Phosphine-Catalyzed γ′-Carbon 1,6-Conjugate Addition of α-Succinimide Substituted Allenoates with Para-Quinone Methides: Synthesis of 4-Diarylmethylated 3,4-Disubstituted Maleimides

In this paper, an interesting γ′-carbon 1,6-conjugate addition for phosphine-catalyzed α-succinimide substituted allenoates has been disclosed. A wide array of substrates was found to participate in the reaction, resulting in the production of diverse 4-diarylmethylated 3,4-disubstituted maleimides with satisfactory to outstanding yields. Furthermore, a plausible mechanism for the reaction was proposed by the investigators.


Results and Discussion
This investigation commenced by examining the reaction between α-succinimide allenoate 2a and para-quinone methide (p-QM) 1a.A catalyst, MePPh 2 , was employed at 20 mol % with DCM as the solvent.The desired product 3aa was obtained with a yield of 34% (Table 1, entry 1).Various phosphines were also tested for the cascade remote 1, 6-addition reactions.However, no enhancement in reactivity was observed with the phosphines EtPPh 2 and PrPPh 2 (Table 1, entries 2, 3).Fortunately, when the reaction was attempted with Me 2 PPh and PMe 3 , smooth conversion was achieved, yielding the 1,6conjugate addition product 3aa with yields of 67% and 92%, respectively (Table 1, entries 4, 5).It is noteworthy that the presence of PCy 3 or PBu 3 , with their bulky substitution groups, resulted in decreased yields (Table 1, entries 6, 7).Considering the optimal catalyst, PMe 3 , we further optimized the reactions, using different solvents.Solvent screening revealed that DCE yielded similar results to DCM (Table 1, entry 8), while toluene, THF, and EtOAc exhibited low reactivity as solvents (Table 1, entries 9-11).Conversely, CH 3 CN and CH 3 OH resulted in inferior outcomes (Table 1, entries 12,13).By reducing the loading of PMe 3 to 10 mol % and 5 mol %, the yields of 3aa decreased to 85% and 75%, respectively (Table 1, entries 14, 15).Therefore, the optimal reaction conditions were determined to be DCM as the solvent, room temperature, and 20 mol% of PMe 3 as the catalyst.

Results and Discussion
This investigation commenced by examining the reaction between α-succinimide allenoate 2a and para-quinone methide (p-QM) 1a.A catalyst, MePPh2, was employed at 20 mol % with DCM as the solvent.The desired product 3aa was obtained with a yield of 34% (Table 1, entry 1).Various phosphines were also tested for the cascade remote 1, 6addition reactions.However, no enhancement in reactivity was observed with the phosphines EtPPh2 and PrPPh2 (Table 1, entries 2, 3).Fortunately, when the reaction was attempted with Me2PPh and PMe3, smooth conversion was achieved, yielding the 1,6-conjugate addition product 3aa with yields of 67% and 92%, respectively (Table 1, entries 4,  5).It is noteworthy that the presence of PCy3 or PBu3, with their bulky substitution groups, resulted in decreased yields (Table 1, entries 6, 7).Considering the optimal catalyst, PMe3, we further optimized the reactions, using different solvents.Solvent screening revealed that DCE yielded similar results to DCM (Table 1, entry 8), while toluene, THF, and EtOAc exhibited low reactivity as solvents (Table 1, entries 9-11).Conversely, CH3CN and CH3OH resulted in inferior outcomes (Table 1, entries 12,13).By reducing the loading of PMe3 to 10 mol % and 5 mol %, the yields of 3aa decreased to 85% and 75%, respectively (Table 1, entries 14, 15).Therefore, the optimal reaction conditions were determined to be DCM as the solvent, room temperature, and 20 mol% of PMe3 as the catalyst.a Unless otherwise indicated, all reactions were carried out at room temperature using 0.10 mmol of 1a and 0.12 mmol of 2a in a solvent containing 20 mol% of the catalyst.b Isolated yield.c PMe3 (10 mol%).d PMe3 (5 mol%).
Following the determination of optimal conditions for 1,6-conjugate addition, we investigated the substrate scope of this reaction.In Scheme 1, we explored the influence of various functional groups on the benzene ring of p-QMs.Under the optimized conditions, it was observed that the p-QMs carrying various electronically diverse functional groups at the para-position of the phenyl ring facilitated the formation of conjugate adducts with Following the determination of optimal conditions for 1,6-conjugate addition, we investigated the substrate scope of this reaction.In Scheme 1, we explored the influence of various functional groups on the benzene ring of p-QMs.Under the optimized conditions, it was observed that the p-QMs carrying various electronically diverse functional groups at the para-position of the phenyl ring facilitated the formation of conjugate adducts with yields ranging from good to excellent.Smooth conjugate addition was achieved with electron-rich methyl-and methoxy-substituted aryl quinone methides, resulting in excellent yields of the adducts (Scheme 2, 3ba, 3ca).Similarly, the reactions effectively yielded the corresponding products in good yields (Scheme 2, 3da-3ha) when employing arenes containing electron-deficient functional groups such as halogens, nitro groups, and cyano groups.Additionally, satisfactory performance was demonstrated in the reaction with p-QMs containing an ortho-substituted aryl moiety (Scheme 2, 3ia-3la).The applicability of the reaction was expanded to include meta-substituted aryl quinone methides (Scheme 2, 3ma-3oa).Furthermore, trisubstituted aryl quinone methides were investigated, and the conjugate addition yielded the desired in good yields (Scheme 2, 3pa).Moreover, the reaction was employed with p-QMs derived from β-naphthaldehyde, resulting in enhanced product yields (Scheme 2, 3ra).The reaction also showed success with the p-QM substrates generated from thiophene-2-carboxaldehyde and indole-3-carboxaldehyde (Scheme 2, 3qa, 3sa-3ua).The structure of 3sa was confirmed via X-ray analysis (CCDC 2287621) [60].These data are accessible free of charge from the Cambridge Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_request/cif. 9 August 2023.(DOI: 10.5517/ccdc.csd.cc2gsg7z).For further details regarding the crystal structure of 3sa, please refer to the Supplementary Materials.
(DOI: 10.5517/ccdc.csd.cc2gsg7z).For further details regarding the crystal structure of 3sa, please refer to the Supplementary Materials.In addition to p-QMs, we explored the substrate scope of α-succinimide allenoates with various R 2 groups using 1a as the coupling partner (Scheme 3).We were pleased to observe that the reactivity of the substrates remained unaffected when electron-donating substituents were introduced into the benzyl phenyl ring, resulting in yields of 74-81% (Scheme 3, 3ab-3af).However, the yields slightly decreased to 55% and 34% for 3ag and 3ah, respectively, when R' groups with electron-withdrawing properties were employed.Encouragingly, the reaction displayed good tolerance toward the phenyl group, as evidenced by the successful formation of the corresponding products in 84% yield (Scheme 3, 3ai).Additionally, when R 2 was a methyl group or a diphenyl-substituted methyl Scheme 2. Substrate scope of the p-QMs.
In addition to p-QMs, we explored the substrate scope of α-succinimide allenoates with various R 2 groups using 1a as the coupling partner (Scheme 3).We were pleased to observe that the reactivity of the substrates remained unaffected when electron-donating substituents were introduced into the benzyl phenyl ring, resulting in yields of 74-81% (Scheme 3, 3ab-3af).However, the yields slightly decreased to 55% and 34% for 3ag and 3ah, respectively, when R' groups with electron-withdrawing properties were employed.Encouragingly, the reaction displayed good tolerance toward the phenyl group, as evidenced by the successful formation of the corresponding products in 84% yield (Scheme 3, 3ai).Additionally, when R 2 was a methyl group or a diphenyl-substituted methyl group, the products were obtained with respective yields of 74% (Scheme 2, 3aj) and 57% (Scheme 3, 3ak).To demonstrate the applicability of our method, we conducted a scale-up reaction.As depicted in Scheme 4, the reaction between 1a and allenoate 2a proceeded smoothly under optimal conditions, yielding desired product 3aa at the gram scale without any noticeable loss in yield.
A plausible reaction mechanism is proposed in Scheme 5.This addition reaction begins with the nucleophilic addition of a phosphine to the allenoates 2a, forming zwitterionic intermediates (A⟷A′).To demonstrate the applicability of our method, we conducted a scale-up reaction.As depicted in Scheme 4, the reaction between 1a and allenoate 2a proceeded smoothly under optimal conditions, yielding desired product 3aa at the gram scale without any noticeable loss in yield.To demonstrate the applicability of our method, we conducted a scale-up reaction.As depicted in Scheme 4, the reaction between 1a and allenoate 2a proceeded smoothly under optimal conditions, yielding desired product 3aa at the gram scale without any noticeable loss in yield.
A plausible reaction mechanism is proposed in Scheme 5.This addition reaction begins with the nucleophilic addition of a phosphine to the allenoates 2a, forming zwitterionic intermediates (A⟷A′).

Materials and Methods
All chemical reactions were carried out under an argon atmosphere using oven-dried glassware.This setup included magnetic stirring to ensure proper mixing of reagents.Unless otherwise stated, all chemicals were purchased from commercial suppliers and used as received without any additional purification.However, all solvents used in the reactions were purified and dried prior to use, according to standard laboratory procedures.The progress of the chemical reactions was monitored by thin-layer chromatography (TLC) on glass plates precoated with silica gel, and fluorescence quenching with UV light at a wavelength of 254 nm was used to visualize the chromatograms.Any necessary purification of the products was carried out by flash column chromatography using the Qingdao Haiyang flash silica gel (Qingdao, China)with a particle size range of 100-200 mesh.Nuclear magnetic resonance (NMR) spectra, both proton ( 1 H) and carbon ( 13 C), were recorded in deuterated CDCl3 or DMSO-d6 using the 500 MHz NMR spectrometer.The melting points of the compounds were determined using an X-4 digital micro-melting point apparatus from Shanghai Jingke (Shanghai, China) to ensure accuracy.An Agilent instrument using electrospray ionization mass spectrometry (ESI-MS) (Campus Drive Stanford, CA, USA) was used to obtain accurate mass measurements.In addition, X-ray crystallographic data were collected using a Bruker D8 VENTURE instrument (Billerica, Germany) to provide detailed structural information on the synthesized compounds.

Materials and Methods
All chemical reactions were carried out under an argon atmosphere using oven-dried glassware.This setup included magnetic stirring to ensure proper mixing of reagents.Unless otherwise stated, all chemicals were purchased from commercial suppliers and used as received without any additional purification.However, all solvents used in the reactions were purified and dried prior to use, according to standard laboratory procedures.The progress of the chemical reactions was monitored by thin-layer chromatography (TLC) on glass plates precoated with silica gel, and fluorescence quenching with UV light at a wavelength of 254 nm was used to visualize the chromatograms.Any necessary purification of the products was carried out by flash column chromatography using the Qingdao Haiyang flash silica gel (Qingdao, China) with a particle size range of 100-200 mesh.Nuclear magnetic resonance (NMR) spectra, both proton ( 1 H) and carbon ( 13 C), were recorded in deuterated CDCl 3 or DMSO-d6 using the 500 MHz NMR spectrometer.The melting points of the compounds were determined using an X-4 digital micro-melting point apparatus from Shanghai Jingke (Shanghai, China) to ensure accuracy.An Agilent instrument using electrospray ionization mass spectrometry (ESI-MS) (Campus Drive Stanford, CA, USA) was used to obtain accurate mass measurements.In addition, X-ray crystallographic data were collected using a Bruker D8 VENTURE instrument (Billerica, Germany) to provide detailed structural information on the synthesized compounds.Characterization data of compounds, NMR spectra of compounds and crystallographic data for product 3sa, See Supplementary Materials.

General Procedure for the Synthesis of Para-Quinone Methides 1
Aldehyde (10 mmol) was added to a solution of the phenol (10 mmol) in toluene (40 mL).The reaction mixture was heated in a Dean-Stark apparatus to reflux.Piperidine (20 mmol) was added dropwise over 1 h, and heating continued until all the starting material had been consumed.After the mixture had cooled just below the boiling point of toluene (100 • C), acetic anhydride (20 mmol) was added.The solution was stirred for 15 min.The residue was extracted three times with dichloromethane.The combined organic layers were sequentially washed with water and brine, dried over magnesium sulfate, filtered, and concentrated.The crude product was purified by flash column chromatography on silica gel to afford the corresponding product 1.

General Procedure for the Phosphine-Catalyzed Direct 1,6-Conjugate Addition
Under argon atmosphere, 1 mL of DCM was added to a mixture of para-quinone methide 1 (0.10 mmol), α-succinimide substituted allenoate 2 (0.12 mmol) and catalyst PMe 3 (20 mol%, 0.02 mmol) in a Schlenk tube at room temperature.The resulting mixture was stirred until the starting material was completely consumed (monitored by TLC) and then concentrated to dryness.The residue was purified through flash column chromatography (PE/EtOAc = 8:1) to afford corresponding cycloaddition products 3.

Conclusions
In conclusion, we have introduced a novel method for synthesizing functionalized 4diarylmethylated 3,4-disubstituted maleimides in satisfactory yields.This method involves a phosphine-catalyzed 1,6-conjugated addition reaction between α-succinimide substituted allenoates and p-QMs.Considering the extensive research on the biological activity of natural products and industrially useful compounds containing the 3,4-disubstituted maleimide moiety, our methodology presents a new and efficient protocol for their synthesis.

Supplementary Materials:
The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/molecules29112593/s1,Full experimental procedures, characterization data, NMR spectra for all new compounds, as well as crystallographic data for product 3sa are available [61,62].
Author Contributions: Z.G. and X.W. were responsible for conceptualization and data validation, L.L. were responsible for writing, review, and editing; X.Z. and D.L. were responsible for the catalysis experiments; B.N. and X.C. were responsible for the spectroscopic and analytical analysis.J.W. and H.L. were responsible for the data curation.All authors have read and agreed to the published version of the manuscript.
Subsequent proton transfer leads to intermediate B, followed by the formation of intermediate D through isomerization and proton transfer.Intermediate D then attacks p-QM 1a, forming intermediate E. Subsequently, intermediate E undergoes a series of H-transfers to form intermediate G.The elimination of PR3 from G produces product 3aa, which regenerates PR3 to complete the catalytic cycle.

Scheme 4 .Scheme 4 . 11 Scheme 5 .
Scheme 4. The scale-up reaction.Scheme 4. The scale-up reaction.A plausible reaction mechanism is proposed in Scheme 5.This addition reaction begins with the nucleophilic addition of a phosphine to the allenoates 2a, forming zwitterionic intermediates (A←→A ′ ).Subsequent proton transfer leads to intermediate B, followed by

Scheme 5 .
Scheme 5. Proposed mechanism.The letter numbers A-G indicate possible intermediate structures in the plausible reaction mechanism.

Funding:
This research was funded by the Natural Science Foundation of Shandong Province (ZR2021MB110), the National Natural Science Foundation of China (No. 22101002), the Support Plan on Science and Technology for Youth Innovation of Universities in Shandong Province (2022KJ111)", Innovation and Entrepreneurship Training Program Liaocheng University (CXCY2023464), and the Special Construction Project Fund for Shandong Province Taishan Scholars.Institutional Review Board Statement: Not applicable.Informed Consent Statement: Not applicable.

Table 1 .
Reaction yields under different reaction conditions.

Table 1 .
Reaction yields under different reaction conditions.