Asymmetric Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene

A new chiral Brønsted acid-catalyzed aza-Diels–Alder reaction of cyclic C-acylimines with cyclopentadiene has been developed. The reaction provides optically active aza-tetracycles in good yields with high diastereo- and enantioselectivities under mild reaction conditions.


Results and Discussion
Our initial study began with the examination of the the aza-Diels-Alder reaction of cyclic C-acylimine 1 with cyclopentadiene (2) in the presence of BINOL-derived phosphoric acid diesters and N-triflylphosphoramides 4-6 ( Table 1) [33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51] as the catalysts. We were delighted to see that the reaction proceeded smoothly at different temperatures and that the product could be obtained with an enantiomeric excess of 8% ee when the reaction was performed in toluene at −60 °C in the presence of catalyst 4a (Table 1, entry 1). A slight increase in enantioselectivity was observed when the reaction was conducted at −78 °C (Table 1, entry 2). Subsequently, different catalysts were applied in the Brønsted acid catalyzed hetero-Diels-Alder reaction. From the different catalysts tested, phosphoric acid diester 4b, with the 2,4,6-triisopropylphenyl substituent in the 3,3'-position of the BINOL backbone, proved to be the best catalyst, and the product was obtained with an encouraging enantiomeric excess of 74% (Table 1, entry 3). To optimize the reaction conditions further we evaluated the catalyst loading and solvent. However, the reduction of catalyst loading from 5 to 1 mol % resulted in a significant decrease in enantioselectivity ( Table 1, entries 8 and 9).
In our previous studies in asymmetric Brønsted acid catalysis, we noticed that solvent mixtures can strongly influence both the reactivity and selectivity. Thus, we evaluated different solvent mixtures. When a 1:1 mixture of toluene and CHCl 3 was used the enantioselectivity dropped considerably. The same effect was observed when a mixture of toluene and CH 2 Cl 2 was used ( Table 1, entries 10 and 11). Hence, the chlorinated solvents were replaced by hexane. Interestingly, use of a 1:1 mixture of toluene and hexane afforded the corresponding product without loss of selectivity, but, as anticipated, the reaction time was longer (Table 1, entry 12). Pleasingly, when the reaction was carried out in a 2:1 mixture of hexane/toluene the product exhibited excellent enantioselectivity (Table 1, entry 13). Further improvement of selectivity was obtained by increasing the hexane/toluene ratio to 3:1, which delivered the product with an excellent enantiomeric excess of 94% (Table 1, entry  14). With the optimal reaction conditions in hand, the substrate scope of the aza-Diels-Alder reaction was examined ( Table 2).
Various substituted cyclic C-acylimines 1a-i with electrondonating and electron-withdrawing groups, as well as different substitutions patterns, were applied. In all cases the corresponding tetracyclic products were obtained in high yields and with excellent diastereo-and enantioselectivities. However, the use of less reactive dienes including cyclohexadiene or linear 1,3-pentadienes resulted in reduced product formation or provided the desired products with low enantioselectivities [52][53][54][55].

Conclusion
In conclusion, we have developed an enantioselective Brønsted acid catalyzed aza-Diels-Alder reaction of C-acylimines with cyclopentadiene. The corresponding aza-tetracycles were obtained in high yields and with excellent enantio-and diastereoselectivities under mild reaction conditions. The results reported not only show that chiral BINOL derived phosphoric acid diesters can be efficient catalysts for [4 + 2] cycloaddi-tions involving less-electron-rich dienes but additionally demonstrate the high potential of these acidic Brønsted acids in asymmetric catalysis.

Experimental
The starting materials 1a-i were synthesized according to a known literature procedure [56].
General procedure for the aza-Diels-Alder reaction: In a typical experiment the imine and cyclopentadiene were suspended in a mixture of hexane/toluene (3:1) in a screw-capped test tube and stirred at −78 °C for 10 min. The catalyst (5 mol %) was added to the solution and the mixture was stirred until consumption of the imine. The crude reaction mixture was directly charged on silica gel and purified by column chromatography (hexane/ethyl acetate as eluent) to afford the desired products.

Supporting Information
Supporting Information File 1 Experimental details and characterization of the synthesized compounds.