A quadruple cascade protocol for the one-pot synthesis of fully-substituted hexahydroisoindolinones from simple substrates

A new and efficient synthetic method to obtain fully-substituted hexahydroisoindolinones was developed by using bifunctional tertiary amine-thioureas as powerful catalysts. As far as we know, there is no efficient synthetic method developed toward fully-substituted hexahydroisoindolinones. The products were obtained in good yield and diastereoselectivity. The one-pot cascade quadruple protocol features readily available starting materials, simple manipulation, mild conditions and good atom economy.


Results and Discussion
We initiated this study by using 2-benzylidenemalononitrile (1a) and 2-oxo-N,3-diphenylpropanamide (2a) [61][62][63][64] in 0.5 mL of CH 3 CN in the presence of 10 mol % of DABCO. After 12 h at room temperature, the reaction afforded the expected product rac-3a in 59% yield (Table 1, entry 1). We then tested different catalysts to optimize the reaction. When Et 3 N was used, the reaction afforded the product with 41% yield ( Table 1, entry 2). However, a complex mixture was observed when DBU was used ( Table 1, entry 3), while no reaction was observed when K 2 CO 3 was used as the catalyst (Table 1, entry 4). When thioureas were used as the catalysts, we also did not get the expected product (Table 1, entries 5 and 6). Since bifunctional tertiary amine-thioureas have been proved as powerful catalysts that can catalyze a variety of organocascade reactions, we also tested thiourea catalysts, cat-1 to cat-3. Interestingly, the thioureas cat-1 and cat-2 were able to promote the reaction (Table 1, entries 7 and 8), but we obtained an even better yield when the tertiary amine-thiourea cat-3 was used as the catalyst (Table 1, entry 9). All products were racemic even when chiral catalysts were used (see Supporting Information File 1 for details). Next, we performed a solvent screening. As shown in Table 1, when DCM and THF were used as the solvent, the yield of the desired product was 33% and 34%, respectively (Table 1, entries 10 and 11). Only traces of the product were seen when toluene or methanol was used as the solvent ( Table 1, entries 12 and 13). Furthermore, raising the reaction temperature was not beneficial for the diastereoselectivity of the reaction (Table 1, entry 14).
With the optimal conditions in hand, we next examined the reaction scope ( Table 2). All reactions afforded the corresponding products 3a-t with medium to good yield and diastereoselectivity using the simple protocol at room temperature. To our delight, with our optimized reaction system, various types of substrates 1 showed very good reaction activities. Different types of substrates 1, bearing either electron withdrawing or donating groups in para-, metaand ortho-positions, gave the desired products in good yield and diastereoselectivity ( Table 2, Scheme 1: An example of scalable synthesis.

Scheme 2:
Hydrolysis reaction to produce a useful product. entries 1-10 and 12), although 4-NO 2 C 6 H 4 gave the product in medium yield due to its poor solubility ( Table 2, entry 11). A heteroaromatic substrate such as thiophene could also be successfully employed to afford rac-3 with medium yield and diastereoselectivity ( Table 2, entry 13). 3,4-Dichloro-substituted and 3,5-dimethoxy-substituted substrates produced the desired products in 84% and 55% yield with 20:1 and 15:1 diastereoselectivity, respectively ( Table 2, entries 14 and 15). When substrates with different R 2 and R 3 were used in this reaction, the corresponding products were obtained in medium yield and diastereoselectivity ( Table 2, entries [16][17][18][19][20]. The structure of 3p was determined by X-ray analysis [65]. However, substrates with aliphatic R 1 , R 2 or R 3 did not produce the desired products ( Table 2, entries [21][22][23][24][25][26]. This bifunctional catalysis cascade reaction was also amenable to scale-up. When the reaction was carried out on a 3 mmol scale, the desired product was obtained in 84% yield. Therefore, this method is fast and easy to implement, and it is suitable for large-scale synthesis (Scheme 1).
Finally, we propose a mechanism for the reaction. Initially, substrate 1 is activated by catalyst (I), which reacts with substrate 2 via two Michael addition reactions to sequentially produce II and III. Then, IV is generated from III by an aldol reaction. Finally, the product is produced after the nucleophilic reaction, and the catalyst is regenerated (Scheme 3).

Conclusion
In summary, we have developed a one-pot quadruple cascade protocol to obtain fully-substituted hexahydroisoindolinones. This new, synthetic method is simple, efficient and atomeconomic. This reaction can be widely used in organic synthesis due to its advantages such as simple operation, availability of raw materials, mild conditions and high efficiency.

Experimental
General procedure for the synthesis of fullysubstituted hexahydroisoindolinones Benzylidenemalononitrile (0.1 mmol), 2-oxo-N,3-diphenylpropanamide (0.25 mmol) and cat-3 (0.01 mmol) were added to a test tube, then CH 3 CN (0.5 mL) was added to the mixture. The reaction mixture was stirred at 300 rpm at 21 °C in a stoppered carousel tube for 12 h. The solvent was removed in vacuo and the product was purified by silica gel flash column chromatography to give the corresponding product 3.