Highly Chemoselective Access to 2,2-Diaminobiaryls via Ni-Catalyzed Protecting-Group-Free Coupling of 2-Haloanilines

Catalyzed Protecting-Group-Free Coupling of 2 ‑Haloanilines

Research Article

Highly Chemoselective Access to 2,2′-Diaminobiaryls via Ni-

⊥

Cheng-Yu Long, Shao-Fei Ni, Min-Hui Su, Xue-Qiang Wang,* and Weihong Tan

Cite This: ACS Catal. 2020, 10, 13641 −13649

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ABSTRACT: The development of strategies to access 2,2′-

diaminobiaryl derivatives via a transition-metal-catalyzed coupling

reaction from protecting-group-free starting materials is a

challenging task to accomplish, owing to the easy occurrence of

undesired side reactions. The exploitation of Ni-catalyzed direct

homocoupling of unprotected 2-haloaniline analogues to produce

,2′-diaminobiaryls with a readily available and inexpensive

bipyridine ligand has been described. This approach was high-

lighted by its high chemoselectivity, broad substrate scope, and

functional group compatibility. The mechanistic and calculation

studies indicated that Ni(0), Ni(I), Ni(II), and Ni(III) species might be involved in the catalytic cycle.

KEYWORDS: Ni-catalyzed, chemoselective, protecting-group-free coupling, 2-haloaniline, 2, 2′-diaminobiaryls

INTRODUCTION

■

The synthesis community has witnessed the power and

potential of transition-metal catalysis over the past few decades

with the development of a multitude of unprecedented new

reactions in various research areas. Among these, the design of

synthesis protocols toward 2,2′-diaminobiaryls is an attractive

topic, owing to their broad range of applications in an array of

ﬁelds including auxiliary ligands, catalysis, and molecular

imaging. Nevertheless, achieving high selectivity while

retaining high activity during transition-metal-catalyzed

protecting-group-free synthesis of 2,2′-diaminobiaryl remains

challenging. Currently, one representative technique for

assembling 2,2′-diaminobiaryls is anodic oxidation, entailing

an electrochemical process. Interestingly, this approach

usually requires the utilization of electron-rich aniline

derivatives as reactive substrates, and common electron-

withdrawing functional groups are not well tolerated (Figure

a). Alternatively, Pd- or Rh-catalyzed oxidative C−H/C−H

coupling reactions have emerged as a powerful strategy for the

synthesis of both symmetrical and unsymmetrical 2,2′-

diaminobiaryls. As demonstrated by the You, Xie, and Lu

groups, the introduction of an acyl group as a protecting and a

directing group was essential for precise regioselectivity control

in the oxidative couplings; a mixture of undesired compounds

would be produced otherwise (Figure 1b). Therefore, the

development of a 2,2′-diaminobiaryl synthesis strategy using

protecting-group-free substrates would be particularly appeal-

ing.

Figure 1. Previously described protocols for the synthesis of 2,2′-

diaminobiaryls and this work.

Received: August 6, 2020

Revised: October 26, 2020

Commercially available derivatives of 2-haloaniline have

been extensively utilized in transition-metal-catalyzed cou-

plings. However, the direct synthesis of 2,2′-diaminobiaryls

XXXX American Chemical Society

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ACS Catal. 2020, 10, 13641−13649

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using unprotected 2-haloanilines as starting materials remains

challenging, and thus is somewhat unexplored. In 1987,

Perichon et al. reported Ni-catalyzed electrochemical homo-

coupling of ortho-substituted halides; a single 2,2′-diaminobi-

phenyl product was obtained in 71% yield using 2-bromoani-

line as the substrate. In 2005, Yoon and his co-workers

described a biaryl synthesis via Pd catalysts in the presence of

indium, where 2,2′-diaminobiaryl, for example, was delivered

in 76% yield under harsh reaction conditions. In 2018, the Li

group presented an elegant protocol for biaryl preparation

using a Ni catalyst in the presence N H as a traceless

mediator, likewise, only one example of 2,2′-diaminobiphenyl

was presented. This scenario may be explained by the

occurrence of several undesired competing reactions, including

reduction of the carbon−halogen bond (3a), the formation of

,10-dihydrophenazine (4), and the formation of phenazine

enabled by palladium or copper catalysts. We envisioned that

the implementation of Ni catalysts would overcome these

issues because of its unique properties compared with those of

Pd catalysts. For instance, nickel has a small atomic radius that

enables facile oxidative addition, and the variation between the

diﬀerent oxidation states allows for distinct modes of

reactivity.

Recently, transition-metal-catalyzed reductive couplings

have emerged as an essential technique in complex synthesis

settings, especially when nickel is used as a catalyst.

Homocouplings and cross-couplings of various electrophiles,

including alkyl (pseudo)halides, aryl (pseudo)halides,

carbon dioxide, and many others have been established.

In the reported examples, Ni(I) and Ni(III) species have often

been proposed in hypothesized catalytic cycles. Inspired by

these ﬁndings and the inherent coordinating property of the

amino group within 2-haloanilines, we envisaged that the

adoption of a Ni-catalyzed reductive homocoupling strategy

would allow us to achieve the direct synthesis of 2,2′-

diaminobiaryls from 2-haloanilines without protecting and

deprotecting operations while addressing the chemoselectivity

issue (Figure 1c).

RESULTS AND DISCUSSION

■

Optimization of Reaction Conditions. The investigation

was initiated by exploiting the chemoselective 2,2′-diamino-

biaryl synthesis methodology, proceeding via the protecting-

group-free coupling of 2-bromoaniline in the presence of a

nickel catalyst (Figure 2). After extensive optimization, the

catalytic system is composed of NiCl ·dimethoxyethane

(

DME) (10 mol %), L1 (20 mol %), and Mn (3.0 equiv) as

the reducing agent in dimethylformamide (DMF) (1 mL) at

5 °C for 20 h was found to be optimal. The desired product

a was obtained in an isolated yield of 95%, and no other side

products were detected (entry 1, 0.2 mmol scale). The use of

NiCl instead of the optimized precatalyst led to a signiﬁcantly

decreased yield of 38%, along with 16% of the reduced side

product 3a (entry 2). Likewise, utilizing phosphine ligands

such as PPh or dppf to replace the optimal ligand L1 resulted

in a decrease in the production of the targeted product 2a and

an increase in that of the unwanted side product 3a (entries 3

Supporting Information, Tables S1 −S4). The optimization of

bidentate 2,2′-bipyridine ligands allowed us to ﬁnd out that the

introduction of strong electron-donating groups at the 4,4′-

positions of bipyridine gave rise to the opposite selectivity

proﬁle, wherein 3a was obtained in 40% yield as the major

product (entry 6). Unexpectedly, the replacement of methyl in

L1 with tert-butyl likewise led to inferior yield and chemo-

selectivity (entry 7). Moreover, varying the position of methyl

and 4). Low valent Ni sources such as Ni(COD) were capable

of catalyzing this transformation, although a moderate yield of

5% of 2a was observed while aﬀording 3a in 15% yield (entry

). These results demonstrated that the Ni-catalyst source had

a profound inﬂuence on both the reactivity and chemo-

selectivity of this approach (for optimization details, see the

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ACS Catal. 2020, 10, 13641−13649

Figure 3. Substrate scope of the chemoselective coupling reaction. Reaction conditions: 2-bromoaniline (1a, 0.5 mmol), Ni catalyst (10 mol %),

ligand (20 mol %), Mn (1.5 mmol, 3.0 equiv), DMF (1.5 mL), 25 °C, and 20 h.

substitution on the bipyridine ligand also signiﬁcantly aﬀected

the coupling; while the use of L4 nearly terminated the

reaction, the employment of L5 provided a high conversion

but low chemoselectivity (67:21, entries 8 and 9). The L6

ligand gave a moderate yield of 57% and poor chemoselectivity

performed further optimization for these two starting materials.

To our delight, by simply changing of the ligand from L1 to

L6, high reactivity and chemoselectivity were obtained,

generating 2a in yields of 80 and 90%, respectively.

Substrate Scope of the Protecting-Group-Free Cou-

pling. Upon determining the optimal reaction conditions, we

investigated the generality of this newly developed coupling. As

shown in Figure 3, substituents such as methyl, tert-butyl,

benzyl, and phenyl groups at the para-position of 2-

bromoaniline did not have a profound inﬂuence on the

reactivity and chemoselectivity, and the corresponding

products 2b, 2c, 2d, and 2e were produced in good to high

yields. The diﬀerence between 2b and 2c with respect to the

yield could be explained by the decreased reactivity of 1c due

to steric eﬀects. Generally, the presence of strong electron-

donating substituents, such as alkoxy groups, led to a decrease

in reactivity, delivering the desired products in moderate to

good yields (2f, 2g, 2h, and 2i). Notably, aryl acetate (2j), aryl

pivalate (2k), and alkyl pivalate (2o) were all compatible, as

these molecules have been successfully used as partners in Ni-

catalyzed coupling reactions, oﬀering potential opportunities

for further transformations. Our strategy also exhibited good

functional group compatibility, with thioether (2l), amide

(2m), esters (2n, 2r), silyl ether (2p), and nitrile (2s) being

(

entry 10). These observations indicated that the homocou-

pling reaction was sensitive to ligand choice. Then, we tried

using Zn as a reducing agent; however, a lower yield and poor

chemoselectivity were observed (entry 11), which may be

rationalized by the diﬀerence in reducing ability as a result of

the distinct redox potentials of these two reductants. The

control experiments showed that replacing the solvent with

dimethylacetamide (DMA) and N-methyl-2-pyrrolidone

(

NMP) resulted in a lowered yield of 82 and 77%, respectively

entries 12 and 13). Other polar solvents, such as acetonitrile,

toluene, or tetrahydrofuran did not allow this transformation to

occur (see the Supporting Information, Table S4). Couplings

without a nickel catalyst, ligand, or reducing agent did not

proceed, demonstrating their necessity in this protocol (entries

4−16). In addition to 2-bromoaniline, we evaluated the

reactivity and chemoselectivity of 2-chloroaniline and 2-

iodoaniline. The conversion of these two substrates was

considerably lower, and a small amount of 2a could be

detected under optimized reaction conditions. Therefore, we

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Figure 4. Mechanistic studies for the coupling reaction.

well tolerated, and the corresponding 2,2′-diaminobiaryls were

generated in moderate to good yields. It is worth noting that

not only a wide range of electron-rich aniline derivatives but

also substrates bearing electron-withdrawing groups, including

triﬂuoromethyl, methoxycarbonyl, and cyano, were suitable for

this coupling. Surprisingly, N-methylation signiﬁcantly aﬀected

the reactivity, and 2t was isolated in a 33% yield. In addition,

the utilization of 7-bromoindoline gave the corresponding

product in 33% yield. These results suggested that decreased

yields of secondary amine homocoupling were not only

associated with steric eﬀorts because the alkyl group on the

nitrogen was tied back on indoline (Scheme S1). Heterocycles

such as furan, thiophene, and unprotected pyrrole were

likewise well tolerated. Then, we decided to study the

representative scope of 2-chloroanilines under similar reaction

conditions by employing L6 as a supportive ligand. As

presented, electron-deﬁcient, electron-neutral, and electron-

rich 2-chloroaniline derivatives underwent this coupling.

However, the eﬃciency of this protocol was lower than that

using 2-bromoanilines, yielding the desired products in

moderate to good yields. This may be explained by the high

dissociation energy of the Csp −Cl bond and the formation of

a complex product mixture, the composition of which could

not be identiﬁed. In contrast, 2-iodoaniline derivatives

displayed superior reactivity to that of 2-bromoaniline, with

the majority of tested examples, such as 1ag, 1ai, 1aj−1ao, and

1aq, reacting smoothly except for 1ah, 1ap, and 1ar.

Unsurprisingly, the use of 2-iodo-N-methylaniline again

resulted in a reduced yield of 44%. To further examine the

utility of this newly developed homocoupling, we carried out a

gram-scale reaction using 2-iodoaniline as the starting material,

and the desired product 2a was generated in 88% isolated yield

without the observation of 3a.

Mechanistic Studies of Protecting-Group-Free Cou-

pling. To shed light on the mechanism of this highly

chemoselective Ni-catalyzed homocoupling reaction, we

synthesized nickel complexes that are possibly involved in

this transformation and performed stoichiometric or catalytic

reactions. As shown in Figure 4, the Ni(0)-complex C1 was

prepared via the ligand exchange of Ni(COD)₂with a

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ACS Catal. 2020, 10, 13641−13649

Figure 5. Theoretical studies of the coupling mechanism.

bipyridine-type ligand L1 in 60% isolated yield. C1 was then

subjected to stoichiometric reactions with 2-bromoaniline.

Noteworthy, the reaction that was in the absence of Mn

proceeded well, and 2a was delivered in 75% yield. This result

demonstrated that a stoichiometric reaction had occurred via

the classical Ullmann reaction mechanism without the

and 2-bromoaniline. Unexpectedly, the Ni(II)-complex C3 was

produced in 85% isolated yield, while the target complex C2

was not formed. Stoichiometric reactions were then performed

to determine their reactivity. The reaction lacking the reducing

agent Mn produced the desired product 2a in only 2%, while

the addition of Mn to the stoichiometric reaction led to the

generation of 2a in 50% yield (Figure 4b). These mechanistic

observations suggested that catalytic cycles entailing Ni(II)

and Ni(IV) are likely not involved in our newly developed

coupling reaction. We also performed a catalytic reaction using

C3 as a precatalyst, and 2a was formed in a yield of less than

10%, while no reduced product 3a was obtained, suggesting

that C3 is likely not the active intermediate in this

participation of the Mn reducing agent. The addition of

Mn improved the yield of stoichiometric reaction to 90%,

indicating that Mn plays an important role in the

stoichiometric coupling. Interestingly, Ni(0) was not only

being stabilized by the two bipyridine ligands, as indicated by

its complexation with the remaining cycloocta-1,5-diene

(

COD) ligand (Figure 4a). We additionally attempted to

prepare and isolate the Ni(II) species using Ni(COD) , L1,

transformation probably, owing to its good stability.

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Figure 6. Proposed mechanism of the Ni-catalyzed coupling: reductive coupling or the Ullmann-type pathway.

In addition, we evaluated the possibility of a radical pathway

for this transformation. While the addition of (2,2,6,6-

tetramethylpiperidin-1-yl)oxyl (TEMPO) to the catalytic

system as a radical trapper led to a lower yield of 70%; the

presence of butylated hydroxytoluene (BHT) and 1,1-

diphenylethylene did not aﬀect coupling eﬃciency (Figure

the Gibbs energy change when Ni(II) was reduced to Ni(I) by

a Ni(0) species, and it was found to be approximately −15.0

kcal/mol. That is to say, both Mn and Ni(0) could mediate the

generation of the Ni(I) intermediate due to the small Gibbs

energy diﬀerence, indicating that the Mn-promoted reductive

coupling mechanism and Ni(0)-mediated Ullmann-type path-

way are both possible (Scheme S2). As shown in Figure 5, the

oxidative addition of another 2-bromoaniline molecule to the

Ni(I) center via the three-membered transition state TS5-6

would then take place to deliver the stable Ni(III) species I6,

which is exergonic by 15.1 kcal/mol, thus rendering the

catalytic system completely irreversible. The desired 2,2′-

diaminobiaryl product will then be produced through rapid

reductive elimination from Ni(III) species I6, together with

the reduction of Ni(III) to Ni(I) I3. Mn would trigger another

SET process to complete the catalytic cycle and regenerate I1

with a Gibbs energy change of −47.1 kcal/mol for this step

(Scheme S3).

Based on our mechanistic studies and density functional

theory (DFT) calculations, a more detailed Ni(0)−Ni(II)−

Ni(I)−Ni(III)−Ni(I)−Ni(0) mechanistic pathway could be

revealed for this Ni-catalyzed 2,2′-diaminobiaryl synthesis

protocol (Figure 6). The reaction starts with the formation of

the Ni(0) intermediate I1 involving a nickel precatalyst, L1,

and 2-bromoaniline in the presence of Mn as a reductant. I1

undergoes rapid oxidative addition of the C−Br bond to aﬀord

the Ni(II) intermediate I2 via TS1-2. A Mn or Ni(0)-enabled

SET process would then take place to generate Ni(I)

intermediate I4, whereby the second oxidative addition occurs

to aﬀord Ni(III) species I6. The reductive coupling process

would happen rapidly to deliver the aimed 2,2′-diaminobiaryl

while oﬀering a Ni(I) species I3. Another SET event would

then reduce I3 to I1, thus restarting the entire catalytic cycle.

We believe that the rate-determining step for this catalytic

cycle is the second oxidative addition of the C−Br bond to the

Ni(I) center of I4 via TS5-6 with a free-energy barrier of 21.9

kcal/mol.

c). These observations indicated that this coupling likely does

not involve radical species. To provide evidence regarding the

generation of Ni(I) species, we decided to monitor the

stoichiometric reaction of C3 with 1a in DMF by electron

paramagnetic resonance (EPR) spectroscopy (Figure 4d). The

comparison of observed g-values with known ones in related

scenarios implied the formation of Ni(I) intermediates.

To further understand the mechanism, we next carried out

theoretical studies. First, the ligand exchange process occurring

prior to the catalytic cycle was studied, and the results

indicated that the formation of η -coordinated intermediate I1

is favorable under the current reaction conditions (see Figure

S3 in the Supporting Information). We set I1 as the starting

point for the reaction, as shown in Figure 5, which would

undergo oxidative addition at the C−Br bond through a three-

member transition state TS1-2 to aﬀord the Ni(II) complex I2.

This is a rapid oxidative addition process with a reaction

barrier of 2.7 kcal/mol. On the other hand, the halide

abstraction process that has been proposed in a previous report

was also considered here. An open-shell singlet transition

state TS1-3 with a barrier of 18.1 kcal/mol was located, which

corresponds to the homolytic cleavage of the C−Br bond to

give the phenyl radical and the Ni(I) complex I3. However,

this homolytic halide abstraction cannot compete with the

oxidative addition pathway, and the generated Ni(II) complex

I2 thus dominates this step.

Ni(II) complex I2 undergoes a single-electron transfer

(

SET) process to produce Ni(I) species I4 in the presence of

Mn, and the free-energy change of this process was calculated

to be −23.4 kcal/mol, indicating that this single-electron

reduction process readily occurs under the current reaction

conditions. To test whether this catalytic reaction would

proceed via an Ullmann-type mechanism, we also calculated

The reactivity of 2-iodoaniline, 2-bromoaniline, and 2-

chloroaniline are reproduced here on the vital rate-determining

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ACS Catal. 2020, 10, 13641−13649

ACS Catalysis

Complete contact information is available at:

Research Article

transition state. Our calculated reaction barriers were 11.5,

Materials of Guangdong Province, Shantou University,

Shantou 515063, Guangdong, China

1.9, and 24.0 kcal/mol for 2-iodoaniline, 2-bromoaniline, and

-chloroaniline, respectively. These results are in good

Min-Hui Su − Molecular Sciences and Biomedicine Laboratory

(MBL), State Key Laboratory for Chemo/Biosensing and

Chemometrics, College of Chemistry and Chemical

Engineering, Collaborative Innovation Center for Chemistry

and Molecular Medicine, Hunan University, Changsha

410082, China

Weihong Tan − Molecular Sciences and Biomedicine

Laboratory (MBL), State Key Laboratory for Chemo/

Biosensing and Chemometrics, College of Chemistry and

Chemical Engineering, Collaborative Innovation Center for

Chemistry and Molecular Medicine, Hunan University,

Changsha 410082, China; Institute of Cancer and Basic

Medicine (IBMC), Chinese Academy of Sciences, The Cancer

Hospital of the University of Chinese Academy of Sciences,

Zhejiang 310022, China; Institute of Molecular Medicine

agreement with the experimentally observed reactivity, lower

yields for 2-choloaniline analogues and high yields for 2-

iodoaniline analogues (Figure S4 in the Supporting Informa-

tion). Moreover, the reaction barriers for the mechanism that

leads to the formation of 3a was also calculated. All of the

routes possess higher reaction barriers when compared with

that of the transition state TS5-6 (21.9 kcal/mol), leading to

the main product (Figure S5 in the Supporting Information).

CONCLUSIONS

■

In summary, we developed a Ni-catalyzed chemoselective 2,2′-

diaminobiaryl synthesis protocol using 2-haloaniline derivatives

as readily available starting materials. 2-Iodo, 2-bromo, and 2-

chloroaniline derivatives all participated in the coupling

smoothly. The good functional group compatibility of this

methodology is demonstrated by the production of a wide

range of products bearing acetate, pivalates, thioethers, silyl

ethers, amines, esters, nitriles, and heterocycles. The

mechanistic investigations and calculation studies allowed us

to propose a detailed catalytic cycle involving Ni(0), Ni(I),

Ni(II), and Ni(III) species. Importantly, this transformation

does not require protecting groups to obtain high reactivity

and selectivity, and we thus expect for further application of

this protocol in the future.

(

IMM), Renji Hospital, School of Medicine, College of

Chemistry and Chemical Engineering, Shanghai Jiao Tong

University, Shanghai 200127, China; orcid.org/0000-

0002-8066-1524

https://pubs.acs.org/10.1021/acscatal.0c03428

Author Contributions

C.-Y.L., S.-F.N., and M.-H.S. contributed equally.

⊥

Notes

The authors declare no competing ﬁnancial interest.

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acscatal.0c03428 .

■

ACKNOWLEDGMENTS

■

This work is supported by the National Key R&D Program of

China (2018YFA0902300), the Huxiang Young Talent

Program from Hunan Province (2019RS2022), and NSFC

grants (21827811 and 91753109). The authors are grateful to

Professor Yu Fang from Hunan University for his help in the

X-ray diﬀraction operation.

The general procedures of starting material preparation,

Ni-catalyzed coupling, and synthesis of Ni complexes;

the characterization of the starting materials, products,

and Ni complexes; H NMR, C NMR, and F NMR

spectra of the starting materials, products, and Ni

complexes; and the X-ray information of Ni complexes

and calculation-related information (PDF )

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AUTHOR INFORMATION

Corresponding Author

■

Xue-Qiang Wang − Molecular Sciences and Biomedicine

Laboratory (MBL), State Key Laboratory for Chemo/

Biosensing and Chemometrics, College of Chemistry and

Chemical Engineering, Collaborative Innovation Center for

Chemistry and Molecular Medicine, Hunan University,

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