Rhodium(III)-Catalyzed C(sp2)-H Chemoselective Annulation to O-Cyclized Isochromen-imines from Benzamides

O ‑Cyclized Isochromen-imines from Benzamides

Letter

Rhodium(III)-Catalyzed C(sp )−H Chemoselective Annulation to

Ping Zhang, Wenju Chang, Yan-Shang Kang, Wenxuan Zhao, Pei-Pei Cui, Yong Liang, Wei-Yin Sun,

and Yi Lu*

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c03425

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sı Supporting Information

ABSTRACT: Through the development of ligands and reaction

conditions, the Rh(III)-catalyzed selective annulation of benzamides

with internal alkynes has been achieved to the formation of O-

cyclized isochromen-imines. Various substituents are well-tolerated

under mild reaction conditions. Density functional theory calcu-

lations indicate that silver carbonate could act as a Lewis acid to assist

the ligand to improve the chemical selectivity of the reaction in a

catalytic system.

eterocycles have received enormous interests due to

their invaluable biological activity in the past few

Scheme 1. Annulation of Benzamides with Alkynes

decades, and various eﬃcient approaches to construct these

heterocycles were developed. In recent years, direct C−H

bond activation has emerged as a powerful tool in organic

synthesis. However, the chemoselective transformation to

diﬀerent products from the same substrates by tuning the

catalysts or the reaction conditions is still a signiﬁcant

challenge. For example, the amide functional group contains

two interchangeable nucleophilic sites; therefore, diﬀerent

cyclization products may be obtained depending on either a N

or O atom acting as a nucleophile. Isoquinolone scaﬀolds have

been constructed via oxidative [4 + 2] annulation of

benzamide derivatives with alkynes catalyzed by diﬀerent

b,d,e,4

transition metals, such as Rh,

Ru, Co, Ni, and others.

4b,f

Previous works by the research groups of Fagnou,

Miura

and Satoh, Rovis, and Li have demonstrated the eﬀective

dehydrogenative annulation reactions of benzamide derivatives

with alkynes by rhodium(III) catalysts to aﬀord the N-

cyclization isoquinolone motifs (Scheme 1a). Fagnou and co-

workers observed a byproduct in the process of condition

optimization, which was identiﬁed as the O-annulation product

coordination ability of metal ions to switch the structure of the

products. We report here a ligand-promoted selective

annulation of benzamides with internal alkynes to construct

O-cyclized isochromen-imines in the presence of rhodium(III)

catalyst, with the assistance of silver salt.

b,8b

later by Huang.

At the same time, Miura, Murakami, and

co-workers applied 2-iodobenzamides with alkynes in the

presence of a nickel(0)/P(4-ClC H ) catalyst to produce O-

4 3

At the outset of our studies, we initiated our attempts on the

oxidative annulation of N-pentaﬂuorophenylbenzamide (1a)

with diphenylacetylene (2a) using [Cp*RhCl ] as a catalyst

cyclization products (Scheme 1b). In all these reports, the

selectivity of the O-cyclized versus N-cyclized formation was

dependent on the structure of the N-substituent groups, where

4c,g,t

NH to OH tautomerization of the amides proceeded.

Received: October 13, 2020

Recently, the Li group has reported a Cp*Rh-(OAc)₂-

catalyzed chemodivergent oxidative [4 + 1] annulation of N-

methoxy benzamides and 1,3-enynes to give either lactam or

iminolactone by the variation of reaction conditions.

Encouraged by these works, we apply the ligands and other

additives to a rhodium(III) catalytic system to adjust the

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

and Ag CO as an oxidant at 100 °C. A mixture of (1H)-

nitro group at the 3-position made the reaction sluggish and

depressed the ratio to 5:1 (L18). Considering the cost of the

ligands, L11 was chosen as the optimized ligand for this

reaction.

isochromen-1-imine (3a) and isoquinolin-1(2H)-one (4a) was

obtained during the screening of solvents. It is worth noting

that 3a was preferred in all the solvents, reaching a ratio of 4/1

(

3a/4a) with the total yield of 96% in CH CN (Table S1,

With the optimized catalytic system in hand, we investigated

the generality of the reaction by exploiting ortho-, meta-, and

para-substituted benzamides, as shown in Scheme 3. Treat-

entry 1). The structure was unambiguously determined by

single-crystal X-ray analysis (see section 2.6 in the Supporting

Information ). The result was consistent with the previous

reports that electron-withdrawing groups on the amides played

Scheme 3. Scope of Benzamides ^,^,

a b c

4c,g,t

prominent roles in the formation of isochromen-imine.

screening of the catalysts, temperature, and oxidants for the

reaction showed that [Cp*RhCl ] , 60 °C, and Ag CO were

optimal for this transformation (Tables S2 −S4). However, the

chemoselectivity remained unsatisfactory with the ratio of 3a/

a for 8/1. Recently, our group has realized a series of ligands

promoted rhodium(III)-catalyzed C−H functionalization of

benzamides, especially the pyridine-based ligands promoted

Rh(III)-catalyzed amination reaction of an aryl C−H bond

11c

with free amnines.

On the basis of these results, we

wondered if we could improve the selectivity by introducing a

proper ligand to potentially tune the steric and electronic

properties of the catalyst. Therefore, a variety of pyridine-based

ligands was examined (Scheme 2). There was no signiﬁcant

Scheme 2. Ligand Evaluation of the Synthesis of 3a ^,^,

a b c

Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), [Cp*RhCl₂]₂

5.0 mol %), L11 (20 mol %), and Ag CO (1.0 equiv) in CH CN

(

1.0 mL) at 60 °C in oil bath for 24 h under air. Isolated yields. The

ratio of 3/4 was based on a H NMR analysis. The ratio of 3/4 is

observed without ligand L11.

ment of benzamides (1) and diphenylacetylene (2a) bearing

diﬀerent substituents in the aromatic ring delivered the desired

products (3a−3o) in moderate to excellent yields. The

substrates with electron-rich substituents at the para position

of the benzamides showed excellent reactivity and high

chemoselectivity (3a−3d). The benzamide 1e gave rise to

the corresponding product 3e with good selectivity. Electron-

deﬁcient functional groups such as phenyl, ﬂuoro, chloro,

triﬂuoromethyl, and acetylandmethoxycarbonyl substituents at

the C-4 position were compatible in the present catalytic

reaction (3f−3k). Ortho-substituted substrates exhibited less

conversion eﬃciency compared to para-substituted ones. Meta-

substituted arene derivatives 1n and 1o occurred at the less-

hindered site. Although the ortho- and meta-substituted

benzamides proceeded with a relatively low selectivity, the

selectivity is much better than the one without ligands.

Furthermore, the product 3e can be easily transformed into the

corresponding (1H)-isochromen-1-one 5e in 89% yield under

aqueous acidic conditions (see section 2.4 in the Supporting

Information).

Reaction conditions: 1a (0.1 mmol), 2a (0.15 mmol), [Cp*RhCl₂]₂

5.0 mol %), and Ag CO (1.0 equiv) in CH CN (1.0 mL) at 60 °C

(

oil bath for 24 h under air. The yield was determined by H NMR

analysis of crude product using 1,3,5-trimethoxybenzene as an internal

standard. The ratio of 3a/4a was based on a H NMR analysis.

improvement in the chemoselectivity of the products upon

addition of pyridine analogues L1−L6. Inspired by previous

work that the introduction of a hydroxyl group at the 2-postion

may be beneﬁcial for chemical selectivity, some 2-pyridone

ligands with various substituents at the 4-, 5-, or 6-positions

(

L8−L13) were applied. Fortunately, 5-chloro-2-pyridone L11

dramatically improved the ratio of 3a/4a to 22:1. L14 was

selected to verify the necessity of the hydroxyl group at the 2-

position of the pyridine. Furthermore, ligands with electron-

donating and -withdrawing groups at the 3-position had been

tested as well. A pyridone ligand with a methyl group at the 3-

position (L15) can improve the ratio of 3a/4a to 24:1, yet the

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Meanwhile, we also made eﬀorts to verify the feasibility of

this transformation with diverse internal alkynes (Scheme 4).

Scheme 5. Transition States of C−H Activation and Alkyne

Insertion

, ,

a b c

Scheme 4. Scope of Alkynes

dramatically decreases the energy barrier of the O-directed

−

pathway by 4.0 kcal·mol . In the alkyne insertion step, the

silver carbonate dimer exhibits an analogous role in stabilizing

the transition states for the catalytic system. According to the

hard−soft acid−base theory, the soft acidic silver ion prefers

the soft basic nitrogen atom to the oxygen atom, reducing the

energy barrier of the alkyne insertion more remarkably. On the

contrary, the N-directed pathway proceeds with a less-

Reaction conditions: 1a or 1b (0.1 mmol), 2 (0.15 mmol),

Cp*RhCl₂]₂(5.0 mol %), L11 (20 mol %), and Ag CO (1.0

−1

favorable activation free energy, which is 0.9 kcal·mol higher

[

than the corresponding O-directed pathway in the presence of

equiv) in CH CN (1.0 mL) at 60 °C in oil bath for 24 h under air.

−1

silver carbonate dimer (TS−N-Ag-2: 24.1 kcal·mol vs TS−

Isolated yields. The ratio of 3/4 was based on a H NMR analysis.

−

O-Ag-1: 23.2 kcal·mol ). This indicated that the O-cyclization

product 3e would be obtained as the major product, which is

consistent with the observed moderate chemoselectivity (8:1).

In addition, when pyridone L11 was added, the energy

barrier of the C−H activation in the O-directed pathway was

The O-cyclization products (3p−3t) could be obtained with

good to excellent yields (70−97%) and high selectivity

(

>20:1). Notably, the oxidative annulation of unsymmetrical

−

-phenyl-1-pentyne with 1b worked well to obtain the

further lowered by 0.9 kcal·mol . Accordingly, the overall

activation free energy of the O-directed pathway is 1.8 kcal·

regioisomeric mixture of 3u and 3u′ in 88% and 8% yield,

respectively. Propargyl alcohol 2v was tested as well and

provided a 6:1 mixture of isomers.

To understand the chemoselectivity of this reaction, we

performed a series of density functional theory (DFT)

calculations using diphenylacetylene (2a) and amide 1e as

the substrates in the catalytic system. The calculations have

shown that the reaction proceeded through a C−H activation,

alkyne insertion, and metallallylcarbenoid annulation. We

found that the silver salt can act as a Lewis acid to coordinate

with the deprotonated amide moiety in intermediates and

transition states. Diﬀerent from previous reports on silver

additives serving as either a halide scavenger or a terminal

oxidant for the regeneration of catalytic centers in C−H

transformation, silver carbonate also acts as a Brønsted base

and a Lewis acid to assist the ligands to control the selectivity

of the products in the catalytic system in our work. The silver

carbonate dimer was used as a computational model to

illustrate this eﬀect (see section 2.7.2 in the Supporting

−

mol lower than that of the N-directed pathway (TS−N-Ag-

−

−1

2: 24.1 kcal·mol vs TS−O-Ag-Py-1: 22.3 kcal·mol ), in

good agreement with the enhanced chemoselectivity of this

reaction (17:1).

The kinetic isotope experiments were conducted with 1e

and 1e-d under standard reaction conditions. Ambiguous

kinetic isotope eﬀect (KIE) values were obtained (parallel

experiment: k_H_/k_D= 1.26; intermolecular: k /k_D= 1.57),

indicating that the C−H activation step has a slightly higher

barrier than the next steps. According to our calculations, the

C−H activation step (via TS−O−Ag-Py-1) is only 1.1 kcal

−

mol higher than the alkyne insertion (via TS−O-Ag-2) in

the O-directed pathway, which is consistent with isotope

experiments.

On the basis of the experimental results and DFT

calculations, a proposed catalytic cycle is presented in Scheme

6. The catalytic cycle is initiated by the coordination of amide

1e to the activated Rh(III) species, which is dissociated from

the rhodium dimer precatalyst, leading to Rh-amidate

intermediate A. Subsequently, the cyclic rhodium complex

Int-O-3 was furnished through the C−H activation transition

state TS−O-Ag-Py-1 in the presence of silver carbonate dimer.

Information).

The free energies of C−H activation and alkyne insertion

transition states are illustrated in Scheme 5. In the C−H

activation step, coordination of silver carbonate dimer

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Complete contact information is available at:

Letter

Scheme 6. Proposed Mechanism

Authors

Ping Zhang − Coordination Chemistry Institute, State Key

Laboratory of Coordination Chemistry, School of Chemistry

and Chemical Engineering, Nanjing National Laboratory of

Microstructures, Collaborative Innovation Center of

Advanced Microstructures, Nanjing University, Nanjing

210023, China

Wenju Chang − State Key Laboratory of Coordination

Chemistry, Jiangsu Key Laboratory of Advanced Organic

Materials, School of Chemistry and Chemical Engineering,

Nanjing University, Nanjing 210023, China

Yan-Shang Kang − Coordination Chemistry Institute, State

Key Laboratory of Coordination Chemistry, School of

Chemistry and Chemical Engineering, Nanjing National

Laboratory of Microstructures, Collaborative Innovation

Center of Advanced Microstructures, Nanjing University,

Nanjing 210023, China

Wenxuan Zhao − State Key Laboratory of Coordination

Chemistry, Jiangsu Key Laboratory of Advanced Organic

Materials, School of Chemistry and Chemical Engineering,

Nanjing University, Nanjing 210023, China

Pei-Pei Cui − Coordination Chemistry Institute, State Key

Laboratory of Coordination Chemistry, School of Chemistry

and Chemical Engineering, Nanjing National Laboratory of

Microstructures, Collaborative Innovation Center of

Advanced Microstructures, Nanjing University, Nanjing

Seven-membered cyclic rhodium Int−O-Ag-5 was generated

from complex Int-O-3 and alkyne 2a via the alkyne insertion

transition state TS−O-Ag-2. Finally, through the metal-

lallylcarbenoid annulation, the O-cyclized isochromen-imine

was obtained together with the Rh(I) species, which is

oxidized to the Rh(III) species.

210023, China

Yong Liang − State Key Laboratory of Coordination

Chemistry, Jiangsu Key Laboratory of Advanced Organic

Materials, School of Chemistry and Chemical Engineering,

Nanjing University, Nanjing 210023, China; orcid.org/

In summary, we have demonstrated that, through the

development of the reaction conditions, the transformation of

O-cyclized isochromen-imines was successfully achieved

through the Rh(III)-catalyzed annulation of benzamides with

internal alkynes. On the basis of the experimental results and

DFT calculations, it is indicated that ligands together with the

silver salts are essential in controlling the chemical selectivity of

the reaction. This transformation exhibits a broad substrate

scope and good functional group tolerance.

0000-0001-5026-6710

Wei-Yin Sun − Coordination Chemistry Institute, State Key

Laboratory of Coordination Chemistry, School of Chemistry

and Chemical Engineering, Nanjing National Laboratory of

Microstructures, Collaborative Innovation Center of

Advanced Microstructures, Nanjing University, Nanjing

210023, China; orcid.org/0000-0001-8966-9728

ASSOCIATED CONTENT

sı Supporting Information

https://pubs.acs.org/10.1021/acs.orglett.0c03425

■

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.0c03425.

Notes

The authors declare no competing ﬁnancial interest.

Experimental details and characterization data of all new

compounds (PDF )

ACKNOWLEDGMENTS

■

Accession Codes

We gratefully acknowledge the National Natural Science

Foundation of China (Grant Nos. 21671097 and 21573106)

and the Fundamental Research Funds for the Central

Universities for ﬁnancial support.

CCDC 2034550 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_request@ccdc.cam.ac.uk, or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, U.K.; fax: + 44 1223 336033.

REFERENCES

■

1) (a) Powers, J. C.; Asgian, J. L.; Ekici, O. D.; James, K. E.

Irreversible Inhibitors of Serine, Cysteine, and Threonine Proteases.

Chem. Rev. 2002, 102, 4639−4750. (b) Liu, G.; Zhou, Y.; Ye, D.;

Zhang, D.; Ding, X.; Jiang, H.; Liu, H. Silver-Catalyzed Intramolecular

Cyclization of o -(1-Alkynyl)benzamides: Efficient Synthesis of (1H )-

Isochromen-1-imines. Adv. Synth. Catal. 2009 , 351 , 2605 −2610.

AUTHOR INFORMATION

Corresponding Author

■

Yi Lu − Coordination Chemistry Institute, State Key

Laboratory of Coordination Chemistry, School of Chemistry

and Chemical Engineering, Nanjing National Laboratory of

Microstructures, Collaborative Innovation Center of

Advanced Microstructures, Nanjing University, Nanjing

c) Bian, M.; Yao, W.; Ding, H.; Ma, C. Highly efficient access to

iminoisocoumarins and alpha -iminopyrones via AgOTf-catalyzed

intramolecular enyne-amide cyclization. J. Org. Chem. 2010, 75,

69 −272. (d) Ackermann, L.; Pospech, J.; Graczyk, K.; Rauch, K.

10023, China; orcid.org/0000-0002-8767-7801;

Versatile Synthesis of Isocoumarins and α -Pyrones by Ruthenium-

Catalyzed Oxidative C −H/O −H Bond Cleavages. Org. Lett. 2012, 14,

Email: luyi@nju.edu.cn

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Improved Catalyst Architecture for Rhodium(III) Catalyzed C −H

Letter

30−933. (e) Miura, T.; Hiraga, K.; Toyoshima, T.; Yamauchi, M.;

Activation and its Application to Pyridone Synthesis. Chem. Sci. 2011,

2 , 1606 −1610. (g) Su, Y.; Zhao, M.; Han, K.; Song, G.; Li, X.-W.

Synthesis of 2-Pyridones and Iminoesters via Rh(III)-Catalyzed

Oxidative Coupling between Acrylamides and Alkynes. Org. Lett.

2010, 12, 5462 −5465. (h) Wang, H.; Grohmann, C.; Nimphius, C.;

Glorius, F. Mild Rh(III)-catalyzed C −H activation and annulation

with alkyne MIDA boronates: short, efficient synthesis of heterocyclic

boronic acid derivatives. J. Am. Chem. Soc. 2012 , 134 , 19592 −19595.

(i) Xu, X.; Liu, Y.; Park, C. M. Rhodium(III)-catalyzed intramolecular

annulation through C −H activation: total synthesis of (±)-antofine,

(±)-septicine, (±)-tylophorine, and rosettacin. Angew. Chem., Int. Ed.

Murakami, M. Synthesis of (1H )-Isochromen-1-imines by Nickel-

catalyzed Reaction of 2-Iodobenzamides with Alkynes. Chem. Lett.

012, 41, 798−800. (f) Mohamed, H. M.; Abd El-Wahab, A. H.;

Ahmed, K. A.; El-Agrody, A. M.; Bedair, A. H.; Eid, F. A.; Khafagy, M.

M. Synthesis, reactions and antimicrobial activities of 8-ethoxycou-

marin derivatives. Molecules 2012, 17, 971−988. (g) Ueberschaar, N.;

Dahse, H. M.; Bretschneider, T.; Hertweck, C. Rational design of an

apoptosis-inducing photoreactive DNA intercalator. Angew. Chem.,

Int. Ed. 2013, 52 , 6185 −6189. (h) Yang, S.; Banwell, M. G.; Willis, A.

C.; Ward, J. S. A Chemoenzymatic Route to the (+)-Form of the

Amaryllidaceae Alkaloid Narseronine. Aust. J. Chem. 2015 , 68 , 241 −

46. (i) Mohamed, K. S.; Elbialy, E. E. Synthesis, Characterization,

2012, 51, 9372−9376. (j) Quin

ones, N.; Seoane, A.; García-Fandino,

̃ ̃

and Cytotoxicity Evaluation of Some New Benzo[f]coumarin

Derivatives. J. Heterocyclic Chem. 2018 , 55 , 893 −898.

R.; Mascarenas, J. L.; Gulías, M. Rhodium(iii)-catalyzed intra-

molecular annulations involving amide-directed C −H activations:

synthetic scope and mechanistic studies. Chem. Sci. 2013 , 4 , 2874 −

2879. (k) Wang, N.; Li, B.; Song, H.; Xu, S.; Wang, B. Investigation

and comparison of the mechanistic steps in the [(Cp *MCl ) ] (Cp *

2) (a) Dyker, G. Transition Metal Catalyzed Coupling Reactions

under C −H Activation. Angew. Chem., Int. Ed. 1999 , 38 , 1698 −1712.

b) Ritleng, V.; Sirlin, C.; Pfeffer, M. Ru-, Rh-, and Pd-Catalyzed C −

C Bond Formation Involving C −H Activationand Addition on

Unsaturated Substrates: Reactions and Mechanistic Aspects. Chem.

Rev. 2002, 102 , 1731 −1769. (c) Colby, D. A.; Bergman, R. G.;

Ellman, J. A. Rhodium-Catalyzed C −C Bond Formation via

Heteroatom-Directed C −H Bond Activation. Chem. Rev. 2010 , 110 ,

= C Me ; M = Rh, Ir)-catalyzed oxidative annulation of isoquinolones

5 5

with alkynes. Chem. - Eur. J. 2013, 19, 358−364. (l) Yu, D.-G.; de

Azambuja, F.; Gensch, T.; Daniliuc, C. G.; Glorius, F. The C −H

activation/1,3-diyne strategy: highly selective direct synthesis of

diverse bisheterocycles by Rh(III) catalysis. Angew. Chem., Int. Ed.

2014 , 53 , 9650 −9654. (m) Li, B.; Yang, J.; Xu, H.; Song, H.; Wang, B.

Rhodium(III)-Catalyzed C −H Activation and Annulation with 1-

Alkynylphosphine Sulfides: A Mild and Regioselective Access for the

Synthesis of Bulky Phosphine Ligands. J. Org. Chem. 2015, 80,

12397−12409. (n) Yu, B.; Chen, Y.; Hong, M.; Duan, P.; Gan, S.;

Chao, H.; Zhao, Z.; Zhao, J. Rhodium-catalyzed C −H activation of

hydrazines leads to isoquinolones with tunable aggregation-induced

emission properties. Chem. Commun. 2015 , 51 , 14365 −14368.

(o) Wang, S.-B.; Zheng, J.; You, S.-L. Synthesis of Ferrocene-Based

Pyridinones through Rh(III)-Catalyzed Direct C −H Functionaliza-

tion Reaction. Organometallics 2016, 35, 1420 −1425. (p) Song, L.;

Tian, G.; He, Y.; Van der Eycken, E. V. Rhodium(iii)-catalyzed

intramolecular annulation through C −H activation: concise synthesis

of rosettacin and oxypalmatime. Chem. Commun. 2017 , 53 , 12394 −

12397. (q) Piou, T.; Rovis, T. Electronic and Steric Tuning of a

Prototypical Piano Stool Complex: Rh(III) Catalysis for C −H

Functionalization. Acc. Chem. Res. 2018 , 51 , 170 −180. (r) Xu, Y.;

Li, B.; Zhang, X.; Fan, X. One-Pot Synthesis of Fused N, O-

Heterocycles through Rh(III)-Catalyzed Cascade Reactions of

Aromatic/Vinylic N -Alkoxy-Amides with 4-Hydroxy-2-Alkynoates.

Adv. Synth. Catal. 2018, 360, 2613−2620. (s) Upadhyay, N. S.;

Thorat, V. H.; Sato, R.; Annamalai, P.; Chuang, S.-C.; Cheng, C.-H.

Synthesis of isoquinolones via Rh-catalyzed C −H activation of

substituted benzamides using air as the sole oxidant in water. Green

Chem. 2017 , 19 , 3219 −3224. (t) Su, B.; Wei, J.-B.; Wu, W.-L.; Shi, Z.-

J. Diversity-Oriented Synthesis through Rh-Catalyzed Selective

Transformations of a Novel Multirole Directing Group. ChemCatCh-

em 2015, 7, 2986−2990.

24 −655. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Recent

advances in the transition metal-catalyzed twofold oxidative C −H

bond activation strategy for C −C and C −N bond formation. Chem.

Soc. Rev. 2011, 40, 5068−5083. (e) Chen, Z.; Wang, B.; Zhang, J.; Yu,

W.; Liu, Z.; Zhang, Y. Transition metal-catalyzed C −H bond

functionalizations by the use of diverse directing groups. Org. Chem.

Front. 2015 , 2 , 1107 −1295. (f) Shin, K.; Kim, H.; Chang, S.

Transition-Metal-Catalyzed C −N Bond Forming Reactions Using

Organic Azides as the Nitrogen Source: A Journey for the Mild and

Versatile C −H Amination. Acc. Chem. Res. 2015 , 48 , 1040 −1052.

g) Song, G.; Li, X. Substrate Activation Strategies in Rhodium(III)-

Catalyzed Selective Functionalization of Arenes. Acc. Chem. Res. 2015,

8, 1007−1020.

3) For selected examples, see: (a) Liu, L.; Zhang, J. Selectivity

Control in Lewis Acid Catalyzed Regiodivergent Tandem Cationic

Cyclization/Ring Expansion Terminated by Pinacol Rearrangement.

Angew. Chem., Int. Ed. 2009 , 48 , 6093 −6096. (b) Shi, Z.-Z.; Tang, C.-

H.; Jiao, N. Chemoselective Synthesis of Naphthylamides and

Isoquinolinones via Rhodium-Catalyzed Oxidative Dehydrogenative

Annulation of Benzamides with Alkynes. Adv. Synth. Catal. 2012 , 354 ,

695 −2700. (c) He, Z.; Huang, Y. Diverting C −H Annulation

Pathways: Nickel-Catalyzed Dehydrogenative Homologation of

Aromatic Amides. ACS Catal. 2016, 6, 7814−7823. (d) Fukui, Y.;

Liu, P.; Liu, Q.; He, Z.-T.; Wu, N.-Y.; Tian, P.; Lin, G.-Q. Tunable

arylative cyclization of 1,6-enynes triggered by rhodium(III)-catalyzed

C −H activation. J. Am. Chem. Soc. 2014 , 136 , 15607 −15614.

e) Hong, S. Y.; Jeong, J.; Chang, S. [4 + 2] or [4 + 1] Annulation:

Changing the Reaction Pathway of a Rhodium-Catalyzed Process by

Tuning the Cp Ligand. Angew. Chem., Int. Ed. 2017, 56, 2408−2412.

(

(5) For selected examples on ruthenium-catalyzed arene C−H

annulation, see: (a) Ackermann, L.; Lygin, A. V.; Hofmann, N.

Ruthenium-catalyzed oxidative annulation by cleavage of C −H/N −H

bonds. Angew. Chem., Int. Ed. 2011 , 50 , 6379 −6382. (b) Ackermann,

L.; Fenner, S. Ruthenium-Catalyzed C −H/N −O Bond Functionaliza-

tion: Green Isoquinolone Syntheses in Water. Org. Lett. 2011, 13,

6548 −6551. (c) Ackermann, L.; Lygin, A. V.; Hofmann, N.

Ruthenium-Catalyzed Oxidative Synthesis of 2-Pyridones through

C −H/N −H Bond Functionalizations. Org. Lett. 2011 , 13 , 3278 −

3281. (d) Ackermann, L. Carboxylate-Assisted Ruthenium-Catalyzed

Alkyne Annulations by C −H/Het −H Bond Functionalizations. Acc.

4) For selected examples on rhodium(III)-catalyzed arene C−H

annulation, see: (a) Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.;

Miura, M. Rhodium-catalyzed Oxidative Coupling/Cyclization of

Benzamides with Alkynes via C −H Bond Cleavage. Chem. Lett. 2010,

9 , 744 −746. (b) Guimond, N.; Gouliaras, C.; Fagnou, K.

Rhodium(III)-Catalyzed Isoquinolone Synthesis: The N −O Bond

as a Handle for C −N Bond Formation and Catalyst Turnover. J. Am.

Chem. Soc. 2010 , 132 , 6908 −6909. (c) Hyster, T. K.; Rovis, T.

Rhodium-Catalyzed Oxidative Cycloaddition of Benzamides and

Alkynes via C −H/N −H Activation. J. Am. Chem. Soc. 2010, 132,

0565−10569. (d) Song, G.; Chen, D.; Pan, C.-L.; Crabtree, R. H.;

Chem. Res. 2014 , 47 , 281 −295. (e) Li, B.; Dixneuf, P. H. C(sp )−H

Li, X.-W. Rh-catalyzed oxidative coupling between primary and

secondary benzamides and alkynes: synthesis of polycyclic amides. J.

Org. Chem. 2010 , 75 , 7487 −7490. (e) Guimond, N.; Gorelsky, S. I.;

Fagnou, K. Rhodium(III)-catalyzed heterocycle synthesis using an

internal oxidant: improved reactivity and mechanistic studies. J. Am.

Chem. Soc. 2011, 133, 6449−6457. (f) Hyster, T. K.; Rovis, T. An

bond activation in water and catalytic cross coupling reactions. Chem.

Soc. Rev. 2013 , 42 , 5744 −5767. (f) Allu, S.; Swamy, K. K. C.

Ruthenium-catalyzed synthesis of isoquinolones with 8-aminoquino-

line as a bidentate directing group in C −H functionalization. J. Org.

Chem. 2014, 79, 3963 −3972. (g) Arigela, R. K.; Kumar, R.; Joshi, T.;

Mahar, R.; Kundu, B. Ruthenium(ii)-catalyzed C −H activation/C −N

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

bond formation via in situ generated iminophosphorane as the

Letter

directing group: construction of annulated pyridin-2(1H )-ones. RSC

Adv. 2014 , 4 , 57749 −57753. (h) Garad, D. N.; Mhaske, S. B. Ru-

Catalyzed Regioselective Cascade Annulation of Acrylamides with 2-

Alkynoates for the Synthesis of Various 6-Oxo Nicotinic Acid Esters.

J. Org. Chem. 2019, 84, 1863−1870.

Kinetics, Mossbauer Spectroscopy, and Computation. Angew. Chem.,

Int. Ed. 2019, 58, 12874−12878.

(9) Miura, T.; Hiraga, K.; Toyoshima, T.; Yamauchi, M.; Murakami,

M. Synthesis of (1H )-Isochromen-1-imines by Nickel-catalyzed

Reaction of 2-Iodobenzamides with Alkynes. Chem. Lett. 2012, 41,

798−800.

(

6) For selected examples on cobalt-catalyzed arene C −H

(10) Sun, J.; Bai, D.; Wang, P.; Wang, K.; Zheng, G.; Li, X.

Chemodivergent Oxidative Annulation of Benzamides and Enynesvia

annulation, see: (a) Grigorjeva, L.; Daugulis, O. Cobalt-catalyzed,

(

,4-Rhodium Migration. Org. Lett. 2019, 21, 1789−1793.

aminoquinoline-directed C(sp )−H bond alkenylation by alkynes.

11) (a) Lu, Y.; Wang, H.-W.; Spangler, J. E.; Chen, K.; Cui, P.-P.;

Angew. Chem., Int. Ed. 2014, 53, 10209−10212. (b) Mei, R.; Wang,

H.; Warratz, S.; Macgregor, S. A.; Ackermann, L. Cobalt-Catalyzed

Oxidase C −H/N −H Alkyne Annulation: Mechanistic Insights and

Access to Anticancer Agents. Chem. - Eur. J. 2016, 22, 6759−6763.

Zhao, Y.; Sun, W.-Y.; Yu, J.-Q. Rh(iii)-catalyzed C-H olefination of N -

pentafluoroaryl benzamides using air as the sole oxidant. Chem. Sci.

015, 6, 1923 −1927. (b) Wang, H.-W.; Cui, P.-P.; Lu, Y.; Sun, W.-Y.;

Yu, J.-Q. Ligand-Promoted Rh(III)-Catalyzed Coupling of Aryl C −H

c) Lerchen, A.; Knecht, T.; Koy, M.; Daniliuc, C. G.; Glorius, F. A

Bonds with Arylboron Reagents. J. Org. Chem. 2016, 81, 3416−3422.

General Cp *Co(III)-Catalyzed Intramolecular C −H Activation

Approach for the Efficient Total Syntheses of Aromathecin,

Protoberberine, and Tylophora Alkaloids. Chem. - Eur. J. 2017, 23,

W.-Y.; Yu, J.-Q. Ligand-Promoted Rhodium(III)-Catalyzed ortho -C −

H Amination with Free Amines. Angew. Chem., Int. Ed. 2017, 56,

2149−12152. (d) Kalsi, D.; Dutta, S.; Barsu, N.; Rueping, M.;

449−7453. (d) Kang, Y.-S.; Zhang, P.; Li, M.-Y.; Chen, Y.-K.; Xu,

Sundararaju, B. Room-Temperature C −H Bond Functionalization by

Merging Cobalt and Photoredox Catalysis. ACS Catal. 2018, 8,

H.-J.; Zhao, J.; Sun, W.-Y.; Yu, J.-Q.; Lu, Y. Ligand-Promoted Rh(III)-

Catalyzed Thiolation of Benzamides with a Broad Disulfide Scope.

Angew. Chem., Int. Ed. 2019, 58, 9099−9103.

115−8120. (e) Mei, R.; Sauermann, N.; Oliveira, J. C. A.;

Ackermann, L. Electroremovable Traceless Hydrazides for Cobalt-

Catalyzed Electro-Oxidative C −H/N −H Activation with Internal

Alkynes. J. Am. Chem. Soc. 2018, 140, 7913−7921. (f) Wang, Y.; Du,

C.; Wang, Y.; Guo, X.; Fang, L.; Song, M.-P.; Niu, J.-L.; Wei, D. High-

Valent Cobalt-Catalyzed C −H Activation/Annulation of 2-Benzami-

dopyridine 1-Oxide with Terminal Alkyne: A Combined Theoretical

and Experimental Study. Adv. Synth. Catal. 2018, 360 , 2668 −2677.

(

12) (a) Wang, P.; Li, G. C.; Jain, P.; Farmer, M. E.; He, J.; Shen, P.

X.; Yu, J.-Q. Ligand-Promoted meta -C −H Amination and Alkynyla-

tion. J. Am. Chem. Soc. 2016, 138, 14092−14099. (b) Zhu, R. Y.; Li,

Z. Q.; Park, H. S.; Senanayake, C. H.; Yu, J.-Q. Ligand-Enabled γ -

C(sp )−H Activation of Ketones. J. Am. Chem. Soc. 2018, 140, 3564−

(

568.

13) For computational details, see the Supporting Information .

g) Tang, S.; Wang, D.; Liu, Y.; Zeng, L.; Lei, A. Cobalt-catalyzed

(14) (a) Bay, K. L.; Yang, Y. F.; Houk, K. N. Multiple roles of silver

electrooxidative C −H/N −H [4 + 2] annulation with ethylene or

salts in palladium-catalyzed C −H activations. J. Organomet. Chem.

ethyne. Nat. Commun. 2018, 9, 798−805.

2018 , 864 , 19−25. (b) Schmidbaur, H.; Schier, A. Argentophilic

(

7) For selected examples on nickel-catalyzed arene C−H

Interactions. Angew. Chem., Int. Ed. 2015, 54, 746 −784. (c) Lotz, M.

D.; Camasso, N. M.; Canty, A. J.; Sanford, M. S. Role of Silver Salts in

Palladium-Catalyzed Arene and Heteroarene C −H Functionalization

Reactions. Organometallics 2017 , 36 , 165 −171. (d) Funes-Ardoiz, I.;

Maseras, F. Cooperative Reductive Elimination: The Missing Piece in

the Oxidative-Coupling Mechanistic Puzzle. Angew. Chem., Int. Ed.

2016, 55, 2764−2767.

annulation, see: (a) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.;

Chatani, N. Nickel-catalyzed chelation-assisted transformations

involving ortho C −H bond activation: regioselective oxidative

cycloaddition of aromatic amides to alkynes. J. Am. Chem. Soc.

011 , 133 , 14952 −14955. (b) Obata, A.; Ano, Y.; Chatani, N. Nickel-

catalyzed C −H/N −H annulation of aromatic amides with alkynes in

the absence of a specific chelation system. Chem. Sci. 2017, 8, 6650−

(15) Jiang, J.; Liu, H.; Cao, L.; Zhao, C.; Liu, Y.; Ackermann, L.; Ke,

Z. Metallalkenyl, Metallacyclopropene, or Metallallylcarbenoid? Ru-

Catalyzed Annulation between Benzoic Acid and Alkyne. ACS Catal.

2019, 9, 9387−9392.

655. (c) Yamazaki, K.; Obata, A.; Sasagawa, A.; Ano, Y.; Chatani, N.

Computational Mechanistic Study on the Nickel-Catalyzed C −H/N −

H Oxidative Annulation of Aromatic Amides with Alkynes: The Role

of the Nickel (0) Ate Complex. Organometallics 2019, 38, 248−255.

d) Zhang, X.; Zhao, Q.; Fan, J.-Q.; Chen, D.-Z.; Liu, J.-B. A

computational mechanistic study of Ni(0)-catalyzed annulation of

aromatic amides with alkynes: the effects of directing groups. Org.

Chem. Front. 2019, 6, 618−626.

8) (a) Shi, Z.-Z.; Cui, Y.-X.; Jiao, N. Synthesis of β - and γ -

Carbolinones via Pd-Catalyzed Direct Dehydrogenative Annulation

DDA) of Indole-carboxamides with Alkynes Using Air as the

Wang, S.; Huang, J. Pd-catalysed synthesis of isoquinolinones and

Oxidant. Org. Lett. 2010 , 12 , 2908 −2911. (b) Zhong, H.; Yang, D.;

analogues via C −H and N −H bonds double activation. Chem.

Commun. 2012, 48, 3236−3238. (c) Tang, Q.; Xia, D.; Jin, X.; Zhang,

Q.; Sun, X.-Q.; Wang, C.-Y. Re/Mg bimetallic tandem catalysis for [4

2] annulation of benzamides and alkynes via C −H/N −H

functionalization. J. Am. Chem. Soc. 2013 , 135 , 4628 −4631. (d) Xie,

W.; Li, B.; Xu, S.; Song, H.; Wang, B. Palladium-Catalyzed Direct

Dehydrogenative Annulation of Ferrocenecarboxamides with Alkynes

in Air. Organometallics 2014 , 33 , 2138 −2141. (e) Chen, Y.; Au, Y. K.;

Quan, Y.; Xie, Z.-W. Copper catalyzed/mediated direct B −H

alkenylation/alkynylation in carboranes. Sci. China: Chem. 2019 , 62 ,

4 −79. (f) Matsubara, T.; Ilies, L.; Nakamura, E. Oxidative C −H

Activation Approach to Pyridone and Isoquinolone through an Iron-

Catalyzed Coupling of Amides with Alkynes. Chem. - Asian J. 2016,

1, 380−384. (g) Mo, J.; Muller, T.; Oliveira, J. C. A.; Demeshko, S.;

Meyer, F.; Ackermann, L. Iron-Catalyzed C −H Activation with

Propargyl Acetates: Mechanistic Insights into Iron(II) by Experiment,