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Synlett 2021; 32(06): 626-630
DOI: 10.1055/a-1327-6388
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Synthesis of Spirocyclopropane Oxindoles via Michael-Initiated Cyclopropanation of Pyridinium Salts with 3-Ylidene Oxindoles

Jun-Qi Zhang
a   Advanced Research Institute and Department of Chemistry, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, P. R. of China
,
Yujia Gao
b   Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China
,
Jinyu Song
a   Advanced Research Institute and Department of Chemistry, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, P. R. of China
,
Dandan Hu
a   Advanced Research Institute and Department of Chemistry, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, P. R. of China
,
Maozhong Miao
b   Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, P. R. China
,
Hongjun Ren  ∗
a   Advanced Research Institute and Department of Chemistry, Taizhou University, 1139 Shifu Avenue, Taizhou 318000, P. R. of China
› Author Affiliations

We gratefully acknowledge the Leading Innovative and Entrepreneur Team Introduction Program of Zhejiang (2019R01005) and the launching scientific research funds from Taizhou University.
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Abstract

A Michael-initiated ring-closure reaction of pyridinium salts with arylidene oxindoles has been developed. A wide range of aryl-substituted spirocyclopropane oxindoles has been achieved in moderate to good yields (41–99%). This efficient strategy exhibits good functional group compatibility and may serve as an attractive method for the synthesis of diverse cyclopropanes.


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Key words

pyridinium salts - Michael - cyclopropanation - spirocyclopropane - oxindoles

Spirocyclic oxindoles constitute a large class of pharmacological agents in which the spirocyclic ring is fused at the 3-position of the oxindole core with varying degree of substitution around it.[1] In particular, spiro-3,3′-cyclopropyl oxindole, integrating two significant pharmacophores – the quaternary oxindole and the smallest three-member cyclopropane ring – has been treated as an attractive framework for both medicinal as well as synthetic chemistry research (Figure [1]).[2]

Zoom Image
Figure 1 Selected bioactive spirocyclopropyloxindoles

Due to their significant biological and pharmacological potential, a variety of synthetic pathways have been developed which include diazo-mediated cyclopropanation,[3] cyclopropane C–H activation,[4] Michael-initiated ring closure,[5] P(NMe2)3-mediated reductive cyclopropanation,[6] domino Corey–Chaykovsky reaction,[7] and others.[8]

In 2013, Yan and co-workers[9] reported one cycloaddition reaction of 3-phenacylideneoxindoles with benzylpyridinium bromide or N-diethylcarbamoylmethylpyridinium bromide to provide the anti-spirocyclopropane selectively in the presence of Et3N in EtOH (Scheme [1]). When reacted with N-ethoxycarbonylmethylpyridinium bromide, 3-(2-oxoindolin-3-ylidene)butanoates were afforded instead of spirocyclopropane. A litter bit later after Yan, Dowden, and co-workers[10] reported a similar reaction, however, the 1,3-dipolar cycloaddition product of spirotetrahydroindolizineoxindole was the only product. These results demonstrated that the substituted groups in both pyridinium salts and electron-withdrawing β-position of 3-ylidene oxindoles are significant to the product diversity. In case of the construction of 3-spirocyclopropyl-2-oxindole, Babu and co-workers[11] developed a domino reaction of 3-ylideneoxindoles with α-aryldiazomethanes which generated in situ. Since the aryl-substituted 3-spirocyclopropyl oxindole skeleton is highly demanding in synthetic chemistry and pharmaceutical chemistry, hence we here report an effective synthesis of anti-spirocyclopropane oxindoles from the reactions of alkylidene oxindoles with pyridinium salts.

Zoom Image
Scheme 1 Reactions of 3-ylidene oxindoles with pyridinium salts

At the outset, we initiated our investigation of the ring-closure reaction between (E)-3-benzylideneindolin-2-one (1a, 0.5 mmol) and N-ethoxycarbonylmethylpyridinium bromide (2a, 1 mmol), and the key results are summarized in Table [1]. We first carried out the reaction using DBU as a base in different solvents, such as N,N-dimethylacetamide (DMAC), toluene, and DMF, at 110 °C for 12 h, the desired spiro-3,3′-cyclopropyl oxindole 3a was successfully isolated in 63–69% yields, respectively (Table [1], entries 1–3). Then, in order to get the optimized reaction conditions, several bases, including organic bases (DIPEA, DABCO, and Et3N) and inorganic bases (K2CO3 and Cs2CO3), were surveyed for this transformation (entries 4–8), among which Cs2CO3 was turned out to be the optimal base with 77% yield (entry 8). Moreover, significant erosion of yield was observed when lowering the reaction temperature to 50 °C (entry 9). Furthermore, in view of the satiability of the product, shortened reaction time may be beneficial for this transformation. To our delight, when we carried out the reaction in the presence of diverse bases for 4 h, the starting material was completely consumed and gave the best yield of 82% (entries 10–13). In addition, we also altered the solvent to DCM, after 36 h, the starting material was completely consumed but provided the desired product in only 50% yield (entry 14).

Table 1 Optimization of Reaction Conditionsa

Entry

Solvent

Base

Time (h)

Yield (%)b

 1

DBU

DMAC

12

66

 2

DBU

toluene

12

63

 3

DBU

DMF

12

69

 4

DIPEA

DMF

12

46

 5

DABCO

DMF

12

20

 6

Et3N

DMF

12

63

 7

K2CO3

DMF

12

69

 8

Cs2CO3

DMF

12

77

 9c

Cs2CO3

DMF

36

41

10

Cs2CO3

DMF

 4

82

11

DBU

DMF

 4

77

12

KOAc

DMF

 4

60

13

K2CO3

DMF

 4

80

14

Cs2CO3

DCM

36

50

a Reaction conditions: 1a (0.5 mmol), 2a (1.0 mmol), base (0.5 mmol), solvent (4 mL), 110 °C.

b Isolated yield based on 1a.

c The reaction was performed at 50 °C.

With the optimal reaction conditions in hand, we then investigated the substrate scope for the synthesis of various spirocyclopropyl oxindole derivatives, and the corresponding results are presented in Scheme [2].[12] For the different aromatic substituents on β-position of 3-ylidene oxindoles 1, the substrates containing whether an electron-donating or an electronic-withdrawing group could react well with ethoxycarbonylmethylpyridinium bromide (3b–j) or phenacylpyridinium bromide (3k–s) to provide the corresponding spirocyclopropane oxindoles in modest to excellent yields (41–93%). It is noteworthy that both 3-(2-furylmethylidene)-2-oxindole and 3-(2-thienylmethylidene)-2-oxindole could furnish the desired products (3i,j and 3s) in 41%, 64%, and 88% yields, respectively. Among all the products in Scheme [2], the ortho-substituted substrates (3d–f,h,l,m,p,r) give positive effect of high yields. Substituents such as bromo (3e,f,l,p), chloro (3g,h,q,r), fluoro (3f,h,p,r), trifluoromethyl (3c,o) were all well tolerated. The structure of 3p was unambiguously established by single-crystal X-ray analysis.[13]

Zoom Image
Scheme 2 Scope of cyclopropanation with pyridinium salts. Reagents and conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cs2CO3 (0.5 mmol), DMF (4 mL), 110 °C, 4–8 h. Isolated yields based on 1.

Next, we explored the ring-closure reaction between (E)-3-benzylideneindolin-2-one (1a) and 1-[(piperidinocarbonyl)methyl]pyridinium bromide (6a). Upon heating a DMF solution of (E)-3-benzylideneindolin-2-one (1a) and pyridinium bromide salt 6a in the presence of Cs2CO3, the reaction took place to give anti-spirocyclopropane oxindole 7a in 98% yield. Then we attempted to induce the chirality to the spirocyclopropane system by utilizing a chiral pyridinium salt 8a, derived from the (S)-1-phenylethan-1-amine, as the chiral auxiliary. However, when the reaction was carried out with 1a and 8a, the corresponding spiro-3,3′-cyclopropyl oxindole 9a was obtained as diastereomeric mixture (dr = 1:1) in 70% yield (Scheme [3]).

Zoom Image
Scheme 3 Further scope of cyclopropanation with pyridinium salts. Reagents and conditions: 1a (0.5 mmol), 6a or 8a (1.0 mmol), Cs2CO3 (0.5 mmol), DMF (4 mL), 110 °C, 4-8 h. Isolated yields based on 1a. The dr were determined via 1H NMR analysis of crude reaction mixtures.

In summary, we have developed a new approach for the effective synthesis of anti-spirocyclopropane oxindole derivatives through Michael-initiated ring-closure reactions in the presence of Cs2CO3. This efficient strategy exhibits good functional group compatibility with moderate to good yields. The present reaction may serve as an attractive method for the synthesis of multisubstituted spirocyclopropane oxindoles.


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Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1327-6388.
  • Supporting Information

  • References and Notes

    • 5a Ivashkin P, Couve-Bonnaire S, Jubault P, Pannecoucke X. Org. Lett. 2012; 14: 2270
      CrossrefPubMedSearch in Google Scholar
    • 5b Ošeka M, Noole A, Žari S, Öeren M, Järving I, Lopp M, Kanger T. Eur. J. Org. Chem. 2014; 3599
  • 7 Hajra S, Roy S, Saleh SA. Org. Lett. 2018; 20: 4540
    CrossrefPubMedSearch in Google Scholar
  • 10 Day J, Uroos M, Castledine RA, Lewis W, McKeever-Abbas B, Dowden J. Org. Biomol. Chem. 2013; 11: 6502
    CrossrefPubMedSearch in Google Scholar
  • 11 Ramu G, Krishna NH, Pawar H, Sastry KN. V, Nanubolu JB, Babu BN. ACS Omega 2018; 3: 12349
    CrossrefPubMedSearch in Google Scholar
  • 12 Ethyl (2S*,3R*)-2′-Oxo-3-[4-(trifluoromethyl)phenyl]spiro [cyclopropane-1,3′-indoline]-2-carboxylate (3c) – Typical Procedure The solution of (E)-3-[4-(trifluoromethyl)benzylidene]indolin-2-one (145 mg, 0.5 mmol), ethoxycarbonylmethylpyridinium bromide (245 mg, 1.0 mmol) in dry DMF (4 mL) in the presence of Cs2CO3 (163 mg, 0.5 mmol) was stirred at 110 °C for 4 h. After completion of the reaction, the mixture was quenched by adding 10 mL of water at room temperature and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with H2O (3 × 10 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified with flash silica gel chromatography using EtOAc/hexane (1:5 to 1:3) to afford 3c (147 mg, 78%) as a white solid; mp 183–184 °C (petroleum ether/EtOAc); Rf = 0.50 (petroleum ether/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ = 8.72–8.54 (m, 1 H), 7.56 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.06 (t, J = 8.0 Hz, 1 H), 6.80 (t, J = 8.0 Hz, 1 H), 4.29–4.15 (m, 2 H),3.81 (d, J = 8.0 Hz, 1 H), 3.36 (d, J = 8.0 Hz, 1 H), 1.27 (t, J = 8.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 173.6, 168.0, 141.2, 137.0, 129.6, 127.9, 126.1, 125.02, 124.99 122.8, 122.5 (J C–F = 41 Hz), 122.4, 109.9, 61.8, 39.8, 39.3, 37.1, 14.1. HRMS (ES+–TOF): m/z calcd for C20H17F3NO3 + [M + H]+: 376.1155; found: 376.1166.
  • 13 CCDC 2032994 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

Corresponding Author

Hongjun Ren
Advanced Research Institute and Department of Chemistry, Taizhou University
1139 Shifu Avenue, Taizhou 318000
P. R. of China   

Publication History

Received: 14 October 2020

Accepted after revision: 02 December 2020

Accepted Manuscript online:
02 December 2020

Article published online:
07 January 2021

© 2020. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References and Notes

    • 5a Ivashkin P, Couve-Bonnaire S, Jubault P, Pannecoucke X. Org. Lett. 2012; 14: 2270
      CrossrefPubMedSearch in Google Scholar
    • 5b Ošeka M, Noole A, Žari S, Öeren M, Järving I, Lopp M, Kanger T. Eur. J. Org. Chem. 2014; 3599
  • 7 Hajra S, Roy S, Saleh SA. Org. Lett. 2018; 20: 4540
    CrossrefPubMedSearch in Google Scholar
  • 10 Day J, Uroos M, Castledine RA, Lewis W, McKeever-Abbas B, Dowden J. Org. Biomol. Chem. 2013; 11: 6502
    CrossrefPubMedSearch in Google Scholar
  • 11 Ramu G, Krishna NH, Pawar H, Sastry KN. V, Nanubolu JB, Babu BN. ACS Omega 2018; 3: 12349
    CrossrefPubMedSearch in Google Scholar
  • 12 Ethyl (2S*,3R*)-2′-Oxo-3-[4-(trifluoromethyl)phenyl]spiro [cyclopropane-1,3′-indoline]-2-carboxylate (3c) – Typical Procedure The solution of (E)-3-[4-(trifluoromethyl)benzylidene]indolin-2-one (145 mg, 0.5 mmol), ethoxycarbonylmethylpyridinium bromide (245 mg, 1.0 mmol) in dry DMF (4 mL) in the presence of Cs2CO3 (163 mg, 0.5 mmol) was stirred at 110 °C for 4 h. After completion of the reaction, the mixture was quenched by adding 10 mL of water at room temperature and extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with H2O (3 × 10 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified with flash silica gel chromatography using EtOAc/hexane (1:5 to 1:3) to afford 3c (147 mg, 78%) as a white solid; mp 183–184 °C (petroleum ether/EtOAc); Rf = 0.50 (petroleum ether/EtOAc = 3:1). 1H NMR (400 MHz, CDCl3): δ = 8.72–8.54 (m, 1 H), 7.56 (d, J = 8.0 Hz, 2 H), 7.48 (d, J = 8.0 Hz, 1 H), 7.43 (d, J = 8.0 Hz, 2 H), 7.23 (d, J = 8.0 Hz, 1 H), 7.06 (t, J = 8.0 Hz, 1 H), 6.80 (t, J = 8.0 Hz, 1 H), 4.29–4.15 (m, 2 H),3.81 (d, J = 8.0 Hz, 1 H), 3.36 (d, J = 8.0 Hz, 1 H), 1.27 (t, J = 8.0 Hz, 3 H). 13C NMR (100 MHz, CDCl3): δ = 173.6, 168.0, 141.2, 137.0, 129.6, 127.9, 126.1, 125.02, 124.99 122.8, 122.5 (J C–F = 41 Hz), 122.4, 109.9, 61.8, 39.8, 39.3, 37.1, 14.1. HRMS (ES+–TOF): m/z calcd for C20H17F3NO3 + [M + H]+: 376.1155; found: 376.1166.
  • 13 CCDC 2032994 contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.

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Zoom Image
Figure 1 Selected bioactive spirocyclopropyloxindoles
Zoom Image
Scheme 1 Reactions of 3-ylidene oxindoles with pyridinium salts
Zoom Image
Scheme 2 Scope of cyclopropanation with pyridinium salts. Reagents and conditions: 1 (0.5 mmol), 2 (1.0 mmol), Cs2CO3 (0.5 mmol), DMF (4 mL), 110 °C, 4–8 h. Isolated yields based on 1.
Zoom Image
Scheme 3 Further scope of cyclopropanation with pyridinium salts. Reagents and conditions: 1a (0.5 mmol), 6a or 8a (1.0 mmol), Cs2CO3 (0.5 mmol), DMF (4 mL), 110 °C, 4-8 h. Isolated yields based on 1a. The dr were determined via 1H NMR analysis of crude reaction mixtures.