Jun 27, 2002 - ... THF-THP units via PdII-catalyzed tandem reaction with 1,3-chirality transfer. Nobuyuki Kawai , Yuhei Fujikura , Jun Takita , Jun'ichi Uenishi.
... THF-THF and THF-THP units via PdII-catalyzed tandem reaction with 1,3-chirality transfer. Nobuyuki Kawai , Yuhei Fujikura , Jun Takita , Jun'ichi Uenishi.
A new strategy for effecting cascade cyclization processes using nickel enolates has ..... (a) Link, J. T. In Organic Reactions; Overman, L. E., Ed.; Wiley: New York, 2002; Vol. ... https://chemport.cas.org/services/resolver?origin=ACS&resolution= ..
Long-Distance Asymmetric Induction by a Chiral. Auxiliary. Christoph ... cations9,10 for triggering cascade cyclizations11 of terpenoid polyalkenes to mimic ...
For a general reference to PET, see: Photoinduced Electron Transfer; Fox, M. A., Chandon, M., Eds.; Elsevier: New ... Stork, G.; Burgstahler, A. W. J. Am. Chem.
... via Photoinduced Electron Transfer. Long-Distance Asymmetric Induction by a Chiral Auxiliary. C. HEINEMANN , M. DEMUTH. ChemInform 1997 28, no-no ...
Kande K. D. Amarasinghe, Mary Jane Heeg,â and John Montgomery*. Contribution from the Department of Chemistry, Wayne State UniVersity,. Detroit ...
Thomas J. Beauchamp, Jay P. Powers, and Scott D. Rychnovsky ... Yulai Hu , Geoff D. Head , Lynda J. Brown , William G. Whittingham and Richard C. D. Brown.
Contribution from the Department of Chemistry, Wayne State University, Detroit, ... Aireal D. Jenkins , Ananda Herath , Minsoo Song , and John Montgomery.
Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Hydride Transfer Involved Redox-Neutral Cascade Cyclizations for Construction of Spirocyclic Bisoxindoles Featuring a [3,4]-Fused Oxindole Moiety Shuai-Shuai Li,†,∥ Shuai Zhu,†,∥ Chunqi Chen,†,∥ Kang Duan,† Qing Liu,§ and Jian Xiao*,†,‡ †
College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, China College of Marine Science and Engineering, Qingdao Agricultural University, Qingdao 266109, China § College of Chemical and Environmental Engineering, Shandong University of Science and Technology, Qingdao 266590, China ‡
Org. Lett. Downloaded from pubs.acs.org by TULANE UNIV on 02/05/19. For personal use only.
S Supporting Information *
ABSTRACT: The hydride transfer involved redox-neutral cascade cyclization has been developed to construct the spirocyclic bisoxindoles featuring a [3,4]-fused oxindole moiety from rationally designed C4-amine-substituted isatins, aﬀording the diverse tricyclic [3,4]-fused oxindoles with three consecutive chiral centers in good yields and excellent diastereoselectivities (>20:1). pharyngitis, and pulmonary tuberculosis.2b However, the strategies for direct access to [3,4]-fused oxindoles from simple precursors remain scarce,3 especially for 6/5/6 [3,4]fused oxindoles.4 In 2012, the Jia group described a [4 + 2] cycloaddition of methyleneindolinones with arynes to construct [3,4]-fused oxindoles.5 The subsequent breakthrough was made by the Zhu group, who developed a novel palladium(0)-catalyzed carbopalladation/1,4-palladium shift via a sequential C−H bond activation/C−C bond-forming process from acrylamides.6 Very recently, the Lautens group explored a palladium(0)-catalyzed C(sp2)−H bond activation/ alkyne insertion cascade reaction, aﬀording rapid access to 6/ 5/6 [3,4]-fused oxindoles.7 Obviously, these few pioneering studies largely relied on the transition-metal-catalyzed crosscoupling reactions to achieve the [3,4]-fused oxindole cores. On the other hand, spirooxindoles represent one of the most attractive heterocyclic motifs which widely exist in alkaloids and pharmacologically interesting compounds such as cipargamin and satavaptan (Figure 1, IV−V).1,8 In recent decades, signiﬁcant progress have been made for the synthesis of various functionalized spirooxindoles, owing to their diverse bioactivities and structural complexity.9,10 Presumably, the combination of these two signiﬁcant pharmaphores, i.e., [3,4]-
olycyclic molecules containing oxindole moieties are highly valuable synthetic targets due to their ubiquity in an array of natural products, pharmaceuticals, and agrochemicals.1 Among the naturally occurring oxindole alkaloids, the tricyclic [3,4]-fused oxindoles have distinguished themselves with unique biological activities (Figure 1, I−III).2 For instance, ammosamide B exhibited high activity in modulating tubulin and actin dynamics,2a and prioline has been used in Chinese folk medicine for the treatment of tonsillitis,
DOI: 10.1021/acs.orglett.8b04100 Org. Lett. XXXX, XXX, XXX−XXX
hydride transfer rather than being captured by another nucleophile; (3) the iminium ion III should be attacked by an intramolecular nucleophile instead of an intermolecular one. Moreover, the selective construction of 6/5/6 or 6/5/5 [3,4]fused oxindoles raised another problem. As a continuation of our ongoing eﬀorts toward one-step assembly of molecular complexity,14 herein we report a cascade hydride transfer/ cyclization for the selective access to spirocyclic bisoxindoles featuring a [3,4]-fused oxindole moiety. To validate the feasibility of our hypothesis, the benzylprotected 2-indolinone 2a15 was selected as the model substrate to react with 1-benzyl-4-(pyrrolidin-1-yl)indoline2,3-dione 1a (Table 1). At the outset, 20 mol % of Sc(OTf)3
fused oxindole and spirooxindole moieties, might produce a privileged structure possessing promising bioactivity. However, the synthesis of spirocyclic bisoxindoles featuring a [3,4]-fused oxindole moiety (Figure 1, VI) poses a formidable challenge, and there has been no example available until now. Therefore, there is an urgent need to develop a new strategy for the direct synthesis of spirocyclic bisoxindoles featuring a [3,4]-fused oxindole moiety. To achieve this goal, the selection of a mechanistically unique reaction and the rational design of a new type of substrate constitute the key factors. Inspired by the redox- and step-economy, we intend to develop a strategically distinct route to access spirocyclic bisoxindoles. In this context, we notice that the cascade hydride transfer/cyclization has recently emerged as a powerful tool for construction of various heterocyclic rings owing to its high eﬃciency and environmental sustainability.11−13 However, the inherent drawbacks of these established reactions, such as the essential dependence of phenyl skeleton as a linker between hydride donors and acceptors (Scheme 1A), largely
Table 1. Optimization of the Reaction Conditiona
Scheme 1. Eﬃcient Construction of Spirocyclic Bisoxindoles Featuring a [3,4]-Fused Oxindole Moiety
Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), catalyst (20 mol %), and additive (50 mg) in 1.0 mL of distilled solvent at 80 °C for 12 h. bIsolated yield after column chromatography. cdr was determined by 1H NMR spectroscopy. dAt 80−120 °C for 12 h. e10 mol % of Sc(OTf)3. nr = no reaction.
limited their applications in the synthesis of diverse natural products and drug intermediates.13 To address this challenge, we rationally design a new type of substrate decorated with an amine at the C4 position of isatin, which could react with the external nucleophiles to achieve the redox-neutral cascade hydride transfer/cyclization for rapid construction of privileged [3,4]-fused oxindoles. As depicted in Scheme 1B, initially, the nucleophilic 2-indolinone could attack the C3 carbonyl group of isatin to form an alcohol I under Lewis acid, then dehydration of I occurred to generate intermediate II, which would induce the hydride transfer to furnish iminium ion III. Subsequently, the C3 or C3′ position of bisoxindoles would attack the iminium ion, aﬀording the 6/5/5 or 6/5/6 [3,4]fused oxindole. Remarkbly, harnessing the cascade hydride transfer/cyclization from readily available isatins to synthesize spirocyclic bisoxindoles remains an unknown chemistry. To realize this reaction cascade, several challenges need to be addressed: (1) the nucleophile should be active enough to attack the C3 carbonyl group of isatin, since the electrophilicity of the carbonyl group is largely reduced by the electrondonating nitrogen atom at C4 position; (2) the electrophilic carbon center of intermediate II should prefer triggering the
was used as a catalyst to examine this reaction at 80 °C. Satisfyingly, this reaction proceeded very well, aﬀording the desired 6/5/6 [3,4]-fused oxindole 3a in 76% yield (Table 1, entry 1). Intriguingly, this reaction exhibited excellent stereocontrol (>20:1 dr). Encouraged by this result, a variety of triﬂate salts were further evaluated and they were all ineﬀective, even when the temperature was increased to 120 °C (Table 1, entries 2−4). Moreover, the use of InBr3 and ZnBr2 was also unsuccessful (Table 1, entries 5 and 6). Then Sc(OTf)3 was chosen as the most suitable catalyst for further screening. Afterward, the molecular sieves were employed as additives aiming to improve the eﬃciency. To our delight, the 5 Å molecular sieves turned out to be the most eﬀective additive, furnishing 3a in 92% yield (Table 1, entries 7−9). The subsequent solvent screening indicated that the employment of other solvents gave inferior results (Table 1, entries 10−13). As expected, decreasing the catalyst loading was detrimental for this reaction, albeit without inﬂuence on diastereoselectivity (Table 1, entry 14). Finally, the control B
DOI: 10.1021/acs.orglett.8b04100 Org. Lett. XXXX, XXX, XXX−XXX
Afterward, the generality of 2-indolinones was also examined (Scheme 3). Pleasingly, either electron-donating or electron-
experiment implied that this reaction did not occur in the absence of catalyst (Table 1, entry 15). Having identiﬁed the optimal reaction conditions, the substrate scope with regard to isatins and 2-indolinones were examined to check the generality of this strategy (Scheme 2). It
Scheme 3. Substrate Scope of 2-Indolinonesa
Scheme 2. Substrate Scope of C4-Amine-Substituted Isatinsa
Reaction conditions: 1a (0.1 mmol), 2 (0.15 mmol), Sc(OTf)3 (0.02 mmol), and 5 Å MS (50 mg) in 1.0 mL of distilled DCE at 80 °C for 12 h; isolated yield after column chromatography; dr >20:1, dr was determined by 1H NMR spectroscopy.
withdrawing groups on the aromatic ring of 2-indolinones were totally compatible, giving rise to the corresponding products 3p−s in good yields. Nevertheless, the yields of electrondonating groups were comparably lower than those of the electron-withdrawing groups. Further investigation manifested that 2-indolinones with free N-H and N-Ph groups could also participate in this reaction, yielding 3t−u in high yields. In addition, the large scale synthesis of 3u to demonstrate the scalability of this protocol had been performed (see Supporting Information). The structure and relative conﬁguration of 3u have been unambiguously conﬁrmed by X-ray crystallographic analysis (Figure 2). Remarkably, in all cases, this reaction exhibited high stereocontrol (>20:1 dr). Hence, this methodology provides an eﬃcient synthetic route to these privileged structures, which are of great signiﬁcance for natural products and medicinal chemistry.
Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Sc(OTf)3 (0.02 mmol), and 5 Å MS (50 mg) in 1.0 mL of distilled DCE at 80 °C for 12 h; isolated yield after column chromatography; dr >20:1, dr was determined by 1H NMR spectroscopy.
seemed that the protecting groups on nitrogen of isatins had trivial eﬀect on the eﬃciency. For instance, the benzyl, methyl and ethyl carbamate were well tolerated in this cascade process, delivering the corresponding products 3a−h in good to excellent yields. Gratifyingly, apart from the pyrrolidine ring, the piperidine, morpholine, azepane, and octahydroisoindole rings also worked very well, aﬀording the desired products 3i− m in satisfying yields without loss in diastereoselectivities (>20:1 dr). Besides, the isatins bearing substituents on the phenyl ring showed slightly lower reactivity, aﬀording 3n−o in 61% and 69% yields, respectively.
Figure 2. Single-crystal structure of 3u. C
DOI: 10.1021/acs.orglett.8b04100 Org. Lett. XXXX, XXX, XXX−XXX
Organic Letters ORCID
In order to probe the mechanism of this transformation, the deuterated substrate [D]-1a was prepared and subjected to the optimal conditions (Scheme 4). The deuteration (29% D) at
S.-S. Li, S. Zhu, and C. Chen contributed equally.
The authors declare no competing ﬁnancial interest.
ACKNOWLEDGMENTS We are grateful to NSFC (21702117, 21878167) and the Natural Science Foundation of Shandong Province (JQ201604, ZR2017BB005) as well as the Key Research and Development Program of Shandong Province (2017GSF218073). We thank Dr. Fengying Dong and the Central Laboratory of Qingdao Agricultural University for NMR determination.
the C3 position of product [D]-3a fully corroborated the occurrence of intramolecular [1,5]-hydride transfer, while the loss of deuterated ratio might be ascribed to the enol tautomerism of cyclic amide (eq 1). Furthermore, a deuterium kinetic isotope eﬀect (DKIE) of 2.0 was obtained through competitive reaction between substrates 1a and [D]-1a, implying that the intramolecular [1,5]-hydride transfer process might be involved in the rate-determining step (eq 2). In conclusion, a new scandium-catalyzed cascade [1,5]hydride transfer/cyclization was developed for facile construction of spirocyclic bisoxindoles with a [3,4]-fused oxindole moiety from rationally designed C4-amine-substituted isatins. This methodology enables the rapid synthesis of spirocyclic bisoxindole alkaloids with three consecutive chiral centers in good yields and excellent diastereoselectivities, featuring good functional group compatibility, wide substrate scope as well as ready availability of reactant and simple operation. Considering the vital importance of spirocyclic bisoxindole alkaloids in natural products and pharmaceuticals, this method not only provides a powerful synthetic tool for rapid buildup of the library of [3,4]-fused oxindoles for medicinal evaluation, but also pushes forward the application of the hydride transfer chemistry in one-step construction of complex molecules.
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b04100. Experimental procedures, and characterization data for all the products ((PDF) Accession Codes
CCDC 1815971 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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