C4 Regioselective Heteroarylation of Indoles by Tuning C−H Met

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C2/C4 Regioselective Heteroarylation of Indoles by Tuning C-H Met-alation Modes Shuyou Chen, Min Zhang, Rongchuan Su, Xingyu Chen, Boya Feng, Yudong Yang, and Jingsong You ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.9b01273 • Publication Date (Web): 04 Jun 2019 Downloaded from http://pubs.acs.org on June 4, 2019

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ACS Catalysis

C2/C4 Regioselective Heteroarylation of Indoles by Tuning C−H Metalation Modes Shuyou Chen, Min Zhang, Rongchuan Su, Xingyu Chen, Boya Feng, Yudong Yang,* and Jingsong You* Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry, Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China ABSTRACT: The development of a rational strategy to achieve the complete regioselectivity and the capability to switch regioselectivity is an appealing, yet challenging puzzle in transition metal-catalyzed oxidative Ar–H/Ar–H cross-coupling. Disclosed herein is an iridium-catalyzed C2/C4 regioselective C–H heteroarylation of indoles with the help of a pivaloyl group at the C3 position. The judicious choice of the catalytic systems allows the C2-heteroarylation of indole via a concerted metalation-deprotonation (CMD) process and the C4-heteroarylation via a trimolecular electrophilic substitution (SE3) pathway. The oxidants Cu(OAc)2·H2O and Ag2O are demonstrated to play a vital role in the C2/C4 regioselectivity. In this article, a heteroaryl-Ir(III)-heteroaryl complex prior to reductive elimination is successfully isolated and characterized, which represents the first example of capturing the bis(hetero)aryl metallic intermediate in oxidative Ar–H/Ar–H cross-coupling. The regiodivergent heteroarylation of indoles developed herein provides an opportunity to rapidly assemble diverse C4- and C2-heteroarylated indoles. KEYWORDS: C−H activation, cross-coupling, heteroarylation, regioselectivity, iridium catalysis

INTRODUCTION The development of concise and efficient synthesis of bi(hetero)aryl structures has become a topic of significant interest due to their extensive utility in pharmaceuticals, biologically active molecules, natural products, agrochemicals, and organic functional materials.1 In the past two decades, transition metalcatalyzed direct C–H (hetero)arylation of (hetero)aryls (C– H/C–X type) has emerged as a powerful synthetic tool to access bi(hetero)aryls owing to its advantages such as higher step economy and lower waste production compared with the conventional cross-coupling reactions.2 In recent years, transition metal-catalyzed oxidative cross-coupling reaction between two (hetero)aromatic C–H bonds (C–H/C–H type) has been considered as a more ideal approach to forge bi(hetero)aryl fragments.3 Because the (hetero)arenes typically possess several potentially reactive C–H bonds, it would be highly appealing to realize the regioselective activation/(hetero)arylation of specific C–H bonds in a given (hetero)arene and to further switch the regioselectivity at will, which could pave the way for the exploration of novel pharmaceuticals and organic functional materials.4 Because bi(hetero)aryl structures containing an indole nucleus are found extensively in many bioactive

molecules, pharmaceuticals and natural products, indole–(hetero)arene cross-coupling reactions have received extensive attention.2f,5 However, the bromo indoles, which are typical substrates in conventional cross-couplings, are generally prepared by the ringsynthesis reactions starting from brominated arene precursors, except 3- and 5-bromoindole via the electrophilic bromination of indole and its bisulfite adduct.6 Thus, the regiodivergent C–H (hetero)arylation of indoles becomes a highly attractive approach to access indolyl–(hetero)aryl structures. Usually, the pyrrole core (C2 and C3) of indole preferentially undergoes the direct C–H functionalization rather than the benzene core (C4–C7) due to the inherently poor reactivity of the phenyl ring. For the pyrrole ring, the reactions generally take place preferentially at the more reactive C3–H bond rather than C2–H bond.7 Undoubtedly, it is strongly desired to develop forceful strategies to surmount the naturally occurring selectivity of indole associated with inherent electronic bias and to further achieve regioselectivity switching.8 the most electron-rich site electrophilic process

0.03

0.16 4

0.11

0.26 N 2

0.12 HOMO

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0.12

0.17 0.04 0.09

To enlarge the difference of the electron densities between C2 and C4 positions

O 4 0.08 N 2

0.15 HOMO

acidic site CMD process

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Figure 1. HOMO electron densities of C2-C7 positions of indole. The sizes of red circle represent the atomic contribution (only the investigated carbon atoms are given).

In the directed C–H activation, the incorporated directing group may have an influence on the electronic distribution of parent molecules. The density functional theory (DFT) calculation9 indicates that the introduction of a carbonyl group at the C3 position, blocking the most reactive site, significantly reduces the electron density of HOMO orbital at the C2 position and thus renders C4 position the most electron-rich, as exemplified by N-methyl 3-pivaloyl indole (Figure 1). Based on this result, we envisioned that the C2/C4 regioswitchable C–H heteroarylation of indoles between these two electronically distinct sites might be realized by tuning the C–H metalation modes, in which a concerted metalation-deprotonation (CMD) process could lead to C2-selectivity (acidic site) and an electrophilic substitution-type process could deliver the C4-isomer (the most electron-rich site). Although different metalation mechanisms such as σ-bond metathesis, Heck-type addition, CMD process, electrophilic aromatic substitution (SEAr type) process and trimolecular electrophilic substitution (SE3) pathway have been recognized in C–H activation,2c,10 tuning the metalation mode based on the different electronic nature of C–H bonds to completely switch the regioselectivity is still an appealing yet challenging task. Scheme 1. Regioselective C4–H and Heteroarylation of Indoles with Heteroarenes H H R

2

COR

Het N R1 C-2 selectivity

Cp*Ir(III) (cat.) Cu(OAc)2•H2O

R2

CMD process H

Het

COR H N 1 + R Het

C2–H

Cp*Ir(III) (cat.) Ag2O/PivOH SE3 process

COR R2

H N 1 R C4-selectivity

Herein we wish to disclose a facile iridium catalytic system that enables the regiodivergent oxidative C–H/C– H heteroarylation of indoles with the help of the pivaloyl group at the indole C3 position. We demonstrate that the selectivity at the C4 and C2 positions of a given indole substrate can be modulated at will by tuning the catalytic systems (Scheme 1).11 Furthermore, this protocol provides an opportunity to rapidly build a library of C4and C2-heteroaryl indoles.

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Figure 2. The single crystal X-ray structures of complexes 7 (left) and IM2 (right). Thermal ellipsoids are shown at the 50% probability level. Carbon: grey; nitrogen: blue; oxygen: red; hydrogen: offwhite; iridium: yellow; chloride: green.

RESULTS AND DISCUSSION Preliminary Investigations. With the above hypothesis in mind, we initially decided to probe whether the C2–H bond of indoles could be selectively iridated with the assistance of a proton shuttle, such as a carboxylate. As expected, treatment of 2,2-dimethyl-1(1-methyl-1H-indol-3-yl) propan-1-one (1a) with [Cp*IrCl2]2/AgSbF6 in the presence of NaOAc led to a five-membered cyclometalated Ir(III) complex 7 (eq 1), which was confirmed by X-ray crystallography (Figure 2). However, no iridacycle 7 was formed in the absence of an acetate additive under the otherwise identical conditions. Subsequently, stoichiometric amounts of complex 7 were subjected to react with benzofuran in the presence of AgBF4 and Cu(OAc)2∙H2O to test whether the C2-heteroarylation of indole could take place. To our delight, the desired product 4e was formed in 36% yield (eq 2). In addition, a cyclometalated Ir(III) acetate analogue 8, which was easily prepared by the treatment of complex 7 with AgOAc, could also react with benzofuran 2m in the presence of Cu(OAc)2∙H2O to deliver 4e in 32% yield (eq 3). Furthermore, the addition of catalytic amount of cyclometalated Ir(III) complex 7 or 8 instead of [Cp*IrCl2]2 into the reaction of 1a and 2m delivered 4e in 67% and 56% yields, respectively (eqs 4 and 5). These results indicated that both the iridacycles 7 and 8 could probably be the intermediate in C2–H activation of indoles. The relatively lower yields of the stoichiometric reactions might be attributed to the decomposition of 7 and 8 and the formation of a significant amount of complex unascertained byproducts in the presence of AgBF4 and Cu(OAc)2∙H2O.12

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COtBu [Cp*IrCl ] (1 equiv) 22 AgSbF6 (4 equiv) H NaOAc (10 equiv) N DCE , 80 oC, 24 h 58% 1a (5 equiv) t

N

Bu O Ir Cl

7

DCE, 80 oC, 24 h without NaOAc n.d.

Bu

N

CO Bu O

DCE, 150 C, 24 h, N2

+

Cu(OAc)2•H2O (3 equiv) DCE, 150 oC, 24 h, N2

2m

1a

COtBu O

7 (10 mol%), AgBF4 (20 mol%)

H

O N

Cu(OAc)2•H2O (3 equiv) DCE, 150 oC, 24 h

Ir Cp* O

(4)

Ag2O or no oxidant

t

DCE, 150 oC, 24 h

Bu

H

IM2

4e, 67%

COtBu

CO Bu H

+

O

COtBu O

8 (10 mol%), AgBF4 (20 mol%)

H

Cu(OAc)2•H2O (3 equiv) DCE, 150 oC, 24 h, N2

N 1a

8

AgOAc (3 equiv) DCE, 150 oC, 24 h

N

t

N

2m

4e, 32%

COtBu

N

1a

2m

H+

N

H

1a

4e, 56%

O +

H

NaOAc (3 equiv DCE , 150 oC, 24 h

2m

O N

COtBu

t Bu IM2, 52%

With the success of stoichiometric reaction and these two Ir(III)–heteroaryl intermediates in hand, our investigation next focused on the following benzofuran C–H metalation and reductive elimination steps. Capturing an indolyl–Ir–benzofuranyl complex, which is not only the product of C–H metalation but also the precursor of reductive elimination, will be a highly appealing, yet challenging task. In the past decade, much scientific endeavour has been paid to the isolation of bis(hetero)aryl metallic intermediate in oxidative Ar– H/Ar–H coupling reactions. However, to our knowledge, no successful precedent has been reported. After a great deal of work, the reaction of the iridacycle 8 with benzofuran 2m afforded the bisheteroaryl Ir(III) complex IM2 in 52% yield in the presence of non-oxidizing NaOAc instead of Cu(OAc)2·H2O (eq 6). The structure of complex IM2 was unambiguously identified by single crystal X-ray structure analysis (Figure 2). Notably, the isolation and characterization of this heteroaryl-Ir(III)heteroaryl complex is of great significance because it represents the first bis(hetero)aryl metallic intermediate captured in the oxidative C–H/C–H coupling reactions between two (hetero)arenes and it would be helpful to investigate the mechanism of this type of reactions.13 Furthermore, a catalytic amount of bisheteroaryl Ir(III) complex IM2 instead of [Cp*IrCl2]2 could promote the reaction of 1a and 2m to give 4e in 61% yield (eq 7). Treatment of the iridacyclic complex IM2 in the presence of AgOAc or Cu(OAc)2∙H2O led to 4e in 42% and 37% yields, respectively (eqs 8 and 9). However, only trace

(9)

4e, trace

(10)

COtBu O

N 1a (1 equiv)

H

H N H 1o (1 equiv)

N

Cu(OAc)2•H2O (3 equiv) DCE, 150 oC, 1 h 4e: 4q = 1: 12.2 by 1H NMR

H/D

1a variation

4q

CO Bu H/D

Cu(OAc)2•H2O (3.0 equiv), D2O (20 equiv), DCE (1.0 mL) 150 oC, 2 h

N

(13)

Dn-1a

C4H deuteration

C2H deuteration

no [Cp*IrCl2]2

0%

0%

no variation

74%

77%

79%

36%

no Cu(OAc)2•H2O

(12)

t

[Cp*IrCl2]2 (5 mol%), AgBF4 (20 mol%)

N

4e + COtBu O

N H

COtBu H

COtBu O

2m (2 equiv) [Cp*IrCl2]2 (5 mol%) AgBF4 (20 mol%)

COtBu

H+

(11)

N 4e, 76%

(6)

Ir O

4e, 37%

2m

Bu O Ir Cp* OAc

(8)

Cu(OAc)2•H2O (3 equiv) DCE (1.0 mL) , 150 oC, 24 h

N

(7)

4e, 42%

[Cp*IrCl2]2 (5 mol%) AgBF4 (20 mol%)

O (5)

4e, 61%

Cu(OAc)2•H2O (3 equiv) DCE (1.0 mL), 150 oC, 24 h, N2

N

2m

O

IM2 (10 mol%), AgBF4 (20 mol%)

H

(3)

o

8

t

O

H +

t

AgBF4 (1 equiv) Cu(OAc)2•H2O (3 equiv

O

O Ir Cp* + H OAc

H

COtBu

4e, 36%

N

Bu

N

1a (5 equiv)

amount of 4e was detected in the absence of an oxidant (eq 10). These results indicated that the generation of a high-valent bisheteroaryl Ir species was required to trigger the reductive elimination. Surprisingly, Ag2O proved to be ineffective for the oxidatively induced reductive elimination of IM2 (eq 10).

N

2m t

(1)

(2)

DCE, 150 oC, 24 h, N2

7

H N

COtBu O

AgBF4 (1 equiv) Cu(OAc)2•H2O (3 equiv

O

O H Ir Cp* + Cl

COtBu

[Cp*IrCl2]2 (1 equiv) AgSbF6 (4 equiv)

COtBu O H

COtBu H or N

1a

D

COtBu D N

[D2]-1a

2m (2 equiv) [Cp*IrCl2]2 (5 mol%) AgBF4 (20 mol%) Cu(OAc)2•H2O (3 equiv) DCE, 150 oC kH/kD = 1.45

N D

4e or COtBu O

(14)

N

[D1]-4e

Based on these above observations, a catalytic system consisting of [Cp*IrCl2]2 (5 mol%), AgBF4 (20 mol%) and Cu(OAc)2∙H2O (3.0 equiv) was found to effectively promote the cross-coupling reaction of 1a and 2m in DCE, leading to 4e in 76% yield (eq 11). To shed light on the mechanism of C2–H heteroarylation, the intermolecular competition experiment between 1a and 1o was conducted. The result showed that the less electron-rich substrate (1o) was more favourable in this transformation (eq 12). This result suggested that a CMD process might be involved in the C2–H iridation process. In addition, H/D exchange experiments were carried out (eq 13). In the absence of [Cp*IrCl2]2, no H/D exchange at both C4−H and C2−H was detected, indicating the essential role of iridium catalyst in the C−H activation. In the absence of Cu(OAc)2·H2O, the deuterations on C4

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and C2 were 79% and 36%, respectively, whereas a significant enhanced H/D exchange on the C2-position was observed in the presence of Cu(OAc)2·H2O. These results implied the copper acetate could promote the C2−H activation, which is consistent with the common knowledge that the carboxylate facilitates the CMD pathway. Thus, we envisioned that Cu(OAc)2·H2O served as both an oxidant and a proton shuttle in the C2−H heteroarylation. The kinetic isotope effect (KIE) experiments were performed with 1a or [D2]-1a and 2m, giving a KIE value of 1.45 (eq 14). This result revealed that the C2–H bond cleavage might not be involved in the rate-determining step. H

COtBu

+ H

N

H

Ag2O (3 equiv) DCE, 150 oC, 24 h

2k

1a

COtBu H

N

1a

S

COtBu

Ag2O (3 equiv) DCE, 80 oC, 24 h

2k

(15)

N

5m, 28%

[Cp*IrCl2]2 (5 mol%) AgSbF6 (20 mol%)

S

+

Encouraged by the success of catalytic C2–H heteroarylation of indoles, we next turned our attention to the C4-heteroarylation. To our delight, when a noncarboxylate type oxidant Ag2O was used instead of Cu(OAc)2∙H2O, the regioselectivity was switched, providing the decarbonylated C4-heteroarylated isomer 5m as the major product (eq 15). Further lowering the temperature to 80 °C could regioselectively produce the cross-coupled product 3k in 40% yield (eq 16). The addition of PivOH (1.0 equiv) could efficiently improve the yield of 3k to 78% (eq 17). This selectivity is consistent with H/D exchange experiment, in which a 35% of deuterium incorporation was observed at the C4 position of 1a and

S

[Cp*IrCl2]2 (5 mol%) AgSbF6 (20 mol%)

S

(16)

N

3k, 40%

H

COtBu

[Cp*IrCl2]2 (5 mol%) AgSbF6 (20 mol%)

S H

+ N 1a

S

COtBu

Ag2O (3 equiv), PivOH (1 equiv) DCE, 80 oC, 24 h

2k

(17) N 3k,78%

H

86% D H/D COtBu

COtBu [Cp*IrCl2]2 (5 mol%), AgSbF6 (20 mol%)

H

H

N

[Cp*IrCl2]2 (5 mol%), AgSbF6 (20 mol%)

H

H/D

Ag2O (3 equiv), PivOH (1 equiv) D2O (20 equiv), DCE, 80 oC, 2 h

N 1a

H

COtBu

N Bn 1i (1 equiv)

+

N

2k (2 equiv) [Cp*IrCl2]2 (5 mol%) AgSbF6 (20 mol%)

COtBu

H or N 1a

D

COtBu D N

[D2]-1a

S H

2k (2 equiv) [Cp*IrCl2]2 (5 mol%) AgSbF6 (20 mol%)

Ag2O (1 equiv), PivOH (0.5 equiv) D2O (20 equiv), DCE, 80 oC, 2 h

S

COtBu (20)

N Bn

N Boc

3u 3v 3u:3v > 99:1, by 1H NMR

S

Ag2O (3 equiv), PivOH (1 equiv) DCE, 80 oC kH/kD = 1.07

[Cp*IrCl2]2 (2.5 mol%), AgSbF6 (10 mol%)

COtBu +

N Ag2O (3 equiv), PivOH (1 equiv) Boc DCE, 80 oC, 1 h 1j (1 equiv)

COtBu

(19)

0% D

S

>99% recovery

H

91% D

35% D H/D COtBu

COtBu

H

(18)

H/D

PivOH (1 equiv) D2O (20 equiv), DCE (0.5 mL) 80 oC, 2 h

N 1a

COtBu

S

COtBu

or

D

(21)

N [D1]-3k

N 3k S

(22)

H/D

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addition of PivOH: 9% D no PivOH: 8% D

Scheme 2. Substrate Scope of Regioselective C4–H Heteroarylationa

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ACS Catalysis H

Het

COR

R2

+

Het

H

Ac

O

N

3b, 54%

3a, 70%

b

S

COtBu

COtBu

N

3c, 50%

S

S

COtBu

COtBu

N

N

N 3e, 71%

3d, 80%

N R1

Br

Cl

S

COtBu

N

N

3

EtO2C

S

COtBu

R

2

2

OHC

O

COtBu

COR

Ag2O (3 equiv), PivOH (1 equiv) DCE (0.5 mL) , 80 oC, 24 h

N R1 1

EtO2C

[Cp*IrCl2]2 (5 mol%), AgSbF6 (20 mol%)

3g, 65%

3f, 61%

Br OHC

S

COtBu

Br

Br

MeO2C

S

S

COtBu

N

COtBu

N

N

3h, 58%

S

COtBu

N

3j, 82%

3i, 79%

S

O

COtBu

Cl

N

N

3n, 72%

3m, 35%

3l, 73%

S

COtBu

F

N

N

3k, 78%

S

COtBu

COtBu

3o, 60% MeO2C

S

S

COtBu

N

MeO2C

N

Cl

3p, 85%

S

S

COtBu

COtBu

COtBu

N

N

MeO

3q, 90%

S

S

S

COtBu

N Bn

N Boc

3u, 83%, 70%c

3t, 70%

CO2Me

COtBu

N Bn

N

F 3s, 61%

3r, 55%

S

COtBu

3v, 50%

3w, 40%

aReaction

conditions: 1 (0.2 mmol), 2 (2 equiv), [Cp*IrCl2]2 (5 mol%), AgSbF6 (20 mol%), Ag2O (3 equiv), PivOH (1 equiv), and DCE (0.5 mL) at 80 °C for 24 h. bReaction at 70 °C. c3.5 mmol scale.

Scheme 3. Substrate Scope of Regioselective C2–H Heteroarylationa COR

COR R

2

H +

COtBu O

CO2Et

N

[Cp*IrCl2]2 (5 mol%), AgBF4 (20 mol%)

Het

N

COtBu O

Ac

N 4l, 51%

COtBu O

N

N

Ac

N

N 4m, 62%

CONHtBu O

N Bn

N

4r, 52%

4s, 45%

N

N 4n, 40%

COtBu S N 4t, 63%b

COtBu O N 4e, 76%

COtBu O

COtBu O

MeO2C

N

CO2Me

COtBu O Cl

COtBu O

F

N

4i, 67%

COtBu O MeO2C

CO2Et

4d, 62%

4h, 34%

COtBu O MeO

MeO

COtBu

4g, 30%

COtBu O

Br

N

N

4f, 66%

COtBu O

4c, 75%

COtBu

Br

Het N R1 4

N

COtBu O

2

2

4b, 60%

4a, 55%

R

Cu(OAc)2•H2O (3 equiv) DCE (1 mL) , 150 oC, 24 h

N R1 1

COtBu O

H

N

4j, 42%

4k, 60%

COtBu O

COtBu O

N

N 4o, 70%

COtBu S

N H 4q, 71%

4p, 38%

COtBu S

Cl

N

N

4u, 61%b

S

COtBu

+ N

c

4t, 25%

3k, 47%

Ag2CO3 instead of Cu(OAc)2•H2Od

4t, 33%

3k, 48%

aReaction

Ag2O with Cu(OAc)2•H2O

conditions: 1 (0.2 mmol), 2 (2 equiv), [Cp*IrCl2]2 (5 mol%), AgBF4 (20 mol%), Cu(OAc)2·H2O (3 equiv), and DCE (1 mL) at 150 °C for 24 h. b1 (0.2 mmol), 2 (2 equiv), [Cp*RhCl2]2 (5 mol %), AgSbF6 (20 mol%), Ag2O (3 equiv), PivOH (1 equiv), and DCE (0.5 mL) at 80 °C for 24 h. cAg2O (2 equiv) was added additionally. d AcOH (1 equiv) and Ag2CO3 (3 equiv) instead of Cu(OAc)2·H2O.

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no deuteration was found at the C2 position, whereas the hydrogen atoms at C4 and C2 positions were deuterated in 86% and 91% yields in the absence of Ag2O, respectively (eqs 18 and 19). To further investigate the mechanism and determine the role of PivOH, an intermolecular competition experiment was conducted with an equimolar mixture of electronically different indoles 1i and 1j. The reaction was found to preferentially take place at the more electron-rich substrate 1i and a significant effect of the electronic nature of indole was observed (3u:3v > 99:1). Meanwhile, the N-Boc protected substrate 1j could be recovered with no significant loss (eq 20). It should be noted that both 1i and 1j alone could work well under the standard conditions (Scheme 2, 3u and 3v). These results suggested that the C4−H metalation of indoles might proceed through an electrophilic metalation process. A primary KIE value (kH/kD = 1.07) was observed in the parallel competition reactions between 2k and 1a or [D2]-1a (eq 21), suggesting that the cleavage of C4–H bond might not be involved in the rate-determining step. Finally, the deuteration experiments of benzothiophene showed that PivOH had a negligible effect on the C2– H/D exchange of benzothiophene (eq 22). Based on these observations, we surmised that the C4–H metalation of indoles might involve a trimolecular electrophilic substitution (SE3) mechanism in the presence of PivOH,10c,14 in which pivalate participated in the deprotonation process as an external proton shuttle. Regioselective C4–H Heteroarylation. With the optimized reaction conditions in hand, we next investigated the substrate scope in the C4heteroarylation (Scheme 2). Firstly, the substrate scope with regard to heteroarenes was tested. A set of heteroarenes such as benzo[b]thiophene, thiophenes, benzo[b]furans and furans could react with 1a under the standard conditions, furnishing the C4-heteroarylated indoles in satisfactory yields (3a-3m). Notably, sensitive functional groups such as -CO2R, -Ac, -CHO, -Cl, and -Br could survive from this procedure, which would provide handles for further transformations. Subsequently, a number of substituted indoles were examined. Both electron-donating and -withdrawing substituents at the C5–C7 positions were well compatible, affording the desired products in moderate to excellent yields (3n-3t). When the N–H was substituted with the benzyl or tertbutoxycarbonyl group, the target products were delivered in 83% and 50% yields, respectively (3u and 3v). It is noteworthy that a gram-scale reaction was performed to give 3u in 70% yield, which further demonstrated the synthetic utility of the protocol. Besides the pivaloyl group, the ester group was also a suitable directing group, giving the desired product in 40% yield (3w). However, heteroarenes such as N-methyl

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pyrrole, N-methyl indole, benzoxazole, benzothiazole and electron-rich 1,2-dimethoxybenzene remained intact in our tests. Regioselective C2–H Heteroarylation. Scheme 3 summarizes the C2–selective reactions of a range of indoles with heteroarenes under the standard conditions. N-Methyl 3-pivaloyl indole could react with diverse furans, benzofurans and pyrroles to afford C2heteroarylated products in acceptable yields (4a-4h). Further investigation disclosed that substituted indoles ran smoothly, delivering the C2-heteroarylated products in moderate to good yields (4i-4s). It is worthy of note that free (NH) indole could participate in this reaction, giving the biheteroaryl 4q in 71% yield. The amide group also proved to be an effective directing group in this transformation (4s). However, thiophenes, which are suitable substrates in C4−H heteroarylation, did not participate in the C2−H heteroarylation under the [Cp*IrCl2]2/AgBF4/Cu(OAc)2·H2O catalytic system. Interestingly, with the extra addition of Ag2O (2 equiv) to the standard conditions, the cross-coupling reaction of 1a and 2k gave the C2−H heteroarylated product 4t in 25% yield along with the C4−H heteroarylated product 3k in 47% yield. Subsequently, the cross-coupling reaction of 1a and 2k was conducted in the presence of [Cp*IrCl2]2 (5 mol%)/AgBF4 (20 mol%)/Ag2CO3 (3 equiv)/AcOH (1 equiv), affording 4t in 33% yield and 3k in 48% yield. Based on these results, we surmised that the formation of a thienyl silver species could promote the C2−H heteroarylation when thiophenes were used as the substrates.15 Additionally, the cross-coupling reactions with thiophenes could take place using a rhodium catalytic system ([Cp*RhCl2]2/AgSbF6/Ag2O/PivOH) (4t and 4u). Scheme 4. Cascade Heteroarylation/Decarbonylation of Indolesa

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ACS Catalysis H

R2

+ H

Ag2O (3 equiv), PivOH (1 equiv) toluene (0.5 mL), 120 oC, 36 h

2

R2

S

N

N

N 5a, 63% Br

EtO2C

S

N

5c, 48%

5b, 56%

Br

As depicted above (eq 15), high temperature could lead to decarbonylation of the resulting biheteroaryl product. Thus, a cascade C4heteroarylation/decarbonylation relay was developed by using [Cp*IrCl2]2 (5.0 mol%)/AgSbF6 (20 mol%) as the catalyst and Ag2O (3.0 equiv) as the oxidant in toluene at 120 °C (Scheme 4). A gram-scale C4heteroarylation/decarbonylation was conducted to give 5f in 62% yield, illustrating the practicality of this cascade reaction.

Cl S

S

S

N R1

5

MeO2C

EtO2C

conditions: 1 (0.2 mmol), 2 (2 equiv), [Cp*IrCl2]2 (5 mol%), AgSbF6 (20 mol%), Ag2O (3 equiv), PivOH (1 equiv), and toluene (0.5 mL) at 120 °C for 36 h. b4 mmol scale.

[Cp*IrCl2]2 (5 mol%), AgSbF6 (20 mol%)

Het

N R1

1

aReaction

Het

COtBu

5d, 50%

MeO2C

S

S

S F

N

N Bn

5e, 54%

5f, 74%, 62%

S

S

b

5g, 68%

5h, 70%

N

N Bn

F 5j, 51%

5i, 67%

N

S

N

Cl

N Bn

5k, 52%

Scheme 5. Proposed Catalytic Cycles [Cp*IrCl2]2 Ag(I) 3m

H

COtBu

PivO

AgCl [Cp*Ir X2]

N

X = Cl, SbF6

IrV

O

t

Bu

*Cp

H

H N

PivO

IM6 Ag(0) Ag(I)



X IrIII

O

t

Bu

*Cp

PivOH X IrIII

O

H N

4e

V

Ir O

C-2 Selectivity

Cp*

t

Bu

H

IM3 Cu(0) or Cu(I) O N

HX

2m

IrIII Cp* O

HX

N

H

Cu(II)

t

Bu

IM2

A similar cascade process in the C2-heteroarylation failed to deliver the decarbonylated C2-heteroarylated indoles. As an alternative, the pivaloyl group of the biaryl products could be easily removed in the presence of ptoluenesulfonic acid and glycol via a reversible FriedelCrafts reaction (eq 23). TsOH•H2O (1.5 equiv) ethylene glycol toluene (1 mL), 120 oC, 22 h

O IrIII Cp* X

N

O

H

N

O

Bu

IM1

IM4

C-4 Selectivity Cp* O O t Bu IrIII

CMD process

N

N

2+

t

H

Bu H

+

IM5

COtBu O

AcOH

t

4e

[Cp*IrIII(OAc)X] X = Cl, OAc, BF4

1a

SE3 process via

2+

Cp*

[Cp*IrCl2]2

AgCl

H

III

O

Ag(I), Cu(OAc)2

O

(23)

N 6a, 75%

Proposed Catalytic Mechanism. On the basis of the above results and previous literatures,14a,16 a plausible

mechanism is proposed (Scheme 5). Initially, in the presence of AgBF4 and Cu(OAc)2∙H2O, a catalytically active Cp*Ir(III)(OAc)X species is generated by ligand exchange. Then, with the assistance of the carbonyl group and acetate, this Ir(III) species induces a reversible C2–H cleavage17 via a CMD process, leading to a fivemembered iridacycle IM1. The following C–H iridation of benzofuran 2m provides a bisheteroaryl-Ir(III) species IM2, which is then oxidized to an Ir(V) species IM3.18 Finally, reductive elimination affords the desired product 4e along with regeneration of the active Ir(III) catalyst. Alternatively, the reaction of [Cp*IrCl2]2 with AgSbF6 provides a cationic iridium species, which prefers to

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trigger an electrophilic metalation-deprotonation at the C4 position of indole with the assistance of an external pivalate (SE3 mechanism). The resulting iridacycle IM4 then attacks 2m to yield a bisheteroaryl-Ir(III) species IM5, which subsequently undergoes oxidatively induced reductive elimination to furnish the desired product 3m and release the Cp*Ir(III)catalyst.

CONCLUSION In conclusion, we have developed a C2/C4 regioselective oxidative C–H/C–H heteroarylation of indoles with the aid of a readily incorporated19 and removable pivaloyl group at the C3 position. The C–H heteroarylation takes place at the C2-position of indoles with Cu(OAc)2·H2O as the oxidant, while the use of Ag2O completely switches the regioselectivity to C4-positions. The pivaloyl group can also function as a traceless directing group, enabling a simple and efficient synthesis of C4-indole-heteroaryl frameworks. In particular, this work represents the first example of separating the bisheteroaryl metallic intermediate in oxidative Ar–H/Ar– H cross-coupling reactions. Mechanism investigation suggests that the C2-metalation of indoles undergoes a CMD process and the C4-metalation proceeds through a SE3 pathway. Besides as an oxidant, Cu(OAc)2·H2O provides acetate as a proton shuttle in the C2−H heteroarylation. PivOH in the C4–H heteroarylation is believed to assist the intermolecular deprotonation process. This protocol provides an opportunity to rapidly build a library of C4- and C2-heteroarylated indoles. Further applications of this reaction beyond organic synthesis could be expected.

ASSOCIATED CONTENT Supporting Information Experimental procedures, characterization of related compounds, photophysical data, crystallographic data, and X-ray crystal structures (CIF) of 3g (CCDC-1832938), 4e (CCDC-1832932), 7 (CCDC-1832924), and IM2 (CCDC-1862697) are available in the Supplementary Information. The Supporting Information is available free of charge on the ACS Publications website.

AUTHOR INFORMATION Corresponding Author *[email protected] *[email protected] Notes The authors declare no competing financial interest.

ACKNOWLEDGMENT The authors acknowledge the financial support from the National NSF of China (Nos. 21432005 and

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21502123) and the Comprehensive Training Platform of Specialized Laboratory, College of Chemistry, Sichuan University.

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ACS Catalysis arylation of thiophenes with iodoarenes. Angew. Chem. Int. Ed. 2010, 49, 8946–8949. (d) Ueda, K.; Amaike, K.; Maceiczyk, R. M.; Itami, K.; Yamaguch, J. β-Selective C−H arylation of pyrroles leading to concise syntheses of lamellarins C and I. J. Am. Chem. Soc. 2014, 136, 13226– 13232. (e) Bedford, R. B.; Durrant, S. J.; Montgomery, M. Catalyst-switchable regiocontrol in the direct arylation of remote C−H groups in pyrazolo[1,5-α]pyrimidines. Angew. Chem. Int. Ed. 2015, 54, 8787–8790. (f) Wu, J.; Cheng, Y.; Lan, J.; Wu, D.; Qian, S.; Yan, L.; He, Z.; Li, X.; Wang, K.; Zou, B.; You, J. Molecular engineering of mechanochromic materials by programmed C−H arylation: making a counterpoint in the chromism trend. J. Am. Chem. Soc. 2016, 138, 12803–12812. (g) Yang, Y.; Gao, P.; Zhao, Y.; Shi, Z. Regiocontrolled direct C−H arylation of indoles at the C4 and C5 positions. Angew. Chem. Int. Ed. 2017, 56, 3966– 3971.

(5) (a) Cacchi, S.; Fabrizi, G. Synthesis and functionalization of indoles through palladium-catalyzed reactions. Chem. Rev. 2005, 105, 2873–2920. (b) Sandtorv, A. H. Transition metalcatalyzed C−H activation of indoles. Adv. Synth. Catal. 2015, 357, 2403–2435. (6) For selected examples, see: (a) Russell, H. F.; Harris, B. J.; Hood, D. B.; Thompson, E. G.; Watkins, A. D.; Williams, R. D. 5-Substituted indoles via sodium indoline-2-sulfonate. a reexamination. Org. Prep. Proced. Int. 1985, 17, 391–399. (b) Moyer, M. P.; Shiurba, J. F.; Rapoport, H. Metal-halogen exchange of bromoindoles. a route to substituted indoles. J. Org. Chem. 1986, 51, 5106–5110. (c) Tsuji, Y.; Kotachi, S.; Huh, K.-T.; Watanabe, Y. Ruthenium-catalyzed dehydrogenative N-heterocyclization: indoles from 2aminophenethyl alcohols and 2-nitrophenethyl alcohols. J. Org. Chem. 1990, 55, 580–584. (d) Schumacher, R. W.; Davidson, B. S. Synthesis of didemnolines A-D, N9substituted β-carboline alkaloids from the marine ascidian didemnum sp. Tetrahedron. 1999, 55, 935–942. (e) Newman, S. G.; Lautens, M. The role of reversible oxidative addition in selective palladium(0)-catalyzed intramolecular cross-couplings of polyhalogenated substrates: synthesis of brominated indoles. J. Am. Chem. Soc. 2010, 132, 11416–11417. (f) Guilarte, V.; Castroviejo, M. P.; GarcíaGarcía, P.; Fernández-Rodríguez, M. A.; Sanz, R. Approaches to the synthesis of 2,3-dihaloanilines. Useful precursors of 4-functionalized-1H-indoles. J. Org. Chem. 2011, 76, 3416– 3437. (g) Wang, M.; Li, P.; Chen, W.; Wang, L. Microwave irradiated synthesis of 2-bromo(chloro) indoles via intramolecular cyclization of 2-(gemdibromo(chloro)vinyl)anilines in the presence of TBAF under metal-free conditions. RSC Adv. 2014, 4, 26918– 26923. (h) Gai, S.; Zhang, Q.; Hu, X. Total synthesis of asterredione. J. Org. Chem. 2014, 79, 2111–2114. (i) Shiozawa, M.; Iida, K.; Odagi, M.; Yamanaka, M.; Nagasawa, K. Synthesis of 2,6,7-trisubstituted prenylated indole. J. Org. Chem. 2018, 83, 7276–7280. For a review, see: (j) Ping, L.; Chung, D. S.; Bouffard, J.; Lee, S.-g. Transition metalcatalyzed site- and regio-divergent C−H bond functionalization. Chem. Soc. Rev. 2017, 46, 4299–4328. (7) For selected examples, see: (a) Stuart, D. R.; Fagnou, K. The catalytic cross-coupling of unactivated arenes. Science 2007, 316, 1172–1175. (b) Li, Y.; Wang, W.-H.; Yang, S.-D.;

Li, B.-J.; Feng, C.; Shi, Z.-J. Oxidative dimerization of Nprotected and free indole derivatives toward 3,3'-biindoles via Pd-catalyzed direct C–H transformations. Chem. Commun. 2010, 46, 4553–4555. (c) Ren, X.; Chen, J.; Chen, F.; Cheng, J. The palladium-catalyzed cyanation of indole C–H bonds with the combination of NH4HCO3 and DMSO as a safe cyanide source. Chem. Commun. 2011, 47, 6725– 6727. (d) Wu, W.; Su, W. Mild and selective Ru-catalyzed formylation and Fe-catalyzed acylation of free (N–H) indoles using anilines as the carbonyl source. J. Am. Chem. Soc. 2011, 133, 11924–11927. (e) Leskinen, M. V.; Yip, K.-T.; Valkonen, A.; Pihko, P. M. Palladium-catalyzed dehydrogenative β'-functionalization of β-keto esters with indoles at room temperature. J. Am. Chem. Soc. 2012, 134, 5750–5753. (f) Chen, S.; Liao, Y.; Zhao, F.; Qi, H.; Liu, S.; Deng, G.-J. Palladium-catalyzed direct arylation of indoles with cyclohexanones. Org. Lett. 2014, 16, 1618–1621. (g) Wu, J.; Lan, J.; Guo, S.; You, J. Pd-catalyzed C−H carbonylation of (hetero)arenes with formates and intramolecular dehydrogenative coupling: a shortcut to indolo[3,2-c]coumarins. Org. Lett. 2014, 16, 5862–5865. (8) Leitch, J. A.; Bhonoah, Y.; Frost, C. G. Beyond C2 and C3: transition-metal-catalyzed C−H functionalization of indole. ACS Catal. 2017, 7, 5618–5627. (9) Cheng, Y.; Li, G.; Liu, Y.; Shi, Y.; Gao, G.; Wu, D.; Lan, J.; You, J. Unparalleled ease of access to a library of biheteroaryl fluorophores via oxidative cross-coupling reactions: discovery of photostable NIR probe for mitochondria. J. Am. Chem. Soc. 2016, 138, 4730–4738. (10) For selected reviews and book, see: (a) Ritleng, V.; Sirlin, C.; Pfeffer, M. Ru-, Rh-, and Pd-catalyzed C−C bond formation involving C−H activation and addition on unsaturated substrates: reactions and mechanistic aspects. Chem. Rev. 2002, 102, 1731–1769. (b) Lersch, M.; Tilset, M. Mechanistic aspects of C−H activation by Pt complexes. Chem. Rev. 2005, 105, 2471–2526. (c) Alberico, D.; Scott, M. E.; Lautens, M. Aryl-aryl bond formation by transition-metal-catalyzed direct arylation. Chem. Rev. 2007, 107, 174–238. (d) Balcells, D.; Clot, E.; Eisenstein, O. C−H bond activation in transition metal species from a computational perspective. Chem. Rev. 2010, 110, 749–823. (e) Roger, J.; Gottumukkala, A. L.; Doucet, H. Palladium-catalyzed C3 or C4 direct arylation of heteroaromatic compounds with aryl halides by C−H bond activation. ChemCatChem. 2010, 2, 20–40. (f) Yu, J.-Q.; Shi, Z.-J. Topics in Current Chemistry; Springer: New York, 2010; Vol. 292. (11) The C2–H and C4–H regioselective alkenylations of indoles by using different directing groups were reported by Prabhu and co-workers. See: Lanke, V.; Bettadapur, K. R.; Prabhu, K. R. Electronic nature of ketone directing group as a key to control C–2 vs C–4 alkenylation of indoles. Org. Lett. 2016, 18, 5496–5499. (12) In iridium-catalyzed C–H activation, [Cp*IrCl2]2 is often combined with a silver salt to in situ generate a cationic iridium species. For selective examples, see: (a) Tang, T.; Kim, Y.; Lee, D.; Wang, Z.; Chang, S. Iridium-catalyzed intermolecular amidation of sp3 C−H bonds: Late-stage functionalization of an unactivated methyl group. J. Am. Chem. Soc. 2014, 136, 4141–4144. (b) Kim, J.; Chang, S. Iridium-catalyzed direct C–H amidation with weakly

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coordinating carbonyl directing groups under mild conditions. Angew. Chem. Int. Ed. 2014, 53, 2203–2207. (13) In a recent work on the transition metal-catalyzed C–H arylation with arysilanes (C–H/C–M type coupling reaction), Chang and co-workers disclosed an aryl-Ir-aryl complex synthesized by the transmetalation reaction of an iridacycle complex with pre-synthezied arylsilicate or arylcopper reagent. See: Shin, K.; Park, Y.; Baik, M.-H.; Chang, S. Iridium-catalysed arylation of C–H bonds enabled by oxidatively induced reductive elimination. Nat. Chem. 2018, 10, 218–224. F3C

Si(OEt)3 2a

NHtBu O IrIII OCOCF3 + F3C Cp*

TBAF•xH2O THF, 25 oC, 0.5 h  Si(OEt)3F

t BuHN (nBu)4N Cu(OAc)2

THF, 25 oC IIa

2a

Ia NHtBu O IrIII OCOCF3 Cp* Ia

t

+

F3C

O Cp* IrIII

Cu(Phen)

THF, 25 oC, 12 h

BuHN

CF3

O Cp* IrIII

IIa

CF3

(14) (a) Flegeau, E. F.; 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. (b) Fabre, I.; von Wolff, N.; Duc, G. L.; Flegeau, E. F.; Bruneau, C.; Dixneuf, P. H. D.; Jutand, A. Autocatalytic intermolecular versus intramolecular deprotonation in C−H bond activation of functionalized arenes by ruthenium(II) or palladium(II) complexes. Chem. Eur. J. 2013, 19, 7595–7604. (c) Zhao, D.; Li, X.; Han, K.; Li, X.; Wang, Y. Theoretical investigations on Rh(III)-catalyzed cross-dehydrogenative aryl−aryl coupling via C−H bond activation. J. Phys. Chem. A 2015, 119, 2989– 2997. (15) (a) Lee, S. Y.; Hartwig, J. F. Palladium-catalyzed, siteselective direct allylation of aryl C−H bonds by silver-

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mediated C−H activation: A synthetic and mechanistic investigation. J. Am. Chem. Soc. 2016, 138, 15278–15284. For silver salt-promoted C−H metalation of thiophenes, see: (b) 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 (c) Colletto, C.; Panigrahi, A.; Fernández-Casado, J.; Larrosa, I. Ag(I)−C−H Activation enables near-room-temperature direct αarylation of benzo[b]thiophenes. J. Am. Chem. Soc. 2018, 140, 9638–9643. (16) (a) Shin, K.; Park, S.-W.; Chang, S. Cp*Ir(III)-catalyzed mild and broad C−H arylation of arenes and alkenes with aryldiazonium salts leading to the external oxidant-free approach. J. Am. Chem. Soc. 2015, 137, 8584–8592. (b) Gao, P.; Guo, W.; Xue, J.; Zhao, Y.; Yuan, Y.; Xia, Y.; Shi, Z. Iridium(III)-catalyzed direct arylation of C−H bonds with diaryliodonium salts. J. Am. Chem. Soc. 2015, 137, 12231– 12240. (c) Huang, L.; Hackenberger, D.; Gooβen, L. J. Iridium-catalyzed ortho-arylation of benzoic acids with arenediazonium salts. Angew. Chem. Int. Ed. 2015, 54, 12607–12611. (17) H/D exchange experiments suggested that C2−H and C4−H iridation of indoles might be a reversible process, see eq 13 and eq S7 for more details. (18) An Ir(II)/Ir(IV)-catalyzed direct C−H arylation of benzamides with arylsilanes was reported by Sukbok Chang. See reference 13. (19) The 3-pivaloyl indoles could be easily prepared by the Friedel-Crafts carbonylation reaction of indoles with pivaloyl chloride.

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ACS Catalysis

Table of Contents H R

H

COR

2

Het N R1

t

N

Cp*Ir(III) (cat.) Cu(OAc)2•H2O CMD process

2

Het

COR H+ H

Het N R1 Modulating metalation modes

R

Cp*Ir(III) (cat.) Ag2O/PivOH SE3 process

COR R2

H N R1

Bu O Ir Cl

O N

Ir Cp* O

Cp* t

Bu

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