Solvent-free one-pot efficient and highly regioselective access to functionalized thiazolopyridones from α -enolic dithioesters

An operationally simple, highly convergent and straightforward synthesis of diverse thiazolopyridones has been achieved via three-component domino coupling (3CDC) of α -enolic dithioesters, cysteamine and dialkyl acetylenedicarboxylates under solvent-free conditions. The approach is carbon-economic and relies on sequential cyclic N,S -acetal formation/Michael addition/N-cyclization cascade forming consecutive C-C, C-N and C-S bonds in one-pot.


Introduction
The key goal in modern organic synthesis is to design and develop new synthetic strategies for the rapid generation of function-oriented molecules by improving resource efficiency that provides maximum structural diversity and complexity with step, atom, and cost economy.2][3][4] The synthesis of heterocycles has always been a key aspect, and increasingly attracted the synthetic pursuit of chemists.][7] Among the fused N,S-heterocyclic frameworks, thiazolopyridones are versatile privileged scaffolds present in many biologically important products and pharmaceuticals.They exhibit activities like DNA gyrase B inhibitors 8,9 and antibacterial agents. 10,11Furthermore, thiazolopyridones have also been utilized in the synthesis of natural-product-like heterocycles. 12hiazolo ring-fused 2-pyridones have proven to be highly interesting scaffolds for the development of biologically active compounds particularly introducing a variety of substituents in the 2-pyridone part of the heterocycles. 13Further, thiazolofused 2-pyridones have been halogenated with complete regioselectivity to synthesize 6-bromo-8-iodo-substituted bicyclic 2pyridones in gram scale. 14Recently, a selective intramolecular 5-exo-dig or 6-endo-dig cyclization enroute to 2-furanone or 2-pyrone containing tricyclic scaffolds have been developed. 15An efficient method to synthesize a novel rigid tricyclic peptidomimetic scaffold through ring-closure of amino-functionalized bicyclic 2-pyridones has been discovered. 16mong available reports for the synthesis of benzothiazolopyridones, [17][18][19][20] most of them suffer from significant limitations such as harsh reaction conditions, expensive catalysts / reagents, prolonged reaction times, multistep syntheses and poor availability of starting materials.In combination, the above facts prompted us to develop a new straightforward and widely applicable approach for the synthesis of thiazolopyridones.The carbon-sulfur and carbonnitrogen bond formations constitute a very important class of reactions in biological processes.In view of the spectacular role of domino reaction in chemical transformations, we are interested in developing metal-free and solvent-free multicomponent reactions to construct complex molecules from readily available simple precursors in a single operation.2][23][24][25] Solvent-free MCRs of α-enolic dithioesters are particularly intriguing and have attracted remarkable interest.In continuation of our research interests regarding the synthetic utility of α-enolic dithioesters, [26][27][28][29][30][31] particularly aimed at exploring one-pot solvent-free synthetic protocols, [32][33][34][35][36][37][38] we report herein an operationally simple and expedient one-pot synthesis of thiazolopyridones under metal-free and solvent-free conditions via one-pot multicomponent domino reaction (MDR) involving a sequence of cyclic N,S-acetal formation/Michael addition/N-cyclization cascade in good to excellent yield (Scheme 1).

Results and Discussion
To the best of our knowledge, no report on the synthesis of thiazolopyridones utilizing α-enolic dithioesters is known to date.To optimize the reaction condition for the synthesis of thiazolopyridones, methyl 3-hydroxy-3-phenyl-prop-2-enedithioate (1a), cysteamine (2) and diethyl acetylenedicarboxylate (3a) were taken as model substrates.We performed the model reaction under varying conditions, and the results are listed in Table 1.In an initial study, 1a upon treatment with 2 gave cyclic N,S-acetal, which has been isolated and fully characterized. 39ubsequent treatment of N,S-acetal A with 3a in refluxing methanol afforded the desired thiazolopyridone 4a in 85% yield within 4 h.Next to check the influence of solvents, we screened various solvents such as polar protic, low boiling polar aprotic and high boiling polar aprotic solvents (Table 1, entries 2-8).The high boiling polar aprotic solvents displayed better results (Table 1, entries 6 and 7).In one attempt, we tried the reaction under sonication at 40 °C by adding 2 drops of ethanol for homogenization of reaction mixture.Work up of the reaction afforded the desired product in 85% yield within 3 h.Finally, we performed the model reaction under solvent-free conditions at 110 °C.Satisfyingly, the reaction completed within 10 min consuming the reactants completely and furnished the desired product in 63% yield (Table 1, entry 10).In order to make the reaction milder, we reduced the temperature after formation of cyclic N,S-acetal to 90 °C, when the desired product was obtained in 87% yield within 30 min (Table 1, entry 11).Further lowering in temperature could not improve the result (Table 1, entry 12).Thus, the best reaction conditions for the formation of 4a was found to be 1a (1 mmol), 2 (1 mmol), 3a (1 mmol), at 90 °C under solvent-free condition (Table 1, entry 11).Experiments probing the scope and generality of this protocol under optimized conditions are summarized in Table 2.A broad range of α-enolic dithioesters 1, bearing R 1 as aryl, hetaryl, and extended aromatic groups, were tolerated well.Dialkyl acetylenedicarboxylates 3 bearing both methyl and ethyl as R 2 could be employed to afford thiazolopyridones 4 in good to excellent yields.All reactions proceeded smoothly and afforded the corresponding product 4 in high yield.A range of α-enolic dithioesters bearing R 1 as aryl groups with electron-donating substituents were well tolerated, and gave considerably higher yields than those with electron-withdrawing group (4c-f vs. 4g).Moreover, halogen substitution on the R 1 of dithioester did not disturb the reactivity, and the corresponding products were formed in high yields (4h, i).Importantly, dithioester 1 bearing a heteroaromatic moiety at R 1 was also compatibly providing high yield of the product (4j-l).After successful utilization of aromatic dithioesters, we next extended our study to various extended aromatics such as 1-naphthyl R 1 substituent, which was also tolerated well and furnished the product (4m) in good yield.a All reactions were performed with 1, 2, and 3 (1 mmol of each); b Isolated pure yields.
The structures of all the synthesized thiazolopyridone derivatives 4 were deduced by their satisfactory spectral ( 1 H, 13 C NMR and mass) studies and explicitly established by the single crystal X-ray diffraction analysis (see the ESI) of one representative compound, 4a (CCDC-947810) (Figure 1).

Figure1. ORTEP diagram of 4a.
By taking our entire experimental outcomes into consideration, a plausible reaction mechanism accounting for the formation of compound 4 is outlined in Scheme 2. The first step is believed to be the formation of cyclic N,S-acetal A by the reaction of α-enolic dithioester 1 with cysteamine 2. The cyclic N,S-acetal A has been isolated and fully characterized. 39Next, conjugate addition of N,S-acetal A to dialkyl acetylenedicarboxylate 3 gave an intermediate B, which rapidly undergoes intramolecular regioselective N-cyclization to furnish the desired bicyclic thiazolopyridone 4.During the course of our investigation, we could not observe the formation of pyrrolothiazolone 5 even in a trace.

Conclusions
In summary, we have developed an operationally simple and straightforward one-pot multicomponent reaction involving dithioesters, cysteamine and dialkyl acetylenedicarboxylate under metal-free and solvent-free conditions for the first time.The reaction resulted in a convenient synthesis of diverse highly functionalized thiazolopyridones in high yields from acyclic precursors.This convergent and highly regioselective approach exhibits an unusually high multiple C-C, C-N and C-S bond forming efficiency utilizing all the reactants efficiently in structure, cost, and step economies.It is noteworthy that the reaction tolerates a broad range of functional groups.Significantly, the presence of keto-group and ester groups makes these compounds excellent entrants as precursors for further synthetic renovations.We hope this clean and green MCC protocol may be of immense value for both synthetic and medicinal chemists.

Experimental Section
The commercially available starting materials were used as received without further purification.α-Enolic dithioesters 1 were prepared by the reported procedure. 21 1H and 13 C NMR spectra were recorded on NMR spectrometers operating at 300 and 75 MHz, respectively.Chemical shifts (δ) are given in parts per million (ppm) using the residual solvent peaks as reference relative to TMS.J values are given in Hz.

Table 2 .
Scope of substrate for the synthesis of thiazolopyridones a 4