DABCO-Catalyzed Mono-/Diallylation of N-Unsubstituted Isatin N,N′-Cyclic Azomethine Imine 1,3-Dipoles with Morita-Baylis-Hillman Carbonates

Allylation of N-unsubstituted isatin N,N′-cyclic azomethine imines with Morita-Baylis-Hillman carbonates in the presence of 1–10 mol% DABCO in DCM at room temperature, rapidly gave N-allylated and N, β-diallylated isatin N,N′-cyclic azomethine imine 1,3-dipoles in moderate to high yields. The reaction features mild reaction conditions, easily practical operation, and short reaction times in most cases. Furthermore, the alkylated products were transformed into novel bicyclic spiropyrrolidine oxoindole derivatives through the [3+2] or [3+3]-cycloaddition with maleimides or Knoevenagel adducts.


Results and Discussion
Before starting this work, we found that N-unprotected isatin N,N′-cyclic azomethine imine 1a reacted with MBH carbonate 2a in the presence of 5 mol% DMAP in dichloromethane (DCM) at room temperature in 45 min via N-and Cβ-allylation; this gave the corresponding 3a and 4a, respectively, in 24% and 17% yields ( Table 1, entry 1). Jin's group [20] reported that 1a reacted with 2a, only to obtain a trace amount of β-allylated product in the presence of 20 mol% DMAP in DCM at refluxing (3a or 4a was not observed). The above result encouraged us to explore and develop N-and β-allylation as a supplement to their approach.
Subsequently, we found that DABCO, instead of DMAP, quickly gave N-allylated product 3a with a satisfactory yield in the same condition (entry 2). To improve the yield and regioselectivity of the reaction, the reaction conditions were optimized. First, the solvents were investigated. In the chloroalkanes, both chloroform and dichloroethane (DCE), the reactions led to inferior results in contrast with DCM (entries 3 and 4). The aprotic polar solvents, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA), also gave poor yields and regioselectivities. Other solvents, such as ethyl acetate, acetonitrile (ACN), and ethers (for example, diethyl ether, tetrahydrofuran (THF), and dioxane), led to unsatisfying results. Therefore, DCM was selected as the best solvent. Second, various organic and inorganic bases were screened. When common

Results and Discussion
Before starting this work, we found that N-unprotected isatin N,N -cyclic azomethine imine 1a reacted with MBH carbonate 2a in the presence of 5 mol% DMAP in dichloromethane (DCM) at room temperature in 45 min via Nand C β -allylation; this gave the corresponding 3a and 4a, respectively, in 24% and 17% yields ( Table 1, entry 1). Jin's group [20] reported that 1a reacted with 2a, only to obtain a trace amount of β-allylated product in the presence of 20 mol% DMAP in DCM at refluxing (3a or 4a was not observed). The above result encouraged us to explore and develop N-and β-allylation as a supplement to their approach. formed in 77% yield. The optimal reaction condition for monoallylation was established, and the desired product could be obtained in 91% yield when using isatin N,N′-cyclic azomethine imine 1a (1 equiv.), MBH carbonate 2a (2.2 equiv.), and catalyst DABCO (1 mmol%) in DCM at rt for 30 min (entry 28). The optimal reaction condition for diallylation afforded 77% of the product yield when using isatin N,N′-cyclic azomethine imine 1a (1 equiv.), MBH carbonate 2a (2.2 equiv.), and catalyst DABCO (10 mmol%) in DCM at rt for 7 h (entry 33). Subsequently, we found that DABCO, instead of DMAP, quickly gave N-allylated product 3a with a satisfactory yield in the same condition (entry 2). To improve the yield and regioselectivity of the reaction, the reaction conditions were optimized. First, the solvents were investigated. In the chloroalkanes, both chloroform and dichloroethane (DCE), the reactions led to inferior results in contrast with DCM (entries 3 and 4). The aprotic polar solvents, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF) and N,N-dimethylacetamide (DMA), also gave poor yields and regioselectivities. Other solvents, such as ethyl acetate, acetonitrile (ACN), and ethers (for example, diethyl ether, tetrahydrofuran (THF), and dioxane), led to unsatisfying results. Therefore, DCM was selected as the best solvent. Second, various organic and inorganic bases were screened. When common tertiary amines were used, including triethylamine (TEA), diisopropylethy-lamine (DIPEA), and 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU), the yield of the N-allylated product was lower than using DMAP. In inorganic bases, NaOH, KOH, and NaH, only 7-13% yields were obtained, while in Na 2 CO 3 , K 2 CO 3 , and Cs 2 CO 3 , the reaction did not work at all. Triphenylphosphine made the reaction yield diallylated product 4a with poor yield (26%). Combined with the above results, DABCO was selected as the base. Next, the loading amounts of DABCO were screened. When a 1 mol% loading amount was used, the yield was better than the 5 mol% loading amounts (entry 24), in which 10 mol% loading amounts conversely gave an inferior yield (entry 25). In addition, the concentration of the reaction and equivalent of MBH carbonate 2a were also screened to find that the reaction gave the best yield (91%) in the presence of 2.2 equivalent 2a. When the reaction time was extended to 7 h and 10 mol% DABCO was used, only the diallylated product 4a was formed in 77% yield. The optimal reaction condition for monoallylation was established, and the desired product could be obtained in 91% yield when using isatin N,N -cyclic azomethine imine 1a (1 equiv.), MBH carbonate 2a (2.2 equiv.), and catalyst DABCO (1 mmol%) in DCM at rt for 30 min (entry 28). The optimal reaction condition for diallylation afforded 77% of the product yield when using isatin N,N -cyclic azomethine imine 1a (1 equiv.), MBH carbonate 2a (2.2 equiv.), and catalyst DABCO (10 mmol%) in DCM at rt for 7 h (entry 33).
After establishing the optimal reaction conditions, a wide range of different substituted aryl isatin N,N -cyclic azomethine imines have been explored for this nucleophilic substitution reaction. As summarized in Table 2, various substituent groups employed on the isatin moiety of 1 could be tolerated which afforded the desired products with moderate to excellent yields (49-91%) ( Table 2, entries 1-8), except for 5-nitro isatin N,N -cyclic azomethine imine 1d (entry 9). The reaction of 1a with 2a under a 1 mmol scale with the same yield (91%) compared with under 0.5 mmol at the most optimal conditions. It is worth noting that the corresponding products 3a could be afforded in 84% yield (1.28 g) when istain N,N -cyclic azomethine imine 1a was scaled up to 4.65 mmol. The substituent patterns on the benzene ring of azomethine imines had a vital impact on the yields. Overall, the yields dropped off, whether it is electron-withdrawing or electron-donating groups, particularly the 7-CF 3 group (entry 9). To our surprise, 5-nitro isatin N,N -cyclic azomethine imine reacted with 2a, to give C3and N-diallylated product 3 i, but not 3i within a short time (1 min) (Scheme 2). The structure of 3 i was confirmed unambiguously by single-crystal X-ray diffraction [69]. Various MBH carbonates (R 1 = Me, n-Pr, n-Bu, and t-Bu) also reacted smoothly, in which the yields were 40-80%. Subsequently, the generality of the allylation was further demonstrated using aryl MBH carbonates. As outlined in Table 3, it is regrettable that all the yields of ex were not better than that of the model reaction, regardless of electron-donating and electron-withdrawing groups in phenyl. All the results showed that these re gave a complex when the aryl groups of MBH carbonates were 4-MeOC6H4, 4-F BrC6H4, and 2-NO2C6H4 (entries 7, 10, 14, and 17). These reactions led to the desire ucts in low yields or with an inseparable by-product (see supporting information aryl groups were 2-MeC6H4, 2-MeOC6H4, 2-FC6H4, and 2-ClC6H4 (entries 2, 5, 8, To our surprise, 3-thiophenyl MBH carbonate also afforded the diallylated pro (Scheme 3), similarly to that of isatin N,N′-cyclic azomethine imine bearing a 5-NO in benzene ring (Scheme 3).  patterns on the benzene ring of azomethine imines had a vital impact on the yields. Overall, the yields dropped off, whether it is electron-withdrawing or electron-donating groups, particularly the 7-CF3 group (entry 9). To our surprise, 5-nitro isatin N,N′-cyclic azomethine imine reacted with 2a, to give C3-and N-diallylated product 3′i, but not 3i within a short time (1 min) (Scheme 2). The structure of 3′i was confirmed unambiguously by single-crystal X-ray diffraction [69]. Various MBH carbonates (R 1 = Me, n-Pr, n-Bu, and t-Bu) also reacted smoothly, in which the yields were 40-80%. Subsequently, the generality of the allylation was further demonstrated using various aryl MBH carbonates. As outlined in Table 3, it is regrettable that all the yields of examples were not better than that of the model reaction, regardless of electron-donating groups and electron-withdrawing groups in phenyl. All the results showed that these reactions gave a complex when the aryl groups of MBH carbonates were 4-MeOC 6 H 4 , 4-FC 6 H 4 , 2-BrC 6 H 4 , and 2-NO 2 C 6 H 4 (entries 7, 10, 14, and 17). These reactions led to the desired products in low yields or with an inseparable by-product (see Supporting Information) when aryl groups were 2-MeC 6 H 4 , 2-MeOC 6 H 4 , 2-FC 6 H 4 , and 2-ClC 6 H 4 (entries 2, 5, 8, and 11). To our surprise, 3-thiophenyl MBH carbonate also afforded the diallylated product 6 t (Scheme 3), similarly to that of isatin N,N -cyclic azomethine imine bearing a 5-NO 2 group in benzene ring (Scheme 3).  gave a complex when the aryl groups of MBH carbonates were 4-MeOC6H4, 4-FC6H4, 2-BrC6H4, and 2-NO2C6H4 (entries 7, 10, 14, and 17). These reactions led to the desired products in low yields or with an inseparable by-product (see supporting information) when aryl groups were 2-MeC6H4, 2-MeOC6H4, 2-FC6H4, and 2-ClC6H4 (entries 2, 5, 8, and 11). To our surprise, 3-thiophenyl MBH carbonate also afforded the diallylated product 6′t (Scheme 3), similarly to that of isatin N,N′-cyclic azomethine imine bearing a 5-NO2 group in benzene ring (Scheme 3). Table 3. Synthesis of N-allylated products 6 from isatin N,N′-cyclic azomethine imine 1 and MBH carbonates 5 a .

Entry
Compound Ar Various N-substituted isatin N,N -cyclic azomethine imines 8 (R = alkyl, allyl, Bn, and propargyl) that were not used for testing by Jin's group except for 8c, could also react with MBH-carbonate 2a with moderate to excellent yields (Table 4, entries 2-11) in our optimal condition. It is surprising that N-methyl isatin N,N -cyclic azomethine imine 7a hardly reacted with 2a in the standard condition (entry 1). Among them, N-Bn isatin N,N -cyclic azomethine imine could offer the desired product with a good yield (75%), though not as high as the yield (92%) reported by Jin's group (entry 3). The reaction of N-allyl isatin N,N -cyclic azomethine imine 7d gave the best result (82% yield), using 2a as a partner (entry 4). However, N-propargyl isatin N,N -cyclic azomethine imine only gave a 20% yield, because of some side reactions (entry 5).
To expand the application of the reaction, isatin N,N -cyclic azomethine imines 1 reacted with MBH carbonates 2 in the presence of 10 mol% DABCO and prolonged the reaction time, which afforded diallylated products 4 in 41-77% yield (Table 5). On the whole, the yields of all reactions were not high, except for 4e and 4i. The possible reason is that the prolonged reaction time leads to increasing side reactions. Table 4. Synthesis of N,β-allylated products 8 from N-substituted isatin N,N -cyclic azomethine imine 6 and MBH carbonates 2 a . condition. It is surprising that N-methyl isatin N,N′-cyclic azomethine imine 7a hardly reacted with 2a in the standard condition (entry 1). Among them, N-Bn isatin N,N′-cyclic azomethine imine could offer the desired product with a good yield (75%), though not as high as the yield (92%) reported by Jin's group (entry 3). The reaction of N-allyl isatin N,N′-cyclic azomethine imine 7d gave the best result (82% yield), using 2a as a partner (entry 4). However, N-propargyl isatin N,N′-cyclic azomethine imine only gave a 20% yield, because of some side reactions (entry 5).  To expand the application of the reaction, isatin N,N′-cyclic azomethine imines 1 reacted with MBH carbonates 2 in the presence of 10 mol% DABCO and prolonged the reaction time, which afforded diallylated products 4 in 41-77% yield (Table 5). On the whole, the yields of all reactions were not high, except for 4e and 4i. The possible reason is that the prolonged reaction time leads to increasing side reactions. The reaction of α-methyl isatin N,N′-cyclic azomethine imine 9 with MBH carbonate 2a was tested, which successfully obtained a corresponding product 10 in excellent yield (84%) within 2 min (Scheme 4). Meanwhile, β-phenyl isatin N,N′-cyclic azomethine imines 11 could also obtain the desired product 12 with a satisfied yield (77%) within 10 min. The reaction of α-methyl isatin N,N -cyclic azomethine imine 9 with MBH carbonate 2a was tested, which successfully obtained a corresponding product 10 in excellent yield (84%) within 2 min (Scheme 4). Meanwhile, β-phenyl isatin N,N -cyclic azomethine imines 11 could also obtain the desired product 12 with a satisfied yield (77%) within 10 min. a Reaction conditions: 1 (1 mmol), 2 (2.2 mmol), DABCO (10 mol%), DCM (4 mL), rt, 5-12 h. b Isolated yield via column chromatography.

Scheme 5. Transformation of 3a.
Based on the literature reports [20], our results, and X-ray analysis, a plausible mechanism is proposed for the formation of 3a, 3′I, and 4a (Scheme 6). Based on the literature reports [20], our results, and X-ray analysis, a plausible mechanism is proposed for the formation of 3a, 3 I, and 4a (Scheme 6). First, isatin N,N -cyclic azomethine imine 1 reacted with MBH carbonate 2 in the presence of DABCO, to obtain N-alkylated products 3 or 6. The resonance form In-A of 3 or 6 quickly tautomerized to the delocalized intermediate In-B under DABCO. Second, pyrazolenone intermediate In-C could be generated from In-B, then promote the isatin carbanion to react with MBH carbonate 2 through β-allylation, with the corresponding product 4 obtained. Moreover, when R was a nitro group, the delocalized intermediate In-B preferred to proceed with C3-allylation, followed by a Boc-protected reaction of the hydroxy group, to achieve Nand C3-diallylated product 3 i.

General Methods
All reactions were carried out without strict water-free and oxygen-free conditions. All solvents and reagents were obtained from commercial suppliers and were directly used for reactions without further purification unless otherwise stated. When the reactions were performed at the condition of NaH, DCM was pre-dried with CaH2. Flash chromatography was performed using silica gel (200-300 mesh). Reactions were monitored by TLC or/and colour changes of the reaction solution. Visualization was achieved under a UV lamp (254 nm and 365 nm), I2, and by developing the plates with phosphomolybdic acid. 1 H and 13 C NMR were recorded on 400 and 600 MHz NMR spectrometers with tetramethylsilane (TMS) as the internal standard. The chemical shift values were corrected to 7.26 ppm ( 1 H NMR) and 77.16 ppm ( 13 C NMR) for CDCl3. IR spectra were acquired on an FT-IR spectrometer and are reported in wavenumbers (cm −1 ). High-resolution mass spectra were obtained using electrospray ionization (ESI). 1 H NMR splitting patterns are designated as singlet (s), double (d), broad singlet (br s), triplet (t), quartet (q), doublet of doublets (dd), multiples (m), etc. Coupling constants (J) are reported in Hertz (Hz).

Preparation of Intermediates
Pyrazolidine-3-ones were obtained by the reaction of hydrazone monohydrate with Scheme 6. The plausible reaction mechanism.

General Methods
All reactions were carried out without strict water-free and oxygen-free conditions. All solvents and reagents were obtained from commercial suppliers and were directly used for reactions without further purification unless otherwise stated. When the reactions were performed at the condition of NaH, DCM was pre-dried with CaH 2 . Flash chromatography was performed using silica gel (200-300 mesh). Reactions were monitored by TLC or/and colour changes of the reaction solution. Visualization was achieved under a UV lamp (254 nm and 365 nm), I 2 , and by developing the plates with phosphomolybdic acid. 1 H and 13 C NMR were recorded on 400 and 600 MHz NMR spectrometers with tetramethylsilane (TMS) as the internal standard. The chemical shift values were corrected to 7.26 ppm ( 1 H NMR) and 77.16 ppm ( 13 C NMR) for CDCl 3 . IR spectra were acquired on an FT-IR spectrometer and are reported in wavenumbers (cm −1 ). High-resolution mass spectra were obtained using electrospray ionization (ESI). 1 H NMR splitting patterns are designated as singlet (s), double (d), broad singlet (br s), triplet (t), quartet (q), doublet of doublets (dd), multiples (m), etc. Coupling constants (J) are reported in Hertz (Hz).

Preparation of Intermediates
Pyrazolidine-3-ones were obtained by the reaction of hydrazone monohydrate with methyl acrylate in ethanol under refluxing conditions [21]. All isatin N,N -cyclic azomethine imines 1 were prepared by the condensation of isatins and the above pyrazolidone in menthol under 45 • C or a refluxing condition [21]. All MBH carbonates 2 were prepared by two-step reactions, including the Morta-Maylis-Hillman reaction (1 equiv. DABCO/1 equiv. aldehyde/1.5 equiv. acrylate/1:1 dioxane:H 2 O or THF/2-3 days) [70] and the formation of an O-Boc derivative (0.1 equiv. DMAP/1 equiv. MBH alcohol/1.5 equiv.Boc 2 O/DCM/rt/overnight), with 22-64% total yields [71]. The suspended solution was vigorously stirred at rt-reflux, and then the base was added. When the suspension reaction liquid became completely clear, the reaction had finished. The solution was added by 5 mL H 2 O and 15 mL brine before the resulting mixture was extracted with DCM (5 × 10 mL). The combined organic layers were dry with Na 2 SO 4 , filtered, and concentrated. The residue was purified by flash silica gel chromatography eluated with EtOAc:PE (1:5 to 1:1) to afford the corresponding products 3a and/or 4a.

Conclusions
In summary, we have developed a general method of DABCO-catalyzed mono-/diallylation of isatin N,N -cyclic azomethine imine 1,3-dipoles with MBH carbonates. Various mono and diallyl isatin N,N -cyclic azomethine imines are afforded in moderate to excellent yields (21-91%). All the synthesized compounds 3, 3 i, 4, 6, 6 t, 8, 10, 12, 13, 14, and 15 were confirmed through 1 H and 13 C NMR, IR, and HMRS technologies (see Supplementary Materials). Furthermore, product 3a can be transformed into functionalized compounds by cycloaddition and Michael to demonstrate the synthetic utilities. Further exploration and application of this reaction in organic synthesis are ongoing in our laboratory.