Synthesis of 3,4-Disubstituted Maleimide Derivatives via Phosphine-Catalyzed Isomerization of α-Succinimide-Substituted Allenoates Cascade γ′-Addition with Aryl Imines

3,4-disubstituted maleimides find wide applications in various pharmacologically active compounds. This study presents a highly effective approach for synthesizing derivatives of 3,4-disubstituted maleimides through the direct isomerization of α-succinimide-substituted allenoates, followed by a cascade γ′-addition and aryl imines using PR3 as a catalyst. The resulting series of 3,4-disubstituted maleimides exhibited excellent stereoselectivities, achieving yields of up to 86%. To our knowledge, the phosphine-mediated γ′-addition reaction of allenoates is seldom reported.


Introduction
Maleimide derivatives have been found to possess diverse biological activities.In fact, some 3,4-disubstituted maleimides are frequently found in natural products and bioactive molecules [1]. Figure 1 provides some examples of the different 3,4-disubstituted maleimide skeletons that occur.Rebeccamycin A, an antibiotic, has demonstrated noteworthy effectiveness against certain types of tumor cell lines [2].Additionally, indolylmaleimide derivative B has the ability to inhibit the growth and movement of cancer cells, indicating its potential as an anticancer drug [3].Compound C, a highly active inhibitor of glycogen synthase kinase, has been identified [4].Recently, N-substituted maleimide D has been found to be an attractive inhibitor for GSK-3 and a potential treatment for Alzheimer's disease [5].E is an antifungal derived from the metabolite of the Serpula himantoides strain [6].Additionally, 3,4-di(aryl)maleimide F is an antitumor agent that exhibits antitubulin activity [7].As a result, the synthesis of these interesting molecular structures has presented a constant challenge to synthetic organic chemists.
Our group has recently presented a novel set of α-succinimide-substituted allenoates, demonstrating the ability to undergo [4+2] annulation reactions with 1,1-dicyanoalkenes under phosphine catalysis, specifically involving the γ ′ -carbon of the allenoates [42].However, as far as we know, the phosphine-mediated γ ′ -addition reaction of allenoates has been uncommon until now.
In this work, we introduce a new phosphine-catalyzed direct isomerization of αsuccinimide-substituted allenoates, leading to cascade γ ′ -addition reactions with imine derivatives.It is conceivable that the attack of a phosphine on α-succinimide-substituted allenoates, along with subsequent proton transfers, could result in the formation of a putative intermediate where the remote γ ′ -carbon becomes nucleophilic, initiating fresh reactions.These reactions progress smoothly, yielding good to high yields of corresponding 3,4-disubstituted maleimide adducts under mild conditions (Scheme 1g).
leagues employed vinyl allenoates to achieve the remote activation of the ε-carbon, lead ing to 1,7-addition reactions (Scheme 1d) [39].Aside from nucleophile addition reactions addition reactions of electrophiles with δ-substitute allenoates have also been reported Prior studies have shown that most reactions between allenoates and electrophiles resul in cyclizations.However, Xu and Li separately reported a notable phosphine-catalyzed δ umpolung addition of isatin derivatives (Scheme 1e) or para-quinone methides (Schem 1f) with δ-substitute allenoates [40,41].Despite the recent advances, further diversification of allenoates is still necessary to foster the development of new addition reactions and versatile product motifs.
Our group has recently presented a novel set of α-succinimide-substituted allenoates demonstrating the ability to undergo [4+2] annulation reactions with 1,1-dicyanoalkene under phosphine catalysis, specifically involving the γ′-carbon of the allenoates [42] However, as far as we know, the phosphine-mediated γ′-addition reaction of allenoate has been uncommon until now.
In this work, we introduce a new phosphine-catalyzed direct isomerization of α-suc cinimide-substituted allenoates, leading to cascade γ′-addition reactions with imine de rivatives.It is conceivable that the attack of a phosphine on α-succinimide-substituted al lenoates, along with subsequent proton transfers, could result in the formation of a puta tive intermediate where the remote γ′-carbon becomes nucleophilic, initiating fresh reac tions.These reactions progress smoothly, yielding good to high yields of corresponding 3,4-disubstituted maleimide adducts under mild conditions (Scheme 1g).(1) phosphine-catalyzed umpolung addition reactions with the nucleophiles (2) phosphine-catalyzed umpolung addition reactions with the electrophiles
Under the optimized conditions, we investigated the performance of various imines 1 and allenoates 2 in the γ′-addition reaction.The outcomes are outlined in Table 2.We observed that, when employing different substituted imines 1 (1a-1n) as substrates, the reaction proceeded effectively, yielding the desired product 3 in moderate to good yields (Table 2, entries 1-14).However, the presence of the electron-donating groups on the aromatic rings of the imines exhibited higher reactivity compared to the electron-withdrawing groups.Imine substrates 1b-1i with electron-donating groups on the benzene ring yielded the desired products in moderate to good yields (72-86%) (Table 2, entries 2-9).Conversely, imines 1j-1n with halogen substitutions on the benzene ring resulted in slightly lower yields (49-67%) (Table 2, entries 10-14).Unfortunately, when attempting to use alkyl imine (1o) as a reactant, no desired product was observed (Table 2, entry 15).Substituting the N-substituents in allenoates 2 with the 2-MeCH2C6H4 (2b), 4-MeCH2C6H4 (2c), and 4-OMeCH2C6H4 (2d) groups did not significantly alter the reactivity.Using these allenoates, the reaction proceeded smoothly to yield the desired products 3 in 59-64% yields ( 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 and 30 mol % of the additive.b Isolated yield.c 1a:2a = 1:1.5.
Under the optimized conditions, we investigated the performance of various imines 1 and allenoates 2 in the γ ′ -addition reaction.The outcomes are outlined in Table 2.We observed that, when employing different substituted imines 1 (1a-1n) as substrates, the reaction proceeded effectively, yielding the desired product 3 in moderate to good yields (Table 2, entries 1-14).However, the presence of the electron-donating groups on the aromatic rings of the imines exhibited higher reactivity compared to the electron-withdrawing groups.Imine substrates 1b-1i with electron-donating groups on the benzene ring yielded the desired products in moderate to good yields (72-86%) (Table 2, entries 2-9).Conversely, imines 1j-1n with halogen substitutions on the benzene ring resulted in slightly lower yields (49-67%) (Table 2, entries 10-14).Unfortunately, when attempting to use alkyl imine (1o) as a reactant, no desired product was observed (Table 2, entry 15).Substituting the N-substituents in allenoates 2 with the 2-MeCH 2 C 6 H 4 (2b), 4-MeCH 2 C 6 H 4 (2c), and 4-OMeCH 2 C 6 H 4 (2d) groups did not significantly alter the reactivity.Using these allenoates, the reaction proceeded smoothly to yield the desired products 3 in 59-64% yields (Table 2, entries [16][17][18]. Moreover, the configurations and stereochemical properties of compound 3 were elucidated using NMR, high-resolution mass spectrometry (HRMS) data, and crystallographic analysis via X-ray diffraction (Figure 2).For detailed information on single crystal of 3da, see Tables S1-S6 in the Supplementary Materials.The crystallographic data for 3da have been submitted to the Cambridge Crystallographic Data Centre with deposition number CCDC 2258229 [43].Moreover, the configurations and stereochemical properties of compound 3 were elucidated using NMR, high-resolution mass spectrometry (HRMS) data, and crystallographic analysis via X-ray diffraction (Figure 2).For detailed information on single crystal of 3da, see Tables S1-S6 in the Supplementary Materials.The crystallographic data for 3da have been submitted to the Cambridge Crystallographic Data Centre with deposition number CCDC 2258229 [43].To demonstrate the applicability of our approach, we conducted a reaction at a larger scale.As shown in Scheme 2, under optimal conditions, the reaction between 1a and αsuccinimide-substituted allenoate 2a proceeded smoothly, resulting in the production of the desired product 3aa at the gram scale with no observable loss of yield.To demonstrate the applicability of our approach, we conducted a reaction at a larger scale.As shown in Scheme 2, under optimal conditions, the reaction between 1a and α-succinimide-substituted allenoate 2a proceeded smoothly, resulting in the production of the desired product 3aa at the gram scale with no observable loss of yield.To demonstrate the applicability of our approach, we conducted a reaction at a larger scale.As shown in Scheme 2, under optimal conditions, the reaction between 1a and αsuccinimide-substituted allenoate 2a proceeded smoothly, resulting in the production of the desired product 3aa at the gram scale with no observable loss of yield.

Scheme 2. The scale-up reaction.
A plausible reaction mechanism is presented in Scheme 3 [42].This addition reaction begins with the nucleophilic addition of a phosphine to the allenoates 2, forming zwitterionic intermediates (A ⟷ A′).Subsequently, proton transfer occurs, leading to the formation of intermediate B, followed by the generation of intermediate D through isomerization and proton transfer.Intermediate D then reacts with imines 1, producing intermediate E. Subsequently, the intermediate E undergoes a series of H-transfers to form intermediate G.The elimination of PR3 from G yields product 3 and regenerates PR3 to complete the catalytic cycle.A plausible reaction mechanism is presented in Scheme 3 [42].This addition reaction begins with the nucleophilic addition of a phosphine to the allenoates 2, forming zwitterionic intermediates (A ←→ A ′ ).Subsequently, proton transfer occurs, leading to the formation of

Materials and Methods
Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification.All solvents were filtered and dried according to standard procedures before use.All reactions were performed in dry glass vessels under nitrogen and magnetic stirring.The reaction was monitored by thin-layer chromatography (TLC) on silica precoated glass plates.The chromatogram was viewed under 254 nm UV light.Qingdao Marine flash silica gel (100-200 mesh) (Qingdao, China) was used for flash column chromatography.The 1 H and 13 C NMR spectra of CDCl3 were recorded using a 500 MHz NMR instrument.Melting point was measured using an X-4 digital micromelting point meter (Shanghai, China).Accurate mass measurements were conducted using Agilent instruments and ESI-MS technology (Santa Clara, CA, USA).X-ray crystallographic data were obtained using a Bruker D8 VENTURE instrument (Billerica, Germany).

Materials and Methods
Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification.All solvents were filtered and dried according to standard procedures before use.All reactions were performed in dry glass vessels under nitrogen and magnetic stirring.The reaction was monitored by thin-layer chromatography (TLC) on silica precoated glass plates.The chromatogram was viewed under 254 nm UV light.Qingdao Marine flash silica gel (100-200 mesh) (Qingdao, China) was used for flash column chromatography.The 1 H and 13 C NMR spectra of CDCl 3 were recorded using a 500 MHz NMR instrument.Melting point was measured using an X-4 digital micromelting point meter (Shanghai, China).Accurate mass measurements were conducted using Agilent instruments and ESI-MS technology (Santa Clara, CA, USA).X-ray crystallographic data were obtained using a Bruker D8 VENTURE instrument (Billerica, Germany).

General Procedure for the Synthesis of N-Tosyl Imines 1
Molecular Sieves (MS) 4Å was preactivated by microwave and dried under vacuum.A screw capped vial was charged with aldehyde (1.2 mmol), TsNH 2 (1.0 mmol), and preactivated MS 4Å (1.0 g).Dried dichloromethane (3.0 mL) and pyrrolidine (6.22 µL, 0.10 mmol) were then added to the mixture.The resultant mixture was stirred at 60 • C for 24 h.The mixture was cooled to rt and filtered through a short pad of Celite ® from Tianjin Heowns (Tianjin, China).The organic phase was concentrated under reduced pressure, and the crude product was purified by crystallization (hexane/ethyl acetate system).The resulting solid was collected by filtration and then dried under vacuum.

General Procedure for the Isomerization Cascade γ ′ -Addition Reaction
Under argon atmosphere, to a mixture of N-tosyl imines 1 (0.10 mmol), α-succinimidesubstituted allenoate 2 (0.15 mmol), catalyst PR 3 (20 mol %, 0.02 mmol), and the additive (30 mol %, 0.03 mmol) in a Schlenk tube, 2 mL of DCM was added at room temperature.The resulting mixture was stirred until the starting material was completely consumed (monitored by TLC) and then was concentrated to dryness.The residue was purified through flash column chromatography (EtOAc/PE) to afford the corresponding products 3.

Conclusions
In conclusion, we have established a novel method for synthesizing functionalized 3,4-disubstituted maleimides in good yields.This reaction involves a phosphine-catalyzed isomerization cascade γ ′ -addition reaction between α-succinimide-substituted allenoates and aryl imine derivatives.Given the numerous biologically active natural products and industrially useful compounds containing 3,4-disubstituted maleimide components reported in the literature, our methodology offers a new protocol for efficiently synthesizing these compounds.
Funding: This research was funded by project ZR2021MB110 supported by Shandong Province Natural Science Foundation, 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), Guangyue Young Scholar Innovation Team Foundation of Liaocheng University (LCUGYTD2022-04), and the Special Construction Project Fund for Shandong Province Taishan Scholars.

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

Figure 1 .
Figure 1.Some natural products and bioactive molecules.Compound A: rebeccamycin, an antibioti Compound B: indolylmaleimide derivative, inhibitor for cancer cells; Compound C: inhibitor of gly cogen synthase kinase; Compound D: inhibitor for GSK-3; Compound E: an antifungal derived from the metabolite of the Serpula himantoides strain; Compound F: an antitumor agent.

Figure 1 .
Figure 1.Some natural products and bioactive molecules.Compound A: rebeccamycin, an antibiotic; Compound B: indolylmaleimide derivative, inhibitor for cancer cells; Compound C: inhibitor of glycogen synthase kinase; Compound D: inhibitor for GSK-3; Compound E: an antifungal derived from the metabolite of the Serpula himantoides strain; Compound F: an antitumor agent.

) 4 -
OMeCH2C6H4 (2d) 3ad 64 a Unless otherwise indicated, all reactions were conducted at room temperature for 8 h using 0.10 mmol of compound 1 and 0.15 mmol of compound 2 in 2 mL DCM under the presence of 20 mol % of EtPPh2 and 30 mol % of 3,5-(OH)2C6H3CO2H.b Isolated yield.c 20 mol % of PBu3 was used instead of EtPPh2.d cyclohexyl instead of aryl.

Figure 2 .
Figure 2. X-ray crystal structure of the 3da.Grey balls: carbon atoms; red balls: oxygen atoms; blue balls: nitrogen atoms.

Figure 2 .
Figure 2. X-ray crystal structure of the 3da.Grey balls: carbon atoms; red balls: oxygen atoms; blue balls: nitrogen atoms.

10 Scheme 3 .
Scheme 3. Proposed mechanism.The letter numbers A-G indicate possible intermediate structures in the plausible reaction mechanism.

3. 1 .Scheme 3 .
Scheme 3. Proposed mechanism.The letter numbers A-G indicate possible intermediate structures in the plausible reaction mechanism.

Table 1 .
Reaction yields at different reaction conditions a .

Table 1 .
Reaction yields at different reaction conditions a .