Letter Cite This: Org. Lett. 2018, 20, 1154−1157
pubs.acs.org/OrgLett
Bisannulation of Benzamides and Cyclohexadienone-Tethered Allenes Triggered by Cp*Rh(III)-Catalyzed C−H Activation and Relay Ene Reaction De-Shen Kong,†,‡ Yi-Fan Wang,‡ Yi-Shuang Zhao,‡ Qing-Hua Li,† Yue-Xin Chen,‡ Ping Tian,*,†,‡ and Guo-Qiang Lin*,†,‡ †
Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China ‡ Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China S Supporting Information *
ABSTRACT: The diastereoselective bisannulation of N(pivaloyloxy)benzamides and cyclohexadienone-tethered allenes was accomplished through Cp*Rh(III)-catalyzed C−H activation and relay ene reaction, providing a 3-isoquinolonyl cishydrobenzofuran framework with high yields and diastereoselectivities. This reaction tolerates a wide range of functional groups, enabling further conversions to tricyclic and bridged-ring structures. Moreover, the dearomatization modification of phenol-contained bioactive molecule is also elaborated. he extraordinary advances over the past decade in the field of transition-metal-catalyzed direct C−H bond activation have progressively established this powerful approach as a valuable tool for organic synthesis. Among these transformations, the Cp*Rh(III)-complex unambiguously stands out as a privileged catalyst for direct functionalization of various aromatic and vinylic compounds.1 A variety of directing groups, such as heterocycles,2 hydroxy,3 ketones,4 imines,5 oximes,6 hydrazones,7 nitrones,8 N-oxides,9 azomethine ylides,10 urea,11 carboxylic acid derivatives,12−15 sulfonamides,16 etc., have been developed. In particular, the application of oxidizing directing groups (internal oxidants) proved to be a great breakthrough, as this approach avoided the use of strong external oxidants and enabled milder reaction conditions.6−9,15 Allenes serve as useful synthetic building blocks in organic synthesis due to their characteristic structure and electronic properties.17 During the context of Cp*Rh(III)-catalyzed direct C−H activation, the use of allenes as original coupling partners has also been the focus of much attention. In 2012, Glorius and Wang demonstrated that Cp*Rh(III)-catalyzed intermolecular annulation of N-(pivaloyloxy)-benzamides and monosubstituted allenes could generate the cyclized products with an exocyclic double bond (Scheme 1, eq 1).18 Almost at the same time, Ma and co-workers discovered a different pathway, in which Cp*Rh(III)-catalyzed coupling of N-methoxybenzamides and di- or trisubstituted allenes provided noncyclized monoallylated products (Scheme 1, eq 1).19 Following these pioneering results, various functionalized allenes were subjected to this coupling reaction to prepare valuable scaffolds
T
© 2018 American Chemical Society
(Scheme 1, eq 1).20 However, the allenes containing a Michael acceptor moiety have never been reported in this arena to our knowledge. Herein, we present an intermolecular bisannulation of benzamides and cyclohexadienone-tethered allenes triggered by Cp*Rh(III)-catalyzed C−H activation and the relay ene reaction. As for cyclohexadienone-tethered allene substrates,21 the direct arylrhodation to the Michael acceptor is suppressed by the steric congestion imposed by the neighboring quaternary carbon (Scheme 1, eq 2).22 Thus, the intermolecular annulation of N-(pivaloyloxy)benzamides and monosubstituted allenes preferentially occurs to afford the cyclized products B with an exocyclic double bond. Subsequently, the exocyclic double bond undertakes a relay ene reaction with the Michael acceptor. As a result, the second annulation generates three consecutive stereogenic centers, affording isoquinolone and cis-hydrobenzofuran structures with high diastereoselectivities. With this consideration, the intermolecular bisannulation of benzamides and cyclohexadienone-tethered allene 2a was evaluated and selected results are summarized in Table 1.23 As for N-methoxybenzamide (1a′), no desired product was observed under Ma’s conditions (Table 1, entry 1).19,24 To our delight, the use of N-(pivaloyloxy)benzamide (2a) as a coupling partner at room temperature afforded the bisannulation product 3aa, albeit in poor yield (Table 1, entry 2).18 Increasing the reaction temperature could dramatically improve Received: January 8, 2018 Published: January 26, 2018 1154
DOI: 10.1021/acs.orglett.8b00083 Org. Lett. 2018, 20, 1154−1157
Letter
Organic Letters
cycloalkyl, allyl, benzyl, and phenyl group, were well tolerated, and the reactions proceeded smoothly with high yields (50%− 71%) and diastereoselectivities (dr = ∼85:15, Scheme 2, 3aa− 3ah). The relative stereochemistry of the product 3aa was unambiguously assigned by X-ray crystallography (CCDC 1812845). With a heteroatom (O, Si, or Br) as part of the R1 substituent in allenes 2, the yields and diastereoselectivities remained at a good level (Scheme 2, 3ai−3am). It was specially noted that the highly reactive bromoalkyl group was
Scheme 1. Strategic Design
Scheme 2. Scope of Allenes and Arylamidesa
Table 1. Selected Optimization Studiesa
entry
solvent
temp (°C)
time (h)
drb
yieldc (%)
1 2 3 4 5 6 7 8 9 10 11d 12d,e
MeOH acetone acetone acetone acetone MeOH THF DCE DMF DMSO acetone acetone
−20 25 50 70 100 70 70 70 70 70 70 70
15 33 9 8 8 9 9 9 9 9 9 10
− − − 84:16 84:16 72:28 85:15 73:27 86:14 82:18 85:15 85:15
mess 8 27 66 66 54 57 47 65 46 70 71
a
Reactions were performed under an air atmosphere. bDetermined by H NMR analysis of unpurified mixtures. cYield of isolated product 3aa (major isomer). dWithout PivOH. e[Cp*RhCl2]2 (1.0 mol %) and CsOAc (10 mol %) were used. 1
the yield (Table 1, entries 3−5). Other solvents (MeOH, THF, DCE, DMF, and DMSO) were screened, but no enhancement was observed in either yield or stereoselectivity (Table 1, entries 6−10). Notably, the reaction still proceeded well with a high yield and diastereoselectivity without a pivalic acid (PivOH) additive (Table 1, entry 11). Even with a lower loading of the Rh-catalyst and CsOAc base, the reaction yield and diastereoselectivity were maintained at a comparative level (Table 1, entry 12). With the optimal conditions identified, we next evaluated the scope of allenes 2. Different R1 substituents, such as the alkyl,
a
Reactions were performed under an air atmosphere. bDetermined by H NMR analysis of unpurified mixtures. cYield of isolated product 3 (major isomer). d1.0 mmol of 1a and 1.1 mmol of 2c were used. e DMF, 140 °C, 5 h. fDMF, 150 °C, 8 h. 1
1155
DOI: 10.1021/acs.orglett.8b00083 Org. Lett. 2018, 20, 1154−1157
Letter
Organic Letters
conversion. When 3ak was treated with TBAF, the resulting alkoxy anion underwent an intramolecular Michael addition to furnish the tricyclic product 5ak. As for 3am, the corresponding iodide product was easily obtained through a halogen exchange. Further treatment with LiHMDS led to an intramolecular alkylation, affording the bridged ring product 7am. The phenol structure numerously exists in bioactive molecules. As for estrone (8), the phenol moiety was readily dearomatized to deliver the cyclohexadienone-tethered allene substrate 9 (Scheme 4).21b Using our above optimized procedure, the bisannulation reaction occurred uneventfully to afford optically pure polycyclic product 10 with potential pharmaceutical use (Scheme 4). This synthetic sequence provided an asymmetric dearomatization of phenol, and the absolute configuration of 10 was confirmed by X-ray crystallography (CCDC 1812847). In summary, the diastereoselective bisannulation of N(pivaloyloxy)benzamides and cyclohexadienone-tethered allenes has been established through a Cp*Rh(III)-catalyzed C−H activation strategy and subsequent ene reaction. This reaction proceeded smoothly to deliver a 3-isoquinolonyl cishydrobenzofuran framework with high yields (up to 81% for major isomer) and diastereoselectivities (dr up to 95:5). The bisannulation products could be easily converted to tricyclic and bridged-ring structures. Additionally, this reaction was successfully applied to asymmetric dearomatization modification of a phenol-contained bioactive molecule. Further studies on the applications of di- and trisubstituted allenes tethered with a cyclohexadienone moiety are in progress in our laboratories and will be reported in due course.
comfortably tolerated in such a transformation (Scheme 2, 3am). As for cyclohexadienone-tethered allenes with an α-, βsubstituted, or α,β-disubstituted enone unit, promising yields and high diastereoselectivities were still observed (Scheme 2, 3an−3as). It was interesting that tetrahydroindenone-tethered allene 2t afforded the unexpected cyclization product 3at rather than a spiro-product. The structure of 3at was further confirmed by X-ray crystallography (CCDC 1812846). For the C-linked allene 2u, the reaction proceeded equally well to deliver bisannulation product 3au. Following the substrate studies, we next evaluated the scope of arylamides 1. In line with our expectation, all o-, m-, and psubstituted benzamides, regardless of the electron-donating or -withdrawing ability of the substituent at the phenyl ring, gave moderate yields and good diastereoselectivities (Scheme 2, 3ba−3ha). The replacement of the phenyl ring with a pyridine ring, such as isonicotinamide 1i, also provided the corresponding product 3ia. Electron-rich aromatic heterocycles, such as furan 1j and thiophene 1k, which could potentially be oxidized under oxidative conditions, uneventfully afforded the bisannulation products in high yields (Scheme 2, 3ja−3ka). To verify the ene reaction mechanism, allene d2-2a was subjected to this reaction with 1a at room temperature, and the intermediates d2-4aa could be isolated in 86% yield (Scheme 3). Upon heating at 70 °C for 5 h, the second annulation took Scheme 3. Deuterium-Labeling Experiments
■
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b00083. Experimental procedures, spectra for all new compounds (PDF)
place, leading to deuterium incorporation (100%) onto the αposition of ketone. Such migration of deuterium confirmed that the second annulation underwent an intramolecular ene process. As revealed in Scheme 4, the diverse substituents in the bisannulation products can serve as a flexible handle for further
Accession Codes
CCDC 1812845−1812847 contain 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.
Scheme 4. Several Transformations
■
AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected];
[email protected]. *E-mail:
[email protected]. ORCID
Ping Tian: 0000-0002-5612-0664 Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Financial support was generously provided by the 973 Program (2015CB856600), NSFC (21372243, 21572251, 21572253), and the Collaborative Innovation Center of Chemical Science 1156
DOI: 10.1021/acs.orglett.8b00083 Org. Lett. 2018, 20, 1154−1157
Letter
Organic Letters
(15) For selected examples on of hydroxamic acid as a DG, see: (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010, 132, 6908−6909. (b) Hyster, T. K.; Knörr, L.; Ward, T. R.; Rovis, T. Science 2012, 338, 500−503. (c) Ye, B.; Cramer, N. Science 2012, 338, 504−506. (d) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, 2350−2353. (e) Karthikeyan, J.; Haridharan, R.; Cheng, C.-H. Angew. Chem., Int. Ed. 2012, 51, 12343−12347. (f) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Angew. Chem., Int. Ed. 2013, 52, 6033− 6037. (16) For selected examples on sulfonamide as a DG, see: Li, X.; Gong, X.; Zhao, M.; Song, G.; Deng, J.; Li, X. Org. Lett. 2011, 13, 5808−5811. (17) For comprehensive reviews on allenes, see the themed issue: Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2014, 43, 2886−2887 and references cited therein. (18) Wang, H.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 7318− 7322. (19) Zeng, R.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2012, 134, 9597− 9600. (20) (a) Wang, H.; Beiring, B.; Yu, D.-G.; Collins, K. D.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 12430−12434. (b) Ye, B.; Cramer, N. J. Am. Chem. Soc. 2013, 135, 636−639. (c) Zeng, R.; Wu, S.; Fu, C.; Ma, S. J. Am. Chem. Soc. 2013, 135, 18284−18287. (d) Zeng, R.; Ye, J.; Fu, C.; Ma, S. Adv. Synth. Catal. 2013, 355, 1963−1970. (e) Wu, S.; Zeng, R.; Fu, C.; Yu, Y.; Zhang, X.; Ma, S. Chem. Sci. 2015, 6, 2275− 2285. (f) Xing, Z.; Huang, F.; Sun, C.; Zhao, X.; Liu, J.; Chen, D. Inorg. Chem. 2015, 54, 3958−3969. (g) Zhou, Z.; Liu, G.; Lu, X. Org. Lett. 2016, 18, 5668−5671. (h) Ji, C.; Xu, Q.; Shi, M. Adv. Synth. Catal. 2017, 359, 974−983. (i) Jia, Z. J.; Merten, C.; Gontla, R.; Daniliuc, C. G.; Antonchick, A. P.; Waldmann, H. Angew. Chem., Int. Ed. 2017, 56, 2429−2434. (21) (a) He, Z.-T.; Tang, X.-Q.; Xie, L.-B.; Cheng, M.; Tian, P.; Lin, G.-Q. Angew. Chem., Int. Ed. 2015, 54, 14815−14818. (b) Tan, Y.-X.; Tang, X.-Q.; Liu, P.; Kong, D.-S.; Chen, Y.-L.; Tian, P.; Lin, G.-Q. Org. Lett. 2018, 20, 248−251. (22) (a) Shi, Z.; Grohmann, C.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5393−5397. (b) Yang, W.; Dong, J.; Wang, J.; Xu, X. Org. Lett. 2017, 19, 616−619. (23) For more details, see the Supporting Information. (24) Fukui, Y.; Liu, P.; Liu, Q.; He, Z.-T.; Wu, N.-Y.; Tian, P.; Lin, G.-Q. J. Am. Chem. Soc. 2014, 136, 15607−15614.
and Engineering (Tianjin). We thank Dr. Hanqing Dong (Arvinas Inc.) for manuscript preparation.
■
REFERENCES
(1) For selected recent reviews on Cp*Rh(III)-catalyzed C−H bond functionalizations, see: (a) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Chem. Rev. 2017, 117, 9163−9227. (b) Yang, Y.; Li, K.; Cheng, Y.; Wan, D.; Li, M.; You, J. Chem. Commun. 2016, 52, 2872−2884. (c) Wencel-Delord, J.; Patureau, F. W.; Glorius, F. Top. Organomet. Chem. 2015, 55, 1−27. (d) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007−1020. (e) Kuhl, N.; Schröder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443−1460. (2) For selected examples on heterocycles as a directing group (DG), see: (a) Umeda, N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47, 4019−4022. (b) Tsai, A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248−1250. (c) Li, H.; Li, Y.; Zhang, X.-S.; Chen, K.; Wang, X.; Shi, Z.-J. J. Am. Chem. Soc. 2011, 133, 15244−15247. (d) Kim, J. Y.; Park, S. H.; Ryu, J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134, 9110−9113. (3) For selected examples on hydroxy as a DG, see: (a) Barrett, A. G. M.; Itoh, T.; Wallace, E. M. Tetrahedron Lett. 1993, 34, 2233−2234. (b) Uto, T.; Shimizu, M.; Ueura, K.; Tsurugi, H.; Satoh, T.; Miura, M. J. Org. Chem. 2008, 73, 298−300. (c) Casanova, N.; Seoane, A.; Mascareñas, J. L.; Gulías, M. Angew. Chem., Int. Ed. 2015, 54, 2374− 2377. (4) For selected works on ketone as a DG, see: (a) Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1064−1067. (b) Samanta, R.; Narayan, R.; Antonchick, A. P. Org. Lett. 2012, 14, 6108−6111. For a recent review, see: (c) Zheng, Q.-Z.; Jiao, N. Tetrahedron Lett. 2014, 55, 1121−1126. (5) For selected examples on imines as DG, see: (a) Roesch, K. R.; Zhang, H.; Larock, R. C. J. Org. Chem. 2001, 66, 8042−8051. (b) Fukutani, T.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Chem. Commun. 2009, 45, 5141−5143. (c) Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050−12051. (6) For selected examples on oximes as a DG, see: (a) Too, P. C.; Wang, Y.-F.; Chiba, S. Org. Lett. 2010, 12, 5688−5691. (b) Hyster, T. K.; Rovis, T. Chem. Commun. 2011, 47, 11846−11848. (7) For selected examples on hydrazone as a DG, see: (a) Chuang, S.-C.; Gandeepan, P.; Cheng, C.-H. Org. Lett. 2013, 15, 5750−5753. (b) Muralirajan, K.; Cheng, C.-H. Adv. Synth. Catal. 2014, 356, 1571− 1576. (8) For selected examples on nitrones as DG, see: Dateer, R. B.; Chang, S. J. Am. Chem. Soc. 2015, 137, 4908−4911. (9) For selected examples on N-oxides as a DG, see: (a) Zhang, X.; Qi, Z.; Li, X. Angew. Chem., Int. Ed. 2014, 53, 10794−10798. (b) Sharma, U.; Park, Y.; Chang, S. J. Org. Chem. 2014, 79, 9899− 9906. (10) For selected examples on azomethine ylides as a DG, see: Chen, Y.; Wang, F.; Zhen, W.; Li, X. Adv. Synth. Catal. 2013, 355, 353−359. (11) For selected examples on urea as a DG, see: Yang, X.-F.; Hu, X.H.; Loh, T.-P. Org. Lett. 2015, 17, 1481−1484. (12) For selected examples on carboxylic acids as DG, see: (a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407−1409. (b) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 3024− 3033. (c) Shi, X.; Li, C.-J. Adv. Synth. Catal. 2012, 354, 2933−2938. (d) Gandeepan, P.; Rajamalli, P.; Cheng, C.-H. Chem. - Eur. J. 2015, 21, 9198−9203. (13) For selected examples on N-benzoylsulfonamides as a DG, see: (a) Zhu, C.; Xie, W.; Falck, J. R. Chem. - Eur. J. 2011, 17, 12591− 12595. (b) Zhu, C.; Falck, J. R. Chem. Commun. 2012, 48, 1674−1676. (14) For selected examples on amides as a DG, see: (a) Hyster, T. K.; Rovis, T. J. Am. Chem. Soc. 2010, 132, 10565−10569. (b) Park, J.; Park, E.; Kim, A.; Lee, Y.; Chi, K.-W.; Kwak, J. H.; Jung, Y. H.; Kim, I. S. Org. Lett. 2011, 13, 4390−4393. (c) Wencel-Delord, J.; Nimphius, C.; Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51, 2247− 2251. (d) Quiňones, N.; Seoane, A.; García-Fandiňo, R.; Mascareňas, J. L.; Gulías, M. Chem. Sci. 2013, 4, 2874−2879. 1157
DOI: 10.1021/acs.orglett.8b00083 Org. Lett. 2018, 20, 1154−1157
