Chinese Chemical Letters  2017, Vol. 28 Issue (3): 512-516   PDF    
Construction of polycyclic spirooxindoles through[3+2] annulations of Morita-Baylis-Hillman carbonates and 3-nitro-7-azaindoles
Kai-Kai Wanga,c, Wei Dub, Jin Zhua, Ying-Chun Chenb     
a Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China;
b Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China;
c University of Chinese Academy of Sciences, Beijing 100049, China
Abstract: A mild and efficient dearomatic[3+2] annulation reaction of 3-nitro-7-azaindoles and Morita Baylis Hillman carbonates from isatins was developed catalyzed by DMAP, affording the corresponding polycyclic spirooxindoles containing fused azaindoline architectures andvicinal quaternarycenters in excellent yields (up to 96%) with high regio-and diastereoselectivity (dr>19:1). Moderate enantioselectivity (79% ee) was obtained by employing a chiral DMAP-type Lewis base catalyst.
Key words: Morita-Baylis-Hillman carbonates     [3+2] annulation     Spirooxindoles     Regioselectivity     Dearomatization    
1. Introduction

The polycyclic indole or indoline skeletons are widely distributed in both terrestrial and marine organisms, and a number of synthetic indole derivatives also show interesting biological and pharmacological properties [1]. As a result, the development of efficient methods for the construction of such frameworks triggers increasing interest in organic and medicinal chemistry [2]. In general, the 2, 3-C¼C bond of indole substances is an enamine-type functional group, and exhibits nucleophilic feature in a variety of Friedel-Crafts reactions and cycloaddition reactions [3]. Nevertheless, it was also established that the indoles bearing electron-withdrawing substitutions at both N1-and C3-positions could perform as a class of electron-deficient alkene reagents, thus a few dearomatic cycloaddition reactions have been reported to access polycyclic indoline architectures [4]. Moreover, in 2014, the Arai group first uncovered the asymmetric [3+2] dipolar cycloaddition reaction with N-Ts-3-nitroindoles and azomethine imines catalyzed by a PyBidine/Cu complex [5]. Subsequently, Zhao et al. developed a highly stereoselective asymmetric Michael/cyclization cascade reaction of 3-isothiocyanatooxindoles and 3-nitroindoles [6]. Therefore, the development of other types of dearomatic reactions of 3-nitroindoles, including the potential asymmetric versions, to construct libraries with more structural diversity, is still in demand. On the other hand, we noticed that 3-nitro-7-azaindoles, a type of potentially more promising electrophilic alkenes than the indole analogues owing to the electron-withdrawing effect of pyridine moiety [7], have been barely explored in this field. Thus, in our continuing efforts to expand the synthetic utility of Morita-Baylis-Hillman (MBH) carbonates [8], here we would like to present the previously unexplored dearomatic [3+2] annulation reaction of 3-nitro-7-azaindoles and MBH carbonates from isatins, delivering a spectrum of complex polycyclic spirooxindoles containing fused azaindoline architectures and vicinal quaternary centers.

2. Results and discussion

The initial investigation was conducted with MBH carbonate 1a and readily available N-Ts-3-nitroindole 2a in acetonitrile in the presence of 10 mol% of 1, 4-diaza-bicyclo[2.2.2]octane (DABCO), but no reaction was observed (Table 1, entry 1). The reaction also did not occur catalyzed by either Ph3P or nBu3P even at a higher temperature (Table 1, entries 2 and 3). To our delight, the reaction proceeded smoothly at room temperature when 4-dimethylaminopyridine (DMAP) was used, and the α-regioselective [3+2] annulation product 3a was produced in 89% yield with exclusive diastereoselectivity (Table 1, entry 4) [9]. The yield was significantly decreased by employing less amounts of catalyst (Table 1, entry 5). Pleasingly, N-Ts-3-nitro-7-azaindole 2b showed higher reactivity as expected, and the corresponding product 3b was obtained in a higher yield (96%) for 1 h (Table 1, entry 6). On the other hand, a number of solvents were further examined, while inferior results were generally observed (Table 1, entries 7-13).

Table 1
Screening conditions of [3+2] annulation reactions with MBH carbonate 1a and electrophiles 2a or 2b.a

With the optimized conditions in hand, we next set out to examine the scope and limitations of this dearomatic [3+2] annulation reaction by the catalysis of DMAP. The results are summarized in Table 2. At first, a series of 3-nitro-7-azaindoles 2 bearing different N-protecting groups were explored in the reactions with MBH carbonate 1a. It was found that all the reactions proceeded smoothly to produce the corresponding a-regioselective products 3c-3g in excellent yields and diastereoselectivities (Table 2, entries 2-6). It should be noted that the reactions did not occur when the N-protecting group was replaced by either H or Me, or the 3-nitro group was substituted by other functional groups, demonstrating that both the electron-withdrawing group on nitrogen and the nitro group on C3 position of 7-azaindoles played a key role in this [3+2] annulation reaction. High yields also were obtained by introducing some substitutions on the 7-azaindole ring (Table 2, entries 7 and 8). On the other hand, we tested the reactions of 3-nitro-7-azaindole 2b and MBH carbonates derived from various isatins, and found that the MBH adducts bearing both electron-withdrawing and -donating substituents could afford the corresponding [3+2] annulation products 3j-3q in excellent yields (91%-96%) and exclusive diastereoselectivities (>19:1) (Table 2, entries 9-16). Moreover, the annulation products 3r and 3s were attained with excellent results when the protective group on nitrogen of MBH carbonates was benzyl or Boc, respectively (Table 2, entries 17 and 18). It is worth mentioning that the MBH carbonate derived from isatin and acrylonitrile also provided the annulation product 3t in 96% yield with remarkable diastereoselectivity (Table 2, entry 19).

Table 2
Substrate scope of DMAP-catalyzed dearomatic [3+2] annulation.a

We further explored the reaction of MBH carbonate 1a and N-Ts-2-nitroindole 4. DMAP exhibited high catalytic activity under the same conditions, while other types of Lewis bases also failed to catalyse the reaction. Nevertheless, as outlined in Scheme 1, the dearomtic [3+2] annulation reaction afforded the different g-regioselective product 5 with excellent diastereoselectivity. The absolute configuration of product 5 was confirmed by X-ray analysis (Fig. 1a). The yield was modest because the substance 6 was also produced after elimination of HNO2 according to our previous report [10]. The switched γ-regioselectivity might be ascribed to the steric effect in both addition and annulation steps, avoiding the formation of highly congested vicinal quaternary centres.

Scheme 1. γ-Regioselective [3+2] annulation reaction of N-Ts-2-nitroindole 4.

Figure 1. X-ray structures of 5 (a) and enantiopure 3b (b).

On the other hand, we paid much attention on the asymmetric version of this new reaction. Although a number of chiral tertiary amines and phosphines failed to catalyse the reaction, we found that our previously reported chiral DMAP-type catalysts could promote the desired annulation [11], albeit in much lower activity in comparison with simple DMAP. After extensive screenings, it showed that moderate ee value and yield could be obtained for chiral product 3b when catalyst C1 was applied in dioxane at room temperature for 24h (Scheme 2). The absolute configuration of chiral product 3b was unequivocally established by X-ray analysis (Fig. 1b). In addition, both yield and enantioselectivity were reduced when 3-nitroindole 2a was used.

Scheme 2. Asymmetric [3+2] annulations catalysed by chiral DMAP-type catalyst C1.

To furtherexpand the potentials of this methodology, adduct 3b could be transformed to other synthetically or biologically useful spirocyclic oxindole compounds. As illustrated in Scheme 3, the nitro group of 3b was efficiently reduced by zinc powder and 1mol/L HCl [12], affording product 7 in 96% yield. In addition, the denitronation process also could be conducted with 3b in the presence of DBU, and product 8 was attained in a quantitative yield [10].

Scheme 3. Transformations of product 3b to other polycyclic spirocyclic oxindoles.

3. Conclusion

We have investigated the dearomatic [3+2] annulation reaction of 3-nitro-7-azaindoles and Morita-Baylis-Hillman carbonates from isatins. The reaction proceeded effectively under the mild catalysis of 4-dimethylaminopyridine, and an array of complex polycyclic spirooxindole substances containing fused azaindoline skeletons and vicinal quaternary centres were constructed in excellent yields and diastereoselectivities. In addition, the attempts to developing an enantioselective version of this reaction were conducted, and moderate enantioselectivity was achieved by employing a chiral DMAP-type substance. Further exploration of these multifunctional and drug-like compounds in organic synthesis and biological studies is under way in our laboratory.

4. Experimental

General procedure for dearomatic [3+2] annulation reaction of 3-nitro-7-azaindoles and Morita-Baylis-Hillman carbonates from isatins: 3-Nitro-7-azaindole 2 (0.1mmol, 1.0equiv.) was dissolved in acetonitrile (1mL). To this solution was added DMAP (0.01mmol, 0.1equiv.) and MBH carbonate 1 (0.12mmol, 1.2equiv.). The solution was stirred at room temperature for 1h. After completion, purification by chromatography (petroleum ether/ethyl acetate=5:1-2:1, silica gel) afforded the desired product 3.

The characterization data of some representative products 3 and derivatives arelisted as follows and the othersaresummarized in the Supporting information.

3b, 52.4mg, 96% yield, white solid; 1H NMR (400MHz, CDCl3): δ 8.41 (d, 1H, J=4.0Hz), 8.00 (d, 2H, J=8.0Hz), 7.76 (d, 1H, J=7.2Hz), 7.38 (t, 1H, J=7.6Hz), 7.26-7.22 (m, 3H), 7.05 (t, 1H, J=7.2Hz), 7.01-6.97 (m, 2H), 6.92 (d, 1H, J=7.6Hz), 6.71 (d, 1H, J=2.0Hz), 3.60 (s, 3H), 3.37 (s, 3H), 2.36 (s, 3H). 13C NMR (150MHz, CDCl3): δ 172.1, 161.3, 153.7, 152.5, 152.3, 145.0, 144.2, 139.7, 138.6, 137.2, 135.2, 130.7, 129.7, 128.1, 126.5, 125.9, 122.9, 122.8, 122.7, 118.4, 115.8, 108.9, 102.0, 70.7, 63.1, 52.4, 27.1, 21.6. ESI-HRMS: calcd. for C27H22N4O7S+Na+ 569.1101, found 569.1107.

3f, 47.5mg, 84% yield, white solid; 1H NMR (400MHz, CDCl3): δ 8.09 (t, 1H, J=7.6Hz), 7.90 (d, 1H, J=7.6Hz), 7.60 (d, 2H, J=7.6Hz), 7.54 (t, 1H, J=7.2Hz), 7.44-7.36 (m, 4H), 7.10-7.05 (m, 2H), 7.00-6.94 (m, 2H), 6.85 (d, 1H, J=1.2Hz), 3.59 (s, 3H), 3.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.3, 168.7, 161.5, 153.4, 151.4, 144.1, 139.6, 138.5, 137.6, 134.7, 133.5, 131.5, 130.7, 130.1, 128.7, 128.4, 127.8, 125.9, 123.1, 122.9, 118.7, 116.4, 108.9, 100.6, 69.7, 63.8, 52.4, 27.1. ESI-HRMS: calcd. for C27H20N4O6+Na+ 519.1275, found 519.1274.

3j, 51.5 mg, 92% yield, white solid; 1H NMR (400 MHz, CDCl3): δ 8.40 (dd, 1H, J=4.8, 1.2 Hz), 8.01 (d, 2H, J=8.4 Hz), 7.77 (dd, 1H, J=9.6, 1.2 Hz), 7.27-7.25 (m, 2H), 7.21 (d, 1H, J=2.0 Hz), 7.16 (d, 1H, J=7.2 Hz), 6.97 (dd, 1H, J=7.6, 4.8 Hz), 6.80 (d, 2H, J=7.6 Hz), 6.73 (d, 1H, J=1.6 Hz), 3.60 (s, 3H), 3.35 (s, 3H), 2.36 (s, 3H), 2.31 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.0, 161.3, 153.6, 152.4, 145.0, 141.8, 139.5, 138.7, 137.3, 135.2, 132.6, 131.1, 129.64, 129.60, 128.1, 125.9, 123.5, 118.3, 115.9, 108.6, 101.9, 70.7, 63.1, 52.4, 27.1, 21.6, 21.0. ESIHRMS: calcd. for C28H24N4O7S+Na+ 583.1258, found 583.1260.

3r, 58.5 mg, 94% yield, white solid; 1H NMR (400 MHz, CDCl3): δ 8.39 (d, 1H, J=4.8 Hz), 7.99 (d, 2H, J=8.0 Hz), 7.63 (d, 1H, J=8.0 Hz), 7.47 (d, 2H, J=7.6 Hz), 7.37 (t, 2H, J=7.2 Hz), 7.31 (d, 1H, J=7.2 Hz), 7.25 (d, 4H, J=7.2 Hz), 7.02 (d, 2H, J=4.0 Hz), 6.90 (dd, 1H, J=7.6, 5.2 Hz), 6.77 (d, 1H, J=7.6 Hz), 6.73 (s, 1H), 5.22 (d, 1H, J=16.0 Hz), 4.93 (d, 1H, J=16.0 Hz), 3.57 (s, 3H), 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 172.1, 161.3, 153.6, 152.4, 145.0, 143.5, 139.9, 138.7, 137.1, 135.3, 135.1, 130.7, 129.6, 128.9, 128.0, 127.7, 127.0, 125.8, 122.9, 122.8, 118.4, 115.8, 109.8, 102.2, 70.6, 63.2, 52.4, 44.5, 21.6. ESIHRMS: calcd. for C33H26N4O7S+Na+ 645.1414, found 645.1414.

3t, 49.2 mg, 96% yield, white solid; 1H NMR (400 MHz, CDCl3): δ 8.44 (d, 1H, J=4.4 Hz), 8.00 (d, 2H, J=8.0 Hz), 7.72 (d, 1H, J=7.6 Hz), 7.46 (t, 1H, J=7.6 Hz), 7.28 (d, 3H, J=10.0 Hz), 7.16-7.13 (m, 2H), 7.07 (d, 1H, J=7.2 Hz), 7.01 (dd, 1H, J=8.0, 5.2 Hz), 6.96 (d, 1H, J=8.0 Hz), 6.69 (d, 1H, J=2.0 Hz), 3.35 (s, 3H), 2.38 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 170.0, 153.6, 152.9, 145.4, 144.5, 143.6, 138.2, 134.9, 131.8, 129.80, 129.75, 128.1, 123.5, 118.6, 118.4, 115.1, 111.5, 109.5, 101.2, 70.8, 65.1, 27.2, 21.7. ESI-HRMS: calcd. for C26H19N5O5S+Na+ 536.0999, found 536.0995.

5, 30.0 mg, 55% yield, white solid; 1H NMR (400 MHz, CDCl3): δ 7.93 (d, 2H, J=8.4 Hz), 7.72 (s, 1H), 7.39 (t, 1H, J=8.0 Hz), 7.33 (t, 3H, J=8.8 Hz), 7.24-7.13 (m, 3H), 6.93-6.89 (m, 2H), 6.65 (d, 1H, J=7.6 Hz), 4.54 (s, 1H), 3.66 (s, 3H), 3.05 (s, 3H), 2.39 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 172.9, 161.7, 145.4, 145.1, 143.6, 141.8, 138.7, 135.3, 130.1, 130.04, 129.95, 129.8, 127.7, 124.5, 124.2, 123.7, 123.5, 123.0, 113.1, 112.8, 108.5, 64.2, 63.8, 52.5, 26.6, 21.6. ESI-HRMS: calcd. for C28H23N3O7S+Na+ 568.1149, found 568.1147.

6, 19.9 mg, 40% yield, white solid; 1H NMR (400 MHz, CDCl3): d 8.26 (s, 1H), 8.00 (d, 1H, J=8.8 Hz), 7.80 (d, 2H, J=8.4 Hz), 7.33 (t, 1H, J=7.6 Hz), 7.27-7.22 (m, 3H), 7.04 (dd, 2H, J=13.2, 7.6 Hz), 6.90 (t, 1H, J=7.6 Hz), 6.78 (d, 1H, J=8.0 Hz), 6.62 (d, 1H, J=7.6 Hz), 3.68 (s, 3H), 3.39 (s, 3H), 2.35 (s, 3H). 13C NMR (150 MHz, CDCl3): δ 171.9, 162.4, 145.5, 145.1, 144.0, 142.0, 140.2, 136.2, 134.6, 133.5, 130.1, 129.0, 126.9, 125.5, 125.3, 124.3, 124.1, 122.9, 122.7, 118.8, 114.8, 108.8, 60.0, 51.8, 27.3, 21.6. ESI-HRMS: calcd. for C28H22N2O5S+Na+ 521.1142, found 521.1145.

7, 49.5 mg, 96% yield, white solid; 1H NMR (400 MHz, CDCl3): δ 8.29 (d, 1H, J=4.8 Hz), 7.99 (d, 2H, J=8.4 Hz), 7.40 (dd, 2H, J=16.0, 7.6 Hz), 7.26-7.23 (m, 3H), 7.17 (d, 1H, J=7.2 Hz), 7.10 (t, 1H, J=7.6 Hz), 6.93-6.88 (m, 2H), 5.52 (s, 1H), 5.03 (br, 1H), 3.70 (br, 1H), 3.56 (s, 3H), 3.26 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, d6-DMSO): δ 175.0, 162.5, 155.0, 148.6, 145.2, 144.7, 142.9, 139.0, 136.2, 135.9, 129.9, 129.4, 128.4, 127.1, 125.8, 124.6, 122.0, 118.5, 109.0, 77.6, 72.4, 66.0, 52.5, 26.9, 21.5. ESI-HRMS: calcd. for C27H24N4O5S+Na+ 539.1360, found 539.1365.

8, 49.4 mg, 99% yield, white solid; 1H NMR (400 MHz, CDCl3): δ 8.33 (d, 2H, J=7.6 Hz), 8.14 (d, 2H, J=8.0 Hz), 7.37-7.30 (m, 3H), 7.16 (d, 1H, J=7.6 Hz), 7.04-7.01 (m, 2H), 6.94 (t, 1H, J=7.6 Hz), 6.69 (d, 1H, J=7.2 Hz), 3.69 (s, 3H), 3.40 (s, 3H), 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 171.8, 162.2, 151.1, 145.7, 145.0, 144.9, 143.6, 142.5, 136.3, 134.9, 129.8, 129.2, 128.7, 128.2, 126.7, 125.0, 123.0, 122.7, 119.6, 116.9, 108.9, 60.4, 51.9, 27.3, 21.7. ESI-HRMS: calcd. for C27H21N3O5S+Na+ 522.1094, found 522.1096.


We are grateful for the financial support from the NSFC (21572135 and 21321061).

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at

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