Nickel-Catalyzed Amination of Aryl Nitriles for Accessing Diarylamines through C?CN Bond Activation

Article abstract of DOI:10.1002/adsc.202100641

A nickel-catalyzed amination to access diarylamines has been developed through C?CN bond activation of aryl nitriles with anilines. In this developed catalytic protocol, various aromatic and heteroaromatic nitriles could be utilized as the electrophiles to couple with substituted anilines. A diversity of diarylamines were obtained in 15–95% yields. (Figure presented.).

Full text of DOI:10.1002/adsc.202100641

COMMUNICATIONS
doi.org/10.1002/adsc.202100641
Nickel-Catalyzed Amination of Aryl Nitriles for Accessing
Diarylamines through CÀ CN Bond Activation
Ke Wu,+a Qiang Rong,+a Nan Sun,a Baoxiang Hu,a Zhenlu Shen,a Liqun Jin,a, b,*
and Xinquan Hua,*
a
College of Chemical Engineering
Zhejiang University of Technology
Hangzhou 310032, People’s Republic of China
Phone: (+86)-571-88320416
E-mail: liqunjin@zjut.edu.cn; xinquan@zjut.edu.cn
State Key Laboratory for Oxo Synthesis and Selective Oxidation
b
Lanzhou Institute of Chemical Physics
The Chinese Academy of Sciences
Lanzhou 730000, People’s Republic of China
+
These authors contributed equally.
Manuscript received: May 26, 2021; Revised manuscript received: July 30, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100641
In the past decades, transition metal-catalyzed
coupling reactions with nitriles as alternative electro-
philes to replace aryl halides and pseudohalides have
received considerable achievements. Among them,
Abstract: A nickel-catalyzed amination to access
diarylamines has been developed through CÀ CN
bond activation of aryl nitriles with anilines. In this
developed catalytic protocol, various aromatic and
heteroaromatic nitriles could be utilized as the
nickel-catalyzed CÀ C bond formations of aryl nitriles
with various organometallic reagents have been de-
electrophiles to couple with substituted anilines. A
clared, such as, Grignard reagents,[6] boronic esters[7]
diversity of diarylamines were obtained in 15–95%
yields.
and manganese reagents.[8] Chatani and Tobisu demon-
strated that aryl nitriles could be converted to aryl
silanes,[9] arenes[10] and aryl boronic esters[11] under Rh
catalysis via a silicon or boron-assisted cleavage of
Keywords: Amination; CÀ CN bond activation;
CÀ CN bond. Moreover, nickel-catalyzed CÀ P bond
Nickel; Diarylamines; Aryl nitriles
formations of aryl nitriles and alkyl nitriles were
disclosed by Yang[12] and Han,[13] respectively. Other
than the application of nitriles as the coupling partner
Functional group transformation is a central issue in in the cross-coupling reactions, hydrodecyanation of
organic synthetic chemistry.[1] Nitrile moieties, as a nitriles via CÀ CN bond activation, catalyzed by Fe,[14]
prevalent functional group in organic molecules, are Ni[15] and Rh,[16] were developed with suitable hydride
versatile intermediates in synthetic community that sources.
undergo a wide variety of transformations.[2] Tradition-
Although a manifold of methods for ArÀ N bond
ally, the transformation of a cyano group allows the formations have been demonstrated with aryl halides
installation of various functional groups, such as, or triflates as the coupling partners,[17] a simple and
amide, ester, aldehyde, ketone, amine, and thioamide, efficient transformation of ArÀ CN to ArÀ N is interest-
etc.[3] Recently, the development of transition metal- ing and valuable to be developed. Miller and co-
catalyzed inert CÀ C bond activation has significantly workers firstly reported a Ni-catalyzed amination of
diversified the transformations of CÀ CN bond,[4] aryl nitriles with secondary amines.[6b] However, the
including cross-coupling using nitriles as electrophiles, protocol was only suitable for accessing tertiary
cyanation of aryl halides and arenes using organic amines. In addition, the amine substrate must be
nitriles as cyanating agents, and carbocyanation of employed as its ‘preformed’ lithium amide, whose
unsaturated bonds.[5]
strong basicity led to the issue of low chemoselectivity
Adv. Synth. Catal. 2021, 363, 1–7
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
(e.g., metallation of acidic CÀ H bonds). Recently, we
reported a Ni-catalyzed reductive decyanation of aryl
nitriles.[15e] Based on the protocol and inspired by these
important studies of CÀ CN activation, we are inter-
ested in the exploration of the amination of aryl nitriles
through CÀ CN bond activation. Herein, we reported a
simple and efficient nickel-catalyzed CÀ N coupling of
aryl nitriles with various anilines for the synthesis of
diarylamines via CÀ CN cleavage (Scheme 1).
Table 1. Optimization of Ni-catalyzed coupling between 1-
naphthonitrile and aniline.[a]
We started to investigate the Ni-catalyzed decyana-
tion coupling between aryl nitrile and aryl amine, with
1-naphthonitrile and aniline as the model substrates.
Initially, screening of nickel precatalysts were carried
out with KHMDS as the base in toluene. To our
delight, moderate to good yields of the desired
amination product 3aa were obtained (Table 1, En-
tries 1–4). Then, several bidentate nitrogen ligands
were examined using NiBr2(dme) as the precursor,
which could not provide enhanced effects for the
transformation (Table 1, Entries 5–7). It is noteworthy
that nickel complexes with phosphine ligands could
improve the reactions to deliver the target amination
products 3aa in good to excellent yields, while
NiCl2(dppf) provided an obviously advantage and gave
3aa up to 90% yield (Table 1, Entries 8–10). Different
bases were evaluated as well (Table 1, Entries 11–16).
The results indicated that potassium as the counter
cation was much more effective than their sodium or
lithium analogs, and KHMDS was proven to be the
best choice in all tested bases. Further exploration (see
SI) suggested that 6 h of reaction was suitable, up to
95% isolated yield of 3aa obtained (Table 1, Entry 17).
Besides, the control experiments showed that both
nickel and base were indispensable in this decyanative
amination protocol (Table 1, Entries 18 and 19).
[a] Reaction conditions: 1a (0.5 mmol), 2a (1 mmol), [Ni]
(5 mol%), ligand (6 mol%), base (1 mmol), toluene (2 mL),
°
140 C for 8 h. GC yield with biphenyl as the internal
standard. potassium bis(trimethylsilyl)amide (KHMDS),
dimethoxyethane (dme), bipyridine (bpy), 1,10-phenanthro-
line (phen), bis(diphenylphosphino)ferrocene (dppf), 1,2-bis
(diphenylphosphino)ethane
(diphenylphosphino)propane (dppp).
[b] 6h, Isolated yield.
(dppe),
1,3-bis
With the optimal reaction conditions in hand, we
then examined the generality of this CÀ N coupling.
First, various substituted anilines were explored. As
shown in Table 2, alkyl substituted anilines could
smoothly react with 1-naphthonitrile to provide the
target products in moderate to excellent yields (Ta-
ble 2, Entries 1–6). 2-Methylaniline dramatically di-
minished the transformation for its steric hindrance
(Table 2, Entry 1). Of note is the tolerance of CÀ O
bond in this protocol, since CÀ O bond activation could
be enabled by nickel catalysis in many other reports
(Table 2, Entries 7–11).[18] Gratifyingly, 4-butoxyani-
line and 4-phenoxyaniline provided the amination
products in 87% and 83% yields, respectively (Table 2,
Entries 7 and 8). The results suggested that alkoxyl
and aryloxyl groups binding to anilines were intact in
Scheme 1. Transition metal-catalyzed CÀ X bond formations via
CÀ CN bond activation.
Adv. Synth. Catal. 2021, 363, 1–7
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
experimental section), while only 15% yield of the
target product was given (Table 2, Entry 14).
Table 2. Ni-catalyzed amination of 1-naphthonitrile with vari-
ous anilines.[a]
Having investigated the coupling partner of aryl
amines, we set out exploring the scope of aryl nitriles.
With slightly modified reaction conditions, the results
were listed in Table 3. The coupling of 2-cyanonaph-
thalene with aniline underwent smoothly to deliver the
target product in moderate yield (Table 3, Entry 1).
The fused ring substrate, such as 9-cyanophenanthrene,
was suitable to release the target product in good yield
(Table 3, Entry 2). Several substituted biphenyl nitriles
reacted with aniline under this protocol to provide the
amination products in moderate to good yields,
irrespective of whether the cyano group was located in
ortho-, meta-, or para- position on the phenyl ring
(Table 3, Entries 3–6). Moreover, aniline could
smoothly react with simple benzonitrile and alkyl
substituted benzonitriles to give the corresponding
Table 3. Ni-catalyzed amination of various aryl nitriles with
aniline.[a]
[a] Reaction conditions: 1a (1 mmol), 2 (2 mmol), NiCl2(dppf)
(5 mol%), KHMDS (2 mmol, 0.5 mol/L in toluene, 4.0 mL),
°
140 C, 6 h.
[b]
1
°
NiCl2(dppf) (20 mol%), 150 C, 10 h. H NMR yield was
obtained.
this decyanative amination protocol. Whereas, 4- and
3-anisidines were slightly less efficient (Table 2,
Entries 9 and 10). For the reaction applying 2-
anisidine, again, the steric hindrance effect of -OMe
led to the target product with only 25% isolated yield
(Table 2, Entry 11). 4-Dimethylamino group was also
compatible (Table 2, Entry 12). In addition, heteroar-
omatic amines, such as 2-, 3-, 4-amino pyridine and 5-
aminoquinoline, were tested as well, however, compli-
cated reactions were observed and no target products
were detected. Only N-methyl protected indolyl amine
delivered 25% yield of the desired product (Table 2,
Entry 13). Besides, aliphatic primary amines, such as
n-BuNH2 and CyNH2 were examined, while no or trace
target products were detected. Naphthalene and 1,1’-
binaphthyl were confirmed as the major outcomes by
GCÀ Ms analysis. We propose that decyanation and
reductive coupling of 1a occurred under the strong
basic conditions (see SI, Figure S1). Secondary ani-
lines, such as PhNHCH3 and Ph2NH were explored as
well. We found that PhNHCH3 was not a suitable
substrate in this protocol. Ph2NH can react with 1a
under a modified procedure (procedure B in the
[a] Reaction conditions: 1 (1 mmol), 2a (2 mmol), NiCl2(dppf)
(5 mol%), KHMDS (3 mmol, 0.5 mol/L in toluene, 6.0 mL),
°
150 C, 8 h.
[b]
°
2 mmol KHMDS, 140 C, 6 h.
[c] NiCl2(dppf) (30 mol%).
[d] NiCl2(dppf) (10 mol%).
[e] NiCl2(dppf) (15 mol%).
NiCl2(dppf) (20 mol%), 150 C, 10 h.
[f]
°
Adv. Synth. Catal. 2021, 363, 1–7
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
products in good yields (Table 3, Entries 7–11). Un-
fortunately, 2-methylbenzonitrile was problematic
under the current conditions, and intramolecular
addition of 1m was observed (see SI). This could be
ascribed to the activation of CÀ H bond of methyl
group by the neighboring CN group under strong basic
condition, (Table 3, Entry 12). Furthermore, nitrile
with ArÀ O bond was tolerated (Table 3, Entry 13). In
addition, the reactions employing heterocyclic nitriles
were explored as well, for example 3-(1H-indol-1-yl)
benzonitrile (1o), 2-cyano quinoline (1p), 6-cyano
quinoline (1q) and 2-cyano pyridine (1r) (Table 3,
Entries 14–17). With slightly modified procedure
(procedure B in the experimental section), the desired
products were obtained in moderate yields apart from
less efficient 1r. Aryl nitriles with electron-withdraw-
ing substituents were also tested in our protocol.
Halides, ester and carboxylic acid were not
tolerated.[19] To our delight, 4-cyano-N,N-diethylbenza-
mide (1s) was a suitable substrate and delivered the
target product in 41% yield under a modified condition
(Table 3, Entry 18).
To further demonstrate the efficiency of this
developed protocol, a scale-up reaction was conducted.
As shown in Scheme 2, 10 mmol of 1a successfully
reacted with 2f under the optimal conditions to deliver
2.25 g of 3af in 82% isolated yields (Scheme 2).
Scheme 3. Mechanistic experiments.
To get the insights into this Ni-catalyzed decyana-
tive amination, mechanistic studies were performed. crossover experiment applying 4 and 2f under the
With the reaction between 1a and 2a as the model, the standard conditions was carried out. Both 3aa and 3af
reaction progress was monitored by GC (see SI). The were produced in a ratio of almost 1:1 (Scheme 3,
results clearly exhibited that 1a was completely Eqn. 2, see SI, Figure S69). In addition, when 4 and 2f
°
consumed within two hours and 71% yield of the were mixed in the presence of KHMDS at 140 C,
desired product was obtained. Simultaneously, a amidine 5 and 2a were detected (Scheme 3, Eqn. 3).
comparable amount of amidine 4 was detected in GC. On the basis of these results, we believed that a
As prolonging the reaction time, the decline of amidine balance between amidine and nitrile existed under
4 and the increase of 3aa were observed. When 1a basic conditions, while the possibility of involving
and 2a were mixed at room temperature in the amidine in the catalytic cycle could not be ruled out
presence of KHMDS, 4 was quickly formed almost in (Scheme 4).
a quantitative yield. With these observations in hands,
In our previous work, complex A was assigned as
we thus reckoned that amidine 4 might be an the key species in nickel-catalyzed decyanation of aryl
intermediated to be involved in the catalytic cycle. To nitriles.[15e] To gain more information about the active
verify this assumption, with 4 as the substrate under nickel species, additional stoichiometric experiments
the standard amination conditions, 3aa was obtained were conducted. Mixing complex A with aniline in the
°
in 23% yield (Scheme 3, Eqn. 1). Surprisingly, 1a was presence of KHMDS at 140 C for 6 h provided the
also detected. Therefore, another possibility might amination product 3ca in 74% yield (Scheme 3,
exist, that is, amidine 4 could decompose to generate Eqn. 4). Besides, with complex A as the catalyst, the
nitrile 1a and amine 2a. To clarify the assumption, a amination of 1a with 2a under the optimal conditions
gave 3aa in 88% yield (Scheme 3, Eqn. 5). Thus,
complex A was believed to be the authentic intermedi-
ate in the catalytic cycle and acted as a key
intermediate of the following CÀ CN cleavage.
With all obtained information, a mechanism for this
Ni-catalyzed amination of nitrile is proposed and
shown in Scheme 4. The Ni(0) species I in situ
generated from nickel precatalyst, firstly coordinated
with the C=C double bond of aromatic ring adjacent to
Scheme 2. Scale-up reaction.
Adv. Synth. Catal. 2021, 363, 1–7
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
(silica gel, petroleum ether and ethyl acetate as the eluent) to
afford 208 mg of 3aa (95%).
Procedure B
Representative procedure for the preparation of heteroaromatic
amines 3ao and 3oa-3ra: To a Schlenk tube was added
KHMDS (2 mmol, 0.5 mol/L in toluene, 4 mL), aniline
(186 mg, 2 mmol) was added dropwise with stirring. The
mixture was stirred at room temperature for 10 min and
concentrated in vacuu. Then, heterocyclic nitrile (1 mmol),
NiCl2(dppf) (68 mg, 10 mol%), toluene (4 mL) were added. The
°
tube was put into a preheated oil bath at 150 C for 8 h. The
reaction mixture was cooled down, quenched with water
(50 mL), and extracted with ethyl acetate (30 mL×2). The
organic phase was combined and the solvent was removed in
vacuo. The residue was purified by column chromatography
(silica gel, petroleum ether and ethyl acetate as the eluent).
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21773210, 21972125 and 21776260) and
the Fundamental Research Funds for the Provincial University
of Zhejiang (RF-B2019005).
Scheme 4. Proposed mechanism of Ni-catalyzed amination of
aryl nitrile.
cyano group, to afford intermediate II. The intermedi-
ate II underwent oxidative addition to break CÀ CN
bond affording intermediate III. The aminolysis of III
in the presence of base produced intermediate IV,
which could finally undergo reductive elimination to
release the aminated product and regenerate Ni(0)
species to fulfil the catalytic cycle.
In summary, we have developed a nickel-catalyzed
CÀ N coupling with aryl nitriles as the electrophiles via
CÀ CN bond activation. This catalytic protocol requires
no any additive to activate the CÀ CN bond. Broad
functional groups in anilines, including alkyl, alkoxyl,
aryloxyl and dimethylamino, were compatible. Aryl
and heteroaryl nitriles could be aminated with aniline
in 15–95% yields. Further investigation of expanding
the substrate scope and potential applications of this
methodology is underway in our laboratories.
References
[1] R. C. Larock, Comprehensive organic transformations : a
guide to functional group preparations, 2nd ed., Wiley-
VCH, New York, 1999.
[2] Z. Rappoport, The chemistry of the cyano group,
Interscience Pub., London, New York, 1970.
[3] R. Wang, J. R. Falck, Catal. Rev. Sci. Eng. 2014, 56,
288–331.
[4] a) F. Chen, T. Wang, N. Jiao, Chem. Rev. 2014, 114,
8613–8661; b) L. Souillart, N. Cramer, Chem. Rev. 2015,
115, 9410–9464; c) Y. Nakao, Chem. Rev. 2021, 121,
327–344.
[5] Y. Nakao, in C–C Bond Activation (Ed.: G. Dong),
Springer Berlin Heidelberg, Berlin, Heidelberg, 2014, pp.
33–58.
[6] a) J. A. Miller, Tetrahedron Lett. 2001, 42, 6991–6993;
b) J. Miller, J. Dankwardt, J. Penney, Synthesis 2003, 11,
1643–1648; c) J. A. Miller, J. W. Dankwardt, Tetrahe-
dron Lett. 2003, 44, 1907–1910.
Experimental Section
Procedure A
[7] D.-G. Yu, M. Yu, B.-T. Guan, B.-J. Li, Y. Zheng, Z.-H.
Wu, Z.-J. Shi, Org. Lett. 2009, 11, 3374–3377.
[8] N. Liu, Z.-X. Wang, Adv. Synth. Catal. 2012, 354, 1641–
1645.
[9] a) M. Tobisu, Y. Kita, N. Chatani, J. Am. Chem. Soc.
2006, 128, 8152–8153; b) M. Tobisu, Y. Kita, Y. Ano, N.
Chatani, J. Am. Chem. Soc. 2008, 130, 15982–15989.
[10] Y. Kita, M. Tobisu, N. Chatani, Org. Lett. 2010, 12,
1864–1867.
Representative procedure for the preparation of diaryl amines
3ab-3an, 3ba-3na and 3sa: To a Schlenk tube was added 1-
naphthonitrile (153 mg, 1 mmol), NiCl2(dppf) (34 mg, 5 mol%),
KHMDS (2 mmol, 0.5 mol/L in toluene, 4 mL), and aniline
(186 μL, 2 mmol). Stirred the mixture at room temperature for
°
2 min, then the tube was put into a preheated oil bath at 140 C
for 6 h. The reaction mixture was cooled down, quenched with
water (50 mL), and extracted with ethyl acetate (30 mL×2).
The organic phase was combined and the solvent was removed
in vacuo. The residue was purified by column chromatography
[11] M. Tobisu, H. Kinuta, Y. Kita, E. Remond, N. Chatani, J.
Am. Chem. Soc. 2012, 134, 115–118.
Adv. Synth. Catal. 2021, 363, 1–7
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
asc.wiley-vch.de
[12] M. Sun, H.-Y. Zhang, Q. Han, K. Yang, S.-D. Yang,
Chem. Eur. J. 2011, 17, 9566–9570.
[13] J.-S. Zhang, T. Chen, Y. Zhou, S.-F. Yin, L.-B. Han, Org.
Lett. 2018, 20, 6746–6749.
[14] H. Nakazawa, M. Itazaki, K. Kamata, K. Ueda, Chem.
Asian J. 2007, 2, 882–888.
[15] a) S. Enthaler, M. Weidauer, E. Irran, J. D. Epping, R.
Kretschmer, C. I. Someya, J. Organomet. Chem. 2013,
Acc. Chem. Res. 2008, 41, 1450–1460; c) R. Dorel, C. P.
Grugel, A. M. Haydl, Angew. Chem. Int. Ed. 2019, 58,
17118–17129; Angew. Chem. 2019, 131, 17276–17287;
d) Q. Cai, W. Zhou, Chin. J. Chem. 2020, 38, 879–893;
e) A. D. Averin, A. S. Abel, O. K. Grigorova, G. V.
Latyshev, Y. N. Kotovshchikov, A. Y. Mitrofanov, A.
Bessmertnykh-Lemeune, I. P. Beletskaya, Pure Appl.
Chem. 2020, 92, 1181–1199.
745–746, 262–274; b) T. Patra, S. Agasti, Akanksha, D. [18] M. Tobisu, N. Chatani, Acc. Chem. Res. 2015, 48, 1717–
Maiti, Chem. Commun. 2013, 49, 69–71; c) T. Patra, S. 1726.
Agasti, A. Modak, D. Maiti, Chem. Commun. 2013, 49, [19] When 4-fluorobenzonitrile was applied, no target product
8362–8364; d) M. Weidauer, C. I. Someya, E. Irran, S.
Enthaler, Asian J. Org. Chem. 2013, 2, 150–156; e) K.
Wu, Y. Ling, N. Sun, B. Hu, Z. Shen, L. Jin, X. Hu,
Chem. Commun. 2021, 57, 2273–2276.
was detected. 4-(phenylamino)benzonitrile was isolated
in 30% yield. We proposed that CÀ F bond was activated
by the cyano group. When tert-Butyl 4-cyanobenzoate
was utilized, the amination of tert-butyl ester occurred to
release the corresponding amide and no decyanation
CÀ N coupling product was detected. The reaction of 4-
cyanobenzoic acid was complicated and no desired
product was detected.
[16] M. Tobisu, R. Nakamura, Y. Kita, N. Chatani, J. Am.
Chem. Soc. 2009, 131, 3174–3175.
[17] selected reviews: a) P. Ruiz-Castillo, S. L. Buchwald,
Chem. Rev. 2016, 116, 12564–12649; b) D. Ma, Q. Cai,
Adv. Synth. Catal. 2021, 363, 1–7
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

COMMUNICATIONS
Nickel-Catalyzed Amination of Aryl Nitriles for Accessing
Diarylamines through CÀ CN Bond Activation
Adv. Synth. Catal. 2021, 363, 1–7
K. Wu, Q. Rong, N. Sun, B. Hu, Z. Shen, L. Jin*, X. Hu*