Chiral Phosphine Catalyzed Allylic Alkylation of Benzylidene Succinimides with Morita–Baylis–Hillman Carbonates

Owing to their unique chemical properties, α-alkylidene succinimides generally act as versatile synthons in organic synthesis. Compared with well-established annulations, nucleophilic alkylations of α-alkylidene succinimides are very limited. Accordingly, an organocatalytic allylic alkylation of α-benzylidene succinimides with Morita–Baylis–Hillman (MBH) carbonates was established. In the presence of a chiral phosphine catalyst, α-benzylidene succinimides reacted smoothly with MBH carbonates under mild conditions to furnish a series of optical active succinimides in high yields and enantioselectivities. Different from the reported results, the organocatalytic enantioselective construction of pyrrolidine-2,5-dione frameworks bearing contiguous chiral tertiary carbon centers was achieved via this synthetic strategy. Scaling up the reaction indicated that it is a practical strategy for the organocatalytic enantioselective alkylation of α-alkylidene succinimides. A possible reaction mechanism was also proposed.


Results and Discussion
We started our investigation with the model reaction between 3-benzylidene-1phenylpyrrolidine-2,5-dione 1a and MBH carbonate 2a in CH 2 Cl 2 at room temperature for 16 h (Table 1). Initially, the reaction proceeded smoothly in the presence of phosphine C1 to furnish the desired succinimide 3aa at a 76% yield with 29% ee and 10:1 dr (Table 1, entry 1). To improve the efficiency and stereoselectivity, the chiral nucleophilic phosphine catalyst was carefully screened (Table 1, entries 2-8). Pleasingly, the C3-catalyzed reaction afforded the desired product 3aa at an 85% yield with 56% ee and 10:1 dr (Table 1, entry 3). The use of C4 as a catalyst enabled the formation of product 3aa at a 91% yield with 62% ee and 8:1 dr (Table 1, entry 4). Particularly, the desired product 3aa was obtained at a 95% yield with 85% ee and 11:1 dr when phosphine C6 was employed (Table 1, entry 6). Further modifying the catalyst structure did not enhance the efficiency or the asymmetric induction (Table 1, entries 7 and 8). The effect of the substituent on the nitrogen atom of α-alkylidene succinimides was also surveyed. The C6-catalyzed reaction of 3-benzylidene-1-methylpyrrolidine-2,5-dione 1b furnished the corresponding product 3ba at a 94% yield with 77% ee and 9:1 dr (Table 1, entry 9). Notably, product 3ca was obtained at a 90% yield with 92% ee and 10:1 dr from the C6-catalyzed reaction of 1benzyl-3-benzylidenepyrrolidine-2,5-dione 1c ( Table 1, entry 10). With these encouraging data in hand, we then further optimized reaction conditions to obtain better results. The screening of reaction media disclosed that CH 2 Cl 2 was suitable ( . As a result, we identified the optimal reaction conditions: when 1-benzyl-3-benzylidenepyrrolidine-2,5-dione 1c (0.05 mmol) was treated with MBH carbonate 2a (0.06 mmol) in the presence of catalyst C6 (10 mol%) in CH 2 Cl 2 (0.75 mL) at room temperature for 36 h, the desired succinimide 3ca was obtained at a 96% yield with 92% ee and 11:1 dr.  With the optimized reaction condition in hand, we then examined the substrate scope. As shown in Scheme 2, the scope of α-benzylidene succinimide 1 was investigated with the C6-catalyzed reaction of MBH carbonate 2a. Succinimides with different substitute groups (R 1 ) on the nitrogen atom were tested. Under standard conditions, product 3aa was obtained at a 96% yield with 81% ee and 11:1 dr, and 3ba was obtained at a 91% yield with 81% ee and 5:1 dr, respectively. Furthermore, the succinimide with n-Bu group 3da was isolated at a 91% yield with 82% ee and 11:1 dr. In particular, the C6-catalyzed reaction of 3-benzylidene-1-(t-butyl)pyrrolidine-2,5-dione 1e generated the desired product 3ea at a 94% yield with 92% ee and 14:1 dr. Moreover, the α-benzylidene succinimide With the optimized reaction condition in hand, we then examined the substrate scope. As shown in Scheme 2, the scope of α-benzylidene succinimide 1 was investigated with the C6-catalyzed reaction of MBH carbonate 2a. Succinimides with different substitute groups (R 1 ) on the nitrogen atom were tested. Under standard conditions, product 3aa was obtained at a 96% yield with 81% ee and 11:1 dr, and 3ba was obtained at a 91% yield with 81% ee and 5:1 dr, respectively. Furthermore, the succinimide with n-Bu group 3da was isolated at a 91% yield with 82% ee and 11:1 dr. In particular, the C6-catalyzed reaction of 3-benzylidene-1-(t-butyl)pyrrolidine-2,5-dione 1e generated the desired product 3ea at a 94% yield with 92% ee and 14:1 dr. Moreover, the α-benzylidene succinimide with naphthalen-1-ylmethyl residue 1f was also compatible to afford the corresponding product 3fa at a 91% yield with 81% ee and 13:1 dr. The effect of aromatic group Ar 1 was also surveyed. In general, a wide range of α-benzylidene succinimides 1g-n reacted smoothly with MBH carbonate 2a under standard conditions to give the corresponding succinimides 3ga-na at high yields (86-94%) and stereoselectivities (76-98% ee, 9:1-14:1 dr). Both electron-donating (Me, MeS, and MeO) and electron-withdrawing (F, Cl, and Br) groups could be introduced into the aromatic ring of residue Ar 1 with a slight effect on the efficiency and asymmetric induction. With one exception, the C6-catalyzed reaction of 1-benzyl-3-(2-methoxybenzylidene)pyrrolidine-2,5-dione 1k resulted in the formation of product 3ka at a 94% yield with 28% ee and 3:1 dr. It was found that 1-benzyl-3-(naphthalen-2-ylmethylene)pyrrolidine-2,5-dione 1o was also tolerated to give the desired product 3oa at a 93% yield with 85% ee and 11:1 dr.

Scheme 2. Scope of benzylidene succinimides.
Subsequently, the scope of MBH carbonates was also investigated with the C6-catalyzed reaction of α-benzylidene succinimide 1e (Scheme 3). To our delight, various MBH carbonates 2b-f with different substituents (Ar 2 ) were found to be compatible under standard conditions to afford the corresponding succinimides 3eb-ef at a 90-94% yield Subsequently, the scope of MBH carbonates was also investigated with the C6-catalyzed reaction of α-benzylidene succinimide 1e (Scheme 3). To our delight, various MBH carbon-ates 2b-f with different substituents (Ar 2 ) were found to be compatible under standard conditions to afford the corresponding succinimides 3eb-ef at a 90-94% yield with 92-95% ee and 10:1-15:1 dr. No significant electronic effect on the aromatic moiety was observed. Particularly, the MBH carbonate bearing thiophen-2-yl group 2g reacted smoothly with α-benzylidene succinimide 1e to afford the desired product 3eg at a 91% yield with 92% ee and >20:1 dr. Moreover, the ester groups of MBH carbonate 2 had a slight effect on the efficiency and stereoselectivity, furnishing products 3eh-ek at an 88-94% yield with 91-93% ee and 7:1-15:1 dr. Taken together, these encouraging results indicated that the chiral phosphine-catalyzed allylic alkylation of α-benzylidene succinimides with MBH carbonates was achieved, furnishing succinimide derivatives bearing contiguous chiral tertiary carbon centers at high yields with asymmetric induction.
Molecules 2023, 28, x FOR PEER REVIEW 6 of 10 with 92-95% ee and 10:1-15:1 dr. No significant electronic effect on the aromatic moiety was observed. Particularly, the MBH carbonate bearing thiophen-2-yl group 2g reacted smoothly with α-benzylidene succinimide 1e to afford the desired product 3eg at a 91% yield with 92% ee and >20:1 dr. Moreover, the ester groups of MBH carbonate 2 had a slight effect on the efficiency and stereoselectivity, furnishing products 3eh-ek at an 88-94% yield with 91-93% ee and 7:1-15:1 dr. Taken together, these encouraging results indicated that the chiral phosphine-catalyzed allylic alkylation of α-benzylidene succinimides with MBH carbonates was achieved, furnishing succinimide derivatives bearing contiguous chiral tertiary carbon centers at high yields with asymmetric induction.

Scheme 3. Scope of MBH carbonates.
To demonstrate the synthetic potential, the C6-catalyzed reaction was scaled up to 0.5 mmol of the starting material under standard reaction conditions. The corresponding product 3ea was obtained at a 92% yield with 94% ee and 14:1 dr (Scheme 4A). The absolute configuration of 3la was unambiguously confirmed by X-ray crystallography (CCDC 2244711 (3la) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. For details concerning the crystal structure of 3la see the Supplementary Materials as well). The stereochemistry of other products was assumed by analogy. On the basis of the reported results and our previous work [33], a proposed reaction mechanism was shown in Scheme 4B. To demonstrate the synthetic potential, the C6-catalyzed reaction was scaled up to 0.5 mmol of the starting material under standard reaction conditions. The corresponding product 3ea was obtained at a 92% yield with 94% ee and 14:1 dr (Scheme 4A). The absolute configuration of 3la was unambiguously confirmed by X-ray crystallography (CCDC 2244711 (3la) contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. For details concerning the crystal structure of 3la see the Supplementary Materials as well). The stereochemistry of other products was assumed by analogy. On the basis of the reported results and our previous work [33], a proposed reaction mechanism was shown in Scheme 4B.

Materials and Methods
All chemicals were used without further purification as commercially available unless otherwise noted. Thin-layer chromatography (TLC) was performed on silica gel plates (60F-254) using UV light (254 and 365 nm). Flash chromatography was conducted on silica gel (300-400 mesh). NMR (400, 500, or 600 MHz for 1 H NMR; 100 or 126 MHz for 13 C NMR; 376 MHz for 19 F NMR) spectra were recorded in CDCl3 with TMS as the internal standard. Chemical shifts are reported in ppm, and coupling constants are given in Hz. Data for 1 H NMR are recorded as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet-doublet), coupling constant (Hz), and integration. Data for 13 C NMR are reported in terms of chemical shift (δ, ppm). Data for 19 F NMR are reported in terms of chemical shift (δ, ppm). High-resolution mass spectral (HRMS) analyses were recorded on a Thermo Scientific Q Exactive Orbitrap mass spectrometer (Bremen,Germany)with ESI source. The crystal structure and data were recorded on a Rigaku HomeLab diffractometer. More details can be found in the Supplementary Materials. In addition, the X-ray of 3la, copies of NMR, and chiral HPLC analysis can be found in the Supplementary Materials.

General Procedure for the Synthesis of α-Benzylidene Succinimide 1
Triphenylphosphine (10.5 mmol) was added to a solution of substituted 1-R 1 -1H-pyrrole-2,5-dione (10 mmol) and aldehyde (11 mmol) in EtOH (100 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. When the reaction was completed (monitored by TLC), the reaction mixture was filtered, and the precipitation was washed with ethanol and dried to afford α-benzylidene succinimide 1.

Materials and Methods
All chemicals were used without further purification as commercially available unless otherwise noted. Thin-layer chromatography (TLC) was performed on silica gel plates (60F-254) using UV light (254 and 365 nm). Flash chromatography was conducted on silica gel (300-400 mesh). NMR (400, 500, or 600 MHz for 1 H NMR; 100 or 126 MHz for 13 C NMR; 376 MHz for 19 F NMR) spectra were recorded in CDCl 3 with TMS as the internal standard. Chemical shifts are reported in ppm, and coupling constants are given in Hz. Data for 1 H NMR are recorded as follows: chemical shift (ppm), multiplicity (s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet-doublet), coupling constant (Hz), and integration. Data for 13 C NMR are reported in terms of chemical shift (δ, ppm). Data for 19 F NMR are reported in terms of chemical shift (δ, ppm). High-resolution mass spectral (HRMS) analyses were recorded on a Thermo Scientific Q Exactive Orbitrap mass spectrometer (Bremen, Germany) with ESI source. The crystal structure and data were recorded on a Rigaku HomeLab diffractometer. More details can be found in the Supplementary Materials. In addition, the X-ray of 3la, copies of NMR, and chiral HPLC analysis can be found in the Supplementary Materials.

General Procedure for the Synthesis of α-Benzylidene Succinimide 1
Triphenylphosphine (10.5 mmol) was added to a solution of substituted 1-R 1 -1Hpyrrole-2,5-dione (10 mmol) and aldehyde (11 mmol) in EtOH (100 mL) at room temperature. The reaction mixture was stirred at room temperature overnight. When the reaction was completed (monitored by TLC), the reaction mixture was filtered, and the precipitation was washed with ethanol and dried to afford α-benzylidene succinimide 1.

General
Procedure for the Synthesis of MBH Carbonate 2 1,4-Diazabicyclo[2.2.2]octane (DABCO, 10.5 mmol) was added to a solution of aldehyde (10 mmol) in acrylate (20 mL) at room temperature. The reaction mixture was stirred at room temperature for 3-7 days. When the reaction was completed (monitored by TLC), the reaction mixture was purified by silica gel column chromatography to afford MBH alcohol.
4-(Dimethylamino)pyridine (DMAP, 2.08 mmol) was added to a solution of MBH alcohol and Boc-anhydride (15 mmol) in CH 2 Cl 2 (30 mL) in batches. When the reaction was complete (monitored by TLC), the organic phase was washed with distilled water (2 × 20 mL) and dried over anhydrous Na 2 SO 4 , and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography, affording MBH carbonate 2.

General Procedure for the Phosphine-Catalyzed Allylic Alkylation
α-Benzylidene succinimide 1 (0.05 mmol), MBH carbonate 2 (0.06 mmol), and phosphine C6 (10 mol%) were added to a solution of CH 2 Cl 2 (0.75 mL). The reaction mixture was stirred at room temperature for 36 h. After the removal of the solvent, the crude residue was purified by preparative TLC (petroleum/ethyl acetate = 2:1) to obtain the desired product 3.

Conclusions
In conclusion, we developed an organocatalytic enantioselective allylic alkylation of α-benzylidene succinimides with MBH carbonates. With the aid of a chiral nucleophilic phosphine, a broad scope of α-benzylidene succinimides reacted smoothly with MBH carbonate to furnish functionalized α-benzylidene succinimides at high yields with high stereoselectivities. Importantly, this synthetic strategy not only achieved nucleophilic phosphine catalysis but also realized the asymmetric construction of enantioenriched succinimide derivatives bearing contiguous chiral tertiary carbon centers.
Supplementary Materials: The following supporting information can be downloaded at: https:// www.mdpi.com/article/10.3390/molecules28062825/s1. Author Contributions: J.S. and P.L. were responsible for conceptualization, data validation, and writing-review and editing; C.L. was responsible for the catalysis experiments and the spectroscopic and analytical analysis. All authors have read and agreed to the published version of the manuscript.

Funding:
The authors acknowledge the financial support from the National Natural Science Foundation of China (21871128), Guangdong Innovative Program (2019BT02Y335).

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available in the Supplementary Materials.