Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne An

annulation product 3 was formed in 37% yield after the con-. Page 1 of 6 ... yield. On the other hand, nickel plate could effectively substi- tute for...
0 downloads 13 Views 419KB Size
Subscriber access provided by - Access paid by the | UCSB Libraries

Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne Annulation Fan Xu, Yan-Jie Li, Chong Huang, and Hai-Chao Xu ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b00373 • Publication Date (Web): 09 Mar 2018 Downloaded from http://pubs.acs.org on March 9, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

Ruthenium-Catalyzed Electrochemical Dehydrogenative Alkyne Annulation Fan Xu,† Yan-Jie Li,† Chong Huang, and Hai-Chao Xu* State Key Laboratory of Physical Chemistry of Solid Surfaces, Key Laboratory of Chemical Biology of Fujian Province, Collaborative Innovation Center of Chemistry for Energy Materials, and College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005 (P. R. China) ABSTRACT: A ruthenium-catalyzed electrochemical dehydrogenative annulation reaction of aniline derivatives and alkynes has been developed for the synthesis of indoles. Electric current is used to recycle the active ruthenium-based catalyst and promote H₂ evolution. The electrolysis reaction is operationally convenient as it employs a simple undivided cell, proceeds efficiently in an aqueous solution, and is insensitive to air. KEYWORDS: electrochemistry, C–H activation, ruthenium, annulation, indole

Introduction Transition metal-catalyzed C–H activation reactions have significantly streamlined organic synthesis often by eliminating the need of substrate pre-functionalization. Particularly, dehydrogenative alkyne annulation has emerged as an enabling tool for the preparation of heterocycles.1 However, the method generally requires a stoichiometric amount of organic or metal-based oxidant, which is a common characteristic of oxidative C–H functionalization reactions. Like many other oxidative C–H functionalization reactions, these reactions usually employ stoichiometric amount of metal, such as CuII or AgI, or organic oxidants. The potential safety and environmental impacts of these oxidative reagents, consequently, have substantially limited the application scope and industrial utility of the C–H functionalization reactions.2 Electrosynthesis, which achieves redox reactions with traceless electric current, is an attractive synthetic tool3-9 and has led to the development of various oxidant-free dehydrogenative coupling reactions.10-21 Particularly, few elegant studies have achieved Pd-catalyzed electrochemical C–H activation to form C–C and C–heteroatom bonds (Scheme 1a).22-26 A common theme in these methodologies involves the use of divided cells to avoid the cathodic deactivation or decomposition of the metal catalysts. Very recently, Ackermann and coworkers reported Co-catalyzed electrochemical C–H functionalization reactions.27,28 Ruthenium is an attractive metal for C–H bond activation due to its excellent catalytic reactivity and relatively low cost when compared with Pd and Rh.29-32 Ru-catalyzed annulation reactions via C–H activation33,34 have been developed for the synthesis of various heterocyclic compounds including indoles (Scheme 1b).34 We have been interested in electrochemical dehydrogenative annulation reactions35,36 and have previously described the facile preparation of (aza)indoles via intramolecular C–H/N–H functionalization.35 Here we report a Rucatalyzed electrochemical C–H activation reaction using a simple undivided cell. Our method allows efficient access to

important indole products through (3+2) annulation of aniline derivatives with internal alkynes without the use of chemical oxidants (Scheme 1c). Previous work a) Electrochemical C–H activation/functionalization M

C H

C

X

M = Pd, Co b) CuII -mediated annulation by Ackermann (Ref. 34) R2

1

R

NH N

R2 cat. RuII

+ R3

N

R3

R1 N

Cu(OAc)2 (2 equiv)

N

N

This work c) Ru-catalyzed annulation via H2 evolution R2

R2

1

R

NH N

N

Ru

+

R3

R1 N

3

R

Undivided cell Annulation

N

+ H2

N

Scheme 1. Transition Metal-Catalyzed Electrochemical C– H Activation We began our study by optimizing the reaction conditions for the coupling of N-2-pyrimidyl substituted aniline 1 and diphenylacetylene 2 (Table 1). The 2-pyrimidyl group had been shown by Ackermann to be an effective and removable directing group for ruthenium catalyzed C–H functionalization reactions.34,37 The setup for the constant current electrolysis consisted of an undivided cell (a three-necked round-bottomed flask) equipped with a reticulated vitreous carbon (RVC) anode and a Pt plate cathode. The reaction was conducted using 2 equiv of 2 under reflux in the presence of 20 mol % of KPF638 and 20 mol % of NaOAc.33, 40-42 The salt additives also served as supporting electrolytes. Under these conditions, the annulation product 3 was formed in 37% yield after the con-

ACS Paragon Plus Environment

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

sumption of 3.2 F mol−1 of electricity. A variety of organic cosolvents were tested (entries 2–6). Gratifyingly, the yield of 3 was boosted to 71% by using H2O/EtOH (1:1) as the solvent (entry 2). Other alcohols such as iPrOH (entry 3), tBuOH (entry 4), or tAmOH (entry 5) were more effective than EtOH leading to the formation of 3 in around 90% yield. The use of MeCN afforded only trace amount of 3 (entry 6). iPrOH was selected as the co-solvent for further optimization due to its low cost. The yield was reduced to 70% when the amount of the alkyne was reduced to 1.2 equiv (entry 7). While NaOAc (entry 8) and KPF6 (entry 9) were important for optimal reaction efficiency, the Ru-catalyst was indispensable for product formation (entry 10). Screening of electrode materials revealed that replacing the RVC anode with glassy carbon plate (entry 11) or graphite plate (entry 12) resulted in a sharp drop in yield. On the other hand, nickel plate could effectively substitute for Pt as the cathode (entry 13), but not RVC (entry 14). The method showed no apparent sensitivity to oxygen and therefore could be performed under atmospheric conditions (entry 15). Table 1. Optimization of Reaction Conditionsa

Page 2 of 6

of the less reactive substrates. When the N-(2pyrimidyl)aniline was substituted at one of the meta positions, the electrolytic annulation resulted in regioselective formation of 6-substituted indoles (7, 8). Sterically hindered substrates, such as that derived from 3,5-dimethylaniline, exhibited poor reactivity and did not afford any target products (15). These results suggested the importance of steric effects for regioselectivity and reactivity. On the other hand, diphenylacetylene 2 could be replaced with an internal alkyne functionalized with an alkyl group on one terminus and an aryl on the other, which led to the preferential formation of 2-aryl indoles (16–23). However, a higher catalyst loading was found necessary when R2

R1 +

NH DG

3

R

DG = 2-pyrimidyl

(2 equiv)

Ph

10, 70%

N DG

N DG 21, 72%b (10:1)

Ph N DG 15, 0% nBu S

OH Me

N DG

N DG 20, 63%b (6.9:1)

19, 69% (4.5:1) Me Me

OH

We next explored the reaction scope by varying both coupling substrates (Scheme 2). As shown, the aniline could be unsubstituted (4) or carry functional groups of different electronic properties at various positions (5–14), although substituents such as CO2Me (8) and CF3 (13) showed a detrimental effect on reactivity and thus required a higher catalyst loading to ensure complete substrate conversion. Note that for less efficient substrates, tAmOH was used as the co-solvent instead of iPrOH to provide a higher reaction temperature. Attempts to increase the conversion by passing more charge was unsuccessful suggesting catalyst deactivation during the electrolysis

14, 77%b

R

Ph

Ph Me

nBu

16, 89% (11:1) 17, R = F, 73% (7:1) 18, R = OMe, 83% (6:1)

Reaction conditions: RVC anode (100 PPI), Pt plate cathode, 1 (0.3 mmol), solvent (6 mL), argon, 10 mA, 3.2 F mol−1. bYield determined by 1H NMR analysis using 1,3,5-trimethoxybenzene as the internal standard, unreacted 1 in parenthesis. cIsolated yield. d 1 cm x 1 cm.

N DG

MeO

nBu Ph

Ph

Cl N DG 13, 78%b

Me

11, 86%

Ph

12, 69%

N DG

Me

Ph

F3C N DG

Ph

N DG

Ph Ph

a

F Ph

9, 84%b

Ph

Ph

MeO

N DG

8, 87%b

7, 94% Ph

Ph

Ph

N DG

Me

6, 91%

Ph

N DG

Ph

N DG

F

5, 95% Ph

Me

Ph

N OMe DG

4, 99%

N DG

Ph

Ph

Ph N DG

Et

N DG product, yielda

Ph

Br

R3

R1

KPF6 (20 mol %), NaOAc (20 mol %) H2O/iPrOH (1:1), reflux, 1.8–3.9 h

Ph

MeO2C

R2

RVC Pt [RuCl2(p-cymene)]2 (5 mol %)

Ph N DG 22, 98%b (14:1)

OH

nBu nBu

N DG 23, 39%b

F

N DG 24, 75%b

Scheme 2. Substrate Scope. Reaction conditions: Aniline derivative (0.3 mmol), 10 mA (janode ≅ 0.13 mA cm−2), 2.3–4.9 F mol−1. aIsolated yield. Regioisomeric ratio in parenthesis was determined by 1H NMR analysis of crude reaction mixture. bReaction with 10 mol % [RuCl2(p-cymene)]2 in H2O/tAmOH (1:1).

Scheme 3. Synthetic Application

ACS Paragon Plus Environment

Page 3 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis

the internal alkyne carried a thiophene (20), a secondary (22) or hydroxyl-substituted (21, 23) alkyl group.43 5-Decyne was also compatible with our electrolytic annulation reaction (24). The synthetic utility of our method was further demonstrated by the electrochemical annulation of 25 and 26 (Scheme 3), which was performed on a gram scale and furnished the expected indole derivative 27 in 88% yield (10.6 g). The 2pyrimidyl group could then be removed by following a reported procedure34 to generate the free indole 28, a critical synthetic precursor to the anti-osteoporotic drug bazedoxifene.44

Besides indole synthesis, preliminary results showed that the Ru-catalyzed electrochemical C–H activation method could also be employed to accomplish (4+2) annulation of benzylamine with alkynes for the preparation of isoquinolines as demonstrated by the synthesis of compounds 31 and 33 [Eq. (1)].45

Mechanistic investigation of the Ru-catalyzed electrochemical reaction indicated that the activation of the aryl C–H bond in the aniline derivative was reversible and did not involve the alkyne substrate, as evidenced by the finding that the H/D exchange at the ortho position of 1 in deuterated solvent was independent of 2 (Scheme 4a). The H/D exchange also occurred at rt albeit at a slower rate than reflux. Competition experiments using anilines or alkynes with different electronic properties revealed that the annulation could be facilitated by increased electron density in the coupling partners (Scheme 4b, c), in consistence with what Ackermann et al. observed in the CuII-mediated oxidative C–H activation reactions.34 The reduced yield of compounds 17 and 18 in the competition experiment was due to decreased conversion, which suggested an inhibitory effect of the alkyne coupling partner.43 Indeed, the conversion of 1 was reduced when the alkyne 37 was increased from 2 equiv to 6 equiv (Scheme 4d). Performing the reaction of 1 and 2 in the presence of 1 equiv of RuII but without electricity afforded the product 3 in 71% yield (Scheme 4e). These results suggested that the electric current served to regenerate the active ruthenium catalyst and did not affect other steps of the catalytic cycle.

Scheme 5. Proposed Mechanism

Scheme 4. Mechanistic Studies

A plausible mechanism for the RuII-catalyzed electrolytic annulation reaction was proposed based on the findings in this and previous studies,33,34 though further investigation would be needed to elucidate its details (Scheme 5). In the presence of the NaOAc, the dimeric pre-catalyst [RuCl2(p-cymene)]2 is converted to the ruthenium diacetate complex A. Reaction of A with the alkyne may lead to unproductive complexes and result in the observed inhibitory effect at high concentration of the alkyne.43 Complexation of A with 1, followed by reversible C–H activation, forms the six-membered ruthenacycle C, whose acetate ligand is subsequently displaced by the alkyne substrate 2 as a result of π-coordination to give D. The coordination of 2 prompted its migratory insertion into the Ru–C bond, triggering the metal center to dissociate from the pyrimidyl nitrogen and instead complex with the amino group of the aniline moiety to obtain the six-membered ruthenacycle in the resultant intermediate E. The sensitivity of the annulation reaction to the electronic and steric properties of the aniline ring and the alkyne substituents suggests that the insertion step might be rate-limiting. Eventually, reductive elimination of E

ACS Paragon Plus Environment

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

furnishes the indole product 3 and a Ru0 species (F), the latter of which is oxidized on the anode to regenerate the catalytically active RuII complex. Correspondingly, protons are reduced on the cathode to generate H2, which obviates the need for external oxidants or H-acceptors. In the preparative scale electrolysis, the catalyst resting state was most likely more resistant to cathodic reduction than the protons, allowing the use of an undivided cell. In summary, we have demonstrated that electric current can be used to promote Ru-catalyzed C–H activation/annulation processes. Our method can be used to prepare a diverse range of indole derivatives from easily accessible alkynes and aniline derivatives, and is fully compatible with a simple undivided cell.

AUTHOR INFORMATION Corresponding Author *[email protected]

Author Contributions †

F.X. and Y.-J.L. contributed equally to this work.

Notes The authors declare no competing financial interest.

ASSOCIATED CONTENT Supporting Information. The experimental procedure, characterization data, and copies of 1H and 13C NMR spectra. The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.

ACKNOWLEDGMENT We are grateful for financial support of this research from MOST (2016YFA0204100), NSFC (21672178), the “Thousand Youth Talents Plan”, and Fundamental Research Funds for the Central Universities.

REFERENCES (1) Gulías, M.; Mascareñas, J. L. Metal-Catalyzed Annulations through Activation and Cleavage of C−H Bonds. Angew. Chem., Int. Ed. 2016, 55, 11000–11019. (2) Caron, S.; Dugger, R. W.; Ruggeri, S. G.; Ragan, J. A.; Ripin, D. H. B. Large-Scale Oxidations in the Pharmaceutical Industry. Chem. Rev. 2006, 106, 2943–2989. (3) Francke, R.; Little, R. D. Redox Catalysis in Organic Electrosynthesis: Basic Principles and Recent Developments. Chem. Soc. Rev. 2014, 43, 2492–2521. (4) Frontana-Uribe, B. A.; Little, R. D.; Ibanez, J. G.; Palma, A.; Vasquez-Medrano, R. Organic Electrosynthesis: A Promising Green Methodology in Organic Chemistry. Green Chem. 2010, 12, 2099– 2119. (5) Yoshida, J.-i.; Kataoka, K.; Horcajada, R.; Nagaki, A. Modern Strategies in Electroorganic Synthesis. Chem. Rev. 2008, 108, 2265– 2299. (6) Horn, E. J.; Rosen, B. R.; Baran, P. S. Synthetic Organic Electrochemistry: An Enabling and Innately Sustainable Method. ACS Cent. Sci. 2016, 2, 302–308. (7) Schäfer, H. J. Contributions of Organic Electrosynthesis to Green Chemistry. C. R. Chim. 2011, 14, 745–765. (8) Yan, M.; Kawamata, Y.; Baran, P. S. Synthetic Organic Electrochemical Methods Since 2000: On the Verge of a Renaissance. Chem. Rev. 2017, 117, 13230–13319. (9) Jiang, Y.; Xu, K.; Zeng, C. Use of Electrochemistry in the Synthesis of Heterocyclic Structures. Chem. Rev. 2017, DOI: 10.1021/acs.chemrev.7b00271.

(10) Tang, S.; Liu, Y.; Lei, A. Electrochemical Oxidative Crosscoupling with Hydrogen Evolution: A Green and Sustainable Way for Bond Formation. Chem 2018, 4, 27–45. (11) Hayashi, R.; Shimizu, A.; Yoshida, J.-i. The Stabilized Cation Pool Method: Metal- and Oxidant-Free Benzylic C–H/Aromatic C–H Cross-Coupling. J. Am. Chem. Soc. 2016, 138, 8400–8403. (12) Gao, W.-J.; Li, W.-C.; Zeng, C.-C.; Tian, H.-Y.; Hu, L.-M.; Little, R. D. Electrochemically Initiated Oxidative Amination of Benzoxazoles Using Tetraalkylammonium Halides As Redox Catalysts. J. Org. Chem. 2014, 79, 9613–9618. (13) Rosen, B. R.; Werner, E. W.; O’Brien, A. G.; Baran, P. S. Total Synthesis of Dixiamycin B by Electrochemical Oxidation. J. Am. Chem. Soc. 2014, 136, 5571–5574. (14) Wang, P.; Tang, S.; Huang, P.; Lei, A. Electrocatalytic Oxidant-Free Dehydrogenative C−H/S−H Cross-Coupling. Angew. Chem., Int. Ed. 2017, 56, 3009–3013. (15) Schulz, L.; Enders, M.; Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. Reagent- and Metal-Free Anodic C−C Cross-Coupling of Aniline Derivatives. Angew. Chem., Int. Ed. 2017, 56, 4877–4881. (16) Fu, N.; Li, L.; Yang, Q.; Luo, S. Catalytic Asymmetric Electrochemical Oxidative Coupling of Tertiary Amines with Simple Ketones. Org. Lett. 2017, 19, 2122–2125. (17) Xiong, P.; Xu, H.-H.; Xu, H.-C. Metal- and Reagent-Free Intramolecular Oxidative Amination of Tri- and Tetrasubstituted Alkenes. J. Am. Chem. Soc. 2017, 139, 2956–2959. (18) Wu, Z.-J.; Xu, H.-C. Synthesis of C3-Fluorinated Oxindoles through Reagent-Free Cross-Dehydrogenative Coupling. Angew. Chem., Int. Ed. 2017, 56, 4734–4738. (19) Gieshoff, T.; Kehl, A.; Schollmeyer, D.; Moeller, K. D.; Waldvogel, S. R. Insights into the Mechanism of Anodic N–N Bond Formation by Dehydrogenative Coupling. J. Am. Chem. Soc. 2017, 139, 12317–12324. (20) Wang, Q.-Q.; Xu, K.; Jiang, Y.-Y.; Liu, Y.-G.; Sun, B.-G.; Zeng, C.-C. Electrocatalytic Minisci Acylation Reaction of NHeteroarenes Mediated by NH4I. Org. Lett. 2017, 19, 5517–5520. (21) Folgueiras-Amador, A. A.; Qian, X.-Y.; Xu, H.-C.; Wirth, T. Catalyst- and Supporting-Electrolyte-Free Electrosynthesis of Benzothiazoles and Thiazolopyridines in Continuous Flow. Chem. Eur. J. 2018, 24, 487–491. (22) Jiao, K.-J.; Zhao, C.-Q.; Fang, P.; Mei, T.-S. Palladium Catalyzed C–H functionalization with Electrochemical Oxidation. Tetrahedron Lett. 2017, 58, 797–802. (23) Yang, Q.-L.; Li, Y.-Q.; Ma, C.; Fang, P.; Zhang, X.-J.; Mei, T.-S. Palladium-Catalyzed C(sp3)–H Oxygenation via Electrochemical Oxidation. J. Am. Chem. Soc. 2017, 139, 3293–3298. (24) Amatore, C.; Cammoun, C.; Jutand, A. Electrochemical Recycling of Benzoquinone in the Pd/Benzoquinone-Catalyzed Heck-Type Reactions from Arenes. Adv. Synth. Catal. 2007, 349, 292–296. (25) Shrestha, A.; Lee, M.; Dunn, A. L.; Sanford, M. S. PalladiumCatalyzed C–H Bond Acetoxylation via Electrochemical Oxidation. Org. Lett. 2018, 20, 204–207. (26) Kakiuchi, F.; Kochi, T.; Mutsutani, H.; Kobayashi, N.; Urano, S.; Sato, M.; Nishiyama, S.; Tanabe, T. Palladium-Catalyzed Aromatic C−H Halogenation with Hydrogen Halides by Means of Electrochemical Oxidation. J. Am. Chem. Soc. 2009, 131, 11310–11311. (27) Sauermann, N.; Meyer, T. H.; Tian, C.; Ackermann, L. Electrochemical Cobalt-Catalyzed C–H Oxygenation at Room Temperature. J. Am. Chem. Soc. 2017, 139, 18452–18455. (28) Tian, C.; Massignan, L.; Meyer, T. H.; Ackermann, L. Electrochemical C−H/N−H Activation by Water-Tolerant Cobalt Catalysis at Room Temperature. Angew. Chem., Int. Ed. 2018, 57, 2383–2387. (29) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Ruthenium(II)Catalyzed C–H Bond Activation and Functionalization. Chem. Rev. 2012, 112, 5879–5918. (30) De Sarkar, S.; Liu, W.; Kozhushkov, S. I.; Ackermann, L. Weakly Coordinating Directing Groups for Ruthenium(II)-Catalyzed C–H Activation. Adv. Synth. Catal. 2014, 356, 1461–1479. (31) Thirunavukkarasu, V. S.; Kozhushkov, S. I.; Ackermann, L. C–H Nitrogenation and Oxygenation by Ruthenium Catalysis. Chem. Commun. 2014, 50, 29–39.

ACS Paragon Plus Environment

Page 4 of 6

Page 5 of 6 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Catalysis (32) Leitch, J. A.; Frost, C. G. Ruthenium-catalysed σ-activation for Remote Meta-selective C–H Functionalisation. Chem. Soc. Rev. 2017, 46, 7145–7153. (33) Ackermann, L. Carboxylate-Assisted Ruthenium-Catalyzed Alkyne Annulations by C–H/Het–H Bond Functionalizations. Acc. Chem. Res. 2014, 47, 281–295. (34) Ackermann, L.; Lygin, A. V. Cationic Ruthenium(II) Catalysts for Oxidative C–H/N–H Bond Functionalizations of Anilines with Removable Directing Group: Synthesis of Indoles in Water. Org. Lett. 2012, 14, 764–767. (35) Hou, Z.-W.; Mao, Z.-Y.; Zhao, H.-B.; Melcamu, Y. Y.; Lu, X.; Song, J.; Xu, H.-C. Electrochemical C−H/N−H Functionalization for the Synthesis of Highly Functionalized (Aza)indoles. Angew. Chem., Int. Ed. 2016, 55, 9168–9172. (36) Hou, Z.-W.; Mao, Z.-Y.; Melcamu, Y. Y.; Lu, X.; Xu, H.-C. Electrochemical Synthesis of Imidazo-Fused N-Heteroaromatic Compounds through a C−N Bond-Forming Radical Cascade. Angew. Chem., Int. Ed. 2018, 57, 1636–1639. (37) Song, W.; Ackermann, L. Nickel-catalyzed Alkyne Annulation by Anilines: Versatile Indole Synthesis by C–H/N–H Functionalization. Chem. Commun. 2013, 49, 6638–6640. (38) McCormick, F. B.; Cox, D. D.; Gleason, W. B. Synthesis, Structure, and Disproportionation of Labile Benzeneruthenium Acetonitrile (η6-C6H6)Ru(CH3CN)2Cl+ Salts. Organometallics 1993, 12, 610–612. (39) Fernandez, S.; Pfeffer, M.; Ritleng, V.; Sirlin, C. An Effective Route to Cycloruthenated N-Ligands under Mild Conditions. Organometallics 1999, 18, 2390–2394. (40) Ackermann, L. Carboxylate-Assisted Transition-MetalCatalyzed C−H Bond Functionalizations: Mechanism and Scope. Chem. Rev. 2011, 111, 1315–1345. (41) Davies, D. L.; Macgregor, S. A.; McMullin, C. L. Computational Studies of Carboxylate-Assisted C–H Activation and Functionalization at Group 8–10 Transition Metal Centers. Chem. Rev. 2017, 117, 8649–8709. (42) Ferrer Flegeau, E.; Bruneau, C.; Dixneuf, P. H.; Jutand, A. Autocatalysis for C–H Bond Activation by Ruthenium(II) Complexes in Catalytic Arylation of Functional Arenes. J. Am. Chem. Soc. 2011, 133, 10161–10170. (43) Stuart, D. R.; Alsabeh, P.; Kuhn, M.; Fagnou, K. Rhodium(III)-Catalyzed Arene and Alkene C−H Bond Functionalization Leading to Indoles and Pyrroles. J. Am. Chem. Soc. 2010, 132, 18326–18339. (44) Miller, C. P.; Collini, M. D.; Tran, B. D.; Harris, H. A.; Kharode, Y. P.; Marzolf, J. T.; Moran, R. A.; Henderson, R. A.; Bender, R. H. W.; Unwalla, R. J.; Greenberger, L. M.; Yardley, J. P.; AbouGharbia, M. A.; Lyttle, C. R.; Komm, B. S. Design, Synthesis, and Preclinical Characterization of Novel, Highly Selective Indole Estrogens. J. Med. Chem. 2001, 44, 1654–1657. (45) Villuendas, P.; Urriolabeitia, E. P. Primary Amines as Directing Groups in the Ru-Catalyzed Synthesis of Isoquinolines, Benzoisoquinolines, and Thienopyridines. J. Org. Chem. 2013, 78, 5254– 5263.

ACS Paragon Plus Environment

ACS Catalysis 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Paragon Plus Environment

Page 6 of 6

6