Nickel-Catalyzed Direct Amination of Arenes with Alkylamines

Article abstract of DOI:10.1021/acs.orglett.5b00990

(Figure Presented) The efficient nickel-catalyzed direct amination of arenes with simple alkylamines has been achieved with the assistance of a bidentate directing group through sp² C-H bond functionalization. Preliminary mechanistic investigations indicate that the reaction probably proceeds through a Ni^I/Ni^III catalytic pathway.

Full text of DOI:10.1021/acs.orglett.5b00990

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Direct Amination of Arenes with Alkylamines
Qiangqiang Yan,† Zhengkai Chen,† Wenlong Yu,† Hong Yin,† Zhanxiang Liu,*,† and Yuhong Zhang*,†,‡
†ZJU-NHU United R&D Center, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, China
S
* Supporting Information
ABSTRACT: The efficient nickel-catalyzed direct amination of arenes with simple alkylamines has been achieved with the
assistance of a bidentate directing group through sp2 C−H bond functionalization. Preliminary mechanistic investigations
indicate that the reaction probably proceeds through a NiI/NiIII catalytic pathway.
rylamines are key building blocks that widely exist in
natural products, pharmaceuticals, agrochemicals, and
corresponding arylamines in high yields. The transformation
exhibited a broad substrate scope, and a variety of functional
groups could be well tolerated.
A
organic optoelectronic materials.1 Consequently, research
directed at discovering efficient and high-yielding methods for
the preparation of arylamines has received much attention.
Traditionally, the transition-metal-catalyzed cross-couplings,
such as Ullmann−Goldberg, Buchwald−Hartwig, and Chan−
Lam aminations, have been proven to be the practical methods
for the synthesis of diverse arylamines.2 However, the
prefunctionalization of the substrates is inevitable in these
transformations, which also gives rise to the formation of
undesirable toxic waste.
We commenced our investigation with the substrate 8-
aminoquinoline benzamide (1a) and morpholine (2a) in
toluene using Ni salt as a catalyst. To our delight, the desired
C−N bond coupling product was formed in 29% yield by using
Ni(acac)2 as the catalyst and Ag2CO3 as the oxidant (Table 1,
entry 1). The screening of various commercially available nickel
salts, such as Ni(OTf)2, Ni(OAc)2, (Ph3P)2NiCl2, NiCl2, and
NiBr2, revealed that Ni(OAc)2 was the optimal catalyst and
showed the highest reactivity, giving the product 3a in 70%
yield (entries 2−6). Other silver salts were also tested in the
reaction, and the effects were inferior to that of Ag2CO3
(entries 7−10). A control experiment showed that Ni(OAc)2
and Ag2CO3 were essential for the amination reaction (see
Supporting Information). Some highly valent oxidants, such as
PhI(OAc)2 and K2S2O8, could not give the desired product
(entries 11−12). It was observed that the basic additives had a
positive influence on the reaction and exhibited higher
reactivity than acidic additives. Among different additives
Na2CO3 turned out to be the most efficient in the formation
of product 3a (entries 13−16). The addition of Et3N totally
inhibited the reaction (entry 17). However, only a trace of the
isolated product was obtained in the absence of base (entry 18).
It was worth mentioning that the efficiency of the reaction was
significantly improved when the reaction was carried out under
an air atmosphere (entry 19). Replacing air atmosphere with
O2, the reaction conversion was slightly increased (entry 20). A
temperature screening suggested that the transformation at 140
°C delivered the amination product in the highest isolated yield
(entry 21). Other solvents, such as DCE, NMP, 1.4-dioxane,
DMSO, and DMF, resulted in lower yields (see Supporting
Information).
Recently, transition-metal-catalyzed C−H amination has
emerged as an alternative method for the synthesis of arylamine
derivatives.3 In particular, the direct cross-dehydrogenative
coupling between arenes and simple amines represents an ideal
and environmentally attractive strategy.3,4 The pioneering work
by Yu and Che groups discovered that the amidation of the
ortho C−H bond of 2-phenylpyridine could be achieved by the
copper5a,b or palladium5c catalysis. The Pd-catalyzed direct
amination of arenes with alkylamines was developed by Yu and
co-workers with the assistance of an amide directing group. In
this transformation, benzoyl hydroxylamine was formed in situ
as an aminating agent in the presence of benzoyl peroxide.6 The
copper-catalyzed amination of arenes with alkylamines was
reported by Daugulis where an aminoquinoline directing group
showed special effect on the amination.7 Recently, the group of
Chen and Carretero independently reported the Cu-catalyzed
amination of anilines with alkylamines by the assistance of
different directing groups.8
Nickel is a low-cost and readily available transition metal that
is widely utilized as a catalyst in a huge number of organic
transformations.9 Very recently, the application of a nickel
catalyst in the C−H activation was demonstrated by Chatani
and others.10 In light of these excellent achievements, we are
intrigued by the example of nickel-catalyzed amination of
arenes with alkylamines. We found that the direct amination of
arenes with alkylamines could be successfully performed with
the assistance of an 8-aminoquinolyl auxiliary11 to give the
Received: April 6, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a b
,
Table 1. Optimization of the Reaction Conditions
Scheme 1. Substrate Scope of Carboxamides
b
entry
catalyst
oxidant
additive
yield (%)
29
1
Ni(acac)2
Ni(OTf)2
Ni(OAc)2
(Ph3P)2NiCl2
NiCl2
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
PivOH
K2CO3
K2HPO4
NaOAc
Et3N
2
26
70
15
10
8
3
4
5
6
NiBr2
7
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
Ni(OAc)2
38
46
0
8
AgOAc
AgNO3
AgOTf
9
10
11
12
13
14
15
16
17
18
19
20
trace
0
PhI(OAc)2
K2S2O8
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
0
0
62
63
66
trace
trace
−
c
Na2CO3
Na2CO3
Na2CO3
80
d
82
c
e
f
g
21
62, 66, 78
a
Reaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Ni catalyst (0.02
mmol), oxidant (2 equiv), base (2 equiv), toluene (0.2 M), 140 °C,
b
c
d
e
N2, 10 h. Isolated yield. Under air. Under O2 atmosphere. 120 °C.
f
g
a
b
130 °C. 150 °C.
Yield of isolated product. Reaction conditions: benzamides 1 (0.2
mmol), 2a (0.4 mmol), Ni(OAc)2 (0.02 mmol), Ag2CO3 (0.4 mmol),
Na2CO3 (0.4 mmol), Toluene (2.0 mL), 140 °C, air, 10 h.
With the optimized conditions in hand, the scope of
carboxamide substrates was examined by the employment of
a variety of 8-aminoquinoline benzamides (Scheme 1). To our
delight, the substrates with electron-withdrawing (3b−3k) or
electron-donating substituents (3l−3q) on the aryl ring were
successfully compatible with the reaction, showing the excellent
functional group compatibility. The desired aminated products
were afforded in moderate to good yields. Notably, the good
regioselectivity was observed and the monoaminated product
was solely obtained in the reaction, without the formation of a
diaminated product. The reactivity of para- and meta-
substituted carboxamides (3b−3c) was similar to the ortho-
substituted ones (3d, k), indicating steric hindrance played
little influence on this transformation. It should be noted that
the reaction proceeded exclusively at the less hindered ortho
position for the meta-substituted carboxamides. The reaction
showed good tolerance toward halogenated substituents,
including F, Cl, and Br, to give the corresponding aminated
products in acceptable yields (3l−p, 51−74%). This satisfactory
result provided possible access to further derivatization of the
obtained products. The substrate bearing the strong electron-
withdrawing trifluoromethyl group could also be involved in
the reaction to afford 3q in 65% isolated yield. Gratifyingly, 2-
naphthalenecarboxamide was applicable under the standard
conditions as well and produced the desired product (3r) in
reasonable yield. More importantly, a heteroaromatic substrate
such as thiophene-carboxamide could also participate smoothly
in the reaction to furnish the corresponding product 3s in
moderate yield.
As shown in Scheme 2, we subsequently investigated the
scope of different secondary amines. We were delighted to find
that various functional groups were well tolerated under the
standard reaction conditions. A wide range of 6-membered
cyclic secondary amines, such as 4-methylpiperidine, ethyl
isonipecotate, the ethylene ketal of 4-ketopiperidine, Boc-
protected 4-aminopiperidine, Boc-protected piperazine, and
2,6-dimethylmorpholine, could all afford the corresponding
aminated products in good yields (4a−4e, 4j−4l). In addition,
some simple secondary amines, such as methylbenzylamine,
dibutylamine, and N-methylpropan-1-amine, were smoothly
introduced to deliver the desired products (4f−4i). Unfortu-
nately, primary amines, such as aniline and propan-1-amine,
were inactive under the reaction conditions. In addition, the N-
methylaniline also failed to participate in this amination
reaction.
The 8-aminoquinolyl directing group could be readily
removed under simple conditions. As shown in Scheme 3,
the product 3a was treated with NaOH in ethanol for 72 h to
afford the corresponding 2-morpholinobenzoic acid in high
yield.
To gain further insights into the reaction mechanism, an
intermolecular deuterium-labeling experiment was carried out
(Scheme 4). The kinetic isotope effect (KIE) values of 4.3 and
4.9 were observed from the competitive and parallel reactions
of 1a and 1a-d5 respectively. The above results indicated that
B
DOI: 10.1021/acs.orglett.5b00990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Substrate Scope of Secondary Amines
Scheme 5. Radical Trapping Experiments
Scheme 6. Proposed Reaction Mechanism
a
b
Yield of isolated product. Reaction conditions: benzamides 1 (0.2
mmol), 2a (0.4 mmol), Ni(OAc)2 (0.02 mmol), Ag2CO3 (0.4 mmol),
Na2CO3 (0.4 mmol), Toluene (2.0 mL), 140 °C, air, 10 h.
Scheme 3. Removal of the Directing Group
Scheme 4. Deuterium Labeling Experiments
species followed by a ligand exchange process to genetate nickel
complex A. Cyclonickelation of this intermediate via C−H
activation gives the NiII complex B, which is oxidized to the
NiIII species C. A single electron transfer process may be
involved in this step.5a,13 The analysis of MAIDL-TOF-MS
provided the evidence for the possible formation of the
intermediate C, which partially supported the proposed
mechanism (see Supporting Information). The subsequent
reductive elimination of the intermediate C followed by
protonation delivers the final aminated product 3a and liberates
the NiI species. The oxidation of NiI species by Ag2CO3 and O2
fulfils the catalytic cycle.
In summary, we have developed a new approach for the
direct amination of unactivated arenes with simple alkylamines.
For the first time, nickel was employed as an efficient catalyst
for the amination of arenes with the assistance of a bidentate
directing group. The transformation exhibited high efficiency
and a broad substrate scope, and a variety of functional groups
could be well tolerated. Further investigations to elucidate the
reaction mechanism and extend the practical application of this
methodology are in progress.
the C−H cleavage of benzamide might be involved in the rate-
determining step.
Furthermore, a radical trapping experiment was also
conducted. It should be noted that the addition of a radical
scavenger of TEMPO (2,2,6,6-Tetramethylpiperidine 1-oxyl)
resulted in the dramatic decrease of the reaction yield. Not
surprisingly, the reaction was totally inhibited with the addition
of 2 equiv of BHT (2,4-di-tert-butyl-4-methylphenol) (Scheme
5), and a radical coupling product between morpholine and
BHT was isolated (see Supporting Information). These results
implicated that a single electron transfer (SET) process might
be involved in the reaction.
Based on the preliminary mechanistic investigations and
some relevant publications,12 it is speculated that the reaction
might proceed through a NiI/NiIII catalytic cycle and a plausible
mechanism is proposed as shown in Scheme 6. The reaction
process is initiated by coordination of amide 1a to the NiII
ASSOCIATED CONTENT
* Supporting Information
■
S
1
Experimental details, spectral and analytical data, copies of H
NMR and 13C NMR spectra for new compounds. The
Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b00990.
C
DOI: 10.1021/acs.orglett.5b00990
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Ke.; Wang, Y.; Chen, X.; Kadi, A. A.; Fun, H.-K.; Sun, H.; Zhang, Y.;
Lu, H. Chem. Commun. 2015, 51, 3582. (i) Yan, S.-Y.; Liu, Y.-J.; Liu,
B.; Liu, Y.-H.; Shi, B.-F. Chem. Commun. 2015, 51, 4069. (j) Liu, Y.-J.;
Liu, Y.-H.; Yan, S.-Y.; Shi, B.-F. Chem. Commun. 2015, 51, 6388.
(11) For a pioneering report of the catalyzed directed C−H
functionalization by using bidentate directing groups, see: Zaitsev, V.
G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 13154.
(12) (a) Wu, X.; Zhao, Y.; Ge, H. J. Am. Chem. Soc. 2014, 136, 1789.
(b) Wu, X.; Zhao, Y.; Ge, H. Chem.Eur. J. 2014, 20, 9530. (c) Tang,
H.; Zhou, B.; Huang, X.-R.; Wang, C.; Yao, J.; Chen, H. ACS Catal.
2014, 4, 649. (c) Mayuko, N.; Hirano, K.; Satoh, T.; Miura, M. Angew.
Chem., Int. Ed. 2013, 52, 4457.
(13) (a) Zard, S. Z. Chem. Soc. Rev. 2008, 37, 1603. (b) Bhadra, S.;
Matheis, C.; Katayev, D.; Gooßen, L. J. Angew. Chem., Int. Ed. 2013,
52, 9279. (c) Liwosz, T. W.; Chemler, S. R. Chem.Eur. J. 2013, 19,
12771. (d) Zhou, L.; Tang, S.; Qi, X.; Lin, C.; Liu, K.; Liu, C.; Lan, Y.;
Lei, A. Org. Lett. 2014, 16, 3404. (e) Youn, S. W.; Ko, T. Y.; Jang, M.
J.; Jang, S. S. Adv. Synth. Catal. 2015, 357, 227.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: liuzhanx@zju.edu.cn.
*E-mail: yhzhang@zju.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding from NSFC (No. 21272205, 21472165) and NBRPC
(No. 2011CB936003), the Program for Zhejiang Leading Team
of S&T Innovation (2011R50007) is acknowledged.
REFERENCES
■
(1) (a) Boaen, N. K.; Hillmyer, M. A. Chem. Soc. Rev. 2005, 34, 267.
(b) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284. (c) Rappoport,
Z., Ed. The Chemistry of Anilines; Wiley-VCH: Weinheim, 2007.
(d) Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences;
Wiley-VCH: Weinheim, 2008.
(2) (a) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108,
3054. (b) Beletskaya, I. P.; Cheprakov, A. V. Organometallics. 2012,
31, 7753. (c) Eycken, E. V. der.; Bariwal, J. Chem. Soc. Rev. 2013, 42,
9283.
(3) For selected reviews on C−H amination, see: (a) Collet, F.;
Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061. (b) Lyons, T.
W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (c) Cho, S. H.; Kim, J.
Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068. (d) Collet, F.;
Lescot, C.; Dauban, P. Chem. Soc. Rev. 2011, 40, 1926. (e) Roizen, J.
L.; Harvey, M. E.; Du Bois, J. Acc. Chem. Res. 2012, 45, 911.
(f) Louillat, M.-L.; Patureau, F. W. Chem. Soc. Rev. 2014, 43, 901.
(4) For selected examples on C−H amination, see: (a) Monguchi,
D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607.
(b) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem. Soc.
2010, 132, 6900. (c) Wang, Q.; Schreiber, S. L. Org. Lett. 2009, 11,
5178. (d) Miyasaka, M.; Hirano, K.; Satoh, T.; Kowalczyk, R.; Bolm,
C.; Miura, M. Org. Lett. 2011, 13, 359. (e) Matsuda, N.; Hirano, K.;
Satoh, T.; Miura, M. Org. Lett. 2011, 13, 2860. (f) He, G.; Lu, C.;
Zhao, Y.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14, 2944. (g) Wu, X.;
Zhao, Y.; Zhang, G.; Ge, H. Angew. Chem., Int. Ed. 2014, 53, 3706.
(h) Wang, Z.; Ni, J.; Kuninobu, Y.; Kanai, M. Angew. Chem., Int. Ed.
2014, 53, 3496. (i) Shang, M.; Sun, S.-Z.; Dai, H.-X.; Yu, J.-Q. J. Am.
Chem. Soc. 2014, 136, 3354. (j) Takamatsu, K.; Hirano, K.; Satoh, T.;
Miura, M. Org. Lett. 2014, 16, 2892. (k) Matsubara, T.; Asako, S.; Ilies,
L.; Nakamura, E. J. Am. Chem. Soc. 2014, 136, 646.
(5) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem.
Soc. 2006, 128, 6790. (b) Uemura, T.; Imoto, S.; Chatani, N. Chem.
Lett. 2006, 35, 842. (c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem.
Soc. 2006, 128, 9048.
(6) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 7652.
(7) Tran, L. D.; Roane, J.; Daugulis, O. Angew. Chem., Int. Ed. 2013,
52, 6043.
(8) (a) Martínez, A. M.; Rodríguez, N.; Arrayas, R. G.; Carretero, J.
C. Chem. Commun. 2014, 50, 2801. (b) Li, Q.; Zhang, S.-Y.; He, G.; Ai,
Z.; Nack, W.; Chen, G. Org. Lett. 2014, 16, 1764.
(9) (a) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013, 19.
(b) Tasker, S. Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509,
299. (c) Rouquet, G.; Chatani, N. Angew. Chem., Int. Ed. 2013, 52,
11726. (d) Castro, L. C. M.; Chatani, N. Chem. Lett. 2015, 44, 410.
(10) (a) Shiota, H.; Ano, Y.; Aihara, Y.; Fukumoto, Y.; Chatani, N. J.
Am. Chem. Soc. 2011, 133, 14952. (b) Aihara, Y.; Chatani, N. J. Am.
Chem. Soc. 2013, 135, 5308. (c) Song, W.; Lackner, S.; Ackermann, L.
Angew. Chem., Int. Ed. 2014, 53, 2477. (d) Cong, X.; Li, Y.; Wei, Y.;
Zeng, X. Org. Lett. 2014, 16, 3926. (e) Iyanaga, M.; Aihara, Y.;
Chatani, N. J. Org. Chem. 2014, 79, 11933. (f) Lin, C.; Yu, W.; Yao, J.;
Wang, B.; Liu, Z.; Zhang, Y. Org. Lett. 2015, 17, 1340. (g) Lin, C.; Li,
D.; Wang, B.; Yao, J.; Zhang, Y. Org. Lett. 2015, 17, 1382. (h) Yang,
D
DOI: 10.1021/acs.orglett.5b00990
Org. Lett. XXXX, XXX, XXX−XXX