Rh(III)-Catalyzed Oxidative - ACS Publications - American Chemical

Letter Cite This: Org. Lett. 2018, 20, 6812−6816

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Rh(III)-Catalyzed Oxidative [5 + 2] Annulation Using Two Transient Assisting Groups: Stereospecific Assembly of 3‑Alkenylated Benzoxepine Framework Wei Yi,*,† Liping Li,† Hongzhen Chen,† Kuangshun Ma,† Yuting Zhong,† Weijie Chen,† Hui Gao,*,†,‡ and Zhi Zhou*,†

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†

Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease, School of Pharmaceutical Sciences & the Fifth Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 511436, China ‡ School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou 510006, China S Supporting Information *

ABSTRACT: A unique Rh(III)-catalyzed oxidative [5 + 2] annulation of easily available 2-alkenylphenols with propargyl carbonates have been developed by using two O-containing functional groups as the traceless assisting groups (AGs). The experimental investigations together with the density functional theory (DFT) calculations revealed that this transformation involves the free OH-directed cleavage of one terminal C−H bond of the alkenyl moiety and regioselective alkyne insertion, followed by OBoc-promoted intramolecular nucleophilic substitution and β-H elimination that used an allyl species as the active intermediate, giving direct access to the 3-alkenylated benzoxepine skeleton with broad substrate compatibility and good functional group tolerance.

O

Scheme 1. TM-Catalyzed Divergent Synthesis of Benzoxepines and Spirocyclic Enones and Two DG-Assisted Regioselective Annulations

ver the past few decades, transition metal (TM)-catalyzed and heteroatom-directed C−H functionalization of inert C−H bonds has become a versatile and conceptually attractive approach for the one-pot construction of many organic building blocks and privileged structural motifs.1 As a consequence, a diverse range of heterocyclic scaffolds were smoothly synthesized in an atom-economical and waste-reducing fashion by using this strategy.2 Arguably, the C−H activation/annulation cascade reaction with alkynes are one of the most popular methods of this type, in which the classical [3 + 2] or [4 + 2] annulations were mainly involved to afford five- or sixmembered heterocycles.3 Quite evidently, it is challenging, but extremely attractive to develop the new and efficient C−H activation/annulation cascade with alkynes for direct assembly of important larger ring frameworks.4 ́ and coTo address the above-mentioned issue, in 2014 Gulias workers disclosed a Rh(III)-catalyzed [5 + 2] annulation of readily available o-vinylphenols with alkynes for the formal synthesis of a seven-membered benzoxepine skeleton (Scheme 1a, above),5a which is the basic core of many molecules found in natural products, pharmaceuticals, and biologically active compounds.6 However, a mixture of positional isomers were observed inevitably in those examples that employed the unsymmetrical alkynes as the coupling partners, probably due to their relatively unbiased polarity and weaker coordination with the active Rh(III) catalyst. Furthermore, further studies from them and Lam’s group revealed that, under similar reaction conditions, the introduction of the substituent at the internal position of the vinyl moiety completely changed the reaction © 2018 American Chemical Society

outcome to result in the synthesis of spirocyclic enones (Scheme 1a, below).5b,c Undoubtedly, the relatively poor regioselectivity and narrow substrate scope to some extent limited their synthetic applications. Therefore, it is of the utmost importance to develop a new methodology as an alternative to the existing Received: September 14, 2018 Published: October 24, 2018 6812

DOI: 10.1021/acs.orglett.8b02940 Org. Lett. 2018, 20, 6812−6816

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Organic Letters Scheme 2. Substrate Scope of 2-Vinylphenolsa

methods for the efficient construction of the privileged benzoxepine core with exclusive selectivity and improved substrate scope. However, more recently Glorius and co-workers presented a seminal study for the direct synthesis of N-heterocycles with perfect regioselectivity via a Mn(I)-catalyzed and two transient directing group (DG)-mediated [4 + 2] annulation with unsymmetrical alkyne coupling partners equipped with a traceless DG (Scheme 1b).7 Inspired by the pioneering work, we also developed three independent Rh(III)-catalyzed regioselective [3 + 2] annulations for indenamine8a and benzofuran8b,c syntheses by using the versatile strategy. In addition, other groups also developed many remarkable Rh(III)catalyzed C−H activations for the synthesis of diverse molecular complexes through such strategy.9 To further explore the novel reaction mode, we would like to report the first Rh(III)catalyzed [5 + 2] annulation of various 2-alkenylphenols with propargyl carbonates by using the free OH moiety as the practical DG with the assistance of the OBoc group, in which it was employed as a versatile leaving group to produce an active allyl species (Scheme 1c), thus giving one-pot access to diverse benzoxepines bearing an ethylene functional group at the 3position, which could serve as an important handle for further chemical manipulation. In addition, this transformation features exclusive regioselectivity, broad substrate compatibility, and good functional group tolerance, thus rendering it a highly versatile and meaningful alternative to the existing methods for building the privileged benzoxepine framework. At the outset of this study, we chose readily available 2vinylphenol 1a and OBoc-protected propargyl alcohol 2a as the model substrates under Cp*Rh(III) catalysis in the presence of CsOAc (see Table S1 in the Supporting Information for detailed optimization). To our delight, an unusual [5 + 2] annulation was detected under the initial conditions, giving access to the expected benzoxepine core along with the equipment of an ethylene functional group at the 3-position. Encouraged by this result, we next screened several experimental parameters to define the optimal reaction conditions.10 The addition of an external oxidant was crucial for catalyst regeneration, among which Cu(OAc)2 appeared to be the ideal oxidant and increased the yield up to 45%. Further screening of various solvents revealed that DMF was the optimal solvent, affording the desired benzoxepine in 68% yield, while other solvents gave inferior results. After a number of trials to screen the additives, TMcatalysts, and the reaction temperature, we were pleased to identify the following optimized conditions: 1a (2 equiv), 2a (1 equiv), [Cp*RhCl2]2 (2.5 mol %), CsOAc (1 equiv), and Cu(OAc)2 (2 equiv) in DMF at 120 °C for 24 h under an atmosphere of air, furnishing the desired benzoxepine product in 81% yield. With the established reaction conditions in hand, we next investigated the scope and generality of this methodology by first screening a series of 2-alkenylphenol derivatives bearing different substituents on the phenyl ring (Scheme 2). Fortunately, various commonly encountered functional groups including methyl (3b), methoxyl (3c, 3i, and 3k), halogens (3d−3f, 3h, 3j, and 3l), and ester (3g) were well tolerated to afford the corresponding benzoxepines in moderate to good yields. Noteworthy, 2-alkenylphenols bearing the substituent at the internal position of the vinyl moiety were also good reactants for this [5 + 2] annulation, delivering the desired benzoxepine skeletons (3m−3o) rather than spirocyclic enones reported in precedent work,3b,c revealing that the introduction of the OBoc

a

Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), [Cp*RhCl2]2 (2.5 mol %), CsOAc (1 equiv), and Cu(OAc)2 (2 equiv) in DMF (0.2 M) at 120 °C for 24 h under air; isolated yields were reported. b [Cp*RhCl2]2 (5 mol %) for 48 h.

part was vital for controlling the reaction outcome. Moreover, 2phenylphenol readily participated in this transformation, leading to the synthesis of the fused heterocyclic dibenzo[b,d]oxepine motif (3p). To sum up, the developed Rh(III)-catalyzed [5 + 2] annulation of 2-alkenylphenols and propargyl carbonates proved to be broadly applicable for the specific construction of benzoxepine skeletons. To better probe the versatility of this protocol for the synthesis of benzoxepines, a range of substituted propargyl carbonates were then employed, and the corresponding desired products were constructed effectively (Scheme 3). The reaction was compatible with various tert-butyl (4-(4-substituted phenyl)-2-methylbut-3-yn-2-yl) carbonates regardless of the electronic properties of the substitution on the phenyl ring, affording the desired benzoxepines without significant difference on product yields (4a−4g, 4o, and 4p). Nevertheless, the position of substituent on the phenyl ring had a clear influence on reactivity since para- and meta-methyl substituted propargyl carbonates resulted in good yields (4a and 4h), while orthomethyl substituted substrate led to only a trace amount of desired product 4i. Moreover, thienyl as well as naphthyl substituted propargyl carbonates were also good reactants for this transformation and annulated with various 2-vinylphenol derivatives (4j−4n, 4q). In addition, we were pleased to find that the cycloalkyl and long-chain alkyl substituted propargyl carbonates readily participated in this [5 + 2] annulation to give the corresponding benzoxepines smoothly (4r and 4s). It is noteworthy that phenyl, ethyl, or cyclohexyl at the propargylic position can be well tolerated for this transformation, delivering the desired benzoxepines in moderate yields (4t−4v). Remarkably, the propargyl carbonate derived from the natural product estrone was also tolerated for this transformation, delivering the desired benzoxepine 4w in 56% yield, which illustrated profound potentials for the rapid synthesis of novel analogs of such a complex skeleton. Having established the practical approach for the specific synthesis of benzoxepine skeletons, especially those bearing various substituents at the 2-, 3-, and 5-positions, we were next intrigued to figure out the reaction pathway of this trans6813

DOI: 10.1021/acs.orglett.8b02940 Org. Lett. 2018, 20, 6812−6816

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Organic Letters Scheme 3. Substrate Scope of Propargyl Carbonatesa

exchange. The following C−H cleavage through an intramolecular electrophilic attack/base-assisted deprotonation process afforded the rhodacycle INT-3 with an overall 1.9 kcal/mol exothermicity. The subsequent alkyne coordination and regioselective migratory insertion were involved to yield INT-5 via TS-3 (ΔG‡ = 20.7 kcal/mol). Then, the intramolecular nucleophilic attack of oxygen anion to the allyl moiety occurred on the basis of the good leaving ability of OBoc,11 resulting in the formation of allyl rhodium INT-7 with an energy barrier of 24.3 kcal/mol (from INT-5 to TS-5), which was easily converted into a more stable intermediate INT-8 with 7.0 kcal/ mol exothermicity. Subsequently, the facile β-H elimination was involved to give the final product together with the rhodium(I) species. It should be noted that an alternative keto intermediate bearing spirocyclic structure5b,c,12 was precedently speculated as the main intermediate due to a steric clash, leading to the formation of spirocyclic enones. Interestingly, our DFT calculations showed that the spirocyclic intermediate INT-11 was clearly disfavored both thermodynamically (ΔG‡ = 12.3 vs −17.1 kcal/mol) and dynamically (ΔΔG‡ = 37.2 kcal/mol) in comparison to intermediate INT-5, thus leading to the specific construction of the benzoxepine structure. The results also reveal the crucial role of the OBoc group in this transformation. In addition, the C−O reductive elimination pathway was also ruled out because of the high activation energy barrier of 38.9 kcal/mol (from INT-5 to TS-7). To further cast light on details of the proposed mechanism and validate computational results, a series of experimental studies were carried out (Scheme 4). When tert-butyl (3phenylprop-2-yn-1-yl) carbonate 2t was subjected to the reaction with 1a under the standard conditions, the reaction turned out to be complicated and resulted in an inseparable mixture of complex products (Scheme 4a). As a comparison, tert-butyl (4-phenylbut-3-yn-2-yl) carbonate 2u delivered to the

a

Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), [Cp*RhCl2]2 (2.5 mol %), CsOAc (1 equiv), and Cu(OAc)2 (2 equiv) in DMF (0.2 M) at 120 °C for 24 h under air; isolated yields were reported. bDetected by 1H NMR analysis. c[Cp*RhCl2]2 (5 mol %) for 48 h.

formation, in particular, to clarify the role of two transient AGs for exhibiting such specificity. As shown in Figure 1, DFT calculations were performed by selecting Cp*Rh(OAc)2 (Cat.) as the starting point, which coordinated with 1a via a ligand

Figure 1. Computed Gibbs free energy changes of the reaction pathway. 6814

DOI: 10.1021/acs.orglett.8b02940 Org. Lett. 2018, 20, 6812−6816

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Organic Letters Scheme 4. Experimental Mechanistic Studies

Scheme 5. Proposed Catalytic Cycle

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ASSOCIATED CONTENT

* Supporting Information S

corresponding benzoxepine 4x in 56% yield under the same conditions, indicating that the steric hindrance at propargylic position played an essential role for the [5 + 2] annulation by tuning the regioselectivity. Another control experiment between 1a and 2-methyl-4-phenylbut-3-yn-2-ol 2v resulted in no reaction, further confirming that the OBoc group was an indispensable transient AG for this transformation (Scheme 4b). Additionally, kinetic isotope effect for this transformation was measured by employing 1a-d2 substrate (Scheme 4c). The primary KIE value was determined to be 1.7 from two parallel, side-by-side experiments, implying that the C−H cleavage process might not be involved in the rate-determining step, which was in good agreement with the calculation result that a relatively low energy barrier (15.8 kcal/mol, from Cat. to TS-2) was involved for C−H cleavage process. It is worth noting that, with 2-(prop-1-en-2-yl)aniline 5 and 2a, the Rh(III)-catalyzed C−H annulation proceeded smoothly to generate the benzoazepine product 6 in 21% yield (Scheme 4d), which further verified the potential utility of such OBoc-prompted cyclization strategy. More importantly, it also revealed that an allyl rhodium species might be involved as the key active intermediate. Based on these computational and experimental studies, we proposed the plausible mechanism involving tandem facile C−H activation, regioselective alkyne insertion, OBocprompted intramolecular nucleophilic substitution, and β-H elimination process for this transformation, leading to the specific construction of the benzoxepine framework (Scheme 5). In summary, by employing free OH and OBoc as two transient AGs, an efficient Rh(III)-catalyzed cascade C−H activation/annulation was developed to furnish the 3-alkenylated benzoxepine derivatives. The reaction was demonstrated to be practical for the specific construction of the benzoxepine skeleton with exclusive regioselectivity and good functional group tolerance. Combined DFT and experimental studies revealed the role of the OBoc group in controlling regio- and chemoselectivities in terms of its steric hindrance and good leaving ability. Further investigations on the detailed mechanism and the synthetic application of this transformation are in progress.

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02940. Experimental procedures, characterization of products, and copies of 1H and 13C NMR spectra (PDF) Accession Codes

CCDC 1865924 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

*E-mail: [email protected]. *E-mail: [email protected]. *E-mail: [email protected]. ORCID

Wei Yi: 0000-0001-7936-9326 Hui Gao: 0000-0002-8736-4485 Zhi Zhou: 0000-0002-6521-8946 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the NSFC (81502909 and 21877020), Guangdong Natural Science Funds for Distinguished Young Scholar (2017A030306031) , and Natural Science Foundation of Guangdong Province (2017A030313058) for financial support on this study.

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REFERENCES

(1) For recently selected reviews, see: (a) Wei, Y.; Hu, P.; Zhang, M.; Su, W. Chem. Rev. 2017, 117, 8864. (b) Park, Y.; Kim, Y.; Chang, S. Chem. Rev. 2017, 117, 9247. (c) Xia, Y.; Qiu, D.; Wang, J. Chem. Rev. 2017, 117, 13810. (d) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S.-G. Chem. Soc. Rev. 2017, 46, 4299. (e) Kim, D.-S.; Park, W.-J.; Jun, C.-H. Chem. Rev. 2017, 117, 8977. (f) Yang, Y.; Lan, J.; You, J. Chem. Rev. 2017, 117, 8787. (g) Song, B.; Xu, B. Chem. Soc. Rev. 2017, 46, 1103. 6815

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Organic Letters (h) Gandeepan, P.; Ackermann, L. Chem. 2018, 4, 199. (i) Mihai, M. T.; Genov, G. R.; Phipps, R. J. Chem. Soc. Rev. 2018, 47, 149. (j) Sambiagio, C.; Schö nbauer, D.; Blieck, R.; Dao-Huy, T.; Pototschnig, G.; Schaaf, P.; Wiesinger, T.; Zia, M. F.; Wencel-Delord, J.; Besset, T.; Maes, B. U. W.; Schnürch, M. Chem. Soc. Rev. 2018, 47, 6603. (k) Gensch, T.; James, M. J.; Dalton, T.; Glorius, F. Angew. Chem., Int. Ed. 2018, 57, 2296. (l) Saint-Denis, T. G.; Zhu, R. Y.; Chen, G.; Wu, Q. F.; Yu, J. Q. Science 2018, 359, eaao4798. (m) Vásquez-Céspedes, S.; Wang, X.; Glorius, F. ACS Catal. 2018, 8, 242. (n) Sinha, S. K.; Zanoni, G.; Maiti, D. Asian J. Org. Chem. 2018, 7, 1178. (o) Karimov, R. R.; Hartwig, J. F. Angew. Chem., Int. Ed. 2018, 57, 4234. (p) Santhoshkumar, R.; Cheng, C.-H. Beilstein J. Org. Chem. 2018, 14, 2266. (2) For representative reviews, see: (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41, 1013. (b) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (c) Colby, D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (e) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012, 41, 3651. (f) Li, B.J.; Shi, Z.-J. Chem. Soc. Rev. 2012, 41, 5588. (g) Hartwig, J. F. Acc. Chem. Res. 2012, 45, 864. (h) Wencel-Delord, J.; Glorius, F. Nat. Chem. 2013, 5, 369. (i) Ackermann, L. Acc. Chem. Res. 2014, 47, 281. (j) Kuhl, N.; Schröder, N.; Glorius, F. Adv. Synth. Catal. 2014, 356, 1443. (k) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040. (l) Zhu, R. Y.; Farmer, M. E.; Chen, Y. Q.; Yu, J. Q. Angew. Chem., Int. Ed. 2016, 55, 10578. (m) Mishra, N. K.; Sharma, S.; Park, J.; Han, S.; Kim, I. S. ACS Catal. 2017, 7, 2821. (n) Ackermann, L. Chem. Rev. 2011, 111, 1315. (o) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem. Soc. Rev. 2016, 45, 2900. (p) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155. (3) For selected reviews on TM-catalyzed C−H annulation with alkynes, see: (a) Gulías, M.; Mascareñas, J. L. Angew. Chem., Int. Ed. 2016, 55, 11000. (b) Boyarskiy, V. P.; Ryabukhin, D. S.; Bokach, N. A.; Vasilyev, A. V. Chem. Rev. 2016, 116, 5894. (c) Zheng, L.; Hua, R. Chem. Rec. 2018, 18, 556. (4) For selected examples on TM-catalyzed C−H annulation for the synthesis of large ring frameworks, see: (a) Cui, S.; Zhang, Y.; Wu, Q. Chem. Sci. 2013, 4, 3421. (b) Cui, S.; Zhang, Y.; Wang, D.; Wu, Q. Chem. Sci. 2013, 4, 3912. (c) Shi, Z.; Grohmann, C.; Glorius, F. Angew. Chem., Int. Ed. 2013, 52, 5393. (d) Duan, P.; Lan, X.; Chen, Y.; Qian, S.S.; Li, J. J.; Lu, L.; Lu, Y.; Chen, B.; Hong, M.; Zhao, J. Chem. Commun. 2014, 50, 12135. (e) Chen, D.; Xing, G.; Zhou, H. Org. Chem. Front. 2015, 2, 947. (f) Wu, S.; Zeng, R.; Fu, C.; Yu, Y.; Zhang, X.; Ma, S. Chem. Sci. 2015, 6, 2275. (g) Yang, W.; Dong, J.; Wang, J.; Xu, X. Org. Lett. 2017, 19, 616. (h) Wen, J.; Cheng, H.; Raabe, G.; Bolm, C. Org. Lett. 2017, 19, 6020. (i) Pandey, A. K.; Han, S. H.; Mishra, N. K.; Kang, D.; Lee, S. H.; Chun, R.; Hong, S.; Park, J. S.; Kim, I. S. ACS Catal. 2018, 8, 742. (j) Peneau, A.; Tricart, Q.; Guillou, C.; Chabaud, L. Chem. Commun. 2018, 54, 5891. (5) For selected C−H functionalization of 2-vinylphenols, see: (a) Seoane, A.; Casanova, N.; Quiñones, N.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 834. (b) Seoane, A.; Casanova, N.; Quiñones, N.; Mascareñas, J. L.; Gulías, M. J. Am. Chem. Soc. 2014, 136, 7607. (c) Kujawa, S.; Best, D.; Burns, D. J.; Lam, H. W. Chem. - Eur. J. 2014, 20, 8599. (d) Casanova, N.; Seoane, A.; Mascareñas, J. L.; Gulías, M. Angew. Chem., Int. Ed. 2015, 54, 2374. (e) Liu, X.-G.; Zhang, S.-Z.; Jiang, C.-Y.; Wu, J.-Q.; Li, Q.; Wang, H. Org. Lett. 2015, 17, 5404. (f) Finkbeiner, P.; Kloechner, U.; Nachtsheim, B. Angew. Chem., Int. Ed. 2015, 54, 4949. (g) Ghorai, J.; Reddy, A. C. S.; Anbarasan, P. Chem. Eur. J. 2016, 22, 16042. (h) Kuppusamy, R.; Muralirajan, K.; Cheng, C.H. ACS Catal. 2016, 6, 3909. (i) Duarah, G.; Kaishap, P. P.; Sarma, B.; Gogoi, S. Chem. - Eur. J. 2018, 24, 10196. (6) (a) Rasolofonjatovo, E.; Provot, O.; Hamze, A.; Rodrigo, J.; Bignon, J.; Wdzieczak-Bakala, J.; Lenoir, C.; Desravines, D.; Dubois, J.; Brion, J.-D.; Alami, M. Eur. J. Med. Chem. 2013, 62, 28. (b) Kuntala, N.; Telu, J. R.; Anireddy, J. S.; Pal, S. Lett. Drug Des. Discovery 2017, 14, 1086. (c) O’Boyle, N. M.; Barrett, I.; Greene, L. M.; Carr, M.; Fayne, D.; Twamley, B.; Knox, A. J. S.; Keely, N. O.; Zisterer, D. M.; Meegan, M. J. J. Med. Chem. 2018, 61, 514.

(7) (a) Lu, Q.; Greβies, S.; Cembellín, S.; Klauck, F. J. R.; Daniliuc, C. G.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 12778. For selected examples on TM-catalyzed C−H functionalization with propargyl carbonates as TDGs, see: (b) Wu, S.; Huang, X.; Wu, W.; Li, P.; Fu, C.; Ma, S. Nat. Commun. 2015, 6, 7946. (c) Lu, Q.; Greβies, S.; Klauck, F. J. R.; Glorius, F. Angew. Chem., Int. Ed. 2017, 56, 6660. (d) Wu, S.; Wu, X.; Fu, C.; Ma, S. Org. Lett. 2018, 20, 2831. (8) (a) Gong, W.; Zhou, Z.; Shi, J.; Wu, B.; Huang, B.; Yi, W. Org. Lett. 2018, 20, 182. (b) Chen, W.; Liu, F.-X.; Gong, W.; Zhou, Z.; Gao, H.; Shi, J.; Wu, B.; Yi, W. Adv. Synth. Catal. 2018, 360, 2470. (c) Yi, W.; Chen, W.; Liu, F.-X.; Zhong, Y.; Wu, D.; Zhou, Z.; Gao, H. ACS Catal. 2018, 8, 9508. (9) For selected recent examples on TM-catalyzed C−H annulation with two TDGs, see: (a) Zhou, Z.; Liu, G.; Lu, X. Org. Lett. 2016, 18, 5668. (b) Wu, X.; Wang, B.; Zhou, Y.; Liu, H. Org. Lett. 2017, 19, 1294. (c) Wu, X.; Wang, B.; Zhou, S.; Zhou, Y.; Liu, H. ACS Catal. 2017, 7, 2494. (d) Wu, X.; Ji, H. J. Org. Chem. 2018, 83, 4650. (10) For detailed optimization studies, see Table S1 in the Supporting Information. (11) Zhou, Z.; Liu, G.; Chen, Y.; Lu, X. Org. Lett. 2015, 17, 5874. (12) For the DFT studies on delivering the spirocyclic skeletons, see: (a) Zhang, M.; Huang, G. Chem. - Eur. J. 2016, 22, 9356. (b) Zheng, C.; Zheng, J.; You, S.-L. ACS Catal. 2016, 6, 262.

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DOI: 10.1021/acs.orglett.8b02940 Org. Lett. 2018, 20, 6812−6816