Ag Dual-Catalyzed Cross-Dehydrogenative Biaryl

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Cooperative Au/Ag-Dual Catalyzed Cross-Dehydrogenative Biaryl Coupling: Reaction Development and Mechanistic Insight Jin Xie, Weipeng Li, Dandan Yuan, Guoqiang Wang, Yue Zhao, Shuhua Li, and Chengjian Zhu J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b12929 • Publication Date (Web): 25 Jan 2019 Downloaded from http://pubs.acs.org on January 25, 2019

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Cooperative Au/Ag-Dual Catalyzed Cross-Dehydrogenative Biaryl Coupling: Reaction Development and Mechanistic Insight Weipeng Li,† Dandan Yuan,‡ Guoqiang Wang,‡ Yue Zhao†, Jin Xie,*,† Shuhua Li,*,‡ Chengjian Zhu*,†,# †State

Key Laboratory of Coordination Chemistry, Jiangsu Key Laboratory of Advanced Organic Materials, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. ‡Key Laboratory of Mesoscopic Chemistry of Ministry of Education, Institute of Theoretical and Computational Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210023, China. #State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Shanghai 200032, China ABSTRACT: An operationally simple and highly selective Au/Ag bimetallic-catalyzed cross-dehydrogenative biaryl coupling between pyrazoles and fluoroarenes has been developed. With this reaction, a wide range of biheteroaryl products can be obtained in moderate to good yields with excellent functional group compatibility. The exact role of silver salts, previously overlooked in most gold-catalyzed transformations, has been carefully investigated in this biaryl coupling. Insightful experimental and theoretical studies indicate that silver acetate is the actual catalyst for C-H activation of electron-poor arenes, rather than the previously reported gold(I)-catalyzed process. An unprecedented Au/Ag dual catalysis is proposed, in which silver(I) is responsible for the activation of electron-poor fluoroarenes via a concerted metalation-deprotonation pathway and gold(III) is responsible for the activation of electron-rich pyrazoles via electrophilic aromatic substitution process. Kinetic studies reveal that ArFnAu(III)-mediated C-H activation of pyrazoles is most likely the rate-limiting step.

INTRODUCTION Bimetallic catalysis involving two distinct mechanistic activations is particularly appealing in new reaction development1 but has been explored only minimally. Along with the renaissance of homogeneous gold chemistry,2-5 the combination of gold catalysis with catalysis by other transition metals6-9 can significantly broaden the reaction types and complement the traditional monometallic catalytic system. The seminal work on Au/Pd bimetallic catalysis from Hashmi et al.10-12 and Blum et al.13 has demonstrated the promising features of bimetallic cooperative catalysis in gold chemistry. In 2016, the Nevado group14 developed an Au/Pd co-catalyzed process involving two independent catalytic cycles connected by transmetalation. Very recently, Munoz’s group15 demonstrated the concept of Au/Pt bimetallic catalysis in concise synthesis of multiheteroarenes. The silver salts are frequently used as additives to improve the reaction efficiency in homogeneous gold catalysis.16-21 Investigation of the overlooked “silver effect” has gained increasing attention in recent years.22-25 Despite the impressive progress, to the best of our knowledge, the development of Au/Ag bimetallic catalysis involving Au(I)/Au(III)26-28 catalytic cycles remains a big challenge. There includes three aspects: i) redox potential compatible among Au(I)-, Au(III)- and Ag(I)-intermediates because of the high potential for Au(I)/Au(III) redox couple (+1.41 V29), ii) matched transmetalation rate of organosilver to goldspecies, iii) respectively unvexed catalytic cycle for goldand silver-mediated pathway. Recently, Sanford, Hartwig, Houk and Larrosa have revealed that the silver additives

could serve as a co-catalyst in Pd-catalyzed C-C coupling, in which the resulting arylsilver(I) intermediates is able to undergo transmetalation with Pd-species.30-34 However, the mechanistic understanding of palladium chemistry is currently outpacing the gold chemistry. The influence factor for elementary transmetalation process between gold and silver is still underdeveloped; the effect of ligand-type, solvent and counteranion is still unclear for gold-mediated transmetalation. For example, α-gold(I) enals and arylsilver-bound carbocations were generated respectively in one dual catalytic system, but the transmetalation of arylsilver intermediate to gold(I) center hardly work.35 Scheme 1. Revised Mechanism in Gold-Catalyzed CrossDehydrogenative Biaryl Coupling a) Previous proposal: gold-catalyzed coupling ArFnH AuI L

AuI X

ArFn AuI I

[O]

Fn

Ar H -bond metathesis

ArH ArFn AuIII ArFn AuIII Ar III II AuIII-catalyzed C-H activation

reductive elimination

product

b) Our revised mechanism: bimetallic Au/Ag dual catalysis ArFn

Ar

IV Ar A

u III

III ArH

ArFn

Au catalytic cycle

III

Ag ArFn

I

Au

transmetalation

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

Journal of the American Chemical Society

ArFn

AuI

Au II

ArFn

AgI catalytic cycle ArFnH

AgI

I [O]

synergistic catalytic cycles connected by transmetalation

ACS Paragon Plus Environment

silver: a key role in C-H activation of electron-poor arenes

AuI

Journal of the American Chemical Society 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

Unsymmetrical biaryls, especially biheteroarenes, are important structural motifs in a number of scientific fields including pharmaceuticals, agrochemicals, and organic materials. 36, 37 Although gold-catalyzed biaryl coupling38-42 has enjoyed many advances in conjunction with palladium catalysis, there remains an increasing demand for the synthesis of unsymmetrical biaryls by crossdehydrogenative Ar1-H/Ar2-H coupling which has remarkable atom- and step-economy. The major challenge to such reactions stems from untamed chemo- and regioselectivity. In 2010, Larrosa’s group reported that gold(I) could promote selective C-H activation of electrondeficient arenes via σ-bond metathesis manner43 and one elegant gold-catalyzed cross-dehydrogenative coupling between protected indoles and polyfluoroarenes was developed in 2015 based on this principle (Scheme 1a).44 In both cases, the presence of silver salt was necessary. Although the authors recently suggested the role of silver salts might be beyond a halogen scavenger,44 elucidation of its exact role and characterization of key arylsilver(I) intermediate in gold catalysis, and evaluation of its possibility for aryl-transfer via transmetlation step to gold as well as the clear mechanistic picture have not been described. In this paper, we report a highly selective crossdehydrogenative arylation of pyrazoles through cooperative Au/Ag dual catalysis by experimental and DFT theoretical studies (Scheme 1b), which is different from routinely proposed Au(I)/Au(III) catalytic cycle. Our mechanistic investigation has revealed that silver(I) was the actual species for activation C-H bond of electron-poor arene to form arylsilver(I), which would go through a transmetalation to gold center. An Au/Ag bimetallic catalytic process involves Ag(I)-catalyzed C-H activation of electron-poor arenes and Au(III)-catalyzed C-H activation of electron-rich arenes. This reaction allows an efficient and high-selective access to unsymmetrical biheteroarenes from two different aromatic C-H bonds. Its high selectivity origins from orthogonal C-H activation selectivity of Ag(I) and Au(III) on arenes with different electronic properties. The Ag(I) catalyst favors C-H activation of the most acidic CH bond of electron-poor arenes via a concerted metalationdeprotonation (CMD) process. In contrast, Au(III) shows specific selectivity for C-H auration of the most electronrich position of electron-rich arenes via electrophilic aromatic substitution (SEAr) mechanism. RESULTS AND DISCUSSION

Reaction Optimization Pyrazole derivatives, have witnessed widespread application in pharmacology and drug design due to their vast biological activities.45 However, owing to the strong coordinative ability of the nitrogen atom in pyrazoles, it is highly challenging to achieve site-selective C-C coupling directly from C-H bond on pyrazole scaffolds using catalysts containing for example, Pd,46 Rh47 or Mn48. Given by the unique reactivity and functional group tolerance of gold, our experiments aimed at evaluating the possibility of goldcatalyzed cross-dehydrogenative C-C coupling of pyrazole. We choose C-H/C-H biaryl coupling of N-phenyl-pyrazole (1a) and 2,3,5,6-tetrafluoropyridine (2a) as a model

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reaction (Table 1). Under the optimized reaction conditions, we obtained an exclusively C4 selective cross-coupled product (3a) in 86% yield with 5 mol% of (dimethylsulfide)gold(I) chloride (DMSAuCl), 20 mol% of AgOAc and 1.5 equivalent of phenyliodine diacetate (PIDA) (Entry 1). Although the pyrazole unit has often been used as a directing group,49, 50 no directed arylation by-product was observed and no other homocoupling products were formed. The reaction did not proceed in the absence of either the gold catalyst or silver salt (Entry 2). Further investigation of the reaction revealed that an excess amount of the silver salt was essential for its success. Only a trace amount of 3a were detected with just 5 mol% of AgOAc, but increasing the loading of AgOAc led to a significant improvement in the yield (Entries 3-5). The acetate anion was usually thought to promote metal-mediated C-H bond activation via CMD process,30-32 but the loss of catalytic reactivity with other non-silver acetate salts would rule out this possibility (Entry 6). Interestingly, the use of Ph3PAuOAc without the addition of silver acetate failed to afford the desired product, but the addition of a further 15 mol% of silver acetate together with Ph3PAuOAc resulted in 60% yield (Entries 7 and 8). These experiments further suggest that the silver salt in this cross-dehydrogenative coupling does not function simply as a halogen scavenger. Table 1. Optimization of Reaction Conditions H F + N N F Ph 1a 1 eq.

F DMSAuCl (5 mol%), AgOAc (20 mol%) N

F

PIDA (1.5 eq.),1,4-dioxane (0.1 M) 100 oC

2a 1.5 eq.

F

F

C4

N

N N

N Ph

N

ArF

F

F 3a no directed arylation exclusively at C4 position no homocoupling products

Entry

Variation from optimal conditions

Yield

1

-

86%a

2

no DMSAuCl or AgOAc

-

3

5 mol% AgOAc

trace

4

10 mol% AgOAc

60%b

5

15 mol% AgOAc

76%b

6

15 mol% NaOAc, KOAc, or CsOAc

-

7

5 mol% Ph3PAuOAc

-

8

5 mol% Ph3PAuOAc, 15 mol% AgOAc

60%b

See Supporting Information (SI) for standard conditions and optimization details. a isolated yield. b GC-MS yield with biphenyl as an internal standard.

Mechanistic Studies To gain a better understanding of this interesting experimental result, we first focused our attention on elucidation of the mechanism, especially the role of silver salts and the selectivity in this reaction. In 2018, Larrosa et al. reported that silver salts could carry out highly selective C-H arylation of electron-rich benzo[b]thiophene at C2 position.51 This led us to question whether the high selectivity of this reaction was parallel to that induced by the silver-catalyzed selective C-H activation of Nphenylpyrazole (1a). However, the failure to observe H/D exchange of pyrazole with silver salts under various conditions appears to exclude this possibility (see SI for details). On the other hand, it has been reported that the strong electrophilic feature of gold(III) species can facilitate C-H auration of electron-rich arenes.52 Accordingly, we conducted the reaction of N-phenylpyrazole with


X 1 eq. [AuIII] a) N N Ph

o

1,4-dioxane, 100 C, 2~4 h

N

b) N N Me

[AuIII]= HAuCl4, Au(OAc)3, AuCl3, AuBr3, NaAuCl4

N N Ph 4 Cl

o

HAuCl4 (1 eq.),100 C, 2 h Me

Au

.0

4

a)

0.06 a.u.

N Ph

-0.06 a.u. b)

L1=1,4-dioxane L=pyrazole

26.8 26.9 Au-2Ts Ag-1Ts 19.5

20

Au-1Ts

Au X

1,4-dioxane/H2O (1.5 mL/0.5 mL) 5

Wheland-type intermediates (2.10 Å versus 2.19 Å and 2.16 Å versus 2.34 Å, respectively).

0

0.0

G =26.8

G = 26.9

-0.3 6

16.9 Ph

7

N N

Ag L1 7 OAc Au L OAc 8-1

N N

G =19.5

-9.7 8-2

N N

Ph

-10.6 8-1

-20

N

N

Ph

L1AgOAc LAu(OAc)3 LAu(OAc)2C6F5

Cl

-0

stoichiometric gold(III) salts under optimized conditions. Although the N-phenylpyrazole (1a) was consumed, isolation of the putative Au(III)−pyrazole complex (4) was not realized, possibly due to the instability of the electronrich Ar-Au(III) intermediate (Scheme 2a).53 We designed a pyridine-chelated pyrazole substrate, 2-(1-methyl-1Hpyrazol-3-yl)pyridine (5) with the aim of immediately stabilizing the generated Au(III)−pyrazole intermediate.5456 As expected, the desired C-H auration product (6) was successfully isolated in 45% yield (Scheme 2b), and its structure was confirmed by X-ray single crystal structure analysis. Scheme 2. C-H Auration of Pyrazole with Au(III)

-0.04

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


G(kcal/mol)

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C6F5 Au L OAc 8-2

N N 6 45% yield X-ray structure

The DFT calculations with the M0657 function indicated that the C4 position of N-phenylpyrazole possessed the highest electron density value (Fig. 1a). The high selectivity could be rationalized well by an Au(III)-mediated electrophilic aromatic substitution (SEAr) mechanism which prefer reacting at electron-rich position. Then we investigated the C-H activation of pyrazole with DFT calculations in detail. As shown in Fig. 1b, the C-H cleavage of N-phenylpyrazole with silver acetate to form an Nphenylpyrazole-Ag(I) complex (7) is endothermic by 16.9 kcal mol-1, and an energy barrier of 26.9 kcal mol-1 (Figure 1b, the black curve). In contrast, the formation of Nphenylpyrazole-gold(III) (8-1) with Au(III)-acetate is exothermic by 10.6 kcal mol-1 with a barrier of only 19.5 kcal mol-1 (Fig. 1b, the blue curve). On the other hand, activation of N-phenylpyrazole with a much less electrophilic Au(III)-C6F5 complex is still exothermic by 9.7 kcal mol-1, despite an energy barrier of 26.8 kcal mol-1 (Fig. 1b, the red curve). Although it has a similar energy barrier compared with silver-mediated C-H activation pathway (black curve in Fig. 1b), the significant exothermic reaction process enables it more likely according to Gibbs free energy. These calculations together with experimental results shows that Au(III) species are most likely to selectively activate the C(4)-H bond of N-phenylpyrazole (see SI for computational details). In the transition state Ag1Ts, the formation of the Ag−C bond is concomitant with the breaking of the C−H bond, with the hydrogen atom being transferred to the basic center, suggesting a concerted metalation/deprotonation (CMD) mechanism. However, the Au(III) mediated C-H activation of N-phenylpyzole might occur through an electrophilic aromatic substitution (SEAr) mechanism, as indicated by the formation of the corresponding Wheland-type intermediates (Au-1TS, Au2TS) along the reaction pathway (see supporting information for details). In the Au-1Ts and Au-2Ts, the AuC4 bonds are found to be slightly shorter than their

Ag-1Ts

Au-1Ts

O H Me

N N Ph

H N N Ph O Au OAc AcO Au-1Ts

O Me

O Ag L1 Ag-1Ts O H Me

Au-2Ts

N N Ph O Au OAc C 6F 5 Au-2Ts

Figure 1. (a) Calculated electrostatic potential (ESP) map and the natural bond orbital (NBO) charges of pyrazole. (b) Calculated free energy barrier ( ΔG‡) and free energy change (ΔG) for activation of pyrazole with Ag(I) and Au(III), respectively. All energies are in kcal mol-1.

We next examined the C-H activation step in polyfluoroarenes. To identify the active species that promotes the C-H activation of fluoroarenes, we performed hydrogen isotope exchange (HIE) experiments on C6HF5 with D2O. It was found that in the presence of 20 mol% AgOAc, 65% deuteration of pentafluorobenzene occurred (Scheme 3a). The HIE process could also be observed in other polyfluoroarenes (see SI for details). This fact may suggest that silver acetate is responsible for the activation of electron-poor multifluoroarenes, and the observation of an AgC6F5 intermediate 58 by 19F NMR in-situ also supports this hypothesis (Scheme 3b, see SI for detail). Importantly, it is our surprise to find that under the similar conditions employed by Larrosa we could also observe the HIE phenomenon in either DMF or 1,4-dioxane (Scheme 3c). In contrast, pentafluorobenzene failed to undergo HIE in the presence of various gold(I)- and gold(III)-complexes. Additionally, we could not detect the generation of Au(I)C6F5 or Au(III)-C6F5 intermediate via in-situ 19F NMR spectroscopy (Scheme 3d and 3e). These experiments excluded the possible involvement of gold(I) or gold(III) in the activation of fluoroarene.



transformation. However, two potential transmetalation pathways are possible: in path a arylsilver interacts with Au(I) generating an Au(I)-ArFn intermediate and subsequent oxidation to Au(III)-ArFn (Eq 1); in path b, Au(I) is first oxidized to Au(III) and followed by transmetalation with arylsilver (Eq 2).

Scheme 3. H/D Exchange Experiments on C6F5H a)

b)

c)

AgOAc (20 mol%), 60 oC

C6F5H

C6F5H

e)

C6F5H

65% deuteration

AgOAc (20 mol%), CD3CN, 80 oC

detected by 19F NMR 19 F NMR :-107 ppm

D2O (5 eq.), DMF or 1,4-dioxane, 60 oC, 8h

C6F5D

C6F5D + [AuI-C6F5] not detected no deuteration observed by in-situ 19F NMR [AuI]= Ph3PAuCl, Ph3PAuOAc, DMSAuCl, [AuIII-C6F5] C6F5D + not detected no deuteration 19 observed by in-situ F NMR

[AuIII]= DMSAuCl + PIDA, Au(OAc)3, AuCl3, HAuCl4

This reaction was also probed by DFT calculations. Our results showed that the formation of an AgC6F5 intermediate was very marginally endothermic by 4.5 kcal mol-1 with a barrier of 22.4 kcal mol-1 and formation of AuC6F5 faced a much higher barrier of 30.6 kcal mol-1 (Fig. 2, see SI for computational methodology and detailed results). This combination of experimental and DFT studies ruled out the possibility of gold-mediated C-H bond activation of the pentafluorobenzene. All these results strongly suggest that silver is the actual active species in activation of fluoroarene. The selective activation of the most acidic C-H bond of electron-poor arenes could be explained by the silver-mediated concerted metalationdeprotonation process. 30.6

H O L

Ag O

Me

H O

F5

Au-3Ts

22.4

1

L

PIDA

[AuI]

Scheme 4. Stoichiometric Transmetalation Step a) LAuCl

Me

+

AgC6F5 19

4.5

0.0 0.0

1.33

(Eq 2)

Investigation

1,4-dioxane, rt in minutes

-4.0

-107

F

19

9 F NMR: -117 ppm

Ag

*

F

-117



19

F NMR: -127 ppm

-163 -162 

F

new signal -117, -161, -164 ppm -161  -164 

L Au C6F5

OAc L Au C6F5 OAc

OAc L Au C6F5 OAc 10

F

L Au C6F5

1.28

of

L Au C6F5

OAc 1,4-dioxane, rt AgC6F5 L Au Cl + in minutes OAc in-situ generated 19FNMR :-107 ppm

L1 Ag C6F5

1.35

2.32

AuIII ArFn

L= N-phenylpyrazole

* G =22.4

1.29

(Eq 1)

I

F NMR :-107 ppm

F

L1= 1,4-dioxane L = pyrazole

AuIII ArFn

To understand the transmetalation process, stoichiometric reactions were performed. According to the published procedure, we first synthesized the AgC6F5 intermediate, and its 19F NMR signal was observed at about -107, -162, -163 ppm in CD3CN. The 19F NMR signal of AgC6F5 immediately moved to -117, -161, -164 ppm when AgC6F5 was mixed with equivalent amounts of DMSAuCl at room temperature (Scheme 4a). The signal at -117, -161, 164 ppm, was assigned to an AuI-C6F5 complex (9).59 In addition, a rapid transmetalation between AgC6F5 and Au(III) was observed at room temperature and led to conjecture of a tentative Au(III)-C6F5 intermediate (10) with a 19F NMR signal at -127, -159, -163 ppm (Scheme 4b).

G =30.6

L1 Ag OAc

[AuIII] Ag

*

L Au OAc

PIDA

I

Au O

Au-3TS

Ag-3Ts

Ag-3TS

AuI ArFn Ag

b) F5

Fn

DMF: 22% D 1,4-dioxane: 43% D

[Au ] (20 mol%), 60-120 C 1,4-dioxane, D2O (5 eq.), 8 h

1,4-dioxane, D2O (5 eq.), 8 h

Ag Ar

path (b)

o

[AuIII] (20 mol%), 60-120 oC

path (a)

Ag ArFn

Ag2O(0.3 eq.), K2CO3 (0.55 eq.), PivOH (0.55 eq.)

I

[AuI]

AgC6F5

Cs2CO3 (50 mol%), 2 h

C6F5H

d)

C6F5D

D8-1,4-dioxane, D2O (5 eq.), 8 h

C6F5H

G(kcal/mol)

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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-127

*

new signal -127, -159, -163 ppm -159 -163  

2.48 2.22

2.26

Ag-3TS Au-3TS

Figure 2. Calculated free energy barrier (ΔG‡) and free energy change (Δ G) for activation of fluoroarene with AuI or AgI. All energies are given in kcal mol-1.

As illustrated in Scheme 1b, transmetalation of arylsilver to gold(I) is an elementary step for the

In order to perceive the most possible transmetalation pathway, we next monitored the reaction of C6F5H with Nphenylpyrazole by in-situ 19F NMR analysis. Treatment of C6F5H with N-phenylpyrazole in the presence of DMSAuCl and AgOAc at 60 oC led to AuI-C6F5 complex (9) which turned to AuIII-C6F5 complex (10) after addition of PIDA (Scheme 5a). Then we performed the same reaction with PIDA at the


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beginning, and the results are summarized in Scheme 5b. After 10 min at 60 ℃ , the 19F NMR signal at -117 ppm appeared, indicating the formation of an Au(I)-C6F5 complex (9). After 20 min, Au(III)-C6F5 10 was also observed in the reaction mixture. Interestingly, the signal of 9 increasingly disappeared over the course of the reaction with concomitant signal enhancement of Au(III)-C6F5 10 (Scheme 5b). With an increasing reaction time, the signal of 9 finally disappeared, and only Au(III)-C6F5 10 could be observed. These experimental results indicate that first transmetalation and subsequent oxidation (path a) is possible. However, path b can’t be absolutely ruled out at present because a short induction period was observed in this reaction.60 Scheme 5. 19F NMR Tracer Experiments a)

+ C6F5H N N Ph F

F

F

F

DMSAuCl (0.5 eq.) AgOAc (0.8 eq.) 1,4-dioxane, 60 oC Ar, 1 h

F

C6F5 Au L 9

OAc C6F5 Au L 30 min, 60 oC 10 OAc 1 eq. PIDA

-117

*

*

C6F5 Au L

30 min after addition of PIDA



-127

*

b) N N Ph + C6F5H



OAc C6F5 Au L OAc

DMSAuCl (0.5 eq.), AgOAc (0.8 eq.) 1,4-dioxane, PIDA (1.0 eq.), 60 oC, Ar



C6F5 Au L

+

9



OAc C6F5 Au L OAc 10

N

N Ph

+ DMSAuCl

1 eq.

CD3CN, 60 oC for 30 min then cooling to 0 oC

N 11 Ph

80% yield

1 eq.

L

DMSAuOAc

transmetlation

11

L

L Au C6F5 9

. 





*

C6F5



13

C6F5 Au L OAc

path b

path a

E.

*



Ph

N N

R.



-127

40 min later

*

AgC6F5

L Au OAc

.E

C6F5 Au L

20 min later

*

(Eq 3)

Scheme 6. Proposed Reaction Pathway

3

*

N Ph 341.0348 HRMS found 341.0351

A tentative mechanism based on these experimental results is proposed in Scheme 6.62 Pyrazole first coordinates with DMSAuOAc to form a pyrazole-gold(I) complex (11), which goes through subsequent transmetalation, oxidation and C-H activation, leading to a tricoordinated gold(III) intermediate (12) Then the followed reductive elimination step occurs to give product (3). Reductive elimination is a key product-forming elementary step. The experimental and theoretical study conducted by Toste,63 Lloyd-Jones,64 and other groups65, 66, 67 have demonstrated that the reductive elimination could occur from a four-coordinate square-planar Au(III) complex or a high-energy Y-shaped three-coordinate Au(III) complex. We hypothesize that in our system the reductive elimination may proceed by two possible pathways. In path a, the tricoordinated gold(III) intermediate (12) directly undergoes reductive elimination to form the biaryl product (3) and an Au(I) species, which is trapped by pyrazole to form LAuOAc (L = Nphenylpyrazole). In path b, coordination of pyrazole to 12 generates a tetra-coordinated intermediate (13), followed by reductive elimination to release catalyst LAuOAc and the biaryl product (3). Although addition of extra ligand (such as Ph3P, 2,2'-bipyridine) could severely inhibit the reaction, which generally supports for reductive elimination from three-coordinate Au(III),67,68 path b still can not be absolutely ruled out.69

10 min later -117

Au N

Cl Au N

R

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


AuOAc

L=

N N Ph

3

L

OAc Au L OAc

Ph

60 min later

*

N N

Au 12

C6F5 OAc

PIDA

C-H activation

OAc L Au C6F5 OAc 10

The failure to experimentally observe or isolate the putative gold (III) intermediate 12 or 13 promoted us to explore the reductive elimination using DFT theory (Figure 3). The computational

During the optimization of the reaction conditions, we found that phosphine-free DMSAuCl gave better results than gold catalysts with phosphine ligands (see details in SI). We assumed that pyrazole might function as a ligand in this reaction.61 It was found that reacting DMSAuCl with Nphenylpyrazole at 60 oC for 30 min then cooling to 0 oC indeed led to the formation of a pyrazole-gold(I) complex (11) as a white solid (Eq 3). Further characterization revealed that this complex could slowly liberate Nphenylpyrazole in solution. The resulting [Au(I)-pyrazole] complex was characterized by high resolution mass spectrometry. These results confirm that N-phenylpyrazole serves not only as the substrate but also as a ligand.

results showed that the energy barrier for elimination from three-coordinated intermediate 12 (path a) was 8.4 kcal mol-1 (relative to species 12) which is much lower than that of path b (17.3 kcal mol-1, relative to 13), indicating that reductive elimination directly from Y-shaped intermediate (path a) is more likely (see SI for computational details).



0 12 L

8.4 12-Ts

12.0 13-Ts

L AcO G = 12.0

G = 8.4

AcO Au Path b

Ph

OAc Au C6F5 12

Ph

N N

-41.6 3

Figure 3. Calculated free energy barrier reactions. All energies are in kcal mol-1.

(ΔG‡)

N

Ph

N N

N N Ph

Ph

F

+

Cl

N

F

PIDA (1.5eq.), 100 oC, 1,4-dioxane (5 mL)

Cl F 2c

Ph

F

Cl

3c 15 10

100

5

Ph

C6F5

N N

[Au](5 mol%), AgOAc (20 mol%)

a)

C6F5

F

Cl F

1a

N 12-Ts

AcO Au L C6F5 13

H

C6F5

N 13-Ts

-5.3 13 Path a

N N

Au

Conversion/%

L=pyrazole

G(kcal/mol)

for reductive elimination

80

0.5

1h

3c

60 40

2c

20

1a

0 0

5

10

15

20

25

Time/h reaction rate on concentration of [1a]

reaction rate on loading of [Au] 0.05

reaction rate/(M/h)

reaction rate/(M/h)

0.04 0.03 0.02

1st order

0.01 0

0.025 0.02 0.015 0.01

1st order

0.005

10

8 4 6 [Au]/mol%

2

0

reaction rate on concentration of [2c] 0.125 0.1 zero order

0.075

0.02

0.04

0.06 0.08

0.1

[1a]/M reaction rate on loading of [Ag]

reaction rate/(M/h)

A kinetic analysis of the cross-coupling reaction under optimized conditions was performed (Fig. 4). The total reaction profile showed that the generation of crossingcoupling product (3c) paralleled the consumption of 1a and 2c (Fig. 4a). The initial reaction rate investigation shows an induction period of ~20 min (Fig. 4a, the red window). According to our own experimental observation and previous literature, we assumed that the induction period may originate from the dissociation of ligand from Au(I) precatalyst (DMSAuCl) then gold(I) coordinated to pyrazole to form a new catalyst [pyrazole-AuI-OAc] and/or the oxidation of DMS to DMSO which also consumed the oxidant (PIDA).41 As shown in Figure 4b, a first-order dependence on the amount of gold catalyst was observed, which indicated that the reactive catalyst would be a monometallic gold species. The initial rate also has a first-order dependence on N-phenylpyrazole. On the other hand, a zero-order dependence on both [2c] and [AgOAc] was observed, demonstrating that the reaction rate is independent of the concentration of fluoroarene and silver acetate. Of note, although a zero-order effect was determined for silver salts, an excess of silver salts would favor the generation of AgC6F5 intermediate and thus furnish the coupling product (3a) in a higher yield (Entry 1 vs Entries 4 and 5, Table 1) in a short reaction time. The kinetic results for each factor demonstrate that the C-H auration of N-phenylpyrazole may be the turnover limiting step of Au/Ag-dual catalyzed cross-dehydrogenative biaryl coupling.

b)

reaction rate/(M/h)

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 6 of 11

0.05 0.025 0

0.15 0.1 zero order

0.075 0.05 0.025 0

0.14

0.16

0.18 [2c]/M

0.2

0.22

5

10

20

15

25

[Ag]/mol%

Figure 4. Kinetic profiles of C-H/C-H coupling

Kinetic isotope effect (KIE) experiments were carried out under optimized conditions to gain further insight into the rate-limiting step (Scheme 7). It was found that the kH/kD between N-phenylpyrazole and deuterated Nphenylpyrazole could be as high as 7.6. This suggested that C-H cleavage of N-phenylpyrazole was indeed the rate determining step in the catalytic process. In contrast, the KIE result (kH/kD = ~1.2) for multifluoroarenes indicated that C-H activation of fluoroarene was unlikely to be involved in the rate determining step (see detail in SI). Scheme 7. KIE Studies F

H a)

N N Ph

Cl F

N N Ph >95% D

N N Ph

PIDA (1.5 eq.), 1,4-dioxane, 100 oC, 4 h

Ph

Cl

+ F

F

PIDA (1.5 eq.), 1,4-dioxane, 100 oC, 4 h kH/kD=~7.6

H

Ph

Cl

F

F

+


D 90% D

F Cl F 5% yield F

DMSAuCl (5 mol%), AgOAc (20 mol%) PIDA (1.5 eq.), 1,4-dioxane, 100 oC, 4 h kH/kD=~1.2

Ph

Cl

N N

F Cl

F Cl F 38% yield F

DMSAuCl (5 mol%), AgOAc (20 mol%)

Cl

N N

F Cl

H c)

F

F DMSAuCl (5 mol%), AgOAc (20 mol%)

H

D b)

Cl

+

Cl

N N

F Cl F 33% yield

Page 7 of 11 OH C 6F 5

G(kcal/mol)

H

O

L1 Ag OAc

L1=1,4-dioxane L=pyrazole

L1 Ag

Me

2-int1

C 6F 5

Me

L1

O O

L1 Ag C6F5 2-int2

2-int3

C 6F 5

Au

Me

O

Ag O

9-int1

L

Au

L

Ag

OAc

C6 F 5

N Au C6F5 N Ph 9

L1

OAc

N Au C6F5 N Ph OAc 10

9-int2

Au C6F5

N N Ph

OAc 10-int1

30 22.4 20

2-TS

Ph

N

10

2-int1

0.0

0

LAuOAc

G = 22.4 2-int2

3.2

C 6F 5H

HOAc

4.5

7.8

Au

-2.0

L1AgOAc

-8.5

-10

N

N

9-int2

PIDA

9

-7.8

10-int2 OAc Au N

Ph

G =26.8

N

C 6F 5

12-int1

-14.2 12-TS HOAc

-18.2 -20

Me

C 6F 5

4.6

10-int1

L1AgOAc

HO O

Au

10-int2

-4.1

9-int1

C 6F 5

Ph

8.6 10-TS

9-TS

2-int3

OAc

OAc

N 12

11.2

-22.6

10

12

G =8.4

-30

2.38

1.33

2.32

2.26

-52.9

2.16

2.70

1.40

2.07

2.34

1.29

L

12-int1 -64.2

2.22

2-TS

9-TS

Activate HC6F5

10-TS

Transmetalation

12-TS

Oxidation Conformation change

Activate pyrazole

3b LAuOAc

Reductive elimination

Figure 5. Gibbs free energy profile of the Au/Ag-dual catalyzed cross-coupling reaction between N-phenylpyrazole and C6HF5

Taking these experimental results into consideration, an Au/Ag synergistic catalytic cross-dehydrogenative biaryl coupling is proposed in Scheme 8. First, AgOAc-catalyzed CH activation of the multifluoroarene leads to the formation of Ag-ArFn (ArFn = -C6F5) as evidenced by H/D exchange and in-situ 19F NMR. The rapid transmetalation between Ag-ArFn and [AcOAu-pyrazole] then takes place, giving ArFn-Au(I) intermediate and completing the silver catalytic cycle. Subsequent oxidation of ArFn-Au(I) by PIDA results in the formation of an ArFn-Au(III) intermediate, which proceeds by C-H activation of N-phenylpyrazole, forming the ArFnAu(III)-Ar complex. That the C-H activation process is the rate-limiting step which is supported by kinetic studies and KIE experiments. Reductive elimination from the tricoordinate diaryl-Au(III) complex produces the biaryl products and restarts the gold catalytic cycle. Scheme 8. Au/Ag-Dual Catalyzed C-H/C-H Cross Coupling

Ph

N N

DMSAuOAc

C 6F5

pyrazole reductive elimination

Ph

N N

L

OAc

Au C6F5

Rate C-H determining activation step

OAc Au C6F5 H N Ph

AcO

N N Ph AuI

AuIII-mediated C-H activation

C6F5

AcO

C 6F5

AgI [detected by 19F NMR]

Transmetalation

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


oxididation PIDA

H

C 6F5

Au

N Ph N

N

AgI-catalyzed C-H activation

AgI

[detected by 19F NMR]

The proposed mechanistic pathway of the Au/Ag bimetallic catalyzed cross-dehydrogenative coupling

between N-phenylpyrazole and C6HF5 was studied using DFT calculations with the M06 function and the calculated free energy profile is displayed in Figure 5. The entire pathway consists of the following processes: (1) A C6HF5 molecule first approaches the 1,4-dioxane coordinated AgOAc complex to form the intermediate 2-int1. Then the C-H bond of C6HF5 is cleaved via the transition state 2-TS with a free energy barrier of 22.4 kcal mol-1. This C-H activation process has a concerted metalationdeprotonation mechanism; the breaking of the C-H bond is concomitant with the generation of the AcOH molecule. Liberation of the generated AcOH molecule leads to the formation of the 1,4-dioxane-coordinated AgC6F5 complex 2-int3. (2) Transmetalation occurs between the generated 2-int3 and the pyrazole-chelated AuOAc complex, generating the pyrazole-coordinated AuC6F5 complex (9) and regenerating the silver catalyst. This process is calculated to exergonic by 2.7 kcal mol-1 with a barrier of only 9.8 kcal mol-1 (with respect to the Au-Ag complex 9int1). These results are in line with the experimental observation of a rapid trasnmetalation between AgC6F5 and Au(I) complex (see Scheme 4b). (3) The generated complex (9) is oxidized to the pyrazole-coordinated Au(III)-C6F5 complex (10). This oxidation process is exergonic by 14.1 kcal mol-1. (4) The intermediate 10 can be converted into another conformer (11), in which the C4 position of pyrazole is oriented towards the center of the Au(III) cation. The C4 position of N-phenylpyrazole is the most electronrich. Then the C-H activation of pyrazole occurs through transition state 10-TS forming the intermediate 10-int2, with a free energy barrier of 26.8 kcal mol-1 (relative to 10). This process is calculated to be the rate-determining step. Subsequently, the generated AcOH molecule is liberated to form the tricoordinated Au(III) complex (12). (5) The generated complex (12) undergoes reductive elimination to



generate the intermediate (12-int1). Subsequently, the final cross-coupling product is generated by direct ligand exchange with another pyrazole molecule. At the same time, the pyrazole-coordinated AuOAc complex is restored. This process is exothermic by 41.6 kcal mol-1 and the free energy barrier is 8.4 kcal mol-1 (relative to 12). The whole crosscoupling reaction is therefore exergonic by 64.2 kcal mol-1 (relative to the reactants, pyrazole and C6HF5). These computational results suggest that this reaction is thermodynamically and kinetically feasible under the experimental conditions. Examination of Substrate Scope Scheme 9. Scope of

functionalizations of the remaining C-H bonds by other strategies. The relatively less reactive fluoropyridines (3s, 3t) and 1,3,5- trifluorobenzene (3p) also react smoothly to give the desired products in moderate yields. Scheme 10. Pyrazole Scope a R1

F

F

N

F H 2a

C5F4N

C5F4N

Ph

F

N Ph

F

F F

Ph

N N

F Ph

F 3e, 57% F

Ph

Ph

F 3f, 70% N N

F

F

CN

Ph

F

N N F

Ph

F

N N

F

Ph

N N

F N F 3q, 83%

Ph

Ph

F F 3r, 64%

Ph

N N

Ph

3s, 47%

C3 C5F4N N N Me C5

N N Me

F 3p, 51% b

Ph

N N

3mm, 67%

F N N

Br N F 3t, 50%

b

20%

With this understanding of the novel mechanism, we next explored the reaction scope of Au/Ag-dual catalysis process. Polyfluorinated biaryl compounds have widespread application in medicinal chemistry, agrochemical and material science70,71 and the broad substrate scope of multifluoroarenes, shown in Scheme 9 will support such chemistry. In general, polyfluoroarenes could serve as effective coupling partners in this protocol, providing the corresponding biaryl products in good to excellent yields. When 2,3,5,6-tetrafluoropyridine and pentafluorobenzene were used, the desired biaryl products (3a, 3b) were obtained in 85% and 84% yield, respectively. We found that fluorobenzene bearing chloro, trifluoromethyl, bromo, cyano, formyl or nitro groups were compatible substrates (3c-n) which provide an opportunity for further transformation. The I and Br substituents are also compatible well (3h, 3i, 3o, 3s, 3t). Electron-deficient fluorobenzenes generally provide higher yields presumably due to the increased acidity of the aromatic C–H bonds. When substrates possess two different C-H bonds, the cross-coupling reacts exclusively at C–H bonds between two C–F bonds (3g, 3h, 3j, 3k, 3m, 3n). The high selectivity could be explained by sliver-promoted concerted metalation-deprotonation mechanism which tends to react at the most acidic C-H bond. Only mono-arylated products are obtained even when two or more competing C-H bonds exist (3e, 3f, 3n, 3o, 3p, 3r), which support further

N N Me

Me

Me

N N Me

Me Me

N N Ph

N N 3nn, 56%c

3y, 87%

Br

3cc, 65%

3bb, 91%

C5F4N N

C6F5N

F

C5F4N

C5F4N

C5F4N

C3 C5F4N N N Br Me C5 3ff, 65% C3:C5=4:1b

3ee, 64%

N N

Reactions were carried out in 0.5 mmol scale. Isolated yields. mol DMSAuCl and 40% mol AgOAc. a

3aa, 95%

Me

CN F 3l, 67%

Br N

F

3z, 96%

F F

F 3o, 62% b

N N Et

3x, 91%

3w, 61%

C5F4N

N N Me

F

N N

I

N N

F

N

N N

Ph

F F 3k, 49%

F

F

CHO

F

F F 3n, 54%

3m, 73%

N N

NO2

Br

F

3v, 48%

C5F4N

F 3h, 44%

F

Ph

F

F 3j, 45%

N N

Ph

F F 3g, 63%

CF3 F F 3d, 84% F F

Br

N N

CHO

F Br

F 3i, 56%

F

F

Ph

Cl F 3c, 76%

Ph

N N

F

F

N N

F

N N

Ph

F

N N Ph

F

OCF3

3u, 80%

F

F

N N

F F 3b, 84% F

F

N N Br

Cl

F

F

N N

3a, 85%

C5F4N

N N

N N

C5F4N

N N R 18 examples

C5F4N

Polyfluoroarenesa

F

F

PIDA (1.5 eq.), 1,4-dioxane, 100 oC, 12-15 h

F

1b-1s

R1

DMSAuCl (5 mol%), AgOAc (20 mol%)

+

N N R

Me N N

Page 8 of 11

C5F4N S

Br

C5F4N N N Me

I

3dd, 62% C5F4N O N N Me

N N Me 3gg, 93% C5F4N N N Me 3oo, 79%

3kk, 89% Cl

C5F4N

N N Me 3pp, 75% N

Reactions were carried out with 0.5 mmol scale. Isolated yields. bThe regioselectivity was determined by 1H NMR of isolated isomers. cThe reaction was performed with 20 mol% DMSAuCl and 40 mol% AgOAc. a

The representative results for pyrazole scope are illustrated in Scheme 10. The N-arylpyrazole bearing both electron-donating and electron-withdrawing groups in the benzene ring (3u-w) were good substrates, although only a moderate yield was observed for 3v. 5-Fluoropyrazole, an important building block in medicinal chemistry and agrochemistry, underwent this cross-dehydrogenative coupling smoothly to give the desired biheteroaryl product (3x) in 91% yield. An alkenyl-substituted pyrazole tolerates the optimized conditions, yielding the product (3y) in 87% yield. Various N-alkyl substituted pyrazoles show high reactivity (3z-bb). Au/Ag-Dual catalyzed coupling conditions work well with compounds having bromo- and iodo-substituents (3cc, 3dd, 3ff, 3gg), and afford a promising platform for downstream C-C couplings. In all the above cases, a preference for functionalizing the C–H bonds at C4 position was observed, presumably due to the high electron density at C4 position. When a 4-substituted Nmethylpyrazole was employed, the C3 position could be selectively arylated (3ee, 3ff). However, C3-substituted pyrazoles such as 1,3-dimethyl-1H-pyrazole gave a severely decreased reaction yield probably due to the preventive coordination of pyrazole with gold catalyst (see SI for details). The coupling conditions can be successfully applied to thiophene- and furan-containing substrates. The desired products were obtained in excellent yields, and no byproduct was observed at electron-rich five-membered thiophene or furan rings (3gg, 3kk). Interestingly,


Page 9 of 11 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


bipyrazole formation occurred at the less hindered pyrazole ring (3mm). With an increased loading of DMSAuCl and AgOAc, the pyridine-containing substrate appeared to be an efficient coupling partner for the formation of a biheteroaryl product (3nn) in 56% yield. Good yields were obtained for indazoles (3oo, 3pp). The resulting polyfluoroarenes are useful building blocks for downstream transformations to afford a wide range of multifluorinated compounds via selective C-F bond functionalization (Scheme 11). For example, visible-lightinduced highly selective hydrodefluorination of product 3q could lead to partially fluorinated biaryls with excellent regioselectivity (Scheme 11a).72Of note, when 3d was employed in the presence of 2 equivalent formic acids, an unprecedented hydrodefluorination and hydrodetrifluoromethylation event occurred, which contributes a good access to fluoro-containing molecules that are difficult to obtain via selective fluorination. Photoredox catalyzed defluoroalkylation of 3b with 1phenylpyrrolidine also proceeded smoothly to give 3ss in moderate yield (Scheme 11b).73 In addition, the reaction of 3r with (R)-2-amino-2-phenylacetamide allowed us to obtain 3tt in high selectivity via SNAr substitution (Scheme 11c). These synthetic application fully demonstrates that the resulting fluoro-containing biaryl products hold rich reactivity for downstream modifications. Scheme 11. Downstream Synthetic Transformation of Products a) Hydrodefluorination F F N N

Ph

H fac-Ir(ppy)3 (1 mol%), DMF (0.1 M)

F

o

DIPEA (2 eq.),blue LEDs, 45 C, Ar

N

Ph

N N

F N F 3qq, 95%

F 3q F

Ph

F

N N

H CF3

F

F

F

fac-Ir(ppy)3 (1 mol%), DMF (0.1 M)

F

N N

DIPEA (10 eq.), HCOOH (2 eq.),blue LEDs, 45 oC,Ar Ph

H F F 3rr,52%

3d b) Defluoroalkylation F

Ph

F

N N

F F 3b

Ir(ppy)2(dtbbpy)PF6 (1 mol%), DMF (0.1 M)

+ N Ph

F

blue LEDs, 45 oC, NaOAc (1.5 eq.), Ar Ph 8h

F

F

N F Ph

3ss, 49%

c) Defluoroamination F

F

Ph

N N

O F + N

F 3r

Ph

DMSO, 110 oC NH2

NH2

Ph

N N

ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website. DFT calculation details, characterization data and NMR spectra (PDF) X-ray crystallographic data for 6 (CIF) AUTHOR INFORMATION

Corresponding Author Email: [email protected] (J. X., Lead Contact) [email protected] (S. L.) [email protected] (C. Z.)

Notes

The authors declare no competing financial interest. ACKNOWLEDGMENT We gratefully acknowledge National Natural Science Foundation of China (21702098, 21732003, 21833002 and 21672099), Nanjing University Start-up Funding. Prof. Igor Larrosa at University of Manchester is kindly acknowledged for their helpful manuscript discussion. All calculations in this study have been done on the IBM Blade cluster system in the High Performance Computing Center of Nanjing University.

REFERENCES

F N N

substitution pathway. Kinetic analysis shows that the reaction rate has a first-order dependence on the concentrations of gold and pyrazole and is independent of the silver catalyst and fluoroarenes. The combination of experimental investigations and DFT calculations suggests that the gold(III)-mediated C-H bond cleavage of pyrazole is the rate-limiting step in Au/Ag synergistic catalysis. This study improves our understanding of the mechanisms in gold catalysis and also calls attention to question of the real role of metal salt additives in coupling reactions.

O

NH2

NH

Ph

N F 3tt, 58%

CONCLUSION We have developed an operationally simple and highly selective cross-dehydrogenative biaryl coupling reaction between pyrazoles and fluoroarenes, which is promising for the synthesis of biheteroaryl products with high regioselectivity. Our detailed mechanistic studies reveal that silver is the actual species for C-H activation of electron-poor fluoroarene rather than reported gold(I)catalyst. This new finding supports Au/Ag dual catalysis in Ar1-H/Ar2-H C-C coupling, in which the silver salt is responsible for a C-H cleavage of electron-poor fluoroarenes via concerted metalation-deprotonation process and the gold(III) allows for C-H activation of the electron-rich pyrazoles via electrophilic aromatic

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TOC Graphic [O] AgI ArFn

I

ArFn

H


Ag catalytic cycle

AuI

ArFn

ArFn

II

Nucleophilic C(sp2)-H Addition to Aldehydes and Nitriles. Angew. Chem. Int. Ed. 2015, 54, 13659-13663. (49) Li, J.; Ackermann, L. Cobalt(III)-Catalyzed Aryl and Alkenyl C-H Aminocarbonylation with Isocyanates and Acyl Azides. Angew. Chem. Int. Ed. 2015, 54, 8551-8554. (50) Fan, Z.; Ni, J.; Zhang, A. Meta-Selective CAr–H Nitration of Arenes through a Ru3(CO)12-Catalyzed Ortho-Metalation Strategy. J. Am. Chem. Soc. 2016, 138, 8470-8475. (51) Colletto, C.; Panigrahi, A.; Fernandez-Casado, J.; Larrosa, I., Ag(I)-C-H Activation Enables Near-Room-Temperature Direct alpha-Arylation of Benzo[b]thiophenes. J. Am. Chem. Soc. 2018, 140, 9638-9643. (52) Rocchigiani, L.; Fernandez-Cestau, J.; Budzelaar, P. H. M.; Bochmann, M. Arene C-H Activation by Gold(III): SolventEnabled Proton Shuttling, and Observation of a Premetallation Au-arene Intermediate, Chem Commun. 2017, 53, 4358-4361. (53) Hashmi, A. S. K.; Schwarz, L.; Choi, J-H.; Frost, T. M. A New Gold-Cataltzed C-C Bond Formation. Angew. Chem. Int. Ed. 2000, 39, 2285-2288. (54) Huang, L.; Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Photosensitizer-Free Visible-Light-Mediated GoldCatalyzed 1,2-Difunctionalization of Alkynes. Angew. Chem. Int. Ed. 2016, 55, 4808-4813. (55) Huang, L.; Rominger, F.; Rudolph, M.; Hashmi, A. S. K. A General Access to Organogold(III) Complexes by Oxidative Addition of Diazonium Salts. Chem. Commun. 2016, 52, 6435-6458. (56) Minghetti, G.; Cinellu, M. A.; Pinna, M. V.; Stoccoro, S.; Zucca, A.; Manassero, M. Gold(III) Derivatives with C(4)-aurated 1-Phenylpyrazole, J. Organomet. Chem. 1998, 568, 225-232. (57) Zhao, Y.; Truhlar, D. G. The M06 Suite of Density Functionals for Main Group Thermochemistry, Thermochemical Kinetics, Noncovalent Interactions, Excited States, and Transition Elements: Two New Functionals and Systematic Testing of Four M06-Class Functionals and 12 Other Functionals, Theor. Chem. Acc. 2008, 120, 215-241. (58) AgC6F5 is a relatively stable compound, and can be readily isolated. In order to confirm the signal of -107 ppm as Ag−C6F5 complex, we synthesized AgC6F5 complex, and the spectra is in concordance with literature reports: Kuprat, M.; Lehmann, M.; Schulz, A.; Villinger, A. Synthesis of Pentafluorophenyl Silver by Means of Lewis Acid Catalysis: Structure of Silver Solvent Complexes. Organometallics 2010, 29, 1421-1427. (59) Although we could not directly isolate complex 9, the isolation of Ph3PAuC6F5 by addition Ph3P in the reaction mixture may demonstrate its generation (see detail in SI). (60) Thanks one anonymous reviewer very much to point out that the possibility of sequentially formation of Au(I) and Au(III) complexes may be the resting state. Accordingly, path b cannot be absolutely ruled out. (61) Duan, H.; Sengupta, S.; Petersen, J. L.; Akhmedov, N. G.; Shi, X. Triazole-Au(I) Complexes: A New Class of Catalysts with Improved Thermal Stability and Reactivity for Intermolecular Alkyne Hydroamination. J. Am. Chem. Soc. 2009, 131, 12100–12102.

Transmetalation

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


Au I

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AuI/AuIII catalytic cycle

(Het) Ar

(Het) Ar

H

ArFn

(Het)Ar=pyrazole AgI

AuI

Ag Dual-Catalyzed Cross-Dehydrogenative Biaryl

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