Microwave-assisted three-component domino reaction: Synthesis of indolodiazepinotriazoles

A microwave-assisted three-component protocol involving N-1 alkylation of 2-alkynylindoles with epichlorohydrin, ring opening of the epoxide with sodium azide, and an intramolecular Huisgen azide–internal alkyne 1,3-dipolar cycloaddition domino sequence has been described. The efficacy of the methodology has been demonstrated by treating various 2-alkynylindoles (aromatic/aliphatic) with epichlorohydrin and sodium azide furnishing annulated tetracyclic indolodiazepinotriazoles in satisfactory yields.

we propose a strategy where N-1 of 2-alkynylindole [36,37] can be first functionalized with epoxide by reacting 2-alkynylindole with epichlorohydrin. This can then be followed by ring opening of the oxirane by azide to furnish a bis-functionalized indole intermediate having azide and alkyne groups in close proximity. Such an intermediate may then undergo annulation following an intramolecular 1,3-dipolar cycloaddition pathway and in turn lead to the sequential formation of 7-or 5-membered diazepine and triazole rings in a single step. In this communication, we report a versatile microwave-assisted three component domino reaction to furnish annulated tetracyclic indolodiazepinotriazoles in good yields.

Results and Discussion
We commenced our studies with the development of a one-pot three-component strategy involving the condensation of the 2-(4-methylphenylethynyl)-1H-indole (1a) with epichlorohydrin (2) and sodium azide (3, Scheme 1, Table 1). Initially, a mixture of 1a, 2 and 3 was allowed to react both in the absence and presence of Cs 2 CO 3 in toluene at rt. The reactants under both the conditions remained unchanged even after prolonged stirring for 15 h (Table 1, entries 1-3) and at higher temperature (110 °C).
However, a change in the nature of solvent from toluene to CH 3 CN, DMF or DMSO produced a dramatic effect on the outcome of the reaction, resulting in the formation of products comprising intermediates (4a and/or 5a) and/or indole-based polyheterocycle indolodiazepinotriazole 6a. Use of the polar solvent CH 3 CN at 90 °C for 15 h furnished a single product in 65% isolated yield, which was characterized as 2-[2-(4-methyl- The findings clearly suggest that the formation of indole-based annulated product 6a in the threecomponent domino format occurs via 4a and 5a intermediacy and requires higher temperature and prolonged stirring. This was again evident from the fact that a prolonged stirring up to 18 h led to the complete disappearance of the intermediates 4a and 5a and afforded 6a as a single product in 60% isolated yield ( Table 1, entry 9). The role of intermediates 4a and 5a in the formation of 6a was further substantiated by treating 4a with NaN 3 in DMF at 120 °C and by heating 5a in DMF at 120 °C. As envisaged, both reactions furnished 6a as a single product in 87% and 90% isolated yield, respectively (Scheme 2). Replacing DMF with yet another polar aprotic solvent, i.e., DMSO, produced similar results except for a marginal increase in the isolated yield of 6a to 64% in 15 h (Table 1, entries 10-13).
Next, in order to reduce the reaction times and to enhance the isolated yield of the annulated product 6a, we applied microwave conditions instead of conventional heating and monitored the progress of the reaction at different time intervals. A significant increase in the yield of 6a resulting from the increase in the reaction times under microwave conditions was observed. Initially, a 10 min irradiation of the reaction mixture furnished the intermediate 4a as the only product in 80% isolated yield (Table 1, entry 14), whereas a 30 min irradiation resulted in a mixture of 4a/5a/6a in 20/45/10% yields as evident from HPLC (  [21][22][23][24][25][26]. The observations clearly suggest that the formation of 6a in the three-component format involved intermolecular N-1 alkylation of the 2-alkynylindole 1a with epichlorohydrin to form 4a, ring opening of 4a with sodium azide to form 5a, and finally an intramolecular Huisgen azide-internal alkyne 1,3-dipolar cycloaddition reaction. Once the reaction conditions for the three-component format had been optimized, several 2-alkynylindoles bearing different functional groups were treated with epichlorohydrin and sodium azide in order to establish the scope and limitation of the strategy. In total 22 compounds 6a-v (Scheme 3) were synthesized, with their isolated yields varying from 54-73%. The findings suggest that although the electronic properties of the substitution (R 1 ) on the phenyl ring of the indole had no effect on the outcome of the isolated yield of the final products, the nature of R 2 had a profound effect on the yields. When the aromatic group was used as R 2 , the final products 6a-c and 6e-q were obtained in isolated yields ranging from 66-73%, whereas substituting R 2 with aliphatic/trimethylsilyl moieties furnished the cyclized products (6d and 6r-v) in diminished (54-65%) isolated yields.

Conclusion
In conclusion, we have developed a simple and efficient threecomponent domino reaction for the synthesis of highly substituted indolodiazepinotriazoles in good yields under microwave conditions. The domino sequence comprising N-1 alkylation, ring opening of the epoxide, and intramolecular Huisgen azide-internal alkyne 1,3-dipolar cycloaddition reaction, led to the generation of the diazepine and triazole rings annulated to the indole through the formation of four new sigma bonds in a single step.