Access to Spirooxindole-Fused Cyclopentanes via a Stereoselective Organocascade Reaction Using Bifunctional Catalysis

The present study reports an asymmetric organocascade reaction of oxindole-derived alkenes with 3-bromo-1-nitropropane efficiently catalyzed by the bifunctional catalyst. Spirooxindole-fused cyclopentanes were produced in moderate-to-good isolated yields (15–69%) with excellent stereochemical outcomes. The synthetic utility of the protocol was exemplified on a set of additional transformations of the corresponding spirooxindole compounds.


■ INTRODUCTION
Nowadays, cascade reactions (or domino reactions) 1 represent a formidable challenge for modern synthetic chemistry. 2 Those reactions are generally described as multicomponent one-pot processes involving two or more transformations. That strategy offers many advantages over classical "stop-and-go" sequences, for example, in avoiding protecting groups or isolation of reaction intermediates. Besides operational efficiency (step and pot economy), 3 organocascade reactions showed significant advantages for constructing complex molecular frameworks with high selectivity levels (stereo-, chemo-). Not surprisingly, organocascade reactions were successfully used for the stereoselective preparation of valuable spirocyclic compounds, 4 for example, the privileged scaffold�spirocyclic oxindole derivatives (spirooxindoles). 5 The spirooxindole structural motif appears as part of various natural or synthetic compounds with remarkable biological activity, including medicinally relevant compounds (Figure 1). 6 Organocascade reactions initiated by the Michael reaction are highly efficient for the construction of spirooxindole-fused derivatives, 7 using either oxindoles with nucleophilic C3 (Michael donors) 8−10 or electrophilic methyleneindolinones (Michael acceptors). 11,12 Interestingly, a combination of both types of starting materials was applied by Wang for the preparation of highly rigid bispirooxindoles via a Michael/ spirocyclization reaction promoted by a bifunctional organocatalyst (Scheme 1A). 13 Recently, our group described the Michael/alkylation organocascade reaction of 3-(2bromoethyl)oxindoles with α,β-unsaturated aldehydes efficiently catalyzed by a chiral secondary amine, producing valuable spirooxindole-fused cyclopentanes (Scheme 1B). 14 Considering the above, and in light of our ongoing interest in the enantioselective synthesis of spirocyclic compounds, 15 Special Issue: Modern Enantioselective Catalysis in Organic Chemistry

Scheme 1. Examples of Organocascade Approaches toward Spirooxindole-Fused Cyclopentanes
Article pubs.acs.org/joc we envisioned the construction of novel spirooxindole-fused cyclopentane derivatives having up to three stereocenters via a stereoselective organocascade Michael/spirocyclization reaction promoted by the bifunctional catalyst from 3-bromo-1nitropropane and methyleneindolinones (Scheme 1C).

■ RESULTS AND DISCUSSION
To verify our design strategy, we began our study by mixing easily accessible methyleneindolinone 1a with 3-bromo-1nitropropane (2a), bifunctional organocatalyst, and base (Table 1). To our delight, a reaction conducted with commercially available Takemoto catalyst (C1) and K 2 CO 3 produced spirooxindole derivative 3a as the main diastereomer. Moreover, compound 3a was readily separable on silica and isolated in good yield (58%) with high enantioselectivity (99% ee, entry 1). Besides, we observed the formation of 5a in traces as a product of base-induced HNO 2 elimination. Conversely, the diastereocontrol of the reactions catalyzed by Rawal's and Soos's catalysts was significantly diminished (entries 2 and 3). Apart from C1−C3, we tested other bifunctional organocatalysts (for details, please see the SI file), but no further improvement in reaction efficiency was observed. Interestingly, the reaction rate was significantly decreased when using Na 2 CO 3 (entry 4) and NaHCO 3 (entry 5). Using organic bases, such as DIPEA (entry 6), significantly reduced the diastereocontrol. Then, the effect of solvent on reaction efficiency and the stereochemical outcome was evaluated. Using polar aprotic solvents (ethyl acetate or MTBE) resulted in the highest reaction rates. On the other hand, diastereoselectivities of those reactions were significantly lowered (entries 7 and 8). The model reaction conducted in chloroform (entry 8) produced spirooxindole 3a in high yield, with excellent stereochemical outcome. Additionally, we conducted the model reaction with a reduced amount of 3bromo-1-nitropropane (2a) and organocatalyst C1 (1 mol %), producing 3a with the same efficiency and stereocontrol (entry 11). For complete optimization studies, please see the SI.
After optimizing the reaction conditions, we began exploring the scope of the organocascade reaction by varying Nprotecting groups of methyleneindolinones 1 (Scheme 2A).
We assessed the effect on reactivity and stereoselectivity of organocascade reactions using various N-protected methyleneindolinones. We identified oxycarbonyl-protecting groups as most effective in terms of stereocontrol. Corresponding spirocyclic compounds 3a,b were isolated in good yields (43− 60%) with high stereoselectivity. Reactions were conducted with 1a (0.1 mmol), 2a (0.2 mmol), corresponding base (0.2 mmol), and catalyst (20 mol %) in DCM (1.0 mL) at room temperature. After the full disappearance of methyleneindolinone 1a (monitored by TLC), the reaction mixture was concentrated using rotavap. Crude product was purified using column chromatography. b Determined by 1 H NMR of the crude reaction mixture (3a/4a). c Isolated yield of 3a after column chromatography. d Determined by chiral HPLC analysis. e EtOAc was used. f MTBE was used. g CHCl 3 was used. h Reaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), and C1 (20 mol %) in CHCl 3 (1.0 mL) at room temperature. i Reaction was conducted with 1a (0.10 mmol), 3a (0.15 mmol), and C1 (1 mol %) in CHCl 3 (1.0 mL) at room temperature.
On the other hand, organocascade reactions of other Nprotected methyleneindolinones did not give products with acceptable yields and stereochemical outcomes. For example, the organocascade reaction of unprotected methyleneindolinone 1f produced a mixture of products (3f/4f) with poor stereocontrol. Luckily, substrate 3f can be prepared in high yield by TFA-mediated deprotection of the N-Boc protecting group of 3a (for more details, please see late-stage transformations). Subsequently, the scope of the developed organocascade reaction was investigated by varying substituted methyleneindolinones 1 (Scheme 2B). In general, spirooxindoles 3 were obtained in moderate-to-good yields with excellent stereoselectivity, when oxindole derivatives 1 bearing electron-donating (3g, 3h) and weakly electron-withdrawing groups (3k−n) on the oxindole aromatic ring were used. The reaction of methyleneindolinones bearing a strong electronwithdrawing group, such as the nitro group, led to a complex mixture or to the decomposition of starting material. Additionally, we studied the process using various substituted alkenes of methyleneindolinone derivatives 1. Good efficiency of the developed method was shown in reactions of alkenes bearing various electron-withdrawing groups, especially in reactions of ester-derived alkenes producing spirocycles 3o−r in moderate-to-good yields (36−59%) and excellent stereochemical outcomes (Scheme 2C). Remarkably, other electronwithdrawing groups did not show similar efficiency. For example, the reaction between ketone-derived alkene 1t and 2a produced only elimination product 5t in moderate yield and low enantioselectivity.
The relative configuration of spirooxindole-fused cyclopentanes 3 was adopted on the basis of 1D NOE NMR spectroscopy of mixtures 3l/4l and 3n/4n (for details, please see the SI). In addition, the absolute configuration of 3a was ascertained using X-ray diffraction analysis, and the configuration of 3a was assigned as 2R, 9R, and 10R ( Figure 2, for details, see the SI). Absolute configurations of other spirooxindole derivatives 3 were assigned by the analogy of chemical shifts and J values of the cyclopentane ring.
On the basis of the absolute configuration of products and the previous report, 16 the transition state was proposed to rationalize the stereochemical outcome of the cascade process ( Figure 3). The tertiary amine moiety of catalyst C1 deprotonates an acidic proton of nitroalkane 2a, generating the complex of nitronate noncovalently bonded to the tertiary amine. Simultaneously, the thiourea part of the catalyst activates methyleneindolinone 1a, prompting Si-face addition of nitronate to the electron-deficient alkene. As a result, the corresponding Michael adduct with 9R and 10R configuration is formed. Subsequently, the intramolecular α-alkylation proceeds with good diastereocontrol, forming spirocycle 3 with 2R configuration at the spiro atom. The observed diastereocontrol can be explained by kinetically favored spirocyclization in the presence of bifunctional organocatalyst C1, 11c which can participate in the spirocyclization step by Hbonding to a bromide anion. Noteworthy, the sterical hindrance of the tert-butyl moiety of the N-Boc group may increase the rigidity of the initially formed ternary complex, which seems crucial for high stereocontrol. That hypothesis is supported by lowered diastereocontrol, when methyleneindolinone 3b with a more planar N-CBz protecting group is used.
To expand the developed organocatalytic process toward the construction of spiro compounds containing 3-, 4-, and 6membered rings (Scheme 3), 1-bromonitroalkanes 2 with various lengths of alkyl moiety were subjected to the reaction with methyleneindolinone 1a. With respect to previously reported methods, 17 we isolated the corresponding spirooxindole-fused cyclopropane 6 in good yield and stereochemical outcomes. Despite known examples of spirooxindole-fused cyclobutanes, 11b we did not observe any conversion of starting methyleneindolinone 1a in reaction with 1-bromo-2-nitroethane (2c). Interestingly, reaction of longer 1-bromo-2nitrobutane produced an unseparable complex mixture of products with major uncyclized products of the Michael reaction.
To demonstrate the synthetic utility of the developed organocascade reaction, we performed a reaction between 1a and 2a in gram scale, giving the product 3a in 61% yield with retained stereochemical outcomes (99% ee and dr > 20/1, Scheme 4A). To reduce reaction time, the reaction was performed with a slightly higher amount of C1 (3 mol %). This observation can be explained by the limited stability of C1 in the presence of an excess of 3-bromo-1-nitropropane (2a) and base (for more information, please see the SI). As an example of late-stage transformations, spirooxindole 3a was selectively converted to various derivatives (Scheme 4B). The N-Bocprotecting group was removed by treatment of 3a with an excess of TFA. The reaction provided the corresponding spirooxindole 3f in excellent yield with retained enantioselectivity. Noteworthy, the sequence of the developed organocascade followed by N-deprotection is more appropriate compared to the direct organocascade reaction starting from 1f. Next, DBU-mediated elimination of HNO 2 produced alkene 5a in excellent yield with retained optical purity. Noteworthy, the double bond of alkene 5a can be selectively reduced under catalytic hydrogenation conditions, producing cyclopentane derivative 9 with high diastereocontrol. The relative configuration of 9 was determined by 1D NOE NMR experiments (for more information, please see the SI). Furthermore, ethyl ester 5a can be chemoselectively reduced to the corresponding allylic alcohol 9 by treatment with DIBALH. Spirocyclic allylic alcohol 10 may be used as a valuable building block for synthesizing valuable complex molecules. 18

■ CONCLUSION
In summary, we have developed an enantioselective organocascade Michael/spirocyclization reaction of readily available methyleneindolinone with 1-bromo-3-nitropropane. The reaction is efficiently catalyzed by a chiral bifunctional catalyst, affording chiral spirooxindole-fused cyclopentanes in moderate-to-good yields and excellent stereochemical outcomes. The developed synthetic protocol is suitable for late-stage functionalizations, as shown by a set of additional transformations.

■ EXPERIMENTAL SECTION
Chemicals and solvents were purchased from commercial suppliers and purified using standard techniques. For thin-layer chromatography (TLC), silica gel plates from Merck 60 F 254 were used, and compounds were visualized by irradiation with UV light and/or by treatment with a solution of phosphomolybdic acid (AMC) or vanillin followed by heating. Column chromatography was performed using silica gel Fluka (40−63 μm) or SiliCycle-SiliaFlash P60 (particle size: 40−63 μm, pore diameter: 60 Å). 1 H, 13 C, and 19 F NMR spectra were recorded with Bruker AVANCE III 400. Chemical shifts for protons are given in δ relative to tetramethylsilane (TMS), and they are referenced to residual protium in the NMR solvent (chloroform-d: δ H = 7.26 ppm). Splitting patterns are stated as singlet (s), doublet (d), triplet (t), quartet (q), doublet of doublet (dd), doublet doublet of doublet (ddd), doublet of triplet (dt), doublet triplet of doublet (dtd), doublet of quartet (dq), triplet of doublet (td), quartet of doublet (qd), m (multiplet), and broad singlet (br s). Splitting patterns that could not be easily interpreted were marked as multiplets. Chemical shifts for carbon are referenced to the carbon of NMR solvent (chloroform-d: δ C = 77.16 ppm). The coupling constants J are given in hertz. IR DRIFT or ATR spectra were recorded with Nicolet AVATAR 370 FT-IR in cm −1 . Chiral HPLC was carried out using a LC20AD Shimadzu liquid chromatograph with SPD-M20A diode array detector with columns Daicel Chiralpak IA, Daicel Chiralpak IB, Daicel Chiralpak AD, and Daicel Chiralpak ODH. Samples for measurement of chiral HPLC were prepared by dissolving the corresponding sample in an n-heptane/i-PrOH (8/2, v/ v) mixture. Optical rotations were measured on an AU-Tomatica polarimeter, and Autopol III and specific optical rotation are given in concentrations c [g/100 mL]. Samples for the measurement of specific optical rotation were prepared by dissolving the corresponding sample in chloroform in concentrations which are labeled for each compound. Melting points were measured using a Buchi melting point B-545 apparatus. All melting points were measured in an open glass capillary, and all values are uncorrected. High-resolution mass spectra were recorded with an LCQ Fleet spectrometer. The measurement of low-resolution mass spectra was performed on a GCMS-QP2010 Shimadzu spectrometer. Samples for mass spectrometry were prepared by dissolving the corresponding sample in methanol.
Preparation of Catalyst. Catalyst C1 was purchased from commercial suppliers. Ent-C1, C2, and C3 are known and prepared according to previously reported procedures. 19 Preparation of Methyleneindolinones. Methyleneindolinones 1 are typically known (1i is a new compound), and they were prepared according to previously reported procedures. 20 tert Ethyl 2-(triphenyl-λ 5phosphanylidene)acetate (142 mg, 0.41 mmol, 1.1 equiv) was added in one portion to a stirred solution of 5-trifluoromethylisatin 21 (80 mg, 0.37 mmol, 1.0 equiv) in THF (1 mL). The resulting mixture was stirred at room temperature for 3 h. After the consumption of starting isatin (monitored by TLC), solvent was removed under reduced pressure. Crude product was purified by column chromatography (eluting with hexane/EtOAc = 3/1−1/1). The resulting heterocyclic alkene (quantitative yield) was used in the next step without other purification. Heterocyclic alkene (116 mg, 0.41 mmol, 1.0 equiv) and di-tert-butyldicarbonate (98 mg, 0.45 mmol, 1.1 equiv) were added in one portion to a stirred solution of DMAP (3 mg, 0.02 mmol, 0.05 equiv) in THF (2 mL) at room temperature. The resulting mixture was stirred at room temperature for 14 h. After the consumption of starting alkene (monitored by TLC), the reaction was quenched by adding water (5 mL) and diluted with EtOAc (5 mL). The organic phase was separated, and the water phase was extracted with EtOAc (3 × 10 mL). Collected organic phases were washed with brine (1 × 10 mL) and dried over MgSO 4 . After filtration of drying agent, solvents were removed under reduced pressure. The crude product was purified by column chromatography with toluene as an eluent.
Yellow Amorphous Solid. Yield = 49% (70 mg, over two steps). Preparation of 1-Bromonitrolalkanes. Alkane 2b was purchased from commercial suppliers. 2d is known and was prepared according to a previously reported procedure. 22 General Procedure for the Appel Reaction (GP1). NBS (1.3 equiv) and PPh 3 (1.3 equiv) were added portionwise to a stirred solution of nitroalcohol (1.00 g, 9.51 mmol, 1.0 equiv) in DCM (0.3 M solution of alcohol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. After the full consumption of starting 3-nitropropan-1-ol (monitored by TLC), solvent was removed under reduced pressure. The crude product was purified by column chromatography (eluting with hexane/EtOAc = 7/1).