Letter Cite This: Org. Lett. 2018, 20, 4540−4544
pubs.acs.org/OrgLett
Domino Corey−Chaykovsky Reaction for One-Pot Access to Spirocyclopropyl Oxindoles Saumen Hajra,* Sayan Roy, and SK Abu Saleh Centre of Biomedical Research, Sanjay Gandhi Post-Graduate Institute of Medical Sciences, Campus Raebareli Road, Lucknow 226014, India Org. Lett. 2018.20:4540-4544. Downloaded from pubs.acs.org by UNIV OF MASSACHUSETTS AMHERST on 08/04/18. For personal use only.
S Supporting Information *
ABSTRACT: The development of the sequential Corey−Chaykovsky reactions of isatins, spiroepoxy-, or spiroaziridine oxindoles with sulfur ylide has led to the discovery of a unique reaction mode that allows easy and direct one-pot access to a range of spirocyclopropyl oxindoles.
S
pirocyclic oxindoles have garnered considerable research enthusiasm for their unique structures and diverse but target-specific pharmacological profiles.1 In particular, spiro 3,3′-cyclopropyl oxindole, integrating two significant pharmacophores 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.2 The unusual bonding with characteristic angular as well as torsional strain make the cyclopropane ring an exceptional among various carbocycles. Significant pharmaceutical properties including intrinsic lipophilicity, metabolic stability, and alteration of pKa have been imposed by the cyclopropane ring. For instance, molecules shown in Figure 1 containing
However, the reports suggest that the unsubstituted spirocyclopropyl oxindoles/indolines 1 have received more attention than the mono- and disubstituted spirocyclopropyl oxindoles.6 Regarding the C−C bond forming reaction, the Corey− Chaykovsky reaction (CCR) is efficient for organic synthesis. It involves the addition of sulfur ylide to the electrophiles such as carbonyl, imine, and enone, leading to the formation of corresponding 3-membered rings such as epoxide, aziridine, and cyclopropane, respectively (Scheme 1, eq 1).7 Mono- and disubstituted spirocyclopropyl oxindoles have been frequently synthesized by CCR using a suitable sulfur ylide.5a,8 However, the synthesis of spirocyclopropyl oxindoles 1 is not successful by CCR, which may be due to the instability of the 3methylene-2-oxindole and the lack of a suitable method for its generation (Scheme 1, eq 2).9 Thus, spirocyclopropyl oxindole 1 is mostly synthesized by base-promoted double alkylation of N-protected 2-oxindole using 1,2-dibromoethane.10 There are other notable routes, but the use of costly reagents and substrates make them less attractive (Scheme 1, eq 3).11 Scrutinizing all the importance of spirocyclopropyl oxindoles and their reported routes, the development of an effective synthetic method, in particular for spirocyclopropyl oxindole 1, is highly appealing. Herein, we report the domino Corey− Chaykovsky reaction of isatins, spiroepoxides, and spiroaziridines with sulfur ylide derived from trimethylsulfoxonium iodide for the direct one-pot synthesis of spirocyclopropyl oxindoles 1 (Scheme 1, eq 4). Our continuous research interest in the ring-opening reaction of spiroepoxide and spiroaziridine oxindoles12 led us to wonder whether spiroepoxides 2 could undergo a ringopening reaction with sulfur ylide derived from trimethyl sulfoxonium iodide (TMSOI). It was also envisioned that
Figure 1. Representative bioactive spirocyclopropyl oxindoles and -indolins.
spirocyclopropyl oxindole have emerged as potential drug candidates because of its conformational restraint and lipophilicity.3 Spirocyclopropyl indolines also exhibit significant biological activity acting as an EP4 receptor antagonist and selective adrenaline α1A receptor agonist.4 Moreover, from a synthetic point of view, spirocyclopropyl oxindoles have also been considered to be a donor−acceptor cyclopropane.5 © 2018 American Chemical Society
Received: June 13, 2018 Published: July 23, 2018 4540
DOI: 10.1021/acs.orglett.8b01840 Org. Lett. 2018, 20, 4540−4544
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Organic Letters Scheme 1. Corey−Chaykovsky Reaction (CCR) for the Synthesis of Spirocyclopropyl Oxindoles
Table 1. Optimization of Reaction Conditions
a
ylide source (equiv)
base (equiv)
1
Me3SOI (2)
2
Me3SOI (2)
3
Me3SOI (2)
4 5 6 7
Me3SOI (2) Me3SOI (3) Me3SOI (3) Me3SI (3)
Cs2CO3 (3) Cs2CO3 (3) Cs2CO3 (3) NaH (3) NaH (4) NaH (4) NaH (4)
yielda (%)
solvent
temp (°C)
t (h)
MeCN
50
12
DMSO
50
4
22
DMSO
25
4
40
DMSO DMSO DMF DMSO
25 25 25 25
1 1 2 2
56 76 46 55
Isolated yield.
Once armed with the optimized conditions, we began an exploration of the scope of this domino cyclopropanation reaction with a wide range of spiroepoxides (Scheme 3). Irrespective of the N-protection on spiroepoxides, we acquired high yields in all cases. Substituted spiroepoxyoxindoles participated in this transformation with good yield. Electrondonating as well as electron-withdrawing groups on oxindoles Scheme 3. One-Pot Synthesis of Spirocyclopropyl Oxindoles 1 from Spiroepoxides 2
alkoxide intermediate 3 could undergo a retro-aldol reaction, and a subsequent elimination of DMSO and formaldehyde might bestow 3-methylene-2-oxindole 4.13 This reactive enone 4 could produce spirocyclopropyl oxindoles 1 by CCR with an excess sulfur ylide (Scheme 2). Alternatively, we anticipated that the cyclization of alkoxide 3 by analogy with the known homologous CCR of epoxide would give spirooxetanes.7d Scheme 2. Proposed Domino CCR of Spiroepoxy Oxindole 2
As a proof of concept, we commenced our journey with the model substrate N-methyl spiroepoxyoxindole 2a altering solvents, temperature, ylide sources, bases, and their stoichiometry (Table 1). Gratifyingly, exclusive formation of spirocyclopropyl oxindole 1a was achieved when spiroepoxide 2a was treated with trimethyl sulfoxonium iodide (TMSOI; 3 equiv) and NaH (4 equiv) in DMSO at rt within 1 h (entry 5). Interestingly, no spirooxetane was detected by the MS analysis of the crude reaction mixture. Other conditions mostly afforded low yields with incomplete conversion. 4541
DOI: 10.1021/acs.orglett.8b01840 Org. Lett. 2018, 20, 4540−4544
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Organic Letters
found to be a better solvent over DMSO for the synthesis of spiroaziridine oxindoles.12b Thus, changing the solvent to DMF and further lowering the temperature to 0 °C eventually optimized the cyclopropanation of spiroaziridine 6a with a high yield of 75%. The scope of this cyclopropanation reaction of spiroaziridines was also generalized. Satisfyingly, a wide range of spiroaziridineoxindoles with electron-donating or -withdrawing substituents on the oxindole ring participated smoothly to afford the corresponding spirocyclopropyl oxindole with moderate to good yields (Scheme 5).
did not hamper the cyclopropanation reaction. With an additional equiv of NaH, we also accomplished the reaction with unprotected spiroepoxyoxindoles to yield the corresponding spirocyclopropyl oxindoles 1u−w. The spiroepoxides are commonly synthesized by CCR of isatins.12 Thus, we desired to explore the cyclopropanation reaction directly from isatin. Similar reaction conditions were established for the domino CCR of isatin as well. Because it begins with one-step back, the reaction required additional amounts of ylide source as well as base. Reaction of isatin with 5 equiv of TMSOI and 6 equiv of NaH at rt (25 °C) in DMSO was found to be the optimum conditions for the complete conversion of isatin to spirocyclopropane oxindole. As expected, the formation of intermediate spiroepoxide was observed during the course of the reaction. It diminished with the complete transformation to the spirocyclopropyl oxindole. The scope of this direct cyclopropanation reaction was further generalized with a wide range of isatins through complete displacement of the oxygen atom in a one-pot fashion (Scheme 4). With N-methyl, N-benzyl, or N-PMB isatins, we obtained
Scheme 5. One-Pot Synthesis of Spirocyclopropyl Oxindoles 1 from Spiroaziridines 6
Scheme 4. One-Pot Synthesis of Spirocyclopropyl Oxindoles 1 from Isatins 5
To reinforce our presumption, we performed two control experiments. Initially, the domino CCR of substituted spiroepoxyoxindoles 7 was executed under the standardized conditions. Interestingly, these afforded spirocyclopropane 1a exclusively. No substituted spirocyclopropyl oxindole 9 was obtained. Moreover, epoxides 8, which were actually generated by the CCR of the corresponding expelled aldehydes, were detected in the mass spectrometry analysis (for details, see Supporting Information) of the crude reaction mixture (Scheme 6). Scheme 6. Domino CCR of Substituted Spiroepoxy Oxindoles 7
good yields of the corresponding spirocyclopropyl oxindoles 1. On the other hand, substituted isatins also rendered the corresponding spirocyclopropyl oxindoles with good yields irrespective of the protecting group on the nitrogen atom. We could also synthesize unprotected spirocyclopropyl oxindoles 1u and 1w from the corresponding isatins with good yields. For unprotected isatins, an additional equiv of NaH was needed. Our interest12 in ring-opening reactions of small spirocyclic oxindoles further motivated us to utilize this unique cyclopropanation reaction on analogous spiroaziridineoxindole, which may provide insight into the reaction mechanism. Standardized conditions for the cyclopropanation of spiroepoxy oxindoles was executed on N-methyl spiroaziridineoxindole 6a, but only a moderate yield was obtained. DMF was
Next, we performed the CCR of spiroepoxide 2a and spiroaziridine 6a with tetrahydrothiophene-derived substituted sulfur ylide and obtained disubstituted spirocyclopropane 10 from both substrates. Here, monosubstituted spirocyclopropane 9c was also not detected in the crude reaction mixture by MS analysis. When CCR of 3-benzylidene oxindole 11 was again performed with substituted sulfur ylide under similar conditions, it also furnished the substituted spirocyclopropane 10 with the same selectivity (Scheme 7). These experimental outcomes strongly supported our presumption of in situ 4542
DOI: 10.1021/acs.orglett.8b01840 Org. Lett. 2018, 20, 4540−4544
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Organic Letters Scheme 7. Domino CCR of Spiroepoxide 2a and Spiroaziridine 6a with Substituted Sulfur Ylide vs CCR of 3Alkylidene Oxindole 11
Scheme 9. Gram-Scale Domino CCR of Isatin 5u and Their Late Stage Functionalizations
generation of 3-alkylidene oxindole as an intermediate for the cyclopropanation of isatin, spiroepoxide, and spiroaziridine. To demonstrate the general applicability and robustness of the method, the domino CCR of both spiroepoxide and isatin were extended up to gram-scale under the optimized conditions. Spiroepoxide 2j (1 g, 3.3 mmol) underwent smooth reaction with TMSOI in DMSO and endowed spirocyclopropyl oxindole 1j in high yield (78%). This compound 1j was employed for the Suzuki coupling reaction with 1-methylindole-2-boronic acid, furnishing the corresponding 5-indolyl spirocyclopropane 12 in 85% yield (Scheme 8).
iodide. This protocol provides a unique and facile one-pot access of spirocyclopropyl oxindoles with diversity under ambient conditions. The gram-scale reactions followed by late stage modifications further prove its flexibility. Thus, the present development can unfold a new route for the spirocyclopropyl oxindole and -indoline based drug discovery and medicinal chemistry research.
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Scheme 8. Gram-Scale Domino CCR of Spiroepoxide 2j
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01840. General procedures and standardization tables for cyclopropanation reactions, spectroscopic data of the products, mass spectrometry analysis of compound 8, and copies of NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected].
On the other hand, N-unprotected spirocyclopropyl oxindole 1u was directly obtained in good yield by gramscale domino CCR of isatin 5u (1.0 g, 6.8 mmol) (Scheme 9). Subsequently, a late stage base-promoted N-alkylation of spirocyclopropane 1u was also achieved with 2-(bromomethyl)-1-butyl-1H-benzo[d]imidazole, providing the corresponding N-alkylated spirocyclopropyl oxindole 13, a similar motif to anti-RSV compound with quantitative yield. Spirocyclopropane 1u could also be an important antecedent for the synthesis of other substituted spirocyclopropyl oxindoles. Hence, it was utilized for electrophilic substitution reactions giving 5-bromo and 5,7-dibromo spirocyclopropyl oxindoles (Scheme 9), which were difficult to obtain from the corresponding isatins or by other means. In conclusion, we present a novel domino Corey− Chaykovsky reaction of isatin, spiroepoxy-, and spiroaziridine oxindoles, which reveals mechanistically new reaction pathways with the in situ generation of 3-methylene oxindole upon reaction with sulfur ylide derived from trimethylsulfoxium
ORCID
Saumen Hajra: 0000-0003-0303-4647 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank SERB, New Delhi (EMR/2016/001161) for providing financial support. S.R. and S.A.S. thank CSIR and UGC, New Delhi, respectively, for their fellowships. We thank the Director of CBMR for providing research facilities.
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REFERENCES
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DOI: 10.1021/acs.orglett.8b01840 Org. Lett. 2018, 20, 4540−4544
