Nickel-catalyzed C–H trifluoromethylation of pyridine N-oxides with Togni's reagent

Article abstract of DOI:10.1016/j.tetlet.2018.02.077

The first nickel-catalyzed C–H trifluoromethylation of pyridine N-oxides with Togni's reagent has been achieved. Trifluoromethylation proceeds smoothly under mild conditions with moderate functional group compatibility. Notable advantages of this method include the using of low cost of nickel catalyst, and its simple convenient operation.

Full text of DOI:10.1016/j.tetlet.2018.02.077

Accepted Manuscript
Nickel-Catalyzed C−H Trifluoromethylation of Pyridine N-oxides with Tog-
ni’s Reagent
Xianying Gao, Yang Geng, Shuaijun Han, Apeng Liang, Jingya Li, Dapeng Zou,
Yangjie Wu, Yusheng Wu
PII:
S0040-4039(18)30277-6
https://doi.org/10.1016/j.tetlet.2018.02.077
TETL 49762
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
31 December 2017
24 February 2018
26 February 2018
Please cite this article as: Gao, X., Geng, Y., Han, S., Liang, A., Li, J., Zou, D., Wu, Y., Wu, Y., Nickel-Catalyzed
C−H Trifluoromethylation of Pyridine N-oxides with Togni’s Reagent, Tetrahedron Letters (2018), doi: https://
doi.org/10.1016/j.tetlet.2018.02.077
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A Nickel-Catalyzed C−H Trifluoromethylation of
Pyridine N-oxides with Togni’s Reagent
Xianying Gao, Yang Geng, Shuaijun Han, Apeng Liang, Jingya Li, Dapeng Zou*, Yangjie Wu*, Yusheng Wu*
Leave this area blank for abstract info.

1
Tetrahedron Letters
journal homepage: www.els evier.com
Nickel-Catalyzed C−H Trifluoromethylation of Pyridine N-oxides with Togni’s
Reagent
Xianying Gaoa, Yang Genga, Shuaijun Hana, Apeng Lianga, Jingya Lib, Dapeng Zoua, ∗, Yangjie Wua, ∗,
Yusheng Wub,c,
∗
aThe College of Chemistry and Molecular Engineering, Henan Key Laboratory of Chemical Biology and Organic Chemistry, Zhengzhou University, Zhengzhou
450052, PR China
bTetranov Biopharm, LLC. And Collaborative Innovation Center of New Drug Research and Safety Evaluation, Zhengzhou, 450052, PR China
cTetranov International, Inc., 100 Jersey Avenue, Suite A340, New Brunswick, NJ 08901, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
The first nickel-catalyzed C−H trifluoromethylation of pyridine N-oxides with Togni’s reagent
has been achieved. Trifluoromethylation proceeds smoothly under mild conditions with
moderate functional group compatibility. Notable advantages of this method include the using of
low cost of nickel catalyst, and its simple convenient operation.
Received in revised form
Accepted
Available online
2017 Elsevier Ltd. All rights reserved.
Keywords:
Nickel
−H
C
trifluoromethylation
pyridine N-oxides
2-trifluoromethylated pyridine
Introduction
cores, while the synthesis of 2-trifluoromethylated pyridines were
rarely reported. Therefore, the development of new facile routes
N-Heteroaromatic compounds containing trifluoromethyl
(CF3) group(s) are versatile components of drugs, agrochemicals
and organic materials (Figure 1) due to their increased
lipophilicity and metabolic resistance.1 Although a variety of
methods for the trifluoromethylation of arenes have been
developed in the past several decades, the incorporation of
trifluoromethyl groups into N-heteroarene core has been studied
to a lesser extent.2 Accordingly, development of new methods for
trifluoromethylation of N-heteroaromatic compounds is an
to build structurally diverse 2-trifluoromethylated pyridine
derivatives is still highly desired.
important task. Recently, significant progress has been made in
−H
the C
3-7
trifluoromethylation of N-heterocycles. Despite well-
established C−H trifluoromethylation methodologies were found,
the development of new strategies for selective introduction of
such groups into the C2-position of six-membered N-
heteroaromatic compounds is of high demand. Heterocyclic N-
oxides widely used as the key synthetic intermediates8 have
recently been applied for the preparation of trifluoromethylated
N-heterocycles in the C2 position.9,10 In 2014, the group of
Larionov developed the trifluoromethylation of heterocyclic N-
oxides with trimethyl(trifluoromethyl)silane at −20 °C.9 At the
same year, the groups of Liu and Wu disclosed a Cu-catalyzed
reaction of isoquinoline-N-oxides with Togni’s reagent.10
Although these works represent very promising advances, these
two methods for the synthesis of trifluoromethylated heterocyclic
moiety were mainly focused on the quinoline and isoquinoline
Figure 1. Examples of bioactive N-heterocycles bearing
trifluoromethyl-groups.
Nickel is one of the most widely used transition-metal
catalysts in organic transformations. Recently, nickel-catalyzed
———
∗ Corresponding author. Tel.: +1 732 253 7326; fax: +1 732 253 7327; e-mail: yusheng.wu@tetranovglobal.com, wyj@zzu.edu.cn，
zdp@zzu.edu.cn

2
Tetrahedron
Entry
Ni source
Base
Equiv.
(1a:2)
Yield (%)b
fluoroalkylation has attracted increasing attention because of
the low cost of nickel catalyst.11-14 Although less studied, Ni-
−H
catalyzed directing C
bond fluoroalkylation reactions have
also been documented.15 To the best of our knowledge, the
nickel-catalyzed directing C−H bond trifluoromethylation
reactions of N-heteroaromatic compounds, especially pyridine
derivatives have not been reported so far. As a part of our
ongoing efforts on the introduction of fluorinated functional
groups into organic molecules,16 we herein demonstrate the first
1
2
NiCl2
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Cs2CO3
DMAP
K2CO3
NaOH
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
1:1.2
38
39
NiCl2·6 H2O
Ni(PPh3)2Cl2
Ni(OAc)2·4 H2O
NiBr2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:2
3
37
4
30
−H
trifluoromethylation of
example of nickel-catalyzed
pyridine N-oxides with Togni’s reagent.
C
5
27
Results and Discussion
6
-
Trace
27
The model reaction of 4-phenylpyridine N-oxide (1a) with
Togni’s reagent (2) was chosen to optimize the reaction
parameters and the results are summarized in Table 1 (for details,
see the Supporting Information (SI)). The desired product 3a was
obtained in a 38% HPLC yield when using NiCl2 as a catalyst,
and in the presence of KOAc (3.0 eq) in N, N-
dimethylformamide (DMF) at 50 °C under argon for 17 h (Table
1, entry 1). Encouraged by this preliminary result, a variety of
nickel catalysts were studied to find that the low-cost NiCl2·6
H2O was the optimum catalyst and provide 3a in 39% yield
(Table 1, entries 2-5). A control experiment indicated that almost
no reaction occurred in the absence of nickel catalyst (Table 1,
entry 6). A number of ligands and additives were also screened
(Table S6; see SI), but no further improvement was observed.
Next, a survey of different bases demonstrated that KOAc was a
better choice in the reaction process (Table 1, entries 7-10) and
only a trace amount of product was formed in the absence of base
(Table S2; see SI). Furthermore, the effects of different solvents
were tested, and DMF was found to be the best solvent (Table S3;
see SI). Changing the substrates ratio has a great influence on the
yield of the reaction (Table 1, entries 11-13). Although an
improved yield was obtained when increasing the substrates ratio
(1a:2) to 1:3 (45%, entry 12), the yield of the corresponding
product 3a is still relatively low due to the formation of other
side product(s), such as the reduced raw material pyridine, 2-
trifluoromethylated pyridine N-oxide. So the substrates ratio was
adjusted to 3:1 (59%, entry 13). In this condition, the Togni’s
reagent 2 could be fully utilized and the excess material 1a could
be recovered. Gratifyingly, when the reaction time was prolonged
to 24 hours, the yield of the corresponding product 3a was
enhanced to 62% (Table 1, entry 14). It is worth noting that either
reducing the amount of solvent or catalyst, the yield of 3a was
improved (Table 1, entries 15-16). Because of the low cost of
nickel catalyst, we selected 10 mol % of the catalyst dosage with
relatively higher yield (Table S8; see SI). The reaction
temperature was also tested and the best yield was obtained under
50 °C (Table S7; see SI). Thus, the use of 1.0 eq Togni’s reagent
and 3.0 eq pyridine N-oxide in the presence of 10 mol % NiCl2·6
H2O as nickel source, 3.0 eq KOAc as base, and DMF as solvent
under argon at 50 °C for 24 h are optimal reaction conditions for
the C-H trifluoromethylation.
7
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
NiCl2·6 H2O
8
7
9
26
10
11
12
13
14c
15c,d
16c,e
11
41
1:3
45
3:1
59
3:1
62
3:1
64
3:1
68 (63)f
aReaction conditions: 1a, 2, 1.0 eq = 0.25 mmol, Ni source (20 mol %), base
(3.0 eq), solvent (1.0 mL), 50 oC, under Ar, 17 h.
bHPLC yield.
c24 h.
dDMF (0.5 mL).
eDMF (0.5 mL), 10 mol % NiCl2·6 H2O.
fIsolated yield based on 2 is shown in parentheses.
With the optimized reaction conditions in hand, we turned our
attention to the generality and scope of the substrates for this
transformation. Firstly, a series of pyridine N-oxides with
Togni’s reagent 2 were evaluated, as presented in Table 2. The
substrates bearing both electron-donating (3a-3h) and electron-
withdrawing (3i, 3j) groups were compatible with the standard
conditions. Meanwhile, various functional groups such as phenyl,
alkyl, acyl, alkoxy and halogens were compatible with the
present reaction conditions. Para-, meta-, and ortho- substituted
pyridine N-oxides are compatible with the reaction conditions
and gave the desired products. Pyridines N-oxides containing
phenyl at ortho- and meta-position were less reactive than that at
para-position. When substrate 1c was used, a mixture of C4 and
C2 trifluoromethylated products were obtained in 48% total yield.
Bis-substituted pyridine N-oxides (3k-3p) were reacted smoothly
as well under the standard condition albeit some of them with
lower yields. In particular, the halogenated substrates could work
well to give the desired products (3l, 3m, and 3p) in moderate to
good yields. In case of substrate with benzoyl, a mixture of 3i
and 3j were obtained in 54% total isolated yield. Probably the
electronic effect of substituents played a key role in controlling
the product type. To expand the scope of this method, some
quinolone N-oxides (1q-1s) were also evaluated in this reaction
to find they proceeded successfully under these conditions and
give the desired products (3q-3s) in modest yields.
Table 1. Optimization of the Reaction Conditions.a

3
Table 2. Nickel-Catalyzed C−H Trifluoromethylation of
Various Pyridine N-oxides with Togni’s Reagent.a,b
O
R
10 mol % NiCl2 • 6 H2O
R
O
+
H
N
CF3
KOAc (3.0 eq), DMF
50 °C, 24 h, Ar
N
I
O
CF3
2
3 (a-p)
1 (a-p)
Ph
4
−H
Scheme 1. Scalability of the Nickel-Catalyzed C
Ph
F
CF3
Trifluoromethylation of 1a.
2
Ph
N
N
CF3
CF3
N
CF3
N
3a, 63%
t-Bu
3b, 34%
OBn
3c, 48%
[C4:C2 = 1:1.8]
3d, 50%
Bn
N
CF3
CF3
N
CF3
N
CF3
N
Scheme 2. The C−H Trifluoromethylation of Hydroquinine N-
3e, 58%
3f, 38%
Ph
3g, 52%
3h, 32%
Cl
oxide.
O
O
Ph
Ph
Ph
To gain some mechanism insights into the nickel-catalyzed C-
H trifluoromethylation reaction, several control experiments were
examined (Scheme 3). When 1aa was used as a substrate under
the optimal reaction conditions, only a trace amount of product
3a was formed [Eq. (1)]. This result suggested that the N-oxide
CF3
N
N
O
CF3
CF3
Ph
N
CF3
3i-3j, 54%c
N
3k, 36%
CF3
3l, 52%
Cl
−H
C
of the substrate is necessary for the success of
[3i:3j = 1:1.1]
trifluoromethylation reaction under our current conditions. No
desired product was observed in the presence of TEMPO (3.0 eq)
and 1,1-diphenylethylene (3.0 eq) as radical scavengers under the
standard conditions. The reaction was completely quenched and
compound 6 and 7 were detected by GC-MS [Eq. (2), (3)]. These
results indicated that this reaction might happen through a radical
pathway.
Br
N
Ph
CF3
Ph
CF3
CF3
CF3
Ph
N
Ph
N
O
N
3m, 54%
Ph
3n, 43%
3o, 27%
3p, 30%
O
CF3
3s, 40%
N
CF3
N
CF3
N
3q, 44%
3r, 35%
aReaction conditions: 1 (1.5 mmol), 2 (0.5 mmol), 10 mol % NiCl2 . 6 H2O,
KOAc (3.0 eq), DMF (1 mL) under Ar, 50 °C, 24 h.
bIsolated yield based on 2.
cTotal isolated yield of 3i and 3j, in the absence of KOAc.
−H
The nickel-catalyzed C
trifluoromethylation method is also
suitable for the application in grams scale experiment (Scheme 1).
A satisfactory result (58% yield) was obtained and with 1.1 g of
1a recovered.
To further demonstrate the importance and practical utility of
this method, the late-stage trifluoromethylation of the cinchona
alkaloid hydroquinine17 was performed. As shown in Scheme 2.
The hydroquinine N-oxide 4 (1.5 mmol, 500 mg) with Togni’s
reagent
2
(0.5 mmol, 158 mg) underwent C-H
trifluoromethylation smoothly to afford 2-trifluoromethylated
hydroquinine 5 (108 mg) in 55% yield under the optimized
reaction conditions. This outcome demonstrates the great
application potential of this direct trifluoromethylation of N-
heteroaromatic in drug discovery and development.
Scheme 3. Preliminary Mechanistic Studies.
Conclusion
In summary, we have described the first one-step nickel-
catalyzed C−H trifluoromethylation method for the synthesis of
2-CF3 pyridine derivatives. The transformation has moderate
functional group tolerance and a broad substrate scope. The
reaction is easily scaled up to gram scale and applied to late-stage

4
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5
Highlights
−H trifluoromethylation of
.The first nickel-catalyzed C
pyridine N-oxides with Togni’s reagent.
.2-CF3 pyridine derivatives are obtained by one-step.
.Tolerance of a wide range of substituents under mild
conditions.