Synthesis of spiropyridazine-benzosultams by the [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes

A simple and efficient method for the synthesis of spiropyridazine-benzosultams has been developed by means of [4 + 2] annulation reaction of 3-substituted benzoisothiazole 1,1-dioxides with 1,2-diaza-1,3-dienes. This approach displays advantages such as mild reaction conditions, wide substrate range tolerance, simple operation, compatibility with gram-scale preparation.


Results and Discussion
To initiate our studies, 3-ethylbenzo[d]isothiazole 1,1-dioxide (1a) and α-halogeno hydrazone 2a were selected as the model substrates.Our aim was to explore the possibility of enamine-iminium tautomerism of N-sulfonyl ketimine and its subsequent [4 + 2] annulation reaction with 1,2-diaza-1,3-diene in the presence of Et 3 N (2.0 equiv) in diethyl ether at room temperature (Table 1, entry 1).However, no product was detected under these conditions.We then replaced diethyl ether with toluene, which resulted in the desired spiropyridazine-benzosultam 3aa with 10% yield and high diastereoselectivity (Table 1, entry 2).Encouraged by this result, we tested several solvents to determine their effect on the [4 + 2] annulation reaction.Acetonitrile showed the best result, providing the highest yield (Table 1, entries 3-7).We also investigated the performance of other organic and inorganic bases, but they did not improve the yield (Table 1, entries [8][9][10][11][12].The structure of spiropyridazine-benzosultam 3aa was determined by 1 H NMR, 13 C NMR, HRMS analysis and single-crystal X-ray crystallography [33].Further experiments conducted with different reac-tion times revealed that the reaction was complete within 2 hours (Table 1, entry 14).We then explored the effect of the temperature on the reaction and found that 25 °C was the most suitable temperature, resulting in a 91% yield (Table 1, entry 14).Lower temperatures of 0 °C and 10 °C led to decreased yields of 24% and 49%, respectively (Table 1, entries 16 and 17). Inreasing the temperature beyond 25 °C resulted in the formation of impurities and a decrease in the yield of the target compound (Table 1, entries 18 and 19).Finally, the optimal reaction conditions were determined as follows: 1a (1.0 mmol), 2a (1.5 mmol), Et 3 N (2.0 mmol), in acetonitrile at 25 °C with stirring for 2 hours (Table 1, entry 14).
With the optimized reaction conditions in hand, we next investigated the scope of the current reaction (Scheme 2).As shown in Scheme 2, a series of α-halogeno hydrazones 2b-l was tested, resulting in the expected spiropyridazine-benzosultams 3ab-al in good to excellent yields with high diastereoselectivity.For N-benzoyl hydrazones 2b-g, the electronic effect of R 3 group on the [4 + 2] annulation reaction was significant.Electron- withdrawing groups gave relatively higher yields than electrondonating groups (Scheme 2, 3aa-af).Remarkably, the nitro group gave the corresponding product 3ag in 94% yield.It was found that electron-donating groups afforded relatively higher dr values than electron-withdrawing groups (Scheme 2, 3aa-af).The effect of the R 4 group was also detected and a similar result was observed as for the R 3 group (Scheme 2, 3ah,ai vs 3aj,ak,al).To further expand the substrate scope, we next tested other 3-substituted benzoisothiazole 1,1-dioxides 1a-c.As seen from Scheme 2, dienophiles with a bulky and branched isopropyl group (1b) could also be employed in the reaction.However, the yield of the corresponding product 3ba was obviously lower than 3aa and 3ca generated from dienophiles bearing linear alkyl groups (Scheme 2, 3ba vs 3aa and 3ca).
On the basis of the transformation of 3aa to 4aa, a tentative reaction mechanism is proposed.As shown in Scheme 5, the spiropyridazine-benzosultam 3aa was firstly oxidized to intermediate A. Next, an aziridine was formed with the hydrolysis of the amide bond under basic conditions.Finally, the ring expansion led to intermediate C which was then hydrolyzed to 4aa.

Conclusion
In conclusion, we have developed a [4 + 2] annulation reaction of 3-substituted benzo[d]isothiazole 1,1-dioxides with 1,2diaza-1,3-dienes for the efficient preparation of spiropyridazinebenzosultams.The electronic effects of substituents and the in-fluence of steric hindrance on the reaction were explored.The configuration of the product was determined by X-ray single crystal diffraction.This method has the advantages of mild reaction conditions, wide substrate scope, and high regioselectivity.
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The definitive version of this article is the electronic one which can be found at: https://doi.org/10.3762/bjoc.20.29

Scheme 1 :
Scheme 1: Comparision of previous work with this work.

Table 1 :
The effects of solvents, bases, reaction time and temperature on the [4 + 2] annulation reaction a .