Cu-catalyzed arylation of 1-acyl-1H-1,2,3-Benzotriazoles via C–N activation

Article abstract of DOI:10.1016/j.jorganchem.2019.05.013

An efficient copper-catalyzed arylation reaction of 1-acyl-1H-1,2,3-benzotriazoles with diaryliodonium salts via C–N activation is explored. The reaction is conducted regioselectively to form 1-aryl-1H-1,2,3-benzotriazoles in MeCN at 80 °C in the presence of cesium carbonate. 29 examples are given with the product yield of up to 84%. The probable reaction mechanism is proposed.

Full text of DOI:10.1016/j.jorganchem.2019.05.013

Accepted Manuscript
Cu-catalyzed arylation of 1-acyl-1H-1,2,3-Benzotriazoles via C–N activation
Wenying Zhang, Yangyang Wang, Xiangru Jia, Zhengyin Du, Ying Fu
PII:
S0022-328X(19)30194-9
DOI:
https://doi.org/10.1016/j.jorganchem.2019.05.013
JOM 20795
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 1 February 2019
Revised Date: 10 May 2019
Accepted Date: 13 May 2019
Please cite this article as: W. Zhang, Y. Wang, X. Jia, Z. Du, Y. Fu, Cu-catalyzed arylation of 1-
acyl-1H-1,2,3-Benzotriazoles via C–N activation, Journal of Organometallic Chemistry (2019), doi:
https://doi.org/10.1016/j.jorganchem.2019.05.013.
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Communication
ACCEPTED MANUSCRIPT
Cu-Catalyzed Arylation of 1-Acyl-1H-1,2,3-Benzotriazoles via
C-N Activation
Wenying Zhang, Yangyang Wang, Xiangru Jia, Zhengyin Du* and Ying Fu*
Gansu International Scientific and Technological Cooperation Base of Water-retention Chemical Functional Materials,
College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou 730070, P. R. China.
* Phone and Fax: +86-931-7971989; E-mail: clinton_du@126.com, fu_yingmail@126.com
Abstract. An efficient copper-catalyzed arylation reaction of 1-acyl-1H-1,2,3-benzotriazoles with diaryliodonium salts
via C-N activation is explored. The reaction is conducted regioselectively to form 1-aryl-1H-1,2,3-benzotriazoles in
o
MeCN at 80 C in the presence of cesium carbonate. 29 examples are given with the product yield of up to 84%. The
probable reaction mechanism is proposed.
Keywords: Copper catalysis; C-N activation; Arylation; Diaryliodonium salts; Tandem reaction
1,2,3-benzotriazole under solvent-free conditions
(Scheme 1b).[18]
1. Introduction
Nitrogen-containing heterocycles are subunits
found in numerous natural products and in many
biologically active pharmaceuticals.[1] N1-Modified
benzotriazoles are important nitrogen-containing
heterocyclic compounds, many of which possess
biological and pharmacological activity.[2-5] They can
be used as anti-inflammatory, anti-tumor, anti-
depressant, anti-fungal, anti-malarial and other
Due to their versatile character, commercial
availability, environmental-friendly behavior and
enormous potential in C-C and C-heteroatom
coupling, diaryliodonium salts have afforded efficient
arylation of diverse nucleophiles, in particular
heteroatom nucleophiles.[19] In 1998, Beletskaya and
coworkers reported six examples of Pd(II) and Cu(II)
salts co-catalyzed 1-arylation reaction of 1H-1,2,3-
drugs,[6-9] as well as has broad applications in fine benzotriazoles with diaryliodonium salts to prepare 1-
aryl-1H-1,2,3-benzotriazoles.[20] Lately, they found
that Pd/Al2O3 could catalyze this reaction
successfully.[21] Kang research group[22] also used
Cu(acac)2 as an efficient catalyst to accomplish N-
arylation of benzotriazole with diaryliodoniums
(Scheme 1c).
chemicals[10] and materials science.[11] Although
copper catalyzed Ullmann-type C-N bond formation
reaction is an important, straightforward and
inexpensive approach to synthesize nitrogen-
containing heterocycles, it has some disadvantages.
For example, the reaction usually requires severe
)
H
o
a
conditions of temperature higher than 200 C, excess
N
Pd or Cu salts
PhX
N
+
N
N
nucleophiles, longer reaction time, the strong bases
and a stoichiometric amount of copper activator.[12]
Therefore a highly efficient, mild C-N bond
construction method has been paid much attention by
chemists.
X=I, Cl, Br
N
N
OH
B
H
b)
Cu(II) complex
N
OH
+
+
N
N
N
N
N
H
c)
d)
Pd-Cu salts
or Pd/Al2O3
or Cu(acac)2
N
Arylation reaction is an important way for the
modification of 1H-1,2,3-benzotriazoles to prepare 1-
aryl-1H-1,2,3-benzotriazoles, which has found wide
applications not only in synthetic organic chemistry
but also in biological,[13] medicine,[14] materials[15] and
other aspects. The new C-N bond formation method
from 1H-1,2,3-benzotriazoles was focused on the use
of various arylating reagents. Aryl halides were the
first arylating reagents reported in the preparation of
1-aryl-1H-1,2,3-benzotriazoles (Scheme 1a).[16,17] In
2017, Hashem Sharghi and coworkers used
phenylboronic acid as an arylating reagent to achieve
Cu(II)-catalyzed N1-phenylation reaction of 1H-
[Ar1IAr2] X
N
N
N
N
N
This Work
O
R1
C
N
R
R1
X
I
Cu powder
+
R3
N
N
R2
R3
N N
N
Scheme 1 Methods for the synthesis of 1-aryl-1H-1,2,3-
benzotriazoles
With our continuous investigation on high efficient
arylation reaction using diaryliodonium salts as
arylating reagents, we report herein copper-catalyzed
regioselective arylation reaction of 1-acyl-1H-1,2,3-
1

ACCEPTED MANUSCRIPT
benzotriazoles with diaryliodonium salts via C-N indicate that copper has better catalytic activity than
activation to form 1-aryl-1H-1,2,3-benzotriazoles, palladium in this reaction. Treatment of 1a with 2a
which involves tandem amide C-N bond cleavaging using potassium carbonate as a base and copper
and a new C-N bond formation (Scheme 1d).
powder as a catalyst in CH3CN affords only 63%
yield of 3aa (entry 8). In the absence of any catalyst
or base, trace of the aimed product was observed
(entries 9 and 10). The effect of solvents on this
reaction was also examined. When the reaction was
conducted in N-methylpyrrolidone (NMP), in 1,2-
dichloroethane (DCE) and in dimethyl sulfoxide
(DMSO), an inferior 3aa yield of 46%, 74% and 52%
than in acetonitrile was obtained, respectively (entries
11-13). The reaction temperature is also sensitive for
this transformation. When the reaction temperature
2. Results and discussion
The reaction conditions were first optimized using
1-acetyl-1H-1,2,3-benzotriazole
(1a)
and
diphenyliodonium tetrafluoroborate (2a) as model
substrates and the results are listed in Table 1. With 8
mol% of commercial copper powder as a catalyst and
cesium carbonate as a base, the reaction was
conducted in acetonitrile at 80 oC for 24 hours and the
product of 1-phenyl-1H-1,2,3-benzotriazole (3aa) was
obtained in 83% yield (entry 1). Only trace of N2-
arylation product was observed. When using Cu2O as
the reaction catalyst, good yield of the desired product
3aa of 77% was obtained (entry 2). So we deduced
that Cu(I) may be benificial for this catalytic reaction
and Cu(I) halides (halide=Cl, Br and I) were used as
catalysts and medium to good yields (60%, 63% and
75%, respectively) were achieved (entries 3-5).
However, when using
o
o
was decreased from 80 C to 50 C, the product yield
was declined dramatically from 82% to 54% even if
prolonged the reaction time to 36 hours (entry 14).
Similarly, when the reaction temperature was arisen
o
to 100 C in a sealed tube, only 76% of yield was
obtained (entry 15). A nitrogen-containing ligand
N2,N2’-diisopropyloxalo-hydrazide ligand which was
proved to be efficient in Cu-catalyzed C-N coupling
reaction[23] was added into this reaction to improve
the product yield, but it did not work (entry 16). We
also tried to increase the amount of the catalyst and
the alkali to make the yield better, but it was 84% and
83%, respectively and did not change significantly
(entries 17 and 18).
Table 1. Optimization of reaction conditions.a
O
C
N
CH3
I
Cu (8 mol%)
+
N
Cs2CO3 (2 eq)
N
BF4
CH3CN, 80 o
C
N
N
N
1a
2a
3aa
2. Results and discussion
Entry Catalyst
Base
Solvent
Yield (%)
83
1
2
3
4
5
Cu
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Cs2CO3
-
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3/L
Cs2CO3
Cs2CO3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
NMP
With the optimized reaction conditions established,
we examined the substrate scope of 1-acyl-1H-1,2,3-
Table 2. Scope of 1-acyl-1H-1,2,3-benzotriazoles.a
Cu2O
CuCl
CuBr
CuI
77
60
63
75
36
44
63
trace
trace
46
74
52
54
76
82
84
O
R
6
7
8
Pd(OAc)2
PdCl2
Cu
R1
I
N
Cu (8 mol%)
R1
+
N
N
Cs2CO3 (2 eq)
CH3CN, 80 o
N
BF4
C
N
N
1
2a
3aa-ga
9
-
10
11
12
13
14b
15c
16
17d
18e
Cu
Cu
Cu
Cu
Cu
Cu
Cu
Cu
R=CH3
DCE
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
3aa, 83%
3ba, 74%
3ca, 77%
3da, 73%
Cu
83
3ea, 65%
a Reaction conditions: 1a (0.2 mol), 2a (0.4 mol), Cu (8 mol %),
Cs2CO3 (2 eq), solvent (3 mL) at 80 oC for 24 hours. Yield is
isolated yield. L = N2,N2’-diisopropyloxalohydrazide.
b The reaction is conducted at 50 oC for 36 hours.
c The reactiom temperature is 100 oC.
R=CH3CH2, 3fa=3aa, 43%
R=n-C4H9, n.r.
R=PhCH2, 3ga=3aa, 38%
R=Ph, n.r.
d The amount of Cu powder is 15 mol%.
e The dosage of Cs2CO3 is 3 equivalents.
R=1-naphthyl, n.r.
a
Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Cu
(8 mol%), Cs2CO3 (2 eq) in 3 mL of solvent at 80 oC for 24
h. Isolated yield is given. n.r. is no reaction.
palladium compounds as catalysts instead of copper
powder, the product yield showed significant decrease
to 36% and 44%, respectively (entries 6 and 7). These
2

ACCEPTED MANUSCRIPT
benzotriazoles in the reaction with 2a. The results are diphenyliodonium tetrafluoroborate, a variety of
summarized in Table 2. It is found that this reaction symmetric and unsymmetric diaryliodonium salts as
can tolerate a variety of substituents on the benzene arylating reagents of 1a were explored in this reaction.
ring of benzotriazoles. Reactions of substrate 1 The results are listed in Table 3. In comparison with
-
containing an electron-donating (e.g., methyl) or BF4 , when TfO- was used as an anion of
electron-withdrawing (e.g., nitro and chloro) groups diphenyliodonium salts, the yield of the product
-
worked well to deliver the corresponding products decreased to 72%; whereas PF6 as an anion instead of
-
3ba-3ea in 64%-77% yields. The effect of acyl BF4 , no reaction was occurred (3ab and 3ac).
groups on the reaction is significant. Acetyl group However, when 1a was treated with di(4-(tert-
(R=CH3) led to good product yield of this reaction. butylphenyl)iodonium hexafluorophosphate, 72% of
With the carbon atom number of chain acyl group product yield was obtained (3ad). These results show
increasing, the product yield decreased drastically that the reactivity of diaryliodonium salts is related
from 43% of 3fa to no reaction with valeyl group not only to the structure of aryl groups, but also to the
(R=n-C4H9). The steric hindrance of acyl groups is type of anions. Symmetric diaryliodonium salts
also a key factor in this reaction. When R was benzyl containing electron-donating groups (e.g., methyl,
group, the yield was 38%; however, when R was tert-butyl and methoxyl) attached to the benzene ring
phenyl and 1-naphthyl, no corresponding products afforded corresponding arylation products with good
were obtained.
yield ranging from 72% to 78% (3ad-3af). However,
electron-withdrawing groups of Br and CF3 connected
to the benzene ring of symmetric diaryliodonium salts
led to reduced product yields of 69% and 54%,
respectively (3ag and 3ah). For the reactions of
unsymmetric diaryliodonium salts with 1a, to our
delight, good selectivity with synthetically useful
yield were obtained. Both electron-donating and
electron-withdrawing substituents were tolerated
under the reaction conditions and moderate yields of
43%-67% were achieved (3ai-3an). Diaryliodonium
salt containing a heterocyclic aryl was also examined.
The reaction of phenyl(2-thienyl)iodonium triflate
with 1a proceeded smoothly to yield 43% of 1-(2-
thienyl)-1,2,3-benzotriazole deacylation arylation
product (3ao).
Table 3. Scope of diaryliodonium salts.a
O
C
N
CH3
I
Cu (8 mol%)
+
X
N
R3
Cs2CO3 (2 eq)
CH3CN, 80 o
C
N
R2
R3
N
N
N
3ab-ao
1a
2
R2=R3=H; X=OTf;
3ab=3aa, 72%
R2=R3=H; X=PF6;
3ac, n.r.
R2=R3=4-Me;
X=BF4; 3ae, 73%
R2=R3=4-t-Bu;
X=PF6, 3ad,
72%
R2=R3=3-CF3;
X=BF4; 3ah,
54%
R2=R3=4-Br;
X=OTf; 3ag,
69%
R2=R3=4-CH3O;
X=BF4; 3af, 78%
To better understand the substitution effect of
different functional groups, competitive reactions
were carried out (Scheme 2A). When 1a was allowed
to
react
simultaneously
with
(4-
R2=H, R3=4-Cl;
X=OTf; 3ak,
54%b
methylphenyl)phenyliodonium triflate (2q) and (4-
bromophenyl)phenyliodonium triflate (2g), 1-(p-
tolyl)-1H-1,2,3-benzotriazole (3aq) and 1-(4-
bromophenyl)-1H-1,2,3-benzotriazole (3ag) were
isolated in 62% and 31% yields, respectively. This
indicates that an electron-donating group on the
diaryliodonium salts reacted more easily than an
electron-withdrawing group.[20,21] It may be the
R2=H, R3=4-
CH3O; X=BF4;
3aj=3af, 67%b
R2=H, R3=2-Me;
X=BF4; 3ai, 66%b
R2=H, R3=3-CF3;
X=BF4; 3an=3ah,
43%b
R2=H, R3=4-Br;
X=OTf; 3al=3ag,
57%b
R2=H, R3=2-Cl;
X=BF4; 3am,
50%b
Phenyl(2-thienyl)iodonium
triflate; 3ao, 43%b
a Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Cu
o
(8 mol%), Cs2CO3 (2 eq) in 3 mL of acetonitrile at 80 C
for 24 h. Isolated yield is given. n.r. is no reaction.
b
3aa was obtained in trace amount or not more than
10% yield.
Inspired by the successful Cu-catalyzed arylation
of
1-acyl-1H-1,2,3-benzotriazoles
with
3

ACCEPTED MANUSCRIPT
O
ArI
CH3
A
I
N
N
N
Cs2CO3
Ar-CuIII
X
TfO
O
CH3
N
N
N
N
H3C
CH3
N
N
A
Ar2IX
2a
2q
B
1a
Cu (8 mol %)
Cs2CO3 (2 eq)
3aq, 62%
N
+
+
CuI
N
Cu0
CO2 + CsOAc
CH3CN, 80 o
C
Cs2CO3
I
N
TfO
1a
N
Br
N
Br
Br
N
Ar
CsX + CO2
2g
N
N
3ag, 31%
CuIII
N
O
N
-Ar
H3C
B
3aa
CH3
N
N
H3C
N
N
C
N
N
N
I
N
Cu (8 mol %)
3ba, 34%
+
1b
BF4
Cs2CO3 (2 eq)
O
Scheme 4. Probable reaction mechanism.
+
CH3CN, 80 o
C
Cl
CH3
Cl
2a
N
N
N
N
1c
N
N
3. Conclusion
3ca, 57%
Scheme 2. Competition experiments.
In summary, we have developed a one-pot
approach to the synthesis of 1-arylbenzotriazoles by
reason that in situ formation of electron-deficient aryl
Cu(III) intermediate is the key step and electron-rich
aryl groups can stabilize this intermediate. Another
Cu-catalyzed
reaction
of
1-acyl-1H-1,2,3-
benzotriazoles with diaryliodonium salts via C-N
activation. The method tolerates diverse functional
groups and is a feasible and alternative arylation
method. The major advantages of this method
includes: cheap and commercial easily available
copper powder catalysis, wide substrate scope, mild
reaction conditions and good step-economy.
competitive
reaction
of
diphenyliodonium
tetrafluoroborate with 1b and 1c afforded 3ba and 3ca
in 34% and 57% yields, respectively (Scheme 2B).
Thus, the presence of an electron-withdrawing group
on the benzene ring of benzotriazoles favored the
reaction than an electron-donating group. The cause
is attributed to the increase of acidcity of NH when
bearing an electron-withdrawing group on
benzotriazoles.
4. Experimental
In order to further study the mechanism, we
conducted control experiments (Scheme 3). The
results show that the reaction is carried out upon two-
step tandem reactions of N-deacylation to generate
1H-1,2,3-benzotriazole in 96% yield and then N-
arylation to deliver 3aa in 89% yield under one-pot
A
catalyst
(8
mol%),
1-acyl-1H-1,2,3-
benzotriazoles (0.2 mmol), Cs2CO3 (0.4 mmol),
diaryliodonium salts (0.4 mmol) and acetonitrile (3.0
mL) were sequentially added into a 25 mL round-
bottom flask, and the mixture was stirred in a
o
preheated oil bath at 80 C for 24 hours. Then the
conditions.
resulting mixture was cooled to r.t. and the solvent
was removed in vacuum. The crude product was
purified by column chromatography on silica gel with
ethyl acetate/petroleum ether (1:10 vol) as an eluent
to give the desired 1-aryl-1H-1,2,3-benzotriazoles.
O
CH3
Cu (8 mol %)
Cs2CO3 (2 eq)
H
N
(1)
N
CH3CN, 80 o
24h, 96 %
C
N
N
N
N
N
H
N
Cu (8 mol %)
I
Cs2CO3 (2 eq)
(2)
BF4
+
CH3CN, 80 o
24h, 89 %
C
N
N
N
N
Scheme 3. Control experiments.
Acknowledgements
Based on these results, a possible reaction
mechanism of 1-acyl-1H-1,2,3-benzotriazoles with
diaryliodonium was deduced (Scheme 4). First, Cu
powder was oxidized to Cu(I) species. Oxidative
addition of the diaryliodinium salt 2a to Cu(I) can
generate the highly electrophilic CuIII-aryl
intermediate A by cleavage of the hypervalentiodine
aryl bond. Then, 1-acetyl-benzotriazole undergoes
electrophilic attack under the presence of cesium
carbonate to form nitrogen anions intermediate B.
Subsequently, nucleophilic substitution is initiated
between intermediates A and B to form N1-
metallation benzotriazole C, which is further
converted into the aimed product 3aa upon reductive
elimination. Cu(I) species is released to participate in
the next catalytic cycle.
We gratefully acknowledge the National
Natural Science Foundation of China (21262028,
21762039, 21762040) for financial support.
Appendix A. Supplementary data
Supplementary data related to this article can
be
found
at
http://dx.doi.org/10.1016/
j.jorganchem.
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5

ACCEPTED MANUSCRIPT
6

ACCEPTED MANUSCRIPT
西北师范大学化学化工学院
CollegeofChemistryandChemicalEngineering,NorthwestNormalUniversity
Feb. 1, 2019
To: Prof. R. D. Adams,
Editor of J. Organomet. Chem.
Dear Prof. Adams,
Our manuscript entitled “Cu-Catalyzed N-Arylation of 1-Acyl-1H-1,2,3-Benzotriazoles via C-N
Activation” will be submitted to J. Organomet. Chem. We hope it can be published on this journal.
We think that the highlights about this manuscript are as follows:
1. This is the first example of N-arylation reaction involving cascade N-deacylation and
N-arylation via C-N activation in a one-step, one-pot conditions.
2. It involves an original C-N bond cleavage and a new C-N bond formation in one-step
reaction.
3. Commercial available copper powder is a high efficient and cheap catalyst for this reaction
without addition of any ligands.
4. The reaction has wide scope of substrates (1-acyl-1H-1,2,3-benzotriazoles and
diaryliodonium salts) and good group tolerance.
o
5. The method has mild reaction conditions (at 80 C in acetonitrile for 24 hours), good
product yields (up to 86%) and excellent regioselectivities (almost 100% N1-arylation).
6. The products of this method contain 1,2,3-benzotriazole building block. They may have
some bioactivities and can be used as pharmaceutical candidates.
Therefore we wish this work could be published on J. Organomet. Chem. Your favorable
consideration about this manuscript would be highly appreciated.
Please do not hesitate to contact me if you have any questions.
Sincerely yours
Zhengyin Du
College of Chemistry and Chemical Engineering
Northwest Normal University
Lanzhou 730070, P. R. China
Email: clinton_du@126.com