Highly Efficient and Diastereoselective Construction of Substituted Pyrrolidines Bearing A Quaternary Carbon Center via 1,3-Dipolar [3 + 2] Cycloaddition

: A general approach to substituted pyrrolidines via [3 + 2] 1,3-dipolar cycloaddition between nonstabilized azomethine ylides and cyanosulfones was developed. The efficient method provides a series of substituted pyrrolidines bearing a quaternary carbon center in high yields (up to 98%) excellent diastereoselectivities (up to >25:1 dr ) under ambient reaction conditions.


Results
Our investigation commenced with -p-toluenesulfonyl-cinnamonitrile 1a and non-stabilized azomethine ylide generated in situ from N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a in the presence of trifluoroacetic acid (TFA) as the model substrates to optimize the reaction conditions. As the results are summarized in Table 1. To our delight, It was found that the [3 + 2] cycloaddition reaction proceeded smoothly and the desired cyclization product 3a was obtained in 90% yield with in high diastereoselective (dr > 25;1) using CH2Cl2 as solvent for 6 h ( Table 1, entry 1). In order to enhance the conversion, the time of the reaction was prolonged to 12 h, providing the cycloadduct 3a in 98% yield (entry 2). In addition, the yield could not change when the reaction time went on prolonging to 18 h (entry 3). Subsequently, the solvent effect was investigated (entries [4][5][6][7][8][9][10][11]. From among the tested solvents, the CH2Cl2 proved to be the best choice with respect to efficiency. When using the CHCl3, DCE or CH3CN as the solvent, the reaction gave the product in higher yield (entries 4-5 and 7). Other the solvent, such as toluene, EtOAc, Et2O, THF or dioxane, affording the product in medium yield (entries 6 and 8-11). Reducing the loading of TFA to 50 mol% resulted in some loss of yield (entry 12). CH2Cl2 24 85 a Unless noted otherwise, reactions were performed with -p-toluenesulfonyl-cinnamonitrile 1a (0.1 mmol) and N-(methoxymethyl)-N-(trimethyl silylmethyl)-benzyl-amine 2a (0.12 mmol), TFA (0.12 mmol, 1 equiv.) in solvent (1.0 mL) at rt. b Yield of the isolated product and dr >25:1 by 1 H NMR analysis. c 0.5 equiv.TFA were used.  1 mmol), N-(methoxymethyl)-N-(trimethyl silylmethyl)-alkyl-amine 2 (0.12 mmol), TFA (0.12 mmol, 1 equiv.) in CH2Cl2 (1.0 mL) at rt for 12 h. b Yield of the isolated product and dr >25:1 by 1 H NMR analysis. c The relative configuration of 3h was determined by X-ray analysis. The other products were assigned by analogy. d The reaction was performed for 24 h.

Discussion
Having the optimized conditions in hand, we set out to investigate the scope and limitation of a range of conjugated arylcyanosulfones 1 for the [3 + 2] 1,3-dipolar cycloaddition reaction with non-stabilized azomethine ylides to provide substituted pyrrolidines. Under the optimized conditions, we were pleased to find that they all exhibited good reactivity. The results of the experiments starting from methyl-, methoxy-, tertiary butyl-, halogen-, trifluoromethyl-, substituted cyanosulfones (1b-k) and other analogues (1l-o, R 1 = 2-furyl, 3-thienyl, 1-naphthyl, 1-naphthyl) are presented in Table 2. The [3 + 2] cycloaddition reactions were tolerated all the screening various conjugated arylcyanosulfones 1 without any detrimental effects on the reactivity or stereoselectivity, regardless of the different positions and electronic properties of substituents and steric hindrance substituents into the aryl ring of arylcyanosulfones when the arylcyanosulfones 1 reacted smoothly with the precursor of non-stabilized azomethine ylides 2a (entries 1-15) or 2b (entry 16). The reaction afforded the corresponding products 3 (3a-p) in high isolated yields (92-98%) with excellent diastereoselectivities (>25:1 dr). Additionally, the effect of the sulfonyl group of cyanosulfone 1q [39][40] and 1r [41][42][43][44][45] was studied to give the corresponding products 3q and 3r in 95% and 95% yields, respectively. It's worth noting that the cycloaddition reaction was also amenable to the present system, and a similar degree of diastereoselectivities was observed when the cyano group or ester group instead of the sulfonyl group (entries [19][20]. However, when the substrate 1u and 1v [46]of the acetyl group or benzoyl group instead of the sulfonyl group and the alkylsulfonyl-substituted cyanosulfone substrate 1w were treated with the [3 + 2] cycloaddition reaction under the standard condition, the reaction was disordered and offered inseparable mixture. Finally, in order to show the broad synthetic utility of pyrrolidines for the preparation of pharmaceutically relevant molecules their gram scale experiment and subsequent transformations were studied. Firstly, 3 mmol of -p-toluenesulfonyl-cinnamonitrile 1a and 3.6 mmol of N-(methoxymethyl)-N-(trimethylsilyl-methyl)-benzyl-amine 2a proceeded smoothly under the standard conditions and offered compound 3a (1.233 g) in 98% yield with dr>25:1 (Scheme 2). Next, we studied the reactivity of the obtained cycloadducts for further modification of the substituted pyrrolidine motif. Cleavage of N-benzyl group and remove the benzyl group by hydrogenolysis of 3a at room temperature using 10% Pd/C as a catalyst afforded the target product 4 in 82% yield (Scheme 3).

Materials and Methods
NMR data were obtained for 1 H at 400 MHz, and for 13 C at 100 MHz. Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard in CDCl3 solution. ESI HRMS was recorded on a Waters SYNAPT G2. Column chromatography was performed on silica gel (200-300 mesh) eluting with ethyl acetate/petroleum ether. TLC was performed on glass-backed silica plates. UV light, I2, and solution of potassium permanganate were used to visualize products. All chemicals were used without purification as commercially available unless otherwise noted. Petroleum ether and ethyl acetate were distilled. THF was freshly distilled from sodium/benzophenone. Unless otherwise noted, experiments involving moisture and/or air sensitive components were performed under a positive pressure of argon in oven-dried glassware equipped with a rubber septum inlet. Dried solvents and liquid reagents were transferred by oven-dried syringes.

Conclusions
In summary, we have successfully shown that ,β-unsaturated ,-disubstituted aryl cyanosulfones behave as C=C dipolarophiles when reacted with a non-stabilized azomethine ylides generated in situ as electron-rich enriched 1,3-dipoles. The transformation features excellent diastereoselectivities, broad substrate scope, low cost of reagents, and convenient operation. The [3 + 2] cycloaddition provides an efficient protocol for affording novel and substituted pyrrolidines bearing a quaternary centre from easily available substrates in high yields (up to 98%) with excellent diastereoselectivities (>25:1 dr) without any metal catalysts. The potential synthetic utility and practicality of the approach were also highlighted by the gram-scale experiment and the synthetic transformation of the product into other heterocyclic compounds. The further application of this strategy is presently under bioactive investigation in our laboratory.
Author Contributions: K.K. Wang, Y.L. Li and Y.C. Zhao participated in the synthesis, purification and characterization of the new compound. R.X. Chen and A.L. Sun participated in the interpretation of spectroscopy of new compounds and the review of the manuscript. R.X. Chen and Z.Y. Wang participated in the interpretation of the results, writing, revision and correspondence to the journal of molecules until the manuscript was accepted. All authors have read and agreed to the published version of the manuscript.