protons are reduced to release H 2 .

Conclusion
In conclusion, we have developed a one-pot electrochemical strategy for the synthesis of 2-amniothiazoles by the reaction of active methylene ketones with thioureas. The electrochemical synthesis was performed in an undivided cell with NH 4 I as the mediator and cheap graphite plate as the working electrode. Various active methylene ketones, including β-keto ester, β-keto amide, β-keto nitrile, β-keto sulfone and 1,3-diones proved to be compatible with the protocol. Since external oxidants and prefunctionalization of substrates are avoided, the present electrochemical protocol represents an appealing alternative for the synthesis of 2-aminothiazoles. Gram-scale synthe-sis also highlighted the synthetic practicability of this electrochemical strategy. Mechanistically, the in situ-generated α-iodoketone was proposed to be a key active species. Further application of this method is underway in our laboratory.

Supporting Information
Supporting Information File 1 Experimental procedures, characterization data and copies of spectra of the all synthesized compounds ( 1 H NMR, 13 C NMR and HRMS).

Funding
This work was financially supported by the National Natural Science Foundation of China (No. 31901619).