Letter Cite This: Org. Lett. 2018, 20, 652−655
pubs.acs.org/OrgLett
Directing Group Participated Benzylic C(sp3)−H/C(sp2)−H CrossDehydrogenative Coupling (CDC): Synthesis of Azapolycycles Yaojia Jiang,*,† Gongtao Deng,† Shuaishuai Zhang,† and Teck-Peng Loh*,†,‡ †
Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China ‡ Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University, Singapore 637616, Singapore S Supporting Information *
ABSTRACT: An efficient method to construct azapolycycles via directing group participated benzylic C(sp3)−H/C(sp2)− H cross-dehydrogenative coupling reactions is described. The reaction proceeded through a palladium catalyzed C(sp3)−H activation followed by coupling with a C(sp2)−H bond of quinoline to afford the azapolycyclic compounds. The reaction works with a broad substrate scope affording the products in moderate to good yields with excellent diastereoselectivities. Control experiments further supported the proposed mechanism.
P
uncovered involving the initial C(sp3)−H bond activation.7 Another strategy employing oxidative single electron transfer (SET) cross-coupling of C(sp3)−H/C(sp2)−H has also recently been achieved by Wang (Scheme 1b).8 However, to the best of our knowledge, there is no report on the use of C(sp3)−H to construct fused rings in polycycles. During the course of searching for new C(sp3)−H activation methods by using amide 1 with 8-aminoquinoline9 as a bidentate directing group in the presence of a palladium catalyst, we unexpectedly obtained 2 in 11% yield.10 This result encouraged us to further optimize the reaction conditions to develop a new method for the construction of useful aza-polycycles. Herein, we disclose a straightforward and efficient method for the construction of aza-tricycles via palladium catalyzed C(sp3)−H/C(sp2)−H cross-dehydrogenative coupling reactions. The reaction works with a broad substrate scope affording the products in moderate to good yields with excellent diastereoselectivities. Initially, we explored the palladium catalyzed reactions using 2-(1, 3-dioxoisoindolin-2-yl)-3-phenyl-N-(quinolin-8-yl) propanamide 1a as a substrate under different reaction conditions (Table 1). As shown in Table 1, we found that when the reaction was carried out in 10 mol % Pd(OAc)2, 15 mol % 2,2′bipyridine, and 2.0 equiv AgOAc in HFIP/HOAc at 160 °C under N2 atmosphere, the desired product 2a was obtained in the highest yield (77% isolated yield) (Table 1, entry 17) as a single diastereomer. The structure of this product 2a was determined by NMR spectroscopies and further confirmed by a single crystal X-ray analysis (CCDC: 1579692) (Figure 1).
olycyclic compounds are featured widely in many pharmaceuticals and advanced materials.1 Many of these compounds have fused rings containing sp3/sp2 carbon−carbon bond linkages.2 A direct and efficient strategy to access this class of compounds is via an intramolecular C(sp3)−H/ C(sp2)−H cross-coupling reaction to construct the fused rings.3 This strategy has recently been elegantly exploited by the Fagnou,4 Shi,5 and Baudoin groups6 for the construction of polycyclic compounds (Scheme 1a). In all these cases, the reactions involved the initial C(sp2)−H activation followed by coupling with a C(sp3)−H bond. There are also some limited intermolecular CDC coupling examples that have been Scheme 1. C(sp3)−H/C(sp2)−H Cross-Coupling Reactions
Received: December 6, 2017 Published: January 12, 2018 © 2018 American Chemical Society
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DOI: 10.1021/acs.orglett.7b03748 Org. Lett. 2018, 20, 652−655
Letter
Organic Letters Table 1. Reaction Conditions Optimizationa
Scheme 2. Substrate Scopea,b
entry
ligand
oxidant
solvent
yieldb
1 2 3 4 5 6 7 8 9 10 11 13 14 15 16 17
PPh3 DPPP 1,10-phen Dp-1,10-phen Dm-2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy
AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc Ag2O AgNO3 AgF AgOTf Ag2CO3 AgOAc AgOAc AgOAc AgOAc AgOAc
DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE DCE TCE PhCl HFIP DMSO HFIP/HOAc
11 8 49 43 49 54 20 30 29 15 − 17 11 60 − 80/77c
a
Unless otherwise noted, reactions were performed using 1a (0.2 mmol), catalyst (10 mol %), ligand (15 mol %), and oxidant (2.0 equiv) in solvent (0.1 M, 1 mL) at 160 °C for 72 h under a nitrogen atmosphere. bYields determined by NMR vs standard. cIsolated yield. 1,10-phen = 1,10-phenanthroline, Dp-1,10-phen = 4,7-diphenyl-1,10phenanthroline, Dm-2,2′-bpy = 5,5′-dimethyl-2,2′-bipyridine, 2,2′-bpy = 2,2′-bipyridine, HFIP = hexafluoroisopropanol.
Figure 1. X-ray of 2a.
With the optimized reaction conditions in hand, we further investigated the substrate scope of the reaction (Scheme 2). Generally, the reactions tolerated a broad range of functionalities to afford the substituted 4-phenyl-3,4-2H-1,10-phenanthroline analogs in good yields with single diastereomers. Subjecting chiral amino acid derivative 1a in the optimized reaction conditions afforded 2a in 75% yield with complete retention of the stereogenicity (99% ee). Substrates with a halogen (F, Cl, Br, and I) substituted at the para-position of phenyl ring were explored and found to furnish the desired products in good yields (2b−2e). It should be noted that the chloro, bromo, and iodo functionalities are common functional groups used in coupling reactions,11 and this will allow further transformation to other useful compounds. The electronic effect was then studied by changing different substitutions on the phenyl group. The result revealed that both substrates containing electron-donating (2f−2i) and electron-withdrawing (2j−2p) groups proceeded smoothly to afford the desired products in moderate to good yields. Reactive functional groups such as CN, ketone, and aldehyde groups are well tolerated under these reaction conditions to give the corresponding
a
Unless otherwise noted, reactions were carried out using 1 (0.2 mmol), Pd(OAc)2 (10 mol %), 2, 2-bipyridine (15 mol %), and AgOAc (2.0 equiv) in HFIP/HOAc (0.1 M, 2 mL) at 160 °C under a nitrogen atmosphere, and the products are obtained as a single diastereomer. bIsolated yields. cThe ee value was determined by HPLC analysis on a chiral stationary phase.
tricycles in 55%, 60%, 60%, and 76% yields, respectively (2n− 2q). Notably, the heterocycles indole group could also be used in this reaction, affording the desired product in 51% yield (2r). However, replacing the R = aryl group with an alkyl, alkenyl, or alkynyl group led to no desired product (2aa−2ac). This result 653
DOI: 10.1021/acs.orglett.7b03748 Org. Lett. 2018, 20, 652−655
Letter
Organic Letters is consistent with C(sp3)−H work using the same substrate reported by other groups.12 With these encouraging results in hand, we turned our attention to the probable reaction pathways of this unique C(sp3)−H/C(sp2)−H cross-coupling reaction (Scheme 3).
A is involved in the reaction (Scheme 4c). On the basis of this result, we proposed that the reaction first involved the complexation of the palladium catalyst to the quinolone ring followed by C(sp3)−H bond activation generating complex A in a highly stereoselective manner. Coupling with the quinoline 7-site C(sp2)−H bond furnished the desired product. Considering that 1,10-phenanthroline derivatives can also function as important ligands in the transition metal catalyzed reactions, we explored the possibility of oxidizing the obtained products to substituted 1,10-phenanthroline derivatives (Scheme 5). To our delight, the desired products were
Scheme 3. Proposed Reaction Pathways
Scheme 5. Transform to 1,10-Phenanthroline Derivativesa,b
Initially, the reaction proceeded via an AQ directed benzylic C(sp3)−H bond activation to generate palladium species A in a stereoselective manner. This step has been well studied by many different groups.13 Subsequently, this intermediate A could proceed through two possible pathways leading to the formation of either β-lactam B or intermediate D. The intermediate A underwent reductive elimination to β-lactam B (Scheme 3, pathway A). On the other hand, the palladium species can also form complex C through C−N bond rotation and activation of the C(sp2)−H bond of the 8-amino quinoline. Reductive elimination with retention of the stereochemistry will lead to the trans-product 4-phenyl-3,4-2H-1,10-phenanthroline 2. To understand the mechanism, we carried out a series of control experiments. First, we conducted the reaction with 3.0 equiv of TEMPO. In this reaction, the desired product was obtained in 21% yield with a 47% yield of the starting material (Scheme 4a). This result, though not conclusive, showed that
a Unless otherwise noted, reactions were carried out using 2 (0.2 mmol) and DDQ (1.5 equiv) in DCE (0.1 M, 2 mL) at 100 °C under a nitrogen atmosphere. bIsolated yields.
obtained in good yields when DDQ was used as the oxidant.14 Various substituents including F, Br, CF3, and NO2 groups are well tolerated in this reaction. These versatile functional groups allow further transformations to other phenanthroline derivatives. In summary, an efficient method for the synthesis of azapolycles was described. This method involves a palladiumcatalyzed C(sp3)−H bond functionalization followed by an intramolecular coupling with the arene sp2 carbon to form an sp3−sp2 carbon−carbon fused ring. This reaction tolerates a wide range of functional groups (halogens, OMe, NO2, CF3, CHO, etc.) and the desired products were obtained in moderate to good yields with excellent diastereoselectivities. Control experiments were explored, and the results supported our proposed mechanism. Furthermore, the obtained products were easily converted to 2-hydroyl-1,10-phenanthrolines which are useful compounds in coordination chemistry. Further work on the use of this strategy to construct other fused rings is in progress.
Scheme 4. Control Experiments
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this reaction may not proceed through a radical pathway. Subjecting the β-lactam 4 to the reaction conditions led to recovery of the starting material. Ring-expansion product 2a was not detected in this reaction, indicating that the compound 4 was not the intermediate of the reaction (Scheme 4b). However, when phenyl iodide was added into the reaction mixture, the arylation product 5 was detected in 20% yield. This further confirms that the C(sp3)−H bond activated Pd complex
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03748. Experimental procedures and characterization data for new compounds (PDF) 654
DOI: 10.1021/acs.orglett.7b03748 Org. Lett. 2018, 20, 652−655
Letter
Organic Letters Accession Codes
(6) Shi, J.-L.; Wang, D.; Zhang, X.-S.; Li, X.-L.; Chen, Y.-Q.; Li, Y.-X.; Shi, Z.-J. Nat. Commun. 2017, 8, 238. (7) Examples on initial C(sp 3 )−H activation followed by intermolecular cross-coupling with C(sp2)−H bond reactions: (a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 3680−3681. (b) Wu, X.; Zhao, Y.; Ge, H. Chem. Sci. 2015, 6, 5978− 5983. (c) Tan, G.; You, J. Org. Lett. 2017, 19, 4782−4785. (d) Wang, X.; Xie, P.; Qiu, R.; Zhu, L.; Liu, T.; Li, Y.; Iwasaki, T.; Au, C.-T.; Xu, X.; Xia, Y.; Yin, S.-F.; Kambe, N. Chem. Commun. 2017, 53, 8316− 8319. (e) Li, B.; Fang, S.-L.; Huang, D.-Y.; Shi, B.-F. Org. Lett. 2017, 19, 3950−3953. (8) Wang, R.; Li, Y.; Jin, R.-X.; Wang, X.-S. Chem. Sci. 2017, 8, 3838− 3842. (9) For pioneering examples of using 8-aminoquinoline as the bidentate directing group in C(sp3)−H activation, see: (a) Zaitsev, V.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154− 13155. (b) Reddy, B. V.; Reddy, L. R.; Corey, E. J. Org. Lett. 2006, 8, 3391−3394. (c) Pan, F.; Shen, P.-X.; Zhang, L.-S.; Wang, X.; Shi, Z.-J. Org. Lett. 2013, 15, 4758−4761. (d) Guo, H.; Chen, M.; Jiang, P.; Chen, J.; Pan, L.; Wang, M.; Xie, C.; Zhang, Y. Tetrahedron 2015, 71, 70−76. (10) A similar fused ring was obtained by Wu group as a byproduct in trace amount (up to 8% yield): (a) Sun, W.-W.; Cao, P.; Mei, R.-Q.; Li, Y.; Ma, Y.- L.; Wu, B. Org. Lett. 2014, 16, 480−483. (b) Zhang, S.J.; Sun, W.-W.; Cao, P.; Dong, X.-P.; Liu, J.-K.; Wu, B. J. Org. Chem. 2016, 81, 956−968. (11) (a) Suryakiran, N.; Prabhakar, P.; Reddy, T. S.; Mahesh, K. C.; Rajesh, K.; Venkateswarlu, Y. Tetrahedron Lett. 2007, 48, 877−881. (b) Powers, L. J.; Fogt, S. W.; Ariyan, Z. S.; Rippin, D. J.; Heilman, R. D. J. Med. Chem. 1981, 24, 604−609. (12) Zhang, Q.; Chen, K.; Rao, W.; Zhang, Y.; Chen, F.-J.; Shi, B.-F. Angew. Chem., Int. Ed. 2013, 52, 13588−13592. (13) (a) Labinger, J. A.; Hart, D. W.; Seibert, W. E., III; Schwartz, J. J. Am. Chem. Soc. 1975, 97, 3851−3852. (b) Fryzuk, M. D.; Bosnich, B. J. Am. Chem. Soc. 1979, 101, 3043−3049. (c) Tran, L. D.; Daugulis, O. Angew. Chem., Int. Ed. 2012, 51, 5188−5191. (14) Kaiser, D.; Torre, A.; Shaaban, S.; Maulide, N. Angew. Chem., Int. Ed. 2017, 56, 5921−5925.
CCDC 1579692 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 data_
[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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AUTHOR INFORMATION
Corresponding Authors
*
[email protected]. *
[email protected]. ORCID
Teck-Peng Loh: 0000-0002-2936-337X Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS The authors gratefully acknowledge funding from the National Natural Science Foundation of China (21502089), Jiangsu Province Funds Surface Project (BK 20161541), and the Starting Funding of Research (39837107) from Nanjing Tech University. We are also thankful for the financial support by SICAM Fellowship by Jiangsu National Synergetic Innovation Center for Advanced Materials. Dr. Li Yongxing (NTU) is thanked for single crystal X-ray diffraction analysis.
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DOI: 10.1021/acs.orglett.7b03748 Org. Lett. 2018, 20, 652−655
