Visible Light-Induced Copper-Catalyzed C—H Arylation of Benzoxazoles?

Article abstract of DOI:10.1002/cjoc.201900527

A general method for visible light-induced copper-catalyzed arylation of sp² C—H bonds of azoles has been developed. The method employs aryl halide as the coupling partner, lithium alkoxide as base. A variety of azoles including benzooxazole and benzothiazole can be arylated. Furthermore, electron-poor heterocycles such as thiophene possessing one electron-withdrawing group can also be arylated.

Full text of DOI:10.1002/cjoc.201900527

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Visible Light-Induced Copper-Catalyzed C-H Arylation of Benzoxazoles
Authors: Xiaodong Ma, Guozhu Zhang*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.201900527.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.201900527.
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Chinese Journal
of Chemistry
Photo-induced, Copper-catalyzed, Visible light, Azole, C-H arylation
Report
CJC
中
国 化 学 - An International Journal
Visible Light-Induced Copper-Catalyzed C-H Arylation of Benzoxazoles
Xiaodong Maa, Guozhu Zhanga, *
a State Key Laboratory of Organometallic Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of
Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 345 Lingling Road,
Shanghai 200032, P. R. China.
Cite this paper: Ma, X.; Zhang, G. Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion A general method for visible light-induced copper-catalyzed arylation of sp2 C-H bonds of azoles has been
developed. The method employs aryl halide as the coupling partner, lithium alkoxide as base. A variety of azoles including benzooxazole and benzothiazole
can be arylated. Furthermore, electron-poor heterocycles such as thiophene possessing one electron-withdrawing group can also be arylated.
studies revealed the key rate-accelerate process of amino acid
ligands. Interestingly, they briefly showed that the copper-
Background and Originality Content
Aryl compounds containing heteroaryl moieties are ubiquitous in a
wide range of natural products, drugs, and dyes. As a consequence,
the regioselective formation of aryl-hetero bonds has attracted
substantial interest over the past dacades.1 Among methods
established, catalyzed C-H activation has emerged as a powerful
platform for the step-economical arylation of heteroarenes
(Scheme 1, eq 1).2 Transition-metal-catalyzed C-H arylations of
heteroarenes are also well established. Among metals employed,
copper-catalyzed C-H arylation of azoles is notable, exemplified by
early elegant contributions from the groups of Daugulis,3 Miura,4
Gaunt,5 Ackermann6 and others. Despite these advances, copper-
catalyzed C-H arylations with easily accessible aryl halides shows
limitations as rather harsh reaction conditions needed, typical
reaction temperatures ranging from 100 to 160 oC. As a result, new
strategies for milder C-H arylation of heteroarene are still highly
desired.
Photoredox catalysis has become a powerful synthetic tool, with
notable feature of generation of highly reactive radical species
under mild reaction conditions. Owing to strong absorption in the
visible region, high redox potentials, and long excited states,
ruthenium and iridium complexes associated with π-deficient
ligands have been the most frequently utilized photocatalysts.7
Organic dyes8 or photoactivatable metal complexes9 were also the
focus of research interest. In the previous works from Kutal,10
Mitani,11 Sauvage,12 Peters, Fu,13 Reiser14 and others, copper
complexes have exhibited unique property as cheaper photoredox
catalyst, capable of activating a broad range of substrates including
organic halides.14,15
catalyzed cross-coupling reaction of benzoxazole and iodobenzene
could process under visible light irradiation in the presence of
Ir(ppy)3 as a photoredox catalyst, with a moderate yield (eq 3).16
Based on these examples, in line with our continuing interest on
photoredox copper catalysis,17 we suspected that it was possible to
achieve C-H arylation of heteroarene under visible light irradiation
in the presence of a single copper-complex by employing a proper
multidentate ligand. Herein, we describe the productive merger
between copper catalysis and photoredox catalysis that enable the
cross-coupling reaction of aryl iodides and aromatic heterocycles
under visible light irradiation. 2,2’-Bipyridine copper compound
serves as the dual functional catalyst (eq 4).
Scheme 1 transition metal-catalyzed arylation of heterocycles
Pd, Cu, Ni, Co, Rh,
ligand
+
(1)
(2)
(3)
Ar
X
Ar
X
Arene
X
100-160 o solvent, base, 10-24 h
C,
H
Arene
cat.CuI
I
N
cat. Me
H
N
2NCH2CO2
R1
R
+
R
t
Et
-BuOLi, 2O
R1
X
X
RT, hv, 16 h
=
X
S
O,
mol
mol
CuI
%)
Me
(20
[Ir(ppy)3] (2.0
DMF
Me
+
I
N
%)
N
t
-BuOLi,
S
35 o Blue LED, 16 h
S
C,
50%
Recently, Ackermann disclosed a copper-catalyzed protocols for
the cross-coupling reactions of various heteroarenes with aryl
halides under ultraviolet (UV) light irradiation (eq 2).16 Mechanistic
work:
this
mol%)
mol%)
[Cu] (5
bpy (5
I
t
-BuOLi
equiv)
(2.5
+
(4)
R1
Het
Het
DMF, RT, BLUE-LED
16 h
R1
3aa
1a
2a
equiv)
equiv)
(4
(1
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First author et al.
Report
With the optimal reaction condition established, efforts were
devoted to exploring the substrate scope with regard to the
diversity of aryl iodides. As demonstrated in Table 2, the reaction
was found to be rather general, the corresponding arylated
benzoxazoles were obtained in fair to moderate yields. Methyl
substitutions could be allowed at para (3ab), meta (3ac) and ortho
(3ad) positions. 3,5-Dimetyl phenyl (3ae), a mesitylene moiety
(3af) and 4-t-Bu (3ag) could be well tolerated. Interestingly, aryl
iodides substituted with a bromide, chloride or a cyanide could be
smoothly and selectively used as arylating reagents, therefore
providing a useful handle for subsequent functionalization and
diversification of corresponding 3ah to 3ai. A strong electron-
donating group such as MeO in Iodobenzene might hinder the
arylation (3aj, 3ak), as the corresponding product was obtained in
lower yield. Electron-poor aryl iodides performed equally well (3al).
Heteroaryl iodides could also be used for the direct arylation, as
demonstrated with the synthesis of 3am in low efficiency. Finally,
Conjugated systems including biphenyl or naphthyl moieties could
be readily introduced (3an, 3ao).
Results and Discussion
We commenced our study by employing benzoxazole 1a and
iodobenzene 2a as the model substrates. The reaction conditions
were adopted from Ackermann’s previous study on the
photoinduced azole arylation reaction by switching the UV light to
BLUE-LED irradiation.16 Firstly, examination of different copper(I)
salts revealed that CuTC was the optimal one (Table 1, entries 1-
3).We screened various well-established pyridyl-metal complexes
as photoredox catalysts and found out the 2,2’-bipyridine gave the
best result (Table 1, entries 3-5). Switch of the solvent from DMF
to other common solvent such as CH3CN, DMSO decreased the
product yield (Table 1, entries 6-8). Finally, the test of base
suggests the unique role of t-BuOLi, as other bases are less
effective (Table 1, entries 9-12). Control experiments suggested
the essential role of copper, light and base because no desired
product was observed in the absence of neither of these three
factors (Table 1, Entries 13-15).
Scheme 1 Scope studies of aryl iodine a,b
CuTc mol%)
(5
mol%)
2,2-bpy
(5
I
N
O
N
O
t-BuOLi
equiv)
(2.5
R1
+
DMF, RT, BLUE-LED
16 h
R1
2a-o
1a
equiv)
3aa
equiv)
(4
(1
Table 1 Optimization of the reaction conditions for the visible light-induced
copper-catalyzed arylation of benzoxazole
Me
Me
Me
Me
N
O
N
O
N
O
N
O
Me
mol%)
[Cu] (5
mol%)
equiv)
Ligand (5
I
3ae
3ad
N
O
N
O
3ac
3ab
t-BuOLi
(2.5
=
=
40%
+
=
35%
=
46%
61%
yield
yield
yield
yield
Solvent, RT, BLUE-LED
16 h
Me
1a
2a
3aa
equiv)
equiv)
(4
N
O
(1
N
O
N
N
O
Cl
Br
Me
O
Entrya
catalyst ligand
solvent
base
Yield (3aa)[%]b
Me
3ah
3ai
3ag
3af
=
=
30%
46%
=
yield
yield
76%
yield
=
54%
yield
1
CuTc
bpy
DMF
t-BuOLi
t-BuOLi
62
30
39
0
OMe
N
N
N
O
N
O
N
O
2
Cu(OTf) bpy
DMF
OMe
CN
O
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuONa
t-BuOK
Cs2CO3
Et3N
3
CuI
bpy
py
DMF
3am
3ak
3al
3aj
=
12%
=
=
yield
=
44%
46%
52%
yield
yield
yield
CuTc
4
DMF
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
CuTc
no
5
Phen
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
no
DMF
32
13
34
0
N
N
O
O
6
MeCN
DMSO
1,4-dioxane
DMF
7
3an
=
3ao
=
20%
22%
yield
yield
8
aReaction condition: 5 mol% of Copper(I) thiophene-2-carboxylate (CuTc)
terpyridine, 0.2 mmol of 1a, 0.8 mmol of 2a, 0.5 mmol of t-BuOLi in 1 mL
DMF. bIsolate yield.
9
34
31
Trace
Trace
0
10
11
12
13
14
15c
DMF
DMF
The arylation procedure was also successfully applied to
various substituted benzoxazoles, substitutions could be methyl,
methoxy, chloro, and fluoro groups (3ba-3ea). Naphthooxazoles
are good substrates as well (3fa). Further efforts to explore the
heteroarenes revealed that the presence of electron-withdrawing
ester and nitriles were important for activation and regiocontrol of
non-benzolide substrate (3ha and 3ia), for non-substituted
thiophene, no arylated product was observed under the standard
conditions.. Notably, benzothiazole (3ja) can also undergo C-H
DMF
t-BuOLi
t-BuOLi
t-BuOLI
DMF
CuTc
CuTc
DMF
12
0
bpy
DMF
a
Reaction condition: 0.2 mmol of 1a, 0.8 mmol of 2a, 5 mol% of Copper,
5 mol% of ligand, 0.5 mmol of t-BuOLi in 1 mL DMF. b Isolated yield. c no
light. Bpy = 2,2’-bipyridine; Phen = phenanthroline; py = pyridine.
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Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

arylation. In addition, the caffeine, as a kind of xanthines, was also
0.1
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
CuTc+bpy+D
MF
0.09
0.08
0.07
0.06
0.05
0.04
0.03
0.02
0.01
0
CuTc+bpy+D
MF
CuTc+t-
BuOLi+DMF
CuTc+t-
BuOLi+DMF
CuTc+bpy+t-
BuOLi+DMF
CuTc+bpy+t-
BuOLi+DMF
CuTc+bpy+t-
BuOLi+A+DM
F
CuTc+bpy+t-
BuOLi+A+DM
F
300
400
500
-0.1
wavelength (nm)
350
400
450
500
wavelength (nm)
Figure 1 UV-vis absorption spectrums. 1a = 5x10-4 mM, CuTc = 2.5x10-5 mM,
2,2-bpy = 2.5x10-5 mM, t-BuOLi = 1.25x10-3 mM, DMF = 2 mL.
suitable for this reaction system (3ka).
Scheme 2 Scope studies: cycloaddition of alkyne.a, b
Figure 2 UV-vis absorption spectrums between 350 to 500 nm and from 0
to 0.1 abs. 1a = 5x10-4 mM, CuTc = 2.5x10-5 mM, 2,2-bpy = 2.5x10-5 mM, t-
BuOLi = 1.25x10-3 mM, DMF = 2 mL.
u
c
mo
C
T
5
(
(
,
l%
(
)
-
,
mo
2 2 bpy
5
l
%
u v
i
)
I
-
.
u
e
t B Li 2 5
q
O
,
)
-
e
+
t
e
H
t
H
H
-
DMF RT BLUE LED
16h
-
a
aa
3
a
u v
q
i
)
e
u v
q
i
e
2
1
4
1
j
(
)
(
The Stern-Volmer experiments indicated that the excited state
of the in-situ-formed CuTc+bpy+t-BuOLi+Benzoxazole complex is
more likely the photocatalyst, as its photoexcited state is quenched
by PhI more efficiently than that of CuTc+bpy+t-BuOLi (Figure 2).
F
Cl
N
O
MeO
N
Me
N
O
N
O
O
3ba
=
3ca
3da
3ea
=
=
64%
69%
=49%
52%
yield
yield
yield
COOEt
yield
CN
N
N
O
O
1.3
CuTc+bpy+t-BuOLi+Benzoxazole (5x10-4 mmol/mL)
S
S
3fa
=
3ha
3ia
=
3ga
yield
CuTc+bpy+t-BuOLi (5x10-4 mmol/mL)
1.25
1.2
=
=
52%
40%
22%
50%
yield
yield
yield
Me
N
O
N
S
N
N
Ksv=0.0148
N
1.15
1.1
I0/I
Me
Me
O
3ka
3ja
=
=
21%
yield
21%
yield
1.05
1
Ksv=0.0089
aReaction condition: 5 mol% of Copper(I) thiophene-2-carboxylate (CuTc)
terpyridine, 0.2 mmol of 1a, 0.8 mmol of 2a, 0.5 mmol of t-BuOLi in 1 mL
DMF. bIsolate yield.
0
4
8
12
16
PhI /μL (0.05 mmol/mL)
To gain some mechanistic insights, several experiments were
performed. The UV-vis spectra of individual reagents or complexes
were recorded at the reaction concentration in DMF. None of the
benzoxazole, CuTc, or ligand absorb at wavelengths around 400 nm.
However, CuTc+bpy+t-BuOLi+benzoxazole (which should form in
situ in the reaction) absorbed in the range of 350-500 nm in terms
of intensity and broadness. CuTc+bpy+t-BuOLi also shows
recognizable absorption during that range (Figure 1). These results
suggest that an aggregation of bpy, copper, and nucleophile
account for the photoactive species under the BLUE-LED irradiation.
Figure 3 Stern-Volmer plot for the emission quenching of in-situ
generated Cu catalyst in DMF by various concentrations of quencher PhI.
I0 and I = luminescence intensities in the absence and presence of the
indicated concentrations of PhI, respectively.
Based on literature16-18 and these findings, we proposed a
reaction mechanism (Scheme 2). In the presence of base and
benzoxazole, the coordination complex of ligand and copper salt
(A) forms LnCu(I)-benzoxazole (B), which serves as the photoactive
species lead to a photoexcited state [LnCu(I)-benzoxazole]* (C), as
confirmed by UV-Vis light absorption experiment and
luminescence quenching experiments19. Then the excited-state
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
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First author et al.
Report
adduct engages in double electron transfer process, in which the
Cu(I) is oxidized to Cu(III), with aryl iodides to generate
intermediate (D). Finally, reductive elimination affords product and
regenerates the copper-ligand coordination complex (A).
respectively) and internally referenced to tetramethylsilane (TMS)
signal or residual protic solvent signals. 19F NMR spectra were
recorded on a Varian instrument (376 MHz), an Agilent instrument
(376 MHz), an Bruker instrument (376 MHz) referenced relative to
CFCl3. Data for 1H NMR are recorded as follows: chemical shift (δ,
ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet
or unresolved, br = broad singlet, coupling constant in Hz,
integration). Data for 13C NMR are reported in terms of chemical
shift (δ, ppm). Infrared Spectroscopy (IR) was processed on an FT-
IR spectrometer named Nicolet 380. The method is denoted in
brackets. For the most significant bands the wave number ṽ (cm-1)
is given. Low resolution mass spectrum (LRMS) were performed by
Agilent Technologies 5973N instrument. High resolution mass
spectrum (HRMS) were performed by Thermo Fisher Scientific LTQ
FT Ultra instrument and Waters Micromass GCT Premier
instrument.
N
A
Ar
O
t-BuOLi
N
N
[CuI]
t
-BuOH+LiI
R.E
N
O
N
N
Chemicals were purchased from commercial suppliers. Unless
stated otherwise, all the substrates and solvents were purified and
dried according to standard methods prior to use. Reactions
requiring inert conditions were carried out in glove box.
N
N
N
O
N
O
III
Ar
[Cu ]
I
D
[CuI]
B
General procedure for arylation products
To a mixture of Copper(I) thiophene-2-carboxylate (CuTc) (2
mg, 0.01 mmol, 5 mol % ), 2,2'-Bipyridine (bpy) (2 mg, 0.01 mmol,
5 mol %) , lithium tert-butoxide (t-BuOLi) (40 mg, 0.5 mmol, 2.5
equiv) and anhydrate N,N- dimethylformamide (DMF) (1 ml, 0.2 M)
were added with magnetic stir bar under nitrogen atmosphere.
After stirring 5 minutes, the color of solvent changed from light
green to light yellow, and the 1 (0.2 mmol) and 2 (0.8 mmol) were
added into the mixture. The resulting solution then was put into
the lightbox with the blue-LED and stirred 16 hours under room
temperature, in which there is 5 centimeters between the bottle
and light. The resulting suspension was filtered over a silica gel pad
using ethyl acetate (EtOAc) as eluent and evaporated in vacuo. The
residue was purified by chromatography (PE: EA = 20:1 ~2:1) to
afford the product.
2-phenylthiophene-3-carbonitrile (3ia), brown oil, 0.018g, 50%
yield. 1H NMR (400 MHz, CDCl3) δ 7.76 (dd, J = 8.1, 1.4 Hz, 2H), 7.51-
7.43 (m, 3H), 7.31 (dd, J = 14.9, 5.3 Hz, 2H). 13C NMR (101 MHz,
CDCl3) δ 153.94, 131.32, 130.45, 129.77, 129.27, 127.79, 125.49,
115.90, 106.13. IR (neat.) cm-1: 3111, 2225, 1491, 1447, 1254, 1076,
944, 911, 832, 760, 723, 689, 647, 533, 461. HRMS (EI) calculated
for C11H7NS: 185.0299 Found: 185.0294.
hv
N
N
*
N
O
Ar-I
[CuI]
C
Scheme 3 Proposed catalytic cycle.
Conclusions
In conclusion, diversified arylated heterocycles have been
synthesised by photo-induced, copper-catalysis C-H arylation. The
mild reaction conditions and reasonably broad substrate scope are
remarkable. The synthetic application of the methodology
established in this work to material and pharmaceutical science is
positively expected. The application of this strategy to
stereoselective functionalization of heterocycles is underway in
this laboratory.
Experimental
Generally information
2-(p-tolyl)benzo[d]oxazole (3ab), white solid, 0.025g, 61% yield.
1H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.0 Hz, 2H), 7.78-7.70 (m,
1H), 7.58-7.52 (m, 1H), 7.32 (d, J = 6.2 Hz, 4H), 2.43 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 163.33, 150.68, 142.16, 142.05, 129.69, 127.64,
124.93, 124.54, 124.34, 119.83, 110.53, 21.67.
Unless stated otherwise, all reactions were carried out in
flame-dried glassware under a dry nitrogen atmosphere. All
solvents were purchased and without further purified and dried.
Copper(I) thiophene-2-carboxylate (CuTc) was purchased from TCI
shanghai. Anhydrous Lithium tert-butoxide and N,N-
dimethylformamide (DMF) were purchased from J&K. Chem Co.,
Ltd. Commercial materials were obtained from Adamas-beta, TCI
shanghai, Alfa Aesar and Bidepharmatech.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
1H and 13C NMR spectra were recorded on an Agilent
instrument (400 MHz and 101 MHz respectively), a Varian
instrument (400 MHz and 101 MHz respectively) and Bruker
instruments (400 MHz and 101 MHz, manual and auto simpler
Acknowledgement
We are grateful to NSFC-21772218, 21421002, XDB20000000,
State Key Laboratory of Organometallic Chemistry, Shanghai
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Institute of Organic Chemistry, and the Chinese Academy of
Sciences.
directions. Chem. Soc. Rev. 2018, 47, 7190-7202. (i) W. Ji.; H. Wang.;
C. -A. Li.; F. Gao.; Z. -F. An.; L. Huang.; H. Wang.; Y. Pan.; D. -R. Zhu.;
J. -Q. Wang.; C. Guo.; J. A. Mayoral.; S. Jing. Cuprous cluster as
effective single-molecule metallaphotocatalyst in white light-driven
C-H arylation. Journal of Catalysis, 2019, 378, 270–276.
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(The following will be filled in by the editorial staff)
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.

First author et al.
Report
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
This article is protected by copyright. All rights reserved.

Entry for the Table of Contents
XXX
mol
CuTc
2,2'-bpy
-BuOLi
%)
mol
(5
%)
equiv)
(5
(2.5
I
t
Het
R1
+
Het
Visible Light-Induced Copper-Catalyzed C-H
Arylation of Benzoxazoles
DMF, RT, BLUE-LED
R1
examples
12-76%
24
4
1
equiv
equiv
A general method for visible light-induced copper-catalyzed arylation of sp2 C-H bonds
of azoles has been developed. The method employs aryl halide as the coupling
partner, lithium alkoxide as base. A variety of azoles including benzoxazole and
benzothiazole can be arylated. Furthermore, electron-poor heterocycles such as
thiophene possessing one electron-withdrawing group can also be arylated.
Xiaodong Ma, Guozhu Zhang*
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.