Nickel-catalyzed C-O bond reduction of aryl and benzyl 2-pyridyl ethers

Article abstract of DOI:10.1039/c7cc09668b

The reduction of aryl and benzyl 2-pyridyl ethers with sodium isopropoxide was carried out via nickel-catalyzed C-OPy bond cleavage, giving reductive products in reasonable to excellent yields. This method allowed the 2-pyridyloxy group to be directly rem

Full text of DOI:10.1039/c7cc09668b

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Nickel-catalyzed C-O bond reduction of aryl and benzyl 2-pyridyl
ethers
Jing Lia and Zhong-Xia Wang*,a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The reduction of aryl and benzyl 2-pyridyl ethers with sodium successful examples have also been reported with reductants
isopropoxide was carried out via nickel-catalyzed C-OPy bond such as hydrogen, hydrosilanes, hydrides and isopropanol.7
cleavage, giving reductive products in reasonable to excellent Alkoxides have been proved to be efficient reductants for the
yields. This method allowed the 2-pyridyloxy group to be directly dehalogenation of aryl halides and deamination of aromatic
removed with high efficiency, mild reaction conditions, and good and benzylic quaternary ammonium triflates.8 On the basis of
compatibility of functional groups.
the excellent performance of nickel catalysts in the activation
of C-O bonds and alkoxide in the reduction of C-halide and C-N
bonds, we proposed that a nickel catalyst combined with an
alkoxide could effect the catalytic reduction of aryl 2-pyridyl
ethers.
The use of a directing group is an effective way to realize
transition-metal-catalyzed regioselective C−H funcꢀonaliza-
tion.1 2-Pyridyloxy group (OPy) was one of the widely used
directing groups in an aromatic system.2 An important feature
of this class of aromatic system is that the OPy or Py group can
be removed after directing C−H funcꢀonalizaꢀon. In an earlier
example, the Py group was removed from a aryl 2-pyridyl
ether through a two-step reaction involving N-methylation
with MeOTf and then the cleavage of the resulting
C(pyridinium)-O bond with MeONa.2b Recently, Chatani et al.
carried out rhodium- or nickel-catalyzed borylation of aryl 2-
pyridyl ethers through cleavage of the CAr−OPy bond.3 More
recently, we performed nickel-catalyzed conversion of the OPy
group of aryl 2-pyridyl ethers into an amino group.4 Although
these progresses have been achieved, the methods to remove
or transform OPy group are still very limited. It is significant to
develop new methodology of the OPy transformation to
increase the synthetic utility of the directing group.
We screened catalysts and reaction conditions using 2-
(biphenyl-4-yloxy)pyridine (1a) as the model substrate (Table
1). Initially, we tried a combination of Ni(acac)2 and PCy3 or N-
heterocyclic carbene (NHC) including IMes and IPr as the
catalyst. However, the reaction of 1a with i-PrONa in dioxane
at 60 °C did not give any desired product (Table 1, entries 1-3).
We thought that maybe the nickel(II) precursors cannot be
reduced to form active catalyst under the present reaction
conditions. So we directly used Ni(0) resource, Ni(COD)2, to
test the reaction. To our delight, it performed smoothly when
combining with IMes or IPr, resulting in the desired products in
86% and 94% yields, respectively (Table 1, entries 4 and 5).
Further tests showed that both IMesMe and SIPr also gave
positive results, while ICy not (Table 1, entries 6-8). The
combination of Ni(COD)2 and phosphine ligands including
BINAP, Dcype and PCy3 was also tested. The combination of
Ni(COD)2 and biphosphines was nonactive, and Ni(COD)2/PCy3
led to 48% product yield (Table 1, entries 9-11). It appeared
that NHC ligands gave the most satisfied yields and IPr
performed best. However, double the amount of the ligand
making a 1:2 ratio of Ni(0) and IPr led to a significant decrease
of the yield (Table 1, entry 12), indicating that excess ligand
retarded the reaction and the active catalytic species seemed
to be a monoligated carbene-nickel complex. Next, the solvent
effect was examined. It showed that solvents had a significant
influence on the reaction and THF was most suitable (Table 1,
entry 13). Other solvents such as toluene, DMF and DME only
showed low to moderate performance (Table 1, entries 14-16).
Other alkoxides involving i-PrOLi, i-PrOK and EtONa were next
The reductive deoxygenation of phenols and their
derivatives is an important transformation in organic
synthesis.5 Usually, phenols could be converted into the
corresponding tosylates, mesylates, or triflates and then the
sulfonates were reduced in the presence of transition metal
catalysts.5a,6 For robust methoxy or acyloxy groups, a few of
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Table 1 Optimization of reaction conditionsa
Table 2 Scope of aryl 2-pyridyl ethers a,b
Entry
1
[Ni]
Ligand (mol %)
PCy3 (6)
solvent
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
1,4-dioxane
1,4-dioxane
1,4-dioxane
THF
yield (%)b
none
none
none
86
Ni(acac)2
Ni(acac)2
Ni(acac)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
Ni(COD)2
2
IMes·HCl (3)
IPr·HCl (3)
IMes·HCl (3)
IPr·HCl (3)
IMesMe·HCl (3)
SIPr·HCl (3)
ICy·HCl (3)
BINAP (3)
3
4
5
94
6
78
7
91
8
trace
trace
trace
48
9
10
11
12
13
14
15
16
17c
18d
19e
20f
21h
22i
Dcype (3)
PCy3 (6)
IPr·HCl (6)
IPr·HCl (3)
IPr·HCl (3)
IPr·HCl (3)
IPr·HCl (3)
IPr·HCl (3)
IPr·HCl (3)
IPr·HCl (3)
IPr·HCl (3)
IPr·HCl (1.5)
IPr·HCl (3)
17
99
Toluene
DME
24
16
DMF
71
THF
14
THF
none
trace
99 (86g)
39
THF
THF
THF
THF
80
a Unless otherwise stated, the reactions were performed with 0.2 mmol of 2-
(biphenyl-4-yloxy)pyridine and 0.6 mmol of i-PrONa in 1 cm3 solvent according
to the conditions indicated by the above equation. b Isolated yield. c i-PrOLi was
a Unless otherwise stated, the reactions were performed with 0.2 mmol of aryl 2-
pyridyl ethers and 0.3 mmol of i-PrONa in THF (1 cm3) according to the conditions
indicated by the above equation. b Isolated yield. c GC yield with dodecane as an
d
e
d
internal standard. The reaction was run for 3 h. e 5 mol% of Ni(COD)2 and 3
employed to replace i-PrONa. i-PrOK was employed to replace i-PrONa.
EtONa was employed to replace i-PrONa. f 1.5 equiv. of i-PrONa was employed. g
equiv. of i-PrONa were employed. f 10 mol% of Ni(COD)2 and 3 equiv. of i-PrONa
were employed. g The reaction was run at 100 °C using 3 equiv. of i-PrONa in 1,4-
dioxane. h The reaction was run for 12 h. i NMR yield.
h
The reaction was performed on a 4 mmol scale. 1.5 mol% of Ni(COD)2 was
employed. i The reaction was run at 50 °C.
examined. They led to either very low product yields or no any
desired product (Table1, entries 17-19). We also noticed that
1.5 equiv. of sodium isopropoxide was enough to accomplish
the reaction (Table 1, entry 20). With this sodium isopropoxide
loading, the reaction can be performed by employing 4 mmol
1a and resulted in only a slightly decreased yield (86%). Finally,
we attempted to run the reaction with lower catalyst loading
(1.5 mol%) or lower reaction temperature. However, the
product yield decreased in each case (Table 1, entries 21 and
22).
good yield. The aryl 2-pyridyl ethers with strong electron-
donating groups such as PhO, BnO, and Me2N on the aryl rings
(1c-1e) all presented excellent reactivity (90-98% product
yields). The benzyloxy group in compound 1d that could easily
be reduced by catalytic hydrogenolysis stayed intact. 2-(4-
Fluorophenoxy)pyridine (1f) resulted in an excellent yield of
desired product leaving fluoro substituent untouched. Other
functional groups on the aromatic rings involving alkenyl,
amide, carbonyl, carbamyl and cyano groups were also well
tolerated (1h-1m). Most of them were vulnerable under a
With the optimized conditions in hand, we first examined
reductive environment. Heteroaromatic substrate like 2-
(pyridin-2-yloxy)quinoline (1n) performed smoothly with an
excellent result (82% yield). Importantly, ortho-substituents
the scope of aryl 2-pyridyl ethers. Substrates 1b−1q were
found to be suitable reaction partners to get reduced products
as shown in Table 2. Unactivated substrates 2-(4-(tert-butyl)
phenoxy)pyridine (1b) was successfully reduced to afford 2b in
were acceptable (1o-1u), allowing for the 2-pyridyloxy groups
being removed after they directed C-H functionalization. The
2 | J. Name., 2012, 00, 1-3
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ortho-substituents included electro-donating and withdrawing The formed compound 1q was subsequently converted to the
ones. Some reactive groups such as F, alkenyl, and carbamyl biaryl product 2q through removal of the OPy group under our
were tolerated. o-Formyl group was not tolerated under conditions (Scheme 1).
current reaction conditions. However, reaction of 2-(2-(1,3-
dioxolan-2-yl)phenoxy)pyridine proceeded smoothly, giving
the reductive product 2t in 76% yield. Reaction of N,N-diethyl-
2-(pyridin-2-yloxy)benzamide (1u) at 100 °C cannot form the
desired product. Hence the reaction was run at 60 °C. In this
case 10 mol% catalyst loading was necessary. Otherwise the
starting material cannot be completely consumed.
Reductive deoxygenation of benzyl ethers is often used as a
model reaction in the study of biomass transformation and has
Scheme 1 The sequential reaction.
attracted considerable attention.9 Ni(COD)2-IPr
HCl/i-PrONa
•
To gain preliminary mechanistic information about this
transformation, we carried out the reduction of 2-(biphenyl-4-
yloxy)pyridine (1a) with a deuterated sodium isopropoxide.
The deuterated biphenyl product 2a-D was obtained in
excellent yield with 93% deuterated (Scheme 2), which was a
solid proof that the hydrogen donor actually came from
sodium isopropoxide. The kinetic isotope effect (KIE)
experiments were also performed separately using i-PrONa
and i-PrONa-D7 as the reducing agents under identical
conditions. We obtained a KIE value of 1.40, suggesting that
the β-hydride elimination may not be the rate-determining
step,10 which is similar to Ni-catalyzed reduction of aryl
ammonium triflates.8e As for the mechanism about the
cleavage of the Ar−OPy bond, we believed that the chelaꢀon
assistance of pyridine may help catalyst to exclusively break
the C-OPy bond. That both 3-(biphenyl-4-yloxy)pyridine and 4-
(biphenyl-4-yloxy)pyridine cannot be reduced under the same
conditions supports this conjecture. Based on the above-
mentioned experimental facts and literature information,8b,c,e
a possible catalytic cycle is outlined in Scheme 3.
system proved applicable in the reduction of benzyl 2-pyridyl
ethers (Table 3). Benzyl ethers showed lower reactivity than
aryl ethers in current reaction system.7c Hence more intense
reaction conditions were required. Under the modified
conditions the substrates containing electron-donating and
electron-withdrawing substituents on the aromatic rings (3a
-
3c) presented reasonable reactivity and led to the desired
reductive products in 57%-83% yields. The ethers with
extended aromatic systems including 2-(naphthalen-2-
ylmethoxy)pyridine (3d) and 6-((pyridin-2-yloxy)methyl)quino-
line (3e) also gave excellent reaction results. Finally, the
branched benzyl ether, 2-(benzhydryloxy)pyridine (3f), was
also suitable, although only with unsatisfied yield.
Table 3 Scope of benzyl 2-pyridyl ethersa,b
R'
R'
Ni(COD)2 (3 mol%)
OPy
IPr•HCl (3 mol%)
H
R
R
+
i-PrONa
1,4-dioxane
100 °C, 3 h
3a-f
4a-f
Scheme 2 Deuterated experiment
.
Ni(COD)2
IPr
(= L)
O
a Unless otherwise stated, the reactions were performed with 0.2 mmol of benzyl
Ar
2-pyridyl ethers and 0.6 mmol of i-PrONa in 1,4-dioxane (1 cm3) according to the
Ar
H
H
N
b
c
conditions indicated by the above equation. Isolated yield. GC yield with
dodecane as an internal standard. d 10 mol% of Ni(COD)2 was employed and run
for 12 h.
Ni(0)L
A
It was well known that 2-pyridyloxy (OPy) group possessing
strong coordination ability of its sp2 nitrogen is one of the
most effective directing groups which could facilitate various
aromatic functionalization reactions with good efficiency and
regioselectivity. The sequential OPy-directed ortho C-H
functionalization and removal of the directing group were
carried out to demonstrate the utility in organic synthesis.
Thus, 2-phenoxypyridine was ortho-arylated under the
catalysis of palladium according to the literature procedure.2b
Ar Ni(II)
O
N
L
Ar Ni(II)
L
D
B
O
i-PrONa
O
Ar Ni(II)
L
PyONa
C
Scheme 3 Proposed catalytic cycle.
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Mizusaki, T. Ikawa, T. Maegawa, Y. Monguchi and H. Sajiki,
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In summary, we have developed an effective method of
nickel-catalyzed removal of OPy group from aryl and benzyl 2-
pyridyl ethers by using sodium isopropoxide as reducing agent.
In both cases no products formed via CPy-O bond cleavage
were observed. The reaction showed a broad scope of
substrates and good compatibility of functional groups, and
gave mostly excellent yields. We believe that this methodology
is a valuable complement to the reductive deoxygenation of
−
7
phenol and benzyl alcohol derivatives and provides
subsequent conversion way for the 2-pyridyloxy directing
group in the functionalization of C H bonds. The catalytic
a
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−
reduction of aryl and benzyl 2-pyridyl ethers using hydrogen or
hydrosilanes as mutually complementary method will be
explored in the near future.
M. Higashino, N. Chatani and M. Tobisu, Synlett, 2017, 28
2569.
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8
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This work was supported by the National Natural Science
Foundation of China (Grant No. 21772186) and the National
Basic Research Program of China (Grant No. 2015CB856600).
We thank Mr. Bo Yang for his help in the preparation of
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Conflicts of interest
There are no conflicts to declare.
Chem.
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Nickel-catalyzed C-O bond reduction of aryl and benzyl 2-pyridyl
ethers
Jing Lia and Zhong-Xia Wang*,a,b
a 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, P. R. China.
b
Collaborative Innovation Center of Chemical Science and Engineering, Tianjin 300072, P. R.
China.
Aryl and benzyl 2-pyridyl ethers were effectively reduced with i-PrONa via Ni-catalyzed C-OPy
bond cleavage.