A facile base-promoted domino Michael/O-alkylation reaction for the construction of succinimide-substituted 3(2 H )-furanones

A novel base-promoted domino Michael/O-alkylation reaction o f maleimides with γ -halogenated- β -ketoesters is described. A variety of new succinimide-substituted 3(2 H )-furanones were obtained in excellent yields (up to 96%) under simple and mild conditions. The structure of the new compound 3a was determined by single-crystal X-ray analysis and a reaction pathway is proposed


Introduction
3(2H)-Furanones are core structural motifs that are widely present in many natural products and pharmaceutically important compounds.][3][4] The significance of these molecules has led to a variety of approaches for the synthesis of substituted 3(2H)furanones, including acid-catalyzed cyclization-dehydration, 5,6 transformations from furans, 7,8 alkynes [9][10][11][12][13][14][15] and allenes. 16However, most of these routes require the use of specific substrates and reaction conditions are often harsh.5][26] This synthetic strategy is efficient and mild.However the activated alkenes were limited only to chain structures such as chain nitroalkenes 21,22 and chain α,β-unsaturated esters. 23Thus it was important to discover whether other diverse activated alkenes, such as cyclic alkenes, would react with γ-halogenated-β-ketoesters to construct diverse substituted 3(2H)-furanones.Maleimides are an important class of activated cyclic alkenes.8][29][30][31] To date, there has been no report of the reaction of γ-halogenated-β-ketoesters with maleimides, which could afford a new class of products combining a biologically significant succinimide with a 3(2H)-furanone.These fused products might show higher or new biological activities.As a part of our continuing interest in the construction of complex and novel drug candidates, 32-36 herein, we report the first domino Michael/O-alkylation reaction of γ-halogenatedβ-ketoesters with maleimides to access a new range of succinimide-substituted 3(2H)-furanones.According to the literature, γ-halogenated-β-ketoesters react with α,β-unsaturated aldehydes to afford cyclopentanone products via Michael/α-alkylation. 37 These reports show variable chemical reactivities of γ-halogenated-β-ketoesters with activated alkenes.Our preliminary studies involved maleimide 1a and ethyl 4-chloroacetoacetate 2a as substrates, these were allowed to react in dichloromethane at room temperature in the presence of 100 mol% Et3N.The reaction worked well and gave succinimide-substituted 3(2H)-furanone 3a via a domino Michael/O-alkylation process -not a Michael/α-alkylation process (Scheme 1).

Results and Discussion
To evaluate the role of the base in this system, the reaction of N-phenylmaleimide 1a with ethyl 4-chloroacetoacetate 2a was used as a model reaction, and a series of bases were investigated in dichloromethane at room temperature, and the results were shown in Table 1.Weak bases such as Na2CO3 and NaHCO3 decreased the reaction rate and afforded poor yields after reaction for 24 h (Table 1, entries 2 and 3).Strong base DABCO also afforded a poor yield because impurities were produced (Table 1, entry 5).Et3N gave the highest yield and was chosen as the most suitable base (92% yield, Table 1, entry 1).Next, the reaction was conducted in various solvents ( Dichloromethane gave the highest yield and was selected as the most suitable reaction media for further optimization (Table 1, entry 1).Increasing or decreasing the amount of Et3N gave a lower yield (Table 2, entries 2-4 vs. 1) so having identified 100 mol% Et3N as the optimal loading for the reaction, we next examined the effect of the reaction temperature (Table 2, entries 5 and 6).A screening of different reaction temperatures showed that the reaction gave the best results at room temperature (Table 2, entry 1).Decreasing reaction temperature slowed down the reaction rate thus decreased the yield (Table 2, entry 5).Increasing the reaction temperature also decreased the yield because impurities were produced (Table 2, entry 6).Finally, the substrate concentration was examined (Table 2, entries 7 and 8).It was found that increasing the substrate concentration slightly decreased the yield (Table 2, entry 7), lowering the substrate concentration decreased the reaction rate and gave lower yield (82% yield, Table 2, entry 8), 0.2 M was the optimal substrate concentration.Consequently, the following reaction conditions are recommended: 100 mol% Et3N with 0.2 M substrate in CH2Cl2 at room temperature (Table 2, entry 1).+ a Unless otherwise noted, reactions were conducted with 0.2 mmol 1a, 0.2 mmol 2a, x mol% base, in 1.0 mL CH2Cl2.b Isolated yields.c 0.5 mL CH2Cl2 was used.d 2.0 mL CH2Cl2 was used.
Under the optimal reaction conditions, the generality of this protocol was studied (Table 3).Firstly, a wide range of maleimides 1a-n was studied (Table 3, entries 1-14).The maleimides included those bearing electronwithdrawing and electron-donating substituents on the aryl ring, as well as N-alkyl maleimides.All gave good yields (85-96%).The electronic properties and position of the substituents on the N-aryl maleimides phenyl ring affected the yield slightly (Table 3, entries 1-9).The N-aryl maleimide with a strong electron-withdrawing nitro group, 1g, gave a slightly lower yield (Table 3, entry 7).Maleimide 1m also gave a slightly lower yield due to the larger steric hindrance (Table 3, entry 13).In addition, methyl 4-chloroacetoacetate 2b and ethyl 4bromoacetoacetate 2c were also tested, both provided excellent yields (Table 3, entries 15 and 16).The structure of 3a was determined by an X-ray analysis of a single crystal (Figure 2). 38

Entry
x

Conclusions
We have demonstrated a facile base-promoted domino Michael/O-alkylation reaction of maleimides and γhalogenated-β-ketoesters. The reaction conditions are simple and mild.With this protocol, a wide range of new succinimide-substituted 3(2H)-furanones were smoothly obtained in good yields (up to 96%).Further, expansion of these new succinimide-substituted 3(2H)-furanones to access products with known biological activities or new biologically significant molecules and testing their pharmacological activities are ongoing in our laboratory.

Experimental Section
General.N-Substituted maleimides 1 were prepared according to the literature method or similarly. 39γ-Halogenated-β-ketoesters 2 were purchased from commercial suppliers and used without further purification.Commercial grade solvents were dried and purified by standard procedures as specified in Purification of Laboratory Chemicals, 4th Ed (Armarego, W. L. F.; Perrin, D. D. Butterworth Heinemann: 1997).All melting points were measured on a SGWX-4 micro melting point apparatus. 1H NMR spectra were recorded at 600 MHz.Chemical shifts were reported in ppm from tetramethylsilane with the solvent resonance as the internal standard (CDCl3, δ = 7.26).Spectra are reported as follows: chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling constants (Hz), integration, and assignment. 13C NMR spectra were collected at 150 MHz with complete proton decoupling.Chemical shifts are reported in ppm from the tetramethylsilane with the solvent resonance as internal standard (CDCl3, δ = 77.0).Mass spectra were recorded on Bruker micrOTOF-QⅡ mass spectrometer.Reactions were monitored by TLC and visualized with ultraviolet light.

Table 1 .
Optimization of reaction conditions a a Unless otherwise noted, reactions were conducted with 0.2 mmol 1a, 0.2 mmol 2a, 100 mol % base, in 1.0 mL solvent at room temperature.b Isolated yields.

Table 2 .
Optimization of reaction conditions a

Table 3 .
Scope of substrates a a Unless otherwise noted, reactions were conducted with 0.2 mmol 1, 0.2 mmol 2, 100 mol % Et3N, in 1.0 mL CH2Cl2 at room temperature.b Isolated yield.