Nickel-Catalyzed Amination of Aryl 2-Pyridyl Ethers via Cleavage of the Carbon-Oxygen Bond

Article abstract of DOI:10.1021/acs.orglett.7b01549

Reaction of aryl 2-pyridyl ethers with amines was carried out via Ni-catalyzed C-O_Py bond cleavage, giving aniline derivatives in reasonable to excellent yields. Both electron-rich and electron-poor aryl 2-pyridyl ethers and a wide range of amines can be used in the transformation. The method provides a conversion way for the 2-pyridyloxy directing group in the C-H bond functionalization reactions.

Full text of DOI:10.1021/acs.orglett.7b01549

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Amination of Aryl 2‑Pyridyl Ethers via Cleavage of
the Carbon−Oxygen Bond
Jing Li† and Zhong-Xia Wang*,†,‡
†CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at Microscale and Department of
Chemistry, University of Science and Technology of China, Hefei, Anhui 230026, People’s Republic of China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, People’s Republic of China
S
* Supporting Information
ABSTRACT: Reaction of aryl 2-pyridyl ethers with amines
was carried out via Ni-catalyzed C−OPy bond cleavage, giving
aniline derivatives in reasonable to excellent yields. Both
electron-rich and electron-poor aryl 2-pyridyl ethers and a wide
range of amines can be used in the transformation. The
method provides a conversion way for the 2-pyridyloxy directing group in the C−H bond functionalization reactions.
2-Pyridyloxy (OPy) group is an excellent ortho directing group
in transition-metal-catalyzed C−H bond functionalization
reactions because of the strong coordination ability of its sp2
nitrogen atom and its stability under various synthetic
conditions.1,2 On the other hand, developing methodology to
remove or convert the OPy group after directing C−H
functionalization is also an important topic. In an earlier
publication Wu et al. reported a method to convert the
directing group via a successive two-step reaction. Thus, aryl 2-
pyridyl ether was treated with MeOTf and subsequently
sodium methoxide to give corresponding phenol via cleavage of
the CPy−O bond.2 More recently Chatani et al. reported
catalytic protocols of directly converting an OPy group into
boryl group with rhodium3 or nickel4 as the catalyst, which
expanded the synthetic utility of the OPy directing group.
Methods to convert the C−OPy bond of the aryl 2-pyridyl
ethers to a C−C bond or other C−heteroatom bonds except
the C−B bond mentioned above are unavailable.
Aniline derivatives are ubiquitous in drug molecules and
natural products.5 Transition-metal-catalyzed amination reac-
tions were considered one of the most powerful approaches to
achieve these compounds.5,6 Although aminations of aryl
halides and reactive phenolic derivatives, such as aryl triflates,
tosylates, and carboxylates, are well-established,6−8 converting
phenolic derivatives with unactivated C−O bonds into aniline
derivatives are still challenging. Chatani et al. carried out Ni-
A combination of Ni(COD)2 and PCy3 was first examined.7
However, no cross-coupling product was detected (Table 1,
entry 1). We thought that perhaps K3PO4 was a too weak base
a
Table 1. Optimization of Reaction Conditions
b
entry
[Ni] (mol %)
ligand (mol%)
solvent
yield (%)
c
1
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
Ni(COD)2 (5)
NiCl2(dme) (5)
Ni(acac)2 (5)
PCy3 (10)
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
toluene
none
trace
trace
trace
14
2
PCy3 (10)
3
BINAP (5)
4
Dcype (5)
5
SIPr·HCl (10)
IMes·HCl (10)
IPr·HCl (10)
ICy·HCl (10)
IPr·HCl (5)
IPr·HCl (10)
IPr·HCl (10)
IPr·HCl (10)
IPr·HCl (10)
IPr·HCl (10)
IPr·HCl (10)
IPr·HCl (10)
IPr·HCl (20)
IPr·HCl (20)
6
55
7
87
8
trace
73
9
10
11
12
55
THF
trace
57
DMF
d
13
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
85
e
14
35
15
16
17
trace
29
catalyzed amination of (hetero)aryl methyl ethers via Csp2
−
f
Ni(COD)2 (10)
Ni(COD)2 (10)
99(90 )
OMe bond cleavage. However, the substrate scope was mainly
limited to π-extended aromatic systems, such as 2-naphthyl
methyl ethers and electron-deficient heteroaryl methyl ethers.9
With all the considerations above, we initiated a study on
transition-metal-catalyzed amination of aryl 2-pyridyl ethers via
C−OPy bond cleavage.
g
18
90
a
Unless otherwise stated, the reactions were run at 100 °C for 12 h;
0.2 mmol of 2-(4-(tert-butyl)phenoxy)pyridine, 1.5 equiv of morpho-
b
c
line, and 1.8 equiv of t-BuOLi were employed. NMR yield. K3PO4 as
d
e
f
g
base. t-BuONa as base. t-BuOK as base. Isolated yield. Reaction
was run at 80 °C.
We screened reaction conditions by choosing 2-(4-tert-
butylphenoxy)pyridine and morpholine as the model substrates
and nickel as the catalyst because nickel was reported to be the
most effective catalysts for the inactive C−O bond cleavage.7−9
Received: May 22, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b
to complete the reaction. Then a stronger base, t-BuOLi, was
used to replace K3PO4. A trace amount of product can be
observed (Table 1, entry 2). These enlightened us that t-BuOLi
might be suitable, while PCy3 might not. So we kept t-BuOLi as
the base and screened a series of ligands which were commonly
used in transition-metal-catalyzed C−O bond cleavage (Table
1, entries 3−8), including rac-BINAP (2,2′-bis-
(diphenylphosphino)-1,1′-binaphthyl), dcype (1,2-bis(dicyclo-
hexylphosphino)ethane), SIPr·HCl (1,3-bis(2,6-diisopropyl-
phenyl)-4,5-dihydroimidazolinium chloride), IMes·HCl (1,3-
bis(2,4,6-trimethylphenyl)-1H-imidazolium chloride), IPr·HCl
(1,3-bis(2,6-diisopropylphenyl)-1H-imidazolium chloride), and
ICy·HCl (1,3-bis(cyclohexyl)imidazolium chloride). The re-
sults showed that ligands exerted a tremendous influence on the
reaction, only N-heterocyclic carbene ligands gave practical
yields and IPr·HCl performed best. The use of 5 mol% of IPr·
HCl led to a slight decrease of the yield (Table 1, entry 9),
implying that the reactivity is not a result of a monoligated
carbene-nickel complex. Next we examined the effect of
solvents and bases. Toluene, THF, and DMF were respectively
tested and the results showed that each of them was less
effective than 1,4-dioxane. Both toluene and DMF gave
moderate performance and THF led to only a trace amount
of product (Table 1, entries 10−12). Two alternative bases, t-
BuONa and t-BuOK, were tested. t-BuONa performed almost
the same well as t-BuOLi (Table 1, entry 13). However, t-
BuOK performed far worse than t-BuOLi (Table 1, entry 14).
Two air-stable nickel sources, NiCl2(dme) and Ni(acac)2, were
used to replace Ni(COD)2 (Table 1, entries 15 and 16).
However, the Ni(II) species exhibited much lower catalytic
activity than the Ni(0) probably due to lacking effective
reducing agents. We also found that in the reaction with the
currently optimized conditions there still existed a little starting
material and some phenol as side product. So we increased the
catalyst loading to 10 mol% and found that all the ether were
consumed and gave an excellent result (Table 1, entry 17).
Expanding reaction scale 10 times to 2 mmol gave similar
isolated yield (85%). Finally, attempts to lower the reaction
temperature to 80 °C (Table 1, entry 18) or reduce the amount
of amine to 1.2 equiv led to inferior results.
Scheme 1. Scope of Aryl 2-Pyridyl Ethers
a
Unless otherwise stated, the reactions were performed with 0.2 mmol
of aryl 2-pyridyl ethers and 0.3 mmol of morpholine in 1,4-dioxane (2
mL) according to the conditions indicated by the above equation.
b
Isolated yield.
and decahydroisoquinoline afforded the cross-coupling prod-
ucts in excellent yields (3p, 3r). 2-Methylpiperidine gave a
lower yield (3q) probably due to steric hindrance in 2-
methylpiperidine. Pyrrolidine with low boiling point performed
excellently demanding an extra equivalent (3s). Reaction with
acyclic amines performed almost as well as cyclic amines (3t).
Even primary aliphatic amines went smoothly (3u). Further-
more, primary anilines performed even better than aliphatic
amines. Substituents with various electron delivery property
and steric hindrance all gave excellent results (3v−3y). Even
less reactive substrate containing methoxy group at ortho
position, 2-(2-methoxyphenoxy)pyridine, also gave excellent
yield of cross-coupling product (3z).
To further demonstrate the utility of this method for organic
synthesis, the sequential OPy-directed ortho C−H functionali-
zation and amination of the directing group were carried out
(Scheme 3). It is known that a pyridine-based directing group is
stable under oxidative conditions, which allows it to function
smoothly in various kinds of oxidative ortho C−H trans-
formations. For example, it was reported that 2-phenoxypyr-
idine underwent palladium-catalyzed oxidative ortho fluorina-
tion to form 1n,2 which can subsequently be converted to the
aniline product 3n through the removal of the OPy group
under our conditions. The OPy directing group can also
promote ortho arylation of 2-phenoxypyridine to form 1o,2 then
led to the aminated product 3o eventually.
With the optimized conditions in hand, we first examined the
scope of aryl 2-pyridyl ethers. Substrates 1b−1o were found to
be suitable reaction partners with morpholine to provide
corresponding anilines as shown in Scheme 1. The extended π-
conjugated aromatic substrates 2-(naphthalen-1-yloxy)pyridine
(1b) and 2-(biphenyl-4-yloxy)pyridine (1c), were successfully
coupled with morpholine to afford products 3b and 3c,
respectively, in excellent yields. Electron-rich aryl 2-pyridyl
ethers (1d-1f) presented slightly lower reactivity and gave good
to excellent yields (60−90%). Activated substrate 2-(4-
fluorophenoxy)pyridine resulted in an excellent yield leaving
fluoro substituent intact (3g).10 Meanwhile, a series of the
functional groups on the aromatic rings, such as F, CF3, COPh,
COOt-Bu, and CN (3g−3k), as well as other alkoxy groups,
such as OMe and OPh, were well tolerated. Furthermore, acetal
also remained intact with moderate yield probably due to
strong deactivated effect (3l). Heteroaromatic substrate like 6-
(pyridin-2-yloxy)quinoline performed smoothly with an ex-
cellent result (3m). Importantly, ortho-substituents were
acceptable, allowing for further amination to occur after
directed C−H functionalization (3n, 3o).2
To gain preliminary mechanistic information about this
transformation, several control experiments were carried out
under the standard conditions. We observed that in situ formed
IPr2Ni can catalyze cross-coupling of 2-(biphenyl-4-yloxy)
Next we examined the scope of amines using 2-(biphenyl-4-
yloxy)pyridine (Scheme 2). Reactions with 4-methylpiperidine
B
DOI: 10.1021/acs.orglett.7b01549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a,b,c,d,e
interaction between the boryl ligand and the 2-pyridyl moiety
via a six membered cyclic transition state, which can be ruled
out in our reaction. The other is direct oxidative addition
pathway, which may be facilitated by the coordination of the
pyridine ring to the metal center. Based on the above-
mentioned experimental facts and literature information, a
possible mechanism is outlined in Scheme 4.
Scheme 2. Scope of Amines
Scheme 4. Proposed Catalytic Cycle
a
Unless otherwise stated, the reactions were performed with 0.2 mmol
of 2-(biphenyl-4-yloxy)pyridine and 0.3 mmol of amines in 1,4-
dioxane (2 mL) according to the conditions indicated by the above
b
c
d
equation. Isolated yield. t-BuOLi as base. Two equiv of amines and
2.4 equiv of bases were employed. 2-(2-Methoxyphenoxy)pyridine
In conclusion, we have performed nickel-catalyzed amination
of aryl 2-pyridyl ethers through cleavage of the C−OPy bond.
The method displays a broad scope of substrates, including
electron-rich and electron-poor aryl 2-pyridyl ethers and
various amines. The reaction gives reasonable to excellent
yields and exhibits good compatibility of functional groups. We
believe that the methodology is a valuable complement to
Buchwald−Hartwig reaction involving phenol derivatives and
provides a subsequent conversion way for the 2-pyridyloxy
directing group in the C−H functionalization reactions.
e
was employed to replace 2-(biphenyl-4-yloxy)pyridine.
Scheme 3. Sequential Reaction
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01549.
Experimental details of the coupling reaction, character-
ization data, and the copies of NMR spectra of the cross-
coupling products (PDF)
pyridine (1c) with morpholine in the presence of t-BuOLi
(82%). And the in situ reaction products of 2-(biphenyl-4-
yloxy)pyridine (0.1 mmol), Ni(COD)2 (0.1 mmol), IPr·HCl
(0.2 mmol) and t-BuOLi (0.2 mmol) can couple with
morpholine (0.15 mmol) in the presence of t-BuOLi (0.15
mmol) to afford aminated product in 73% yield. It seems
apparent that an aryl nickel species was formed in this step and
then transformed into an arylamido nickel intermediate. The
arylamido nickel species underwent reductive elimination to
form arylamine and regenerate active Ni(0) catalyst. This
process is consistent with that of Ni(0)/SIPr complex-catalyzed
coupling of aryl chlorides with amines reported by Fort et al.11
As for the mechanism about the cleavage of the Ar−OPy bond,
Chatani et al. have proposed two possible pathway.3 One is that
Caryl−O bond activation is initiated by the Lewis acid/base
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: zxwang@ustc.edu.cn
ORCID
Zhong-Xia Wang: 0000-0001-8126-8778
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grant No. 21172208) and the National
Basic Research Program of China (Grant No. 2015CB856600).
C
DOI: 10.1021/acs.orglett.7b01549
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
REFERENCES
■
(1) (a) Kakiuchi, F.; Igi, K.; Matsumoto, M.; Hayamizu, T.; Chatani,
N.; Murai, S. Chem. Lett. 2002, 31, 396−397. (b) Ackermann, L.;
Diers, E.; Manvar, A. Org. Lett. 2012, 14, 1154−1157. (c) Niu, L.;
Yang, H.; Wang, R.; Fu, H. Org. Lett. 2012, 14, 2618−2621. (d) Yao,
J.; Feng, R.; Wu, Z.; Liu, Z.; Zhang, Y. Adv. Synth. Catal. 2013, 355,
1517−1522. (e) Liang, Y.-F.; Li, X.; Wang, X.; Yan, Y.; Feng, P.; Jiao,
N. ACS Catal. 2015, 5, 1956−1963. (f) Lou, S.-J.; Chen, Q.; Wang, Y.-
F.; Xu, D.-Q.; Du, X.-H.; He, J.-Q.; Mao, Y.-J.; Xu, Z.-Y. ACS Catal.
2015, 5, 2846−2849.
(2) Chu, J.-H.; Lin, P.-S.; Wu, M.-J. Organometallics 2010, 29, 4058−
4065.
(3) Kinuta, H.; Tobisu, M.; Chatani, N. J. Am. Chem. Soc. 2015, 137,
1593−1600.
(4) Tobisu, M.; Zhao, J.; Kinuta, H.; Furukawa, T.; Igarashi, T.;
Chatani, N. Adv. Synth. Catal. 2016, 358, 2417−2421.
(5) (a) Wolfe, J. P.; Wagaw, S.; Marcoux, J.-F.; Buchwald, S. L. Acc.
Chem. Res. 1998, 31, 805−818. (b) Hartwig, J. F. Angew. Chem., Int. Ed.
1998, 37, 2046−2067.
(6) (a) Fischer, C.; Koenig, B. Beilstein J. Org. Chem. 2011, 7, 59−74.
(b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400−
5449. (c) Kienle, M.; Dubbaka, S. R.; Brade, K.; Knochel, P. Eur. J.
Org. Chem. 2007, 2007, 4166−4176. (d) Hartwig, J. F. Acc. Chem. Res.
2008, 41, 1534−1544. (e) Surry, D. S.; Buchwald, S. L. Angew. Chem.,
Int. Ed. 2008, 47, 6338−6361.
(7) (a) Li, B.-J.; Yu, D.-G.; Sun, C.-L.; Shi, Z.-J. Chem. - Eur. J. 2011,
17, 1728−1759. (b) Tobisu, M.; Chatani, N. Acc. Chem. Res. 2015, 48,
1717−1726. (c) Rosen, B. M.; Quasdorf, K. W.; Wilson, D. A.; Zhang,
N.; Resmerita, A.-M.; Garg, N. K.; Percec, V. Chem. Rev. 2011, 111,
1346−1416. (d) Zeng, H.; Qiu, Z.; Domínguez-Huerta, A.; Hearne, Z.;
Chen, Z.; Li, C.-J. ACS Catal. 2017, 7, 510−519.
(8) (a) Hie, L.; Ramgren, S. D.; Mesganaw, T.; Garg, N. K. Org. Lett.
2012, 14, 4182−4185. (b) Huang, J.-H.; Yang, L.-M. Org. Lett. 2011,
13, 3750−3753. (c) Ramgren, S. D.; Silberstein, A. L.; Yang, Y.; Garg,
N. K. Angew. Chem., Int. Ed. 2011, 50, 2171−2173. (d) Shimasaki, T.;
Tobisu, M.; Chatani, N. Angew. Chem., Int. Ed. 2010, 49, 2929−2932.
(e) Mesganaw, T.; Silberstein, A. L.; Ramgren, S. D.; Nathel, N. F. F.;
Hong, X.; Liu, P.; Garg, N. K. Chem. Sci. 2011, 2, 1766−1771.
(f) Ackermann, L.; Sandmann, R.; Song, W. Org. Lett. 2011, 13, 1784−
1786.
(9) (a) Tobisu, M.; Shimasaki, T.; Chatani, N. Chem. Lett. 2009, 38,
710−711. (b) Tobisu, M.; Yasutome, A.; Yamakawa, K.; Shimasaki, T.;
Chatani, N. Tetrahedron 2012, 68, 5157−5161.
(10) Zhu, F.; Wang, Z.-X. Adv. Synth. Catal. 2013, 355, 3694−3702.
(11) Desmarets, C.; Schneider, R.; Fort, Y. J. Org. Chem. 2002, 67,
3029−3036.
D
DOI: 10.1021/acs.orglett.7b01549
Org. Lett. XXXX, XXX, XXX−XXX