Divergent Annulative C-C Coupling of Indoles Initiated by Manganese

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Divergent Annulative C-C Coupling of Indoles Initiated by Manganese-Catalyzed C-H Activation Bingxian Liu, Jie Li, Panjie Hu, Xukai Zhou, Dachang Bai, and Xingwei Li ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.8b02560 • Publication Date (Web): 31 Aug 2018 Downloaded from http://pubs.acs.org on August 31, 2018

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ACS Catalysis

Divergent Annulative C-C Coupling of Indoles Initiated by Manganese-Catalyzed C-H Activation Bingxian Liu,† Jie Li,† Panjie Hu,† Xukai Zhou,‡ Dachang Bai,† Xingwei Li*,†,‡ †

Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, School of

Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, China ‡

Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China O

O H

N Pym

HO

Me O Mn(I) cat., BPh3 1,4-dioxane

Mn(I) cat. Zn(OAc)2, PivOH N Pym

DCE O

N Pym

Me

OH

ABSTRACT: Manganese(I)-catalyzed C-H activation of indoles and divergent annulative coupling with alkyne-tethered cyclohexadienones has been realized under operationally simple conditions. These annulation systems are under condition control. The coupling in the presence of BPh3 additive followed a C-H activation-alkyne insertion-Michael addition pathway, affording an exocyclic olefin attached to a tetrahydrofuran ring. In contrast, when Zn(OAc)2/PivOH additives were introduced, initial olefination en route to intramolecular Diels-Alder reaction and subsequent elimination of an alcohol was followed to deliver a fused six-membered ring. The selectivity stands in contrast to those reported using rhodium(III) and cobalt(III) catalysts, highlighting the unique reactivity and selectivity of manganese catalysts. KEYWORDS: Manganese catalysis, condition control, indole, C-H activation, enyne INTRODUCTION

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Organic molecules with structural and stereochemical diversity play a vital role in drug discovery and chemical biology.1 Efficient strategies for expansion of molecular diversity are highly desired. Among those, diversity-oriented synthesis (DOS)2 has revolutionized the construction of structurally diverse molecular libraries.3 C-H functionalization, which is in accordance with the concept of DOS owing to its features of complexity-generating, step-economy, and functional group tolerance, has been rapidly applied to synthesis of complex molecules with the continuous development of transition metal-catalyzed C-H activation.4 Although C-H activation initiated transformations can be rapidly applied to construction of complex scaffolds in a single pot,5 which is a complexity-generating process, diversity-generating processes are still limited. Excellent works have been reported to access compound library by C-H activation with both complexity and structural diversity.6

On the other hand, to fulfill the demand of sustainability in synthesis, earth abundant manganese catalysts have been increasingly applied to C-H activation owing to their unique activity and selectivity associated with a polarized Mn-C bond.7 Thus, Mn(I) catalysis has allowed diverse alkylation,8 alkenylation,9 alkynylation,10 amidation11, cyanation12 and simple annulation13 of arenes. Among these catalytic systems, only very few examples have been reported for construction of complex fused rings.14 Of note, the Ackermann group described

manganese-catalyzed

bicyclic

annulation

of

ketimines

and

methylenecyclopropanes (Scheme 1a).14a The Wang group independently realized relay catalysis using Mn(I) and Ag(I) catalysts for synthesis of analogous structures via C-H activation of ketimines followed by Povarov cycloaddition (Scheme 1b).14b The Wang group


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and

Rueping

group

also

independently

developed

a

manganese-catalyzed

C−H

alkenylation/Smiles rearrangement cascade to access pyrroloindolones (Scheme 1c).14c, 14d

Scheme 1. Mn-Catalyzed C-H Activation for Synthesis of Fused Rings

In C-H activation chemistry, generation and subsequent functionalization of a M-C species represent a central topic. To ensure sufficient interactions of the M-C bond with a coupling reagent, our previous strategy was to rely on high valent M(III)-C (M = Co, Rh, and Ir) species owing to the polarized nature of the M-C bond, 6c-6e, 15 where the nucleophilic carbon and the Lewis acidity of the metal are integrated in the same entity, and efficient interactions with the coupling reagent conduce to facile construction of complex cyclic products. In these systems, the reactivity and selectivity of the M-C species is readily tuned by the metal as well the ligand.6d,

6e

For example, we have realized a cascade of C-H

alkenylation-intramolecular Diels-Alder reaction (IMDA) of indoles under catalyst control (Scheme 2).6d The Cp*Rh(III)-catalyzed system afforded fused cycles while the Cp*Co(III)-catalyzed system delivered bridged bicyclic rings, where the divergence of the selectivity originated from the regioselectivity of the alkyne insertion process.15c Given the


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high nucleophilicity of organomanganese species and their unique reactivity, we reasoned that Mn-catalyzed C-H activation of indoles and functionalization with alkyne-tethered cyclohexadienones may follow different selectivity, which is particularly desired in delivering molecular diversity in C-H activation. We now report divergent synthesis of two classes of cyclic products via Mn-catalyzed C-H activation of indoles under condition control. Moreover, the selectivity stays complementary to those in Rh- and Co-catalyzed systems.

Scheme 2. Our Previous Work and this Work on Mn(I) Catalysis

RESULTS AND DISCUSSION We initially examined the feasibility of an alkyne insertion-Michael addition16 cascade in the coupling of N-pyrimidylindole (1a) and a 3,3-dimethyl-substituted 1,6-enyne 2a (Table 1). The desired product 3aa was isolated in 49% yield as a single diastereomer when catalyzed by Mn2(CO)10 (5 mol%) in TFE at 130 °C. The E-configuration of the double bond has been verified by NOESY spectroscopy. MnBr(CO)5 also proved to be an active catalyst for this reaction (entry 3). Increase of the ratio of 2a:1a led to a higher yield (entry 2). The reaction efficiency was sensitive to the temperature, and the yield decreased at a higher or lower temperature. To facilitate the Michael addition, a Lewis acid was employed to activate the enone group. Thus, introduction of BPh3 (0.5 equiv) gave favorable outcomes (76% yield). Moreover, reducing the amount of BPh3 further slightly improved the efficiency, and


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an excellent yield (92%) was isolated when 1,4-dioxane was used as a solvent after a prolonged reaction (Conditions A). We noted that Lin and coworkers have realized a C-H insertion-Michael addition cascade in Rh(III)-catalyzed coupling of arenes and this enyne by C-H activation, but the arene has been limited to secondary bezamides.6a Table 1. Optimization of the C-H Insertion/Michael Addition Reactiona O O H

[Mn], additive N Pym 1a

solvent, temp O 2a

O

N Pym 3aa

entry

solvent

additive (mol %)

temp (°C)

yield (%)

1b

TFE

-

130

49

2

TFE

-

130

69

3c

TFE

-

130

60

4

TFE

-

110

40

5

TFE

-

140

57

6

TFE

NaOAc (50)

130

17

7

TFE

Zn(OAc)2 (50)

130

69

8

TFE

LiBr (50)

130

45

9

TFE

BPh3 (50)

130

76

10

TFE

BPh3 (25)

130

79

11

TFE

BPh3 (100)

130

56

12

DCE

BPh3 (25)

130

11

13

1,4-dioxane

BPh3 (25)

130

86

14d

1,4-dioxane

BPh3 (25)

130

92

a

Conditions A: 1a (0.2 mmol), 2a (0.3 mmol), Mn2(CO)10 (5 mol %) and

additive in a solvent (2 mL) at 110-140 oC for 12 h under argon, isolated yield. b

1a:2a = 1:1.2. cMnBr(CO)5 (10 mol %) was used as a catalyst. d17 h.

A broad scope of indoles has been established for this C-H insertion/Michael addition


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system under the standard Conditions A (Scheme 3). Substituted indoles bearing electron-donating and -withdrawing groups at the 4-, 5-, and 6- positions all coupled smoothly with 2a to afford the corresponding products in moderate to excellent yields (3aa-3pa). Of note, the identity of this alkyne insertion/Michael addition product has been unambiguously confirmed by X-ray crystallography for product 3ea (CCDC 1852502). 7and 3-Methyl-substituted indoles were also viable substrate but with low reactivity (3qa and 3ra), indicative of sensitivity to steric perturbation. Changing the directing group to a pyridyl or to a Me- or OMe-substituted pyrimidyl also led to the desired coupling in good efficiency (3sa-3wa).

The

coupling system seems limited to indole substrates.

Although

N-pyridylisoquinolone also underwent coupling (3xa), the reaction efficiency was poor. Other

well-studied

arenes

such

as

2-phenylpyridine,

2-phenylpyrimidine,

N-phenylpyrimidin-2-amine, 2-phenoxypyridine, and 2-(1H-pyrrol-1-yl)pyrimidine all give negative results. In addition, the substrate N-phenylpyridin-2-amine (1y) offered an aza-Michael addition product instead of the corresponding C-Michael addition product in 54% yield under the modified conditions by changing the solvent from 1,4-dioxane to TFE. The scope of the 1,6-enyne substrates was next explored. Introduction of a β-methyl group into the enone moiety attenuated the reaction (3ab). The coupling of a monomethyl-substituted 1,6-enyne afforded the corresponding product 3ac in 64% in 1:1.2 dr. Introduction of a methyl terminus into the alknye retarded the reaction due to steric effect during the alkyne insertion, and the product (3ad) was isolated in 35% yield under slightly modified conditions using TFE as a solvent (Conditions B). Removal of the gem-dimethyl group in the 1,6-enyne led to the desired coupling in lower yield under the standard Conditions A, likely due to lack of the Thorpe-Ingold effect. Fortunately, by following the conditions B, the corresponding product 3ae was isolated in 62% yield (Scheme 3, see SI for details). Under these conditions, a 5-aryl substituted 1,6-enyne also coupled smoothly to give 3af in moderate yield. Unfortunately, 1,6-dienes were inapplicable in this catalytic system.


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Scheme 3. Scope of the C-H Insertion/Michael Addition System.a aReaction Conditions A: 1 (0.2 mmol), 2 (0.3 mmol), Mn2(CO)10 (5 mol %), BPh3 (25 mol %), 1,4-dioxane (1 mL), 130 oC, Ar, 17 h, isolated yield. bReaction Conditions B: 1 (0.2 mmol), 2 (0.4 mmol), Mn2(CO)10 (5 mol %), TFE (2 mL), 120 oC, Ar, 12 h, isolated yield. cTFE was used as the solvent. During the synthesis of product 3ae under the conditions B, a bridged cycle6d 5ae was also isolated as a minor product in 24% yield. In contrast, product 4ae, a fused phenol, was obtained as the major product when Zn(OAc)2 and PivOH were introduced as additives ACS Paragon Plus Environment

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(Conditions C, Scheme 4). It is likely that this phenol product was generated via C-H insertion into alkyne, intramolecular Diels-Alder (IMDA) Reaction, and subsequent aromatization by alcohol elimination.15c, 17 Of note, this selectivity is different from the that in Rh(III) catalysis where the IMDA adduct constitutes the final product (vide infra).6d

Scheme 4. Condition-Controlled Synthesis of Functionalized Indoles. The scope of synthesis of the fused phenols was next explored (Scheme 5). Various substituted indoles reacted smoothly with enyne 2e to afford the cascade annulation products in generally moderate to good yield (4ae-ce, 4he-re). The coupling of a 7-methyl substituted indole in moderate yield suggested tolerance of steric hindrance (4oe). When 4-CN or 4-COOMe indole was reacted with 2a, the same seven-membered fused ring product 4ge was isolated in moderate yield in both cases as a result of further nucleophilic attack of the phenol OH at the ester or CN group. In case of 4-methyl, 4-Cl and 4-OBn indoles, the coupling afforded [6,5,6]-fused indoles without further aromatization (6de-6fe). This is likely ascribed to the torsional strain that defies subsequent elimination and formation of phenol product. Analogously, when no subsequent elimination of alcohol or aromatization was possible as in case of some enynes bearing methyl substituents in the enone moiety, the IMDA adduct was isolated as the major product (6aj and 6ak). In contrast, the coupling of other substituted 1,6-enyne substrates afforded the corresponding phenol products in moderate yield (4ag-4ai). To further demonstrate the application of this reaction, an estrone-derived 1,6-enyne derivative coupled with 1a to afford the IMDA adduct 6al as the single diastereomeric product. This result may due to the rigidity of the product conformation which would inhibit the interactions of Lewis acid with the oxygen atom of the product.


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ACS Catalysis

O

HO

O

O

[Mn]

OH

N

O

Pym 4

2

1 R HO

RO

H

or

N Pym

H

H R O

H

H

N Pym 6 O

O

O H N Pym

N Pym

OH

R = H, 4ae, 66% (62%)b R = OMe, 4be, 63% R = F, 4ce, 45%

H

N Pym

R = Me, 6de, 88% R = Cl, 6ee, 77% R = OBn, 6fe, 74%

OH

not observed for R = Me, Cl, or OBn

N Pym

R = 4-COOMe, 4ge, 42% R = 4-CN, 4ge, 35%

HO

HO

Br

R

OH

HO

HO

R N Pym

N Pym

OH

R = Me, 4he, 71% R = OMe, 4ie, 90% R = Br, 4je, 62% R = COOMe, 4ke, 65%

OH

R = 5-Me, 4le, 61% R = 5-OMe, 4me, 62% R = 5-Cl, 4ne, 60% R = 7-Me, 4oe, 43% HO

HO

N R

N Py

R = 5-OMepyrimidyl, 4qe, 63% R = 5-Mepyrimidyl, 4re, 59%

4pe, 68%

O

O

H

N Pym OH

R = n-butyl, 4ah, 48% R = benzyl, 4ai, 54%

4ag, 24%

O

H

H

OH

O

O

R N Pym

OH

OH

H N Pym

H

6aj, 70%

N Pym

H

6ak, 42%

H

O H H N Pym

O H

6al, 36%

Scheme 5. Scope of the C-H Alkenylation/IMDA/aromatization System.a aReaction Conditions C: 1 (0.2 mmol), 2 (0.4 mmol), MnBr(CO)5 (10 mol %), Zn(OAc)2 (50 mol %), PivOH (50 mol %), DCE, 120 oC, Ar, 12 h, isolated yield. b2 mmol of 1a was used, 18 h. To demonstrate synthetic utility of the catalytic reaction, chemoselective hydrogenation of 3aa has been performed, delivering product 8aa in 83% yield (Scheme 6). Treatment of 3aa with NaOEt led to the pyrimidyl migration product 7aa in 60% yield likely via Smiles rearrangement.14c,d,15c


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Scheme 6. Derivatization Reactions of Product 3aa. To gain insight into the mechanism of this C-H activation-functionalization system, some mechanistic studies have been carried out (Scheme 7). To probe the C-H activation process, a metallacycle A has been synthesized according to a previous report.8b The two cascade annulation systems each led to the desired product 3aa or 4ae in high yield when A was designated as a catalyst under the corresponding standard conditions (Scheme 7a and 7b). The stoichiometric reactions using metallacycle A with 2a and 2e were also conducted and each yielded the corresponding products in good yields (Scheme 7c and 7d). These results indicated relevancy of C-H activation. In fact, the C-H activation was reversible, as evidenced by the H/D exchange at the C(2) position of the indole when PivOD was employed as a deuterium source (Scheme 7e). In addition, H/D exchange was also observed at the diastereotopically specific β-position of the OH group in the product 4ae-dn, indicating that protonolysis of a Mn-C bond may exist. KIE experiments have been performed for the coupling of 1a and 2e under Conditions C. The KIE was determined to be kH/kD = 1.2 on the basis of two side-by-side reactions using 1a and 1a-d1 at a low conversion (Scheme 7f). This insignificant value indicates that cleavage of the C(2)-H bond is probably not involved in the turnover-determining step. Our control experiments revealed that no Michael addition product was detected by treating 1a with 2e under the Rh(III)-catalyzed C-H olefination-IMDA system6d conditions by introduction of BPh3 (Scheme 7g). This result may indicate that the high nucleophilicity of the intermediate Mn-C species plays a key role to achieve the Michael addition cascade and BPh3 only enhances the efficiency. To probe the intermediacy of a C-H olefination-IMDA adduct in the formation of the phenol product, compound 6ae was prepared.6d Treatment of 6ae with Zn(OAc)2 and PivOH in DCE at 120 o

C afforded the aromatization product 4ae in 60% yield (Scheme 7h), which verified the

intermediacy of this IMDA adduct. To further explore possible reaction intermediates, a phenyl-substituted internal alkyne (2m) was allowed to react with 1a, affording the


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olefination product (9am) in 28% yield (Scheme 7i). This may indicate that a C-H olefinationed species might be involved in the catalytic system, albeit with different regioselectivity with respect to the alkyne insertion. In addition, some control experiments using TEMPO and 1,1-diphenylethylene as the radical scavengers have been conducted (Schemes 7j and 7k). These results indicate that the catalytic system is probably not a radical process.


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a) N Pym

b)

N Pym

+

2a

+

2e

Mn-Int A Conditions A 95%

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3aa

Mn-Int A

4ae

Conditions C 72%

N N

c)

d)

Mn-Int A

Mn-Int A

1,4-dioxane

2a

+

3aa

60 oC 85%

Mn-Int A

DCE 60 oC 80%

2e

+

Mn(CO) 4 N

4ae

O

14% D

HO H/D 17% D

Conditions C

e)

PivOD (10 equiv)

N Pym

N 44% D Pym

O

OH N H/D Pym 15% D

O f)

or

N Pym

N Pym

Conditions C with PivOD or PivOH

D

15 min

KIE = 1.2

O

O

O

H O

g)

Rh(III) cat, BPh3 N Pym

DCE, rt

H not detected

H O

Zn(OAc) 2, PivOH

H N Pym

60%

H

O i)

3ae

N Pym 6ae, trace

O

O h)

H

Ph Conditions A

N Pym 1a

4ae

O 2m

28%

O

N Pym

O

Ph

9am

O j)

3aa

TEMPO: 78% 1,1-Diphenylethylene: 87%

4ae

TEMPO: 5% 1,1-Diphenylethylene: 40%

Conditions A N Pym

radical inhibitor O O Conditions C

k) N Pym

radical inhibitor O

Scheme 7. Mechanistic Studies A plausible pathway is proposed on the basis of our experimental results and literature precedents (Scheme 8).6a,d,9a The C(2)-H activation of the indole substrate gives metallacycle A. Regioselective migratory insertion of the Mn-C bond into the alkyne unit of 1,6-enyne 2e ACS Paragon Plus Environment

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ACS Catalysis

gives alkenyl intermediate B, which might be protonolyzed to produce the olefination intermediate C. Subsequent IMDA generates the adduct 6ae. Zn(OAc)2-mediated intramolecular elimination of an alcohol eventually furnishes the aromatization product 4ae. In contrast, when promoted by the BPh3 additive, the Mn-C bond undergoes diastereoselective Michael additive to give intermediate D, which is a direct precursor to the product 3aa.

Scheme 8. Possible pathways of the Cascade Reactions.

CONCLUSIONS In conclusion, we have realized divergent cascade coupling in Mn(I)-catalyzed C-H activation of indoles and C-C coupling of enynes. Two classes of C(2) functionalized indoles have been conveniently accessed. With BPh3 as an additive, the coupling proceeded via a C-H olefination-Michael addition pathway to afford an exo-cyclized olefin attached to a tetrahydrofuran ring. In the presence of Zn(OAc)2/PivOH additives, the reaction follows a sequence of C-H alkenylation, IMDA, and elimination-aromatization to yield fused phenols as the major product. Given the structural diversity and controllable syntheses of indole derivatives, these cascade annulation systems may find applications in diversity-oriented synthesis of useful complex molecules. Supporting Information The Supporting Information is available free of charge on the ACS Publications website.


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Experimental procedures, NMR and HRMS data, crystal structure of 3ea, copies of NMR spectra (PDF) AUTHOR INFORMATION Corresponding Author *E-mail: [email protected]

Notes The authors declare no competing financial interests. ACKNOWLEDGMENT The NSFC (Nos. 21525208 and 21472186), research fund from Henan Normal University (5101034011009), and start-up fund from Henan Normal University (qd16111, for B.L.) are gratefully acknowledged. REFERENCES [1] Hajduk, P. J.; Galloway, W. R. J. D.; Spring, D. R. Drug Discovery: A Question of Library Design. Nature 2011, 470, 42-43.

[2] Schreiber, S. L. Target-Oriented and Diversity-Oriented Organic Synthesis in Drug Discovery. Science 2000, 187, 1964-1969.

[3] O’Connor, C. J.; Beckmann, S. G.; Spring, D. R. Diversity-Oriented Synthesis: Producing Chemical Tools for Dissecting Biology. Chem. Soc. Rev. 2012, 41, 4444-4456.

[4] For selected recent reviews on transition metal catalyzed C-H activation, see: (a) Mihai, M. T.; Genov, G. R.; Phipps, R. J. Access To The Meta Position Of Arenes Through


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Transition Metal Catalysed C-H Bond Functionalisation: A Focus on Metals other than Palladium. Chem. Soc. Rev. 2018, 47, 149-171. (b) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S. Transition Metal-Catalyzed Site- and Regio-divergent C-H Bond Functionalization. Chem. Soc. Rev. 2017, 46, 4299-4328. (c) He, J.; Wasa, M.; Chan, K. S. L.; Shao, Q.; Yu, J.-Q. Palladium-Catalyzed Transformations of Alkyl C–H Bonds. Chem. Rev. 2017, 117, 8754-8786. (d) Yang, Y.; Lan, J.; You, J. Oxidative C–H/C–H Coupling Reactions between Two (Hetero)arenes. Chem. Rev. 2017, 117, 8787-8863. (e) Dong, Z.; Ren, Z.; Thompson, S. J.; Xu, Y.; Dong, G. Transition-Metal-Catalyzed C-H Alkylation Using Alkenes. Chem. Rev. 2017, 117, 9333-9403. (f) Nairoukh, Z.; Cormier, M.; Marek, I. Merging C-H and C-C Bond Cleavage in Organic Synthesis. Nat. Rev. Chem. 2017, 1, 0035. (g) Hummel, J. R.; Boerth, J. A.; Ellman, J. A. Transition-Metal-Catalyzed C-H Bond Addition to Carbonyls, Imines, and Related Polarized π Bonds. Chem. Rev. 2017, 117, 9163-9227. (h) Baudoin, O. Ring Construction by Palladium(0)-Catalyzed C(sp3)–H Activation. Acc. Chem. Res. 2017, 50, 1114-1123. (i) Wang, F.; Yu, S.; Li, X. Transition Metal-Catalysed Couplings between Arenes and Strained or Reactive Rings: Combination of C-H Activation and Ring Scission. Chem. Soc. Rev. 2016, 45, 6462-6477. (j) Hartwig, J. F.; Larsen, M. A. Undirected, Homogeneous C-H Bond Functionalization: Challenges and Opportunities. ACS Cent. Sci. 2016, 2, 281-292. (k) Moisés, G.; Mascareñas, J. L. Metal-Catalyzed Annulations through Activation and Cleavage of C-H Bonds. Angew. Chem. Int. Ed. 2016, 55, 11000-11019. (l) 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. (m) Wencel-Delord, J.; Glorius,


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F. C-H Bond Activation Enables the Rapid Construction and Late-Stage Diversification of Functional Molecules. Nat. Chem. 2013, 5, 369-375.

[5] (a) Kong, D.-S.; Wang, Y.-F.; Zhao, Y.-S.; Li, Q.-H.; Chen, Y.-X.; Tian, P.; Lin, G.-Q. Bisannulation of Benzamides and Cyclohexadienone-Tethered Allenes Triggered by Cp*Rh(III)-Catalyzed C-H Activation and Relay Ene Reaction. Org. Lett. 2018, 20, 1154– 1157. (b) Lu, H.; Fan, Z.; Xiong, C.; Zhang, A. Highly Stereoselective Assembly of Polycyclic Molecules from 1,6-Enynes Triggered by Rhodium(III)-Catalyzed C-H Activation. Org. Lett. 2018, 20, 3065–3069. (c) Li, M.; Kwong, F. Y. Cobalt-Catalyzed Tandem C-H Activation/C-C Cleavage/C-H Cyclization of Aromatic Amides with Alkylidenecyclopropanes. Angew. Chem. Int. Ed. 2018, 57, 6512-6516. (d) Wang, X.; Lerchen, A.; Gensch, T.; Knecht, T.; Daniliuc, C. G.; Glorius, F. Combination of Cp*RhIII-Catalyzed C-H Activation and a Wagner-Meerwein-Type Rearrangement. Angew. Chem. Int. Ed. 2017, 56, 1381-1384. (e) Chen, J.; Han, X.; Lu, X. Enantioselective Synthesis of Tetrahydropyrano[3,4-b]indoles: Palladium(II)-Catalyzed Aminopalladation/ 1,4- Addition Sequence. Angew. Chem. Int. Ed. 2017, 56, 14698-14701. (f) Fan, L.; Liu, J.; Bai, L.; Wang, Y.; Luan, X. Rapid Assembly of Diversely Functionalized Spiroindenes by a Three-Component Palladium-Catalyzed C-H Amination/Phenol Dearomatization Domino Reaction. Angew. Chem. Int. Ed., 2017 56, 14257-14261. (g) Boerth, J. A.; Hummel,

J.

R.;

Ellman,

J.

A.

Highly

Stereoselective

Cobalt(III)-Catalyzed

Three-Component C-H Bond Addition Cascade. Angew. Chem. Int. Ed. 2016, 55, 12650-12654. (h) Gollapelli, K. K.; Kallepu, S.; Govindappa, N.; Nanubolub, J. B.; Chegondi, R. Carbonyl-Assisted Reverse Regioselective Cascade Annulation of


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ACS Catalysis

2-Acetylenic Ketones Triggered by Ru-catalyzed C-H Activation. Chem. Sci. 2016, 7, 4748-4753. (i) Davies, H. M.; Dai, X.; Long, M.-S. Combined C-H Activation/Cope Rearrangement as a Strategic Reaction in Organic Synthesis: Total Synthesis of (−)-Colombiasin A and (−)-Elisapterosin B. J. Am. Chem. Soc. 2006, 128, 2485-2490. (j) 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-Alkoxyamides with 4-Hydroxy-2-alkynoates. Adv. Synth. Catal. 2018, 360, 2613-2620.

[6] (a) 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. (b) Cui, S.; Zhang, Y.; Wu, Q. Rh(III)-Catalyzed C-H Activation/Cycloaddition of Benzamides and Methylenecyclopropanes: Divergence in Ring Formation. Chem. Sci. 2013, 4, 3421-3426. (c) Bai, D.; Xu, T.; Ma, C.; Zheng, X.; Liu, B.; Xie, F.; Li, X. Rh(III)-Catalyzed Mild Coupling of Nitrones and Azomethine Imines with Alkylidenecyclopropanes via C-H Activation: Facile Access to Bridged Cycles ACS Catal. 2018, 8, 4194-4200. (d) Zhou, X.; Pan, Y.; Li, X. Catalyst-Controlled Regiodivergent Alkyne Insertion in the Context of C-H Activation and Diels-Alder Reactions: Synthesis of Fused and Bridged Cycles. Angew. Chem. Int. Ed. 2017, 56, 8163-8167. (e) Xie, F.; Yu, S.; Qi, Z.; Li, X. Nitrone Directing Groups in Rhodium(III)-Catalyzed C-H Activation of Arenes: 1,3-Dipoles versus Traceless Directing Groups. Angew. Chem. Int. Ed. 2016, 55, 15351-15355.

[7] For reviews of Mn-catalyzed C-H activation, see: (a) Hu, Y.; Zhou, B.; Wang, C. Inert C-H Bond Transformations Enabled by Organometallic Manganese Catalysis. Acc. Chem. 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

Page 18 of 22

Res. 2018, 51, 816-827 (b) Liu, W.; Ackermann, L. Manganese-Catalyzed C-H Activation. ACS Catal. 2016, 6, 3743-3752. (c) Wang, C. Manganese-Mediated C-C Bond Formation via C–H Activation: From Stoichiometry to Catalysis. Synlett 2013, 24, 1606-1613.

[8] For selected papers of Mn-catalyzed C-H alkylation, see: (a) Zhou, B.; Ma, P.; Chen, H.; Wang, C. Amine-Accelerated Manganese-Catalyzed Aromatic C-H Conjugate Addition to α, β-Unsaturated Carbonyls. Chem. Commun. 2014, 50, 14558-14561. (b) Liu, W.; Richter, S. C.; Zhang, Y.; Ackermann, L. Manganese(I)-Catalyzed Substitutive C-H Allylation. Angew. Chem. Int. Ed. 2016, 55, 7747-7750. (c) Zell, D.; Dhawa, U.; Muller, V.; Bursch, M.; Grimme, S.; Ackermann, L. C-F/C-H Functionalization by Manganese(I) Catalysis: Expedient (Per)Fluoro-Allylations and Alkenylations. ACS Catal. 2017, 7, 4209-4213. (d) Ni, J.; Zhao, H.; Zhang, A. Manganese(I)-Catalyzed C-H 3,3-Difluoroallylation of Pyridones and Indoles. Org. Lett. 2017, 19, 3159-3162. (e) Chen, S.-Y.; Li, Q.; Wang, H. Manganese(I)-Catalyzed Direct C-H Allylation of Arenes with Allenes. J. Org. Chem. 2017, 82, 11173-11181. (f) Lu, Q.; Klauck, F. J. R.; Glorius, F. Manganese-Catalyzed Allylation via Sequential C-H and C-C/C-Het Bond Activation. Chem. Sci. 2017, 8, 3379-3383. (g) Meyer, T. H.; Liu, W.; Feldt, M.; Wuttke, A.; Mata, R. A.; Ackermann, L. Manganese(I)-Catalyzed Dispersion-Enabled C-H/C-C Activation. Chem. - Eur. J. 2017, 23,

5443-5447.

(h) Wang,

H.;

Lorion,

M.

M.;

Ackermann,

L.

Air-Stable

Manganese(I)-Catalyzed C-H Activation for Decarboxylative C-H/C-O Cleavages in Water Angew. Chem. Int. Ed. 2017, 56, 6339-6342. (i) Zhou, B.; Hu, Y.; Wang, C. Manganese-Catalyzed Direct Nucleophilic C(sp2)-H Addition to Aldehydes and Nitriles. Angew. Chem. Int. Ed. 2015, 54, 13659-13663. (j) Zhu, C.; Schwarz, J. L.; Cembellín, S.;


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ACS Catalysis

Greßies, S.; Glorius, F. Highly Selective Manganese(I)/Lewis Acid Cocatalyzed Direct C-H Propargylation Using Bromoallenes. Angew. Chem. Int. Ed. 2018, 57, 437-441. (k) Liu, S.-L.; Li, Y.; Guo, J.-R.; Yang, G.-C.; Li, X.-H.; Gong, J.-F.; Song, M.-P. An Approach to 3-(Indol-2-yl)succinimide Derivatives by Manganese-Catalyzed C-H Activation. Org. Lett. 2017, 19, 4042-4045.

[9] For selected papers of Mn-catalyzed C-H alkenylation, see: (a) Zhou, B.; Chen, H.; Wang, C. Mn-Catalyzed Aromatic C-H Alkenylation with Terminal Alkynes. J. Am. Chem. Soc. 2013, 135, 1264-1267. (b) Shi, L.; Zhong, X.; She, H.; Lei, Z.; Li, F. Manganese Catalyzed C-H Functionalization of Indoles with Alkynes to Synthesize Bis/trisubstituted Indolylalkenes and Carbazoles: the Acid is the Key to Control Selectivity. Chem. Commun. 2015, 51, 7136-7139. (c) Lu, Q.; Greßies, S.; Klauck, F. J. R.; Glorius, F. Manganese(I)-Catalyzed

Regioselective

C-H

Allenylation:

Direct

Access

to

2-Allenylindoles. Angew. Chem. Int. Ed. 2017, 56, 6660-6664. (d) Wang, H.; Pesciaioli, F.; Oliveira, J. C. A.; Warratz, S.; Ackermann, L. Synergistic Manganese(I) C-H Activation Catalysis in Continuous Flow: Chemo-Selective Hydroarylation. Angew. Chem. Int. Ed. 2017, 56, 15063-15067. (e) Zell, D.; Dhawa, U.; Müller, V.; Bursch, M.; Grimme, S.; Ackermann, L. C-F/C-H Functionalization by Manganese(I) Catalysis: Expedient (Per)Fluoro-Allylations and Alkenylations. ACS Catal. 2017, 7, 4209-4213. (f) Cai, S.; Ye, L.; Wang, D.; Wang, Y.; Lai, L.; Zhu, C.; Feng, C.; Loh, T. P. Manganese-Catalyzed Synthesis of Monofluoroalkenes via C-H Activation and C-F Cleavage. Chem. Commun. 2017, 53, 8731-8734.

[10] For selected papers of Mn-catalyzed C-H alkynylation, see: Ruan, Z.; Sauermann, N.; 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

Manoni, E.; Ackermann, L. Manganese-Catalyzed C-H Alkynylation: Expedient Peptide Synthesis and Modification. Angew. Chem. Int. Ed. 2017, 56, 3172-3176.

[11] For selected papers of Mn-catalyzed C-H amidation, see: Kong, X.; Ling, N.; Xu, B. Manganese-Catalyzed C–H Amidation of Heteroarenes in Water. Adv. Synth. Catal. 2018, 360, 2801-2805.

[12] For selected papers of Mn-catalyzed C-H cyanation, see: Liu, W.; Richter, S. C.; Mei, R.; Feldt, M.; Ackermann, L. Synergistic Heterobimetallic Manifold for Expedient Manganese(I)-Catalyzed C-H Cyanation Chem. - Eur. J. 2016, 22, 17958-17961.

[13] For selected papers of Mn-catalyzed C-H annulations, see: (a) He, R.; Huang, Z.-T.; Zheng, Q.-Y.; Wang, C. Manganese- Catalyzed Dehydrogenative [4+2] Annulation of N-H Imines and Alkynes by C-H/N-H Activation. Angew. Chem. Int. Ed. 2014, 53, 4950-4593. (b) Lu, Q.; Greßies, S.; Cembellín, S.; Klauck, F. J. R.; Daniliuc, C. G.; Glorius, F. Redox-Neutral Manganese(I)-Catalyzed C-H Activation: Traceless Directing Group Enabled Regioselective Annulation. Angew. Chem. Int. Ed. 2017, 56, 12778-12782. (c) Liu, W.; Zell, D.; John, M.; Ackermann, L. Manganese-Catalyzed Synthesis of cis-β-Amino Acid Esters through Organometallic C−H Activation of Ketimines. Angew. Chem., Int. Ed. 2015, 54, 4092-4096. (d) Hu, Y.; Wang, C. Manganese-Catalyzed Bicyclic Annulations of Imines and α,β-Unsaturated Esters via C-H Activation. Sci. China: Chem. 2016, 59, 1301-1305. (e) Zhou, B.; Hu, Y.; Liu, T.; Wang, C. Aromatic C-H Addition of Ketones to Imines Enabled by Manganese Catalysis. Nat. Commun. 2017, 8, 1169-1177. (f) Lei, C.; Peng, L.; Ding, K. Manganese-Catalyzed C-H Annulation of Ketimines with Allenes:


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ACS Catalysis

Stereoselective Synthesis of 1-Aminoindanes. Adv. Synth. Catal. 2018, 360, 2952-2958. (g) Yahaya, N. P.; Appleby, K. M.; Teh, M.; Wagner, C.; Troschke, E.; Bray, J. T. W.; Duckett, S. B.; Hammarback, L. A.; Ward, J. S.; Milani, J.; Pridmore, N. E.; Whitwood, A. C.; Lynam, J. M.; Fairlamb, I. J. S. Manganese(I)-Catalyzed C-H Activation: The Key Role of a 7-Membered Manganacycle in H-Transfer and Reductive Elimination. Angew. Chem. Int. Ed. 2016, 55, 12455 -12459.

[14] (a) Liang, Y.-F.; Müller, V.; Liu, W.; Münch, A.; Stalke, D.; Ackermann, L. Methylenecyclopropane Annulation by Manganese(I)-Catalyzed Stereoselective C-H/C-C Activation. Angew. Chem. Int. Ed. 2017, 56, 9415-9419. (b) Chen, S.-Y.; Li, Q.; Liu, X.-G.; Wu, J.-Q.; Zhang, S.-S.; Wang, H. Polycyclization Enabled by Relay Catalysis: One-Pot Manganese-Catalyzed C-H Allylation and Silver-Catalyzed Povarov Reaction. ChemSusChem 2017, 10, 2360-2364. (c) Wang, C.; Wang, A.; Rueping, M. Manganese-Catalyzed C-H Functionalizations: Hydroarylations and Alkenylations Involving an Unexpected Heteroaryl Shift. Angew. Chem. Int. Ed. 2017, 56, 9935-9938. (d) Chen, S.-Y.; Han, X.-L.; Wu, J.-Q.; Li, Q.; Chen, Y.; Wang, H. Manganese(I)-Catalyzed Regio- and Stereoselective 1,2-Diheteroarylation of Allenes: Combination of C-H Activation and Smiles Rearrangement. Angew. Chem. Int. Ed. 2017, 56, 9939-9943.

[15] (a) Li, Y.; Xie, F.; Liu, Y.; Yang, X.; Li, X. Regio- and Diastereoselective Access to Fused Isoxazolidines via Ru(II)-Catalyzed C-H Activation of Nitrones and Coupling with Perfluoroalkylolefins. Org. Lett. 2018, 20, 437-440. (b) Zhou, X.; Xia, J.; Zheng, G.; Kong, L.; Li, X. Divergent Coupling of Anilines and Enones by Integration of C-H Activation and Transfer Hydrogenation. Angew. Chem. Int. Ed. 2018, 57, 6681-6685. (c) Zhou, X.; 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

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Luo, Y.; Kong, L.; Xu, Y.; Zheng, G.; Lan, Y.; Li X. Cp*Co(III)-Catalyzed Branch-Selective Hydroarylation of Alkynes via C–H Activation: Efficient Access to α-gem-Vinylindoles. ACS Catal. 2017, 7, 7296–7304.

[16] (a) Cai, S.; Liu, Z.; Zhang, W.; Zhao, X.; Wang, D. Z. Gold-Catalyzed [3+2] Cycloaddition/Hydrolytic Michael Addition/Retro-Aldol Reactions of Propargylic Esters Tethered to Cyclohexadienones. Angew. Chem. Int. Ed. 2011, 50, 11133-11137. (b) He, Z.-T.; Tian, B.; Fukui, Y.; Tong, X.; Tian, P.; Lin, G.-Q. Rhodium-Catalyzed Asymmetric Arylative

Cyclization

of

meso-1,6-Dienynes

Leading

to

Enantioenriched

cis-Hydrobenzofurans. Angew.Chem. Int. Ed. 2013, 52, 5314-5318. (c) Takenaka, K.; Mohanta, S. C.; Sasai, H. Palladium Enolate Umpolung: Cyclative Diacetoxylation of Alkynyl Cyclohexadienones Promoted by a Pd/SPRIX Catalyst. Angew. Chem. Int. Ed. 2014, 53, 4675-4679. (d) Liu, P.; Fukui, Y.; Tian, P.; He, Z.-T.; Sun, C.-Y.; Wu, N.-Y.; Lin, G.-Q. Cu-Catalyzed Asymmetric Borylative Cyclization of Cyclohexadienone-Containing 1,6-Enynes. J. Am. Chem. Soc. 2013, 135, 11700-11703. (e) Tello-Aburto, R.; Harned, A. M. Palladium-Catalyzed Reactions of Cyclohexadienones: Regioselective Cyclizations Triggered by Alkyne Acetoxylation. Org. Lett. 2009, 11, 3998-4000.

[17] (a) Jarvo, E. R.; Boothroyd, S. R.; Kerr, M. A. The High Pressure Diels-Alder Reactions of Quinone-mono-ketals. Synlett 1996, 897-899. (b) Clive, D. L. J.; Fletcher, S. P.; Zhu, M. Formal Radical Cyclization onto Benzene Rings - A General Method Proceeding via Cross-Conjugated Dienones. Chem. Commun. 2003, 526-527.


Divergent Annulative C-C Coupling of Indoles Initiated by Manganese

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