Letter pubs.acs.org/OrgLett
Synthesis of Spiro-dihydroquinoline and Octahydrophenanthrene Derivatives via Palladium-Catalyzed Intramolecular Oxidative Arylation Zhong-Lin Zang,† Shuklachary Karnakanti,† Sheng Zhao, Ping Hu, Zhen Wang, Pan-Lin Shao,* and Yun He* School of Pharmaceutical Sciences and Innovative Drug Research Centre, Chongqing University, 55 Daxuecheng South Road, Shapingba, Chongqing 401331, P.R. China S Supporting Information *
ABSTRACT: A method for intramolecular sp 2 C−H oxidative arylation of unactivated cyclic olefins has been developed to access spiro-dihydroquinoline and octahydrophenanthrene derivatives in a straightforward and efficient manner. Bearing picolinamide as a directing group, the alkenyl anilines cyclized to afford spiro-dihydroquinolines in moderate to excellent yields via direct oxidative arylation, while the alkenyl benzylamines furnished the octahydrophenanthrene derivatives in moderate yields via sequential oxidative arylation and double acetoxylation.
research in palladium-catalyzed C−H activation,7 herein we report the development of an intramolecular Fujiwara− Moritani/oxidative Heck cyclization to synthesize spirodihydroquinoline and octahydrophenanthrene derivatives employing the same palladium catalytic system. The Heck reaction is of great importance to the formation of C−C linkages between aryl/vinyl halides or pseudohalides and activated alkenes.8 The Fujiwara−Moritani reaction, a different strategy of oxidative coupling of an unfunctionalized arene directly with an olefin, thus obviates the need for prehalogenation of the starting material.9 The intermolecular version of this reaction has been under active investigation and proven to be highly fruitful.10 In contrast, the intramolecular oxidative arene/ olefin coupling, especially with unactivated olefins, has been poorly studied.11 We envisioned that such an intramolecular combination of electron-rich arene and unactivated olefin may lead to an efficient synthesis of the difficult-to-access spirocycles. As illustrated in Scheme 1, the spiro-cyclization may proceed via arene palladation with subsequent olefin insertion and βhydrogen elimination. We began investigations of the intramolecular alkenyl sp2 C− H oxidative arylation using anilide 1a as a model substrate, which contains a tethered cycloalkene moiety and a picolinamide (PA) as a directing group (Table 1). After screening various reaction conditions, we isolated the desired spiro-dihydroqunoline 2a in 80% yield employing the following catalytic system [Pd(OAc)2 (0.10 equiv), PhI(OAc)2 (2.50 equiv), 2-chloro-4-cyanopyridine
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piro-hydroquinoline and hydrophenanthrene skeletons have emerged as privileged structure moieties found in a number of biologically active natural products and pharmaceutically important compounds,1 such as (+)-aspernomine,2 sespenine,3 (+)-cassaine,4 estrone,5 and analogous steroids (Figure 1). Moreover, these scaffolds are convenient and versatile building blocks to construct pharmaceutically relevant compounds, yet they have not been thoroughly studied.6 Accordingly, it is highly desirable to synthesize new compounds possessing these substructure moieties for drug discovery. To continue our
Figure 1. Natural products containing spiro-dihydroquinoline and octahydrophenanthrene moieties. © XXXX American Chemical Society
Received: January 22, 2017
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DOI: 10.1021/acs.orglett.7b00228 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Using this catalytic protocol, a wide range of spirodihydroquinolines 2 were prepared as shown in Scheme 2. We
Scheme 1. Synthesis of Spiro-dihydroquinoline via PalladiumCatalyzed Intramolecular Fujiwara−Moritani Oxidative Heck Reactions
Scheme 2. Substrate Scope of Alkenyl Anilinesa−d
Table 1. Optimization of the Arylation Reactiona,b
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16
variation from the “standard” conditions none without Pd(OAc)2 or PhI(OAc)2 PdCl2(PhCN)2 instead of Pd(OAc)2 PdCl2(PPh3)2 instead of Pd(OAc)2 PdCl2(dppf) instead of Pd(OAc)2 FeCl3, RuCl3, Sc(OTf)3, Bi(OTf)3 or In(OTf)3 instead of Pd(OAc)2 without PyClCN PhCN instead of PyClCN 2,2-bipyridine instead of PyClCN 4,5-diazafluoren-9-one instead of PyClCN S-BINAP instead of PyClCN S-BINAL instead of PyClCN DCE instead of toluene DMF instead of toluene CH3CN instead of toluene 80 °C instead of 110 °C
yield (%) 80 0 55 38 51 0 20 68 20:1). Accordingly, we further evaluated various α-aryl substituents, such as p-Me, p-OMe, or pF, which were all tolerated and led to octahydrophenanthrene derivatives in moderate yields (5a−d, 31−60%). The structure and relative configuration of 5c were determined unambiguously via single-crystal X-ray crystallography12 (see the SI).
acetoxylation octahydrophenanthrene products 5a′ and 5a were generated, albeit with very low yields. This result suggests that these transformations are initiated through an alkene sp2 C−H activation with subsequent nucleophilic attack of the arene on the Pd(II)−π complex and acetoxylation to provide the monoacetoxylation product 5a′, followed by intramolecular aryl sp2 C−H activation and acetoxylation to furnish the final doubleacetoxylation derivative 5a. In summary, we have developed a method to access spirodihydroquinoline and octahydrophenanthrene derivatives from C
DOI: 10.1021/acs.orglett.7b00228 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
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simple substrates in a straightforward and efficient manner. Bearing picolinamide as a directing group, the alkenyl anilines (1a−o) cyclized to afford spiro-dihydroquinolines (2a−o) in moderate to excellent yields via direct oxidative arylation, while the alkenyl benzylamines (3a−d) furnished the octahydrophenanthrene derivatives (5a−d) in moderate yields via sequential oxidative arylation and double acetoxylation. Studies to establish asymmetric oxidative arylation are currently ongoing in our laboratory.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00228. Experimental procedures, characterization of the products, X-ray analysis, and NMR spectra (PDF)
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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Yun He: 0000-0002-5322-7300 Author Contributions †
Z.-L.Z. and S.K. contributed equally.
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21372267, 21402150, 21572027, 21602023), a Postdoctoral Research Grant (2016M602658), and Chongqing Research and Frontier Technology (cstc2016jcyjA0403). We thank Dr. Yong-Liang Shao (Lanzhou University) and Xiangnan Gong (Chongqing University) for the X-ray crystallographic analysis.
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DOI: 10.1021/acs.orglett.7b00228 Org. Lett. XXXX, XXX, XXX−XXX
