The development of copper-catalyzed aerobic oxidative coupling of h-tetrazoles with boronic acids and an insight into the reaction mechanism

Article abstract of DOI:10.1002/chem.201302857

The development of a highly efficient and practical protocol for the direct C-N coupling of H-tetrazole and boronic acid was presented. A careful and patient optimization of a variety of reaction parameters revealed that this conventionally challenge reaction could indeed proceed efficiently in a very simple system, that is, just by stirring the tetrazoles and boronic acids under oxygen in the presence of different Cu^I or Cu^II salts with only 5 mol % loading in DMSO at 100 °C. Most significantly, the reaction could proceed very smoothly in a regiospecific manner to afford the 2,5-disubstituted tetrazoles in high to excellent yields. A mechanistic study revealed that both tetrazole and DMSO are crucial for the generation of catalytically active copper species in the reaction process in addition to their role as reactant and solvent, respectively. It is demonstrated that in the reaction cycle, the Cu^I catalyst could be oxidized to Cu^II by oxygen to form a [CuT₂D] complex (T=tetrazole anion; D=DMSO) through an oxidative copper amination reaction. The Cu^II complex thus formed was confirmed to be the real catalytically active copper species. Namely, the Cu^II complex disproportionates to aryl Cu^III and Cu^I in the presence of boronic acid. Facile elimination of the Cu^III species delivers the C-N-coupled product. The results presented herein not only provide a reliable and efficient protocol for the synthesis of 2,5-disubstituted tetrazoles, but most importantly, the mechanistic results would have broad implications for the de novo design and development of new methods for Cu-catalyzed coupling reactions. Copyright

Full text of DOI:10.1002/chem.201302857

DOI: 10.1002/chem.201302857
Full Paper
&
CÀN Bond Formation
The Development of Copper-Catalyzed Aerobic Oxidative
Coupling of H-Tetrazoles with Boronic Acids and an Insight into
the Reaction Mechanism
Chao-You Liu,[a, b] Yu Li,[a, b] Jin-Ying Ding,[a] De-Wen Dong,[a] and Fu-She Han*[a, c]
Abstract: The development of a highly efficient and practi-
cal protocol for the direct CÀN coupling of H-tetrazole and
boronic acid was presented. A careful and patient optimiza-
tion of a variety of reaction parameters revealed that this
conventionally challenge reaction could indeed proceed effi-
ciently in a very simple system, that is, just by stirring the
tetrazoles and boronic acids under oxygen in the presence
of different CuI or CuII salts with only 5 mol% loading in
DMSO at 1008C. Most significantly, the reaction could pro-
ceed very smoothly in a regiospecific manner to afford the
2,5-disubstituted tetrazoles in high to excellent yields. A
mechanistic study revealed that both tetrazole and DMSO
are crucial for the generation of catalytically active copper
species in the reaction process in addition to their role as re-
actant and solvent, respectively. It is demonstrated that in
the reaction cycle, the CuI catalyst could be oxidized to CuII
by oxygen to form a [CuT2D] complex (T=tetrazole anion;
D=DMSO) through an oxidative copper amination reaction.
The CuII complex thus formed was confirmed to be the real
catalytically active copper species. Namely, the CuII complex
disproportionates to aryl CuIII and CuI in the presence of bor-
onic acid. Facile elimination of the CuIII species delivers the
CÀN-coupled product. The results presented herein not only
provide a reliable and efficient protocol for the synthesis of
2,5-disubstituted tetrazoles, but most importantly, the mech-
anistic results would have broad implications for the de
novo design and development of new methods for Cu-cata-
lyzed coupling reactions.
Introduction
Thus, alternative protocols for accessing triazoles through
the 1,3-dipolar cycloaddition of an alkyne and an azide, that is,
click-chemistry, have been well- developed.[4] However, the
analogous reaction of an azide and a nitrile for the construc-
tion of tetrazoles is extremely difficult. Such a cycloaddition
could proceed only intramolecularly[5] or required strong elec-
tron-deficient nitrile substrates such as acyl cyanides and sulfo-
nyl cyanides if the intermolecular version is under consider-
ation.[6] Recently, Jiao disclosed a straightforward method for
accessing tetrazoles from the simple styrene derivatives and
TMSN3.[7] In addition, the Pd-catalyzed Suzuki–Miyaura cross-
coupling of 5-halo-1-aryl(alkyl)tetrazoles has also been report-
ed.[8]
Transition-metal-catalyzed aryl CÀN bond-forming reactions are
one of the most popularly investigated reactions in modern or-
ganic synthesis because of the ubiquity of aromatic CÀN
bonds in a broad spectrum of areas including natural product,
pharmaceutical, agrochemical, catalysis, coordination chemis-
try, and polymer science.[1] The complementary use of Buch-
wald–Hartwig[2] and Chan–Evans–Lam[3] (CEL) couplings allow
for a flexible and efficient construction of CÀN bonds from
a rich variety of NH-containing substrates, including primary
and second alkyl and aryl amines, amides, imides, ureas, carba-
mates, sulfonamides, and hydrazine derivatives. However, de-
spite of all these significant progresses, the coupling reactions
for electron-deficient azoles such as triazoles and tetrazoles re-
mains a considerable challenging by using either approach.
Although these methods have significantly advanced the
synthesis of 1,5-disubstituted tetrazoles, more efficient and reli-
able protocols remain highly desirable because of the broad
utility of tetrazole derivatives.[1] Moreover, the methods for the
synthesis of 2,5-disubstituted tetrazoles are neither general nor
practical. The Kakehi tetrazole synthesis[9] using aldehydes re-
quired several synthetic steps. Alternatively, the Pd- or Cu-cata-
lyzed N-2-arylation of 5-substituted tetrazoles has been investi-
gated [Eq. (1)].[10]
[a] C.-Y. Liu, Y. Li, J.-Y. Ding, Prof. Dr. D.-W. Dong, Prof. Dr. F.-S. Han
Changchun Institute of Applied Chemistry
Chinese Academy of Sciences, 5625 Renmin Street
Changchun, Jilin 130022 (China)
E-mail: fshan@ciac.ac.cn
[b] C.-Y. Liu, Y. Li
The University of Chinese Academy of Sciences
Beijing 100864 (China)
[c] Prof. Dr. F.-S. Han
State Key Laboratory of Fine Chemicals
Dalian University of Technology, Dalian 116024 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201302857.
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However, these methods necessitated the conversion of the
tetrazoles into the more reactive N-metalated tetrazoles (M=
SnR3 and Na) prior to coupling. Moreover, diaryliodonium salts
were used as the coupling partners. As a result, such methods
are not only operationally tedious, but also generate stoichio-
metric amounts of toxic wastes such as organotin and arylio-
dide. In addition, high catalyst-loading was required in many
cases. As a structural motif featuring the presence of four nitro-
gen atoms in a five-membered aromatic ring, tetrazoles exhibit
unique physical and chemical nature. They can serve as meta-
bolically stable surrogates of carboxylic acid group.[11] More im-
portantly, they exhibit not only interesting biological proper-
ties but also good resistance against biological degradation.[12]
Furthermore, terazoles are highly stable under a wide range of
chemical environments[13] such as strong basic/acidic, and oxi-
dizing/reducing conditions. Therefore, tetrazoles should find
ample applications in a broad spectrum of areas if methods for
facile synthesis of such compounds are established. In fact,
a number of previous works have exemplified the importance
of tetrazole compounds in materials science,[14] pharmaceuti-
Table 1. Effect of oxidants on the coupling reaction.[a]
Entry
Oxidant [(equiv)]
Yield [%][b]
1
2
3
4
PIFA (2.0)
PIDA (2.0)
BPO (1.0)
52
<30[c]
<19[c]
<34[c]
mCPBA (1.0)
[a] Reaction conditions: tetrazole 1a (0.5 mmol, 1.0 equiv), boronic acid
2a (0.6 mmol, 1.2 equiv), [Cu(OAc)2] (0.5 mmol, 1.0 equiv), pyridine
(1.5 mmol, 3.0 equiv), in DMF (4 mL) under nitrogen at 1208C for 12 h.
[b] Yield of the isolated product. [c] Contaminated by some inseparable
impurities.
mization of various reaction parameters including catalyst,
base, solvent, reaction time, and atmosphere, afforded the
coupled product 3a in 26% yield with the presence of
1.5 equiv of [Cu(OAc)2] and 3.0 equiv of pyridine base. Al-
though the outcome was less satisfactory, this preliminary
result provided an important clue for the direct coupling of
tetrazole and boronic acid by employing copper catalysts. In
our initial study, we examined the effect of the oxidants on the
reaction. An extensive screening of organic and inorganic oxi-
dants showed that although most of the oxidants proved to
be futile, four organic oxidants, [bis(trifluoroacetoxy)iodo]ben-
zene (PIFA), (diacetoxyiodo)benzene (PIDA), benzoyl peroxide
(BPO), and meta-chloroperbenzoic acid (mCPBA), could provide
the desired products (Table 1). Notably, the yield of 2,5-disub-
stituted product 3a could be increased to 52% in the presence
of PIFA (Table 1, entry 1).
cal,[15] and biological applications[16]
.
With our constant interest in the use of first row transition-
metal-catalyzed cross-couplings of boron compounds,[17] we
have previously developed a simple, clean, and highly efficient
protocol that allows for flexible synthesis of 2,5-disubstituted
tetrazoles through the direct coupling of H-tetrazoles and non-
toxic boronic acids in a regiospecific manner [Eq. (2)].[18] The re-
action proceeded in high yields in the presence of only
5 mol% of [Cu2O] catalyst under oxygen in DMSO solvent at
1008C. As the most important advantage, the protocol avoids
the use of metalated tetrazoles and high-valent iodonium salts
as reactants. In addition, external bases, ligands, and other ad-
ditives routinely used in classic CEL couplings were not
needed. After establishing the most practical and efficient
method, we became interested in why the conventionally chal-
lenging reaction could indeed proceed so efficiently in such
a simple system. Therefore, we initiated an in-depth study
toward clarifying the reaction mechanism. Such an investiga-
tion would be valuable not only for a deeper understanding of
CEL coupling, but also would have further implications for the
de novo design and development of new methods for Cu-cata-
lyzed coupling reactions. The important results will be present-
ed herein.
Having found a promising oxidant, we then examined the
effect of solvents and bases (Table 2). Disappointingly, screen-
ing of various solvents revealed that only aprotic polar DMF
and N,N-dimethylacetamide (DMAc) were the best solvents to
afford the products in moderate yields (Table 2, entries 1 and
2). Other solvents gave only poor yields (Table 2, entries 3–6)
or completely ineffective. Attempted improvement of the yield
by varying the base was also fruitless. In most of the cases, re-
placement of pyridine by a range of inorganic and organic
bases gave only a trace amount of product (data not shown).
Table 2. Effect of solvents on the coupling reaction of 1a and 2a.[a]
Entry
Solvent
T [oC]
t [h]
Yield [%][b]
1
2
3
4
5
6
DMF
120
120
120
90
80
80
12
12
12
24
24
24
52
43
17
20
22
31
DMAc
DMSO
tBuOH
THF
DCE
Results and Discussion
[a] Reaction conditions: tetrazole 1a (0.5 mmol, 1.0 equiv), boronic acid
2a (0.6 mmol, 1.2 equiv), [Cu(OAc)2] (0.5 mmol, 1.0 equiv), PIFA (1.0 or
2.0 equiv), pyridine (1.5 mmol, 3.0 equiv), in solvent (4 mL) under nitro-
gen. [b] Yield of the isolated product; DMAc=N,N-dimethylacetamide.
In an early report by Lam and co-workers,[19] the Cu-mediated
cross-coupling of 5-phenyltetrazole 1a and 4-methyphenyl
boronic acid 2a was investigated (Table 1). An extensive opti-
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Table 3. Effect of copper salts on the coupling reaction of 1a and 2a.[a]
Table 4. Optimization of the reaction conditions.[a]
Entry [Cu2O] [mol%] Py. [equiv] Solvent T [oC]/t [h] Yield [%][b]
Entry
Cu salt [mol%]
Oxidant [(equiv)]
t [h]
Yield[b] [%]
1
2
3
4
5
6
7
8
9
[CuI] (100)
[CuBr] (100)
[CuCl] (100)
[CuCl2] (100)
[Cu(acac)2] (100)
[Cu(OTf)2] (100)
[Cu(OAc)2] (100)
[Cu2O] (100)
[Cu2O] (100)
[Cu2O] (100)
PIFA (2.0)
PIFA (2.0)
PIFA (2.0)
PIFA (1.0)
PIFA (1.0)
PIFA (1.0)
PIFA (1.0)
PIFA (1.0)
air
38
38
14
24
24
12
12
24
24
24
trace[c]
trace[c]
trace[c]
trace[c]
trace[c]
47
52
60
50
67[d]
1
2
3
4
5
6
7
8
100
100
50
50
20
10
5
5
5
5
5
3.0
3.0
3.0
3.0
3.0
3.0
2.0
2.0
–
DMF
120/24
120/24
120/24
120/12
1200.5
120/1
100/5.5
80/24
100/4
77
92
96
95
95
92
94
n.c.[c]
95[d]
27
12[e]
n.r.[f]
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
9
10
air
10
11
12
–
–
–
100/24
100/48
100/28
DMSO
DMSO
[a] Reaction conditions: tetrazole 1a (0.5 mmol, 1.0 equiv), boronic acid
2a (0.6 mmol, 1.2 equiv), Cu salt (0.5 mmol, 1.0 equiv), PIFA (1.0 or
2.0 equiv), pyridine (1.5 mmol, 3.0 equiv), in DMF (4 mL) under nitrogen
at 1208C. [b] Yield of the isolated product. [c] Monitored by TLC.
[d] 2.0 equiv of 2a was used; acac=acetylacetonate.
–
[a] Reaction conditions: tetrazole 1a (0.5 mmol, 1.0 equiv), boronic acid
2a (1.0 mmol, 2.0 equiv), [Cu2O], pyridine in solvent (4 mL). [b] Yield of
the isolated product. [c] The reaction was not completed. [d] Pyridine
base was omitted. [e] The reaction was carried out under nitrogen. [f] No
reaction in the absence of [Cu2O].
Next, by fixing the PIFA as the oxidant, pyridine as the base,
and DMF as the solvent, we carried out a survey of copper
salts (Table 3). Among a range of CuI and CuII salts (Table 3, en-
tries 1–8), only [Cu(OTf)2], [Cu(OAc)2], and [Cu2O] could affect
the reaction to give the product in moderate to moderately
high yields (Table 3, entries 6–8); the best result was afforded
by [Cu2O] in 60% yield (entry 8).
amount of [Cu2O] and less equivalents of pyridine. Fortunately,
a systematic examination on these parameters exemplified
that the conditions could be considerably simplified. Namely,
the loading amount of [Cu2O] catalyst could be reduced to as
low as 5 mol% and the pyridine base could be entirely omitted
from the reaction system (Table 4, entries 3–9). In addition, the
reaction temperature could be further lowered to 1008C.
Under such simplified conditions, the reaction was completed
within 4 h to afford the coupled product 3a in 95% yield
(Table 4, entry 9). As a comparison, the reaction was rather
sluggish in DMF solvent (Table 4, entry 10) or under nitrogen
atmosphere even if the reaction time was elongated (Table 4,
entry 11). In addition, the product was not observed in the ab-
sence of the [Cu2O] catalyst (Table 4, entry 12). These results
clearly demonstrated that DMSO and oxygen is of crucial im-
portance for the transformation.
Although the result was still not satisfactory after the ex-
haustive optimization, a yield of 60% was a significant im-
provement compared with the reported result.[19] More to the
point, we recognized through these studies that a suitable
choice of solvent, oxidant, and base would be essentially im-
portant for achieving an efficient cross-coupling. On the other
hand, we were also aware that although the yield might be im-
proved to a satisfactory level after further optimization, practi-
cal application of the method under the current conditions
would be reduced due to the use of stoichiometric amounts of
copper catalyst, organic oxidant, and pyridine base. As such,
our efforts were then devoted to simplifying the reaction con-
ditions. Delightedly, we found that the coupled product 3a
could be obtained in 50% yield when the reaction was carried
out under air in the absence of PIFA (Table 3, entry 9). Increase
of boronic acid 2a from 1.2 to 2.0 equiv could improve the
yield to 67% (Table 3, entry 10).
The crucial importance of a combination use of DMSO as
solvent and oxygen as oxidant for the direct coupling of tetra-
zoles and boronic acids was firmly exemplified by the highly
effective coupling of 1a and 2a by employing an array of
other copper salts. As shown in Table 5, rapid conversion as
well as excellent yield was observed not only for various CuI
(entries 1–3), but also for several CuII salts (entries 4–6), albeit
With this highly promising result in hand, we re-examined
the reaction parameters by omitting the organic oxidant from
the reaction system. After a brief optimization, we found that
the yield of 3a could be improved to 77% when the reaction
was carried out under oxygen and in the presence of 2.0 equiv
of boronic acid (Table 4, entry 1). More pleasingly, an excellent
yield (92%) was obtained by replacing DMF with DMSO
(Table 4, entry 1 vs. 2). Here, the use of undistilled DMSO as
the solvent makes the reaction more convenient for operation.
Thus, through this extensive optimization, we achieved the
direct coupling of tetrazole and boronic acid in high yield with
the presence of 100 mol% [Cu2O] and 3.0 equiv of pyridine
base under oxygen in DMSO at 1208C. At this juncture, we
became further interested in whether the reaction could pro-
ceed in a more efficient manner, that is., with a catalytic
Table 5. Catalytic efficiency of various copper salts on the coupling reac-
tion of 1a and 2a in DMSO under oxygen.[a]
Entry
Cu salt [mol%]
t [h]/T [oC]
Yield [%][b]
1
2
3
4
5
6
[CuI] (10)
[CuBr] (10)
[CuCl] (10)
[Cu(acac)2] (10)
[Cu(OAc)2] (10)
[CuO] (10)
4/100
3.5/100
4/100
4/100
3.5/100
120/100
98
90
85
90
92
87
[a] Reaction conditions: tetrazole 1a (0.5 mmol, 1.0 equiv), boronic acid
2a (1.0 mmol, 2.0 equiv), copper salt (10 mol%) under oxygen in DMSO
(4 mL) at 1008C. [b] Yield of the isolated product.
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[CuO] required a prolonged reaction time (entry 6). In stark
contrast, these salts were inactive or displayed only poor activi-
ty even presented in stoichiometric amount if either DMSO or
oxygen was replaced by other solvents or oxidants (Tables 1–3,
and entries 10 and 11 in Table 4).
of solvent; whereas we have unambiguously demonstrated
that solvent is crucial for effective reaction herein. In addition,
the critical role played by oxygen also awaits clarification be-
cause, unlike the coupling of imidazole and boronic acid,[21]
oxygen is indispensable in promoting the coupling of tetra-
zoles and boronic acids. As such, the coupling of tetrazoles
and boronic acids should undergo a different reaction model
from those proposed in literatures for the coupling of alcohols
or electron-rich azoles with boronic acids. Therefore, we carried
out a detailed investigation into the reaction mechanism of
tetrazoles and boronic acids.
Now, through a careful and patient investigation, we have
established a very simple and robust methodology for the re-
giospecific synthesis of 2,5-disubstituted tetrazoles through
the direct coupling of H-tetrazole and boronic acid. Most sig-
nificantly, the method exhibited a broad generality and reliabil-
ity that allowed for the diverse synthesis of 2,5-disubstituted
tetrazoles through a flexible combination of various tetrazoles
and boronic acids (Table 6).[18] Undoubtedly, the success on this
conventionally challenging reaction should expand significant-
ly the original scope of CEL coupling.
Initial control experiments showed that heating the mixture
of [Cu2O] and boronic acids in DMSO resulted in a complex
mixture generated from the homocoupling, protonolysis, and
hydrolysis of boronic acids. In addition, the dehydrated boroxin
might also be detected. In fact, these side-reactions were often
observed in CEL coupling.[3] Interestingly, when [Cu2O] was
stirred with a large excess of 5-phenyltetrazole 1a (1:4 mol/
mol) in DMSO, we observed two entirely different results de-
pending on the reaction atmosphere. Namely, the particles of
the brownish-red [Cu2O] remained almost unchanged under ni-
trogen after heating at 1008C for over 12 h. In sharp contrast,
the color of Cu2O and 1a mixture was changed gradually to
sky-blue under oxygen (Figure S1 in the Supporting Informa-
tion). The insoluble blue precipitates were collected by filtra-
tion and washed thoroughly with water and ethyl acetate. The
dried powder was then analyzed by using various spectroscop-
ic techniques.
Next, to gain a deeper understanding on this transformation,
we carried out the mechanistic investigations. Although plenty
of mechanisms for the copper-catalyzed CEL coupling have
been proposed based on the empirical observations since its
discovery,[3] systematic investigations have been rarely carried
out. In 2009, Stahl and co-workers[20] reported the first detailed
mechanistic study on the [Cu(OAc)2]-catalyzed CÀO bond-form-
ing reaction using tolylboronic ester and MeOH as substrates.
In another report in 2010,[21] Tromp and co-workers studied the
mechanism of a CuII complex, [Cu(OH)(tmeda)]2·Cl2 (tmeda=
tetramethylethylenediamine), -catalyzed cross-coupling of phe-
nylboronic acid with imidazole using a multitechnique ap-
proach.
Although these systematic studies, along with those empiri-
cal proposals, provided valuable information for an in-depth
understanding of CEL coupling, they are inconvincible when
used to elucidate the reaction mechanism of tetrazoles and
boronic acids because none of them has considered the effect
The X-ray photoelectron spectroscopic (XPS) analysis re-
vealed that the 2p3/2 binding energy of the copper species was
935.2 eV, indicating that the CuI species was oxidized to CuII
under oxygen atmosphere (Figure 1a). The oxidative genera-
tion of CuII species was strongly supported by the comparison
experiment using [Cu(OAc)2]. This CuII salt could also form
blue-colored complexes with tetrazole 1a either under nitro-
gen or under oxygen, and exhibited identical 2p binding
energy (Figure 1b, the 2p3/2 binding energy was 934.9 eV) to
that of the complex prepared from [Cu2O] and 1a under
oxygen. Furthermore, the solid state NMR spectroscopic stud-
ies showed that both complexes formed from [Cu2O] and
[Cu(OAc)2] have the same spectral data, which implies that the
two complexes possess the same structure (Figure 2a and b).
Table 6. Cu-catalyzed coupling of various tetrazoles 1 with boronic acids
2.[a]
Figure 1. XPS spectra of: a) the complex from [Cu2O] and tetrazole 1a; and
b) the complex from [Cu(OAc)2] and 1a.
[a] See ref. [18] for detailed results and discussion.
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quently used as a common ligand in coordination chemistry
with various transition metals.[22] IR spectroscopic testing con-
firmed that the strong and broad bands around 2500–
3100 cmÀ1, due to the NÀH in free tetrazole 1a were missing
in both Cu complexes (data not shown), indicating the loss of
hydrogen atom in tetrazole during the complex formation.
Thus, on the basis of the XPS, NMR spectroscopy, XRD, IR,
and elemental analysis, we may confirm that the [Cu2O] and
[Cu(OAc)2] formed the same complexes with a common unit
formula as [(Cu2+){(1a)À}2(dmso)]. Namely, a CuII center con-
nected with two tetrazole anions through a CuÀN covalent
bond and one DMSO molecule through a coordination bond.
The deduced structure of the complex was strongly supported
by the mass analysis (Figure S2 in the Supporting Information).
MALDI-TOF mass spectroscopic study on the copper complex
revealed a strong peak at m/z 353.0, corresponding to the
[(Cu2+){(1a)À}2] complex (calcd m/z 353.0). DMSO was lost due
to the relatively weak coordination bond. In addition, a rather
weak peak at m/z 561.0 appeared. This single peak can be as-
signed to a [(Cu2+)2{(1a)À}3] species (calcd m/z 561.0) due pre-
sumably to the recombination of fragment ions. As a result,
the comprehensive spectroscopic study not only clarified the
structure of the copper complex, but also most interestingly,
we have found an unprecedented reaction that the CuI species
could form a CuII complex through an oxidative copper amina-
tion. To facilitate the following discussion, the CuII complexes
formed from [Cu2O] and [Cu(OAc)2] were defined as CuT2D-
1 and CuT2D-2, respectively (T=tetrazole anion, and D=
DMSO). Here, it should be mentioned that although we have
confirmed the unit structure of the complexes, their poor solu-
bility makes it difficult to confirm whether the complexes exist
in the monomeric or polymeric form. Indeed, we noted that
the tetrazole-based CuII complexes have been reported in
1961.[23] However, little is known about the nature of such type
of complexes due to their poor solubility.
Figure 2. Solid state 13C NMR spectra of: a) the complex from [Cu2O] and tet-
razole 1a; b) the complex from [Cu(OAc)2] and tetrazole; c) free 1a.
In the 13C NMR spectra, a set of signals at the aromatic region
appeared. In addition, a singlet at d=30.5 ppm was also pre-
sented. These observations suggested that the CuII center con-
nects with tetrazole 1a and the DMSO molecule. Moreover,
compared with the free 1a (Figure 2c), the signals of the
phenyl ring in the CuII complex are shifted largely downfield of
up to about d=45 ppm. Such a large shift implies that there is
a strong bond affinity between tetrazole 1a and CuII species.
The structural identity of the two complexes was further con-
firmed by the powder X-ray diffraction (XRD; Figure 3). Both
complexes exhibited exactly the same XRD patterns.
In good agreement with the NMR data and XRD patterns, el-
emental analysis showed that both the complexes derived
from [Cu2O] and [Cu(OAc)2] have identical element contents
consisting of Cu, tetrazole 1a, and DMSO in 1:2:1 ratio
(Table 7). These results indicate that DMSO may serve as
a ligand to coordinate with CuII. In fact, DMSO has been fre-
Having clarified the structure of the copper complexes, we
then investigated the coupling reaction of CuT2D-1 complex
with boronic acid 2a. For parallel comparison, the reaction of
CuT2D-2 was also performed (Table 8). Interestingly, we found
that when CuT2D-1 or CuT2D-2 was treated with boronic acid
2a in 1:4 molar ratio (corresponding to 1:2 ratio of 1a/2a as
used in the optimized conditions; Table 4), the coupled prod-
uct 3a was obtained in about 25% yield under nitrogen based
Figure 3. Powder X-ray diffraction pattern of: a) the complex from [Cu2O]
and tetrazole 1a; and b) the complex from [Cu(OAc)2] and 1a.
Table 8. Coupling reaction of Cu complexes with boronic acid 2a.[a]
Entry
Cu Complex
Atmosphere
t [h]
Yield [%][b]
1
2
3
4
CuT2D-1
CuT2D-2
CuT2D-1
CuT2D-2
N2
N2
O2
O2
13
13
13
13
23[c]
25[d]
49[e]
52[d]
Table 7. Elemental analysis data of copper complexes formed from
[Cu2O] (CuT2D-1) and [Cu(OAc)2] (CuT2D-2).[a]
Cu Complexes
Cu [%]
C [%]
H [%]
N [%]
S [%]
[a] Reaction conditions: Cu complex (0.25 mmol, 1.0 equiv), boronic acid
2a (1.0 mmol, 4.0 equiv) in DMSO (4 mL) at 1008C. [b] Yield of the isolat-
ed product based on the equiv of tetrazole anions in the copper com-
plexes; 1 mol of complex contains 2 mol of tetrazole anions. [c] Average
yield for three runs. [d] Average yield for two runs. [e] Average yield for
four runs.
CuT2D-1
CuT2D-2
[(Cu2+){(1a)À}2(dmso)]
14.64
15.27
14.71
44.03
44.00
44.49
3.54
3.57
3.73
25.77
25.84
25.94
7.39
7.22
7.42
[a] Average value from two batches of samples, each batch was mea-
sured three times.
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Figure 4. Color changes of the reaction mixture of CuT2D-1 with boronic
acid 2a under nitrogen (left) and oxygen (right): A) starting mixture; B) heat-
ing after 2 h; and C) heating after 10 h.
on the equivalents of tetrazole anions in the complexes
(Table 8, entries 1 and 2). However, the yields were increased
to about 50% under oxygen (Table 8, entries 3 and 4). The un-
reacted tetrazole 1a could be recovered almost quantitatively
after cracking the copper complexes with diluted aqueous HCl,
indicating that no other side reaction occurs. The results exhib-
ited good duplicability for several trials. Correlated with the re-
action yields, an apparently different color change was ob-
served for the reaction systems under the different atmos-
phere. As shown in Figure 4, with the progress of the reaction,
the blue colored starting mixture of CuT2D-1 (or CuT2D-2) and
boronic acid 2a (Figure 4A or Figure S3 in the Supporting In-
formation) changed to dark gray under nitrogen (Figure 4B,
left). In stark contrast, the color turned grass-green under
oxygen (Figure 4B, right). Further heating of the reaction ves-
sels resulted in an off-white (Figure 4C, left) and a dark-green-
colored mixture (Figure 4C, right) for the nitrogen and oxygen
systems, respectively. XPS analyses of the precipitates recov-
ered from the reaction mixture revealed that the redox state of
the CuII species under oxygen atmosphere remained un-
changed. The 2p3/2 binding energy was 935.1 eV (Figure 5,
spectrum c). This value is identical to that of the starting com-
plex CuT2D-1 or CuT2D-2 (Figure 1). In contrast, the 2p3/2 bind-
ing energy was changed to 931.7 eV for the insoluble residues
recovered from the reaction mixture under nitrogen (Figure 5,
spectrum d). This data strongly evidenced that the CuII species
was converted into CuI during the reaction under nitrogen. As
an important hint, the formation of CuI suggested that the
product was formed through the reductive elimination of CuIII
rather than CuII intermediates, since Cu0 was not detected.
Scheme 1. Proposed reaction processes of CuII complex with boronic acid
under nitrogen (A cycle) and oxygen (B cycle).
On the basis of the above experimental results and some
recent compelling reports by the groups of Stahl,[20,24]
Tromp,[21] and Ribas,[25] who demonstrated that CuII is ready to
undergo disproportionation to generate CuIII and CuI, we could
propose a reasonable explanation to the results obtained in
Table 8. As illustrated in Scheme 1, in the presence of boronic
acid 2a and DMSO, disproportionation of 1.0 equiv of the CuII
complex CuT2D-1 (or CuT2D-2) may proceed to generate
0.5 equiv of [CuIIIT2(Ar)D], [CuITD], and T, respectively, either
under nitrogen or under oxygen. Subsequently, the
[CuIIIT2(Ar)D] complex thus formed undergoes facile reductive
elimination to deliver 0.5 equiv of product 3a and CuIT, respec-
tively. At this juncture, the reaction is terminated if the reaction
is carried out under nitrogen because the CuIT cannot be oxi-
dized to CuII in the absence of oxidant (A cycle). As a result,
only a quarter equivalent of tetrazole anions in CuT2D-1 (or
CuT2D-2) can be converted into the product 3a. Thus, the
maximum theoretical yield under nitrogen is 25%. Alternative-
ly, if the reaction is carried out under oxygen (B cycle), the
“side-products” [CuITD] and 0.5 equiv of T formed in the first
cycle could regenerate 0.5 equiv of [CuIIT2D] through an oxida-
tive copper amination reaction.[26] Then, disproportionation of
the regenerated [CuIIT2D], followed by reductive elimination to
give 0.25 equiv of 3a associated with the formation of
0.25 equiv of “side-products” [CuITD] and T. Such a reaction cir-
culates round by round until [CuIIT2D] cannot be formed, and
affords theoretically (0.5)n+1 equiv of product in each reaction
cycle (n=the number of the reaction cycles). Consequently,
the maximum theoretical yield of the coupled product 3a
under oxygen is 50% as a sum of (0.5)2 +(0.5)3 +(0.5)4 +…+
(0.5)n+1
.
To further confirm the reaction model as shown in
Scheme 1, we carried out some comparison reactions through
a one-pot operation (Table 9). Namely, a mixture of [Cu2O] and
tetrazole 1a in 1:4 or [Cu(OAc)2] and 1a in 1:2 molar ratio (the
ratio of Cu species to 1a=1:2) was stirred at 1008C under
a given atmosphere for 48 h to ensure the complete formation
of 1:2 copper complex (step 1). Then boronic acid 2a was re-
charged in situ and the resulting mixture was continuously
heated for additional hours (step 2). Consequently, 21% and
25% of the coupled product 3a were obtained, respectively,
from [Cu2O] and [Cu(OAc)2] under nitrogen (Table 9, entries 1
and 2). On the other hand, 49% and 48% of 3a were obtained,
Figure 5. XPS spectra of the insoluble residues recovered from the reaction
mixture of the copper complex and boronic acid 2a under: c) oxygen, and
d) nitrogen.
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Table 9. One-pot coupling of tetrazole 1a and boronic acid 2a.[a]
Table 10. Coupling reaction of tetrazole 1a and boronic acid 2a (or the
corresponding boroxin) in the presence of a catalytic amount of Cu com-
plexes.[a]
Entry
Cu complex Boron source Solvent T [oC] Yield 3a[b] [%]
1
2
3
4
5
6
7
8
9
CuT2D-1
CuT2D-2
CuT2D-1
CuT2D-1
CuT2D-1
CuT2D-1
CuT2D-1
CuT2D-1
CuT2D-1
CuT2D-1
2a
2a
2a
2a
2a
2a
boroxin
2a
boroxin
2a
DMSO
DMSO
DMSO
DMSO
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
100
100
80
89
79
90
trace[c]
57
93[d]
94[d]
93[d,e]
93[d,e]
87[f]
Entry
Cu salt
Atmos/t [h]
step 1
Atmos/t [h]
step 2
Yield 3a [%][b]
70
1
2
3
4
[Cu2O]
[Cu(OAc)2]
[Cu2O]
O2/48
N2/48
O2/48
N2/48
N2/23
N2/23
O2/23
O2/23
21
25
49
48
100
100
100
100
100
100
[Cu(OAc)2]
[a] Reaction conditions: Cu2O (0.25 mmol) or [Cu(OAc)2] (0.5 mmol), tetra-
zole 1a (1.0 mmol) in DMSO (4 mL) at 1008C for 48 h under the corre-
sponding atmosphere as in the Table; then, boronic acid 2a (1.2 mmol)
was recharged in situ and stirred for 23 h under the atmosphere as as-
signed in the Table. [b] Yield of the isolated product based on tetrazole.
10
[a] Reaction conditions: tetrazole 1a (0.4 mmol), boronic acid 2a
(1.0 mmol), CuT2D-1 or CuT2D-2 (5 mol%) under oxygen in solvent (4 mL)
for 10 h. [b] Yield of the isolated product. [c] Monitored by TLC. [d] Dried
DMSO was used; [e] 1.0 equiv of H2O was added; [f] 1.0 equiv of TEMPO
was added.
respectively, when the reaction was carried out under oxygen
(Table 9, entries 3 and 4). These results were in very good
agreement with those obtained from the direct reaction of
CuT2D-1 and CuT2D-2 complexes with boronic acid 2a
(Table 8), and further reinforced the rationality of the proposed
reaction model.
the yield was diminished markedly when DMF was used in-
stead of DMSO (Table 10, entry 5). This observation, again,
demonstrated that the use of DMSO as solvent is crucial for ac-
celerating the reaction through its coordination effect with
copper.
From these experiments, we can draw several important
conclusions: 1) disproportionation of CuII to CuIII and CuI spe-
cies can proceed without the assistance of oxygen since about
25% of product is formed under nitrogen; 2) the cleavage of
the CuÀN bond in a copper complex having only one tetrazole
anion, for example, [CuITD] or [CuIITDX] formed in the reaction
cycle, is difficult during the reaction. Otherwise, a CuII complex
possessing two tetrazole anions such as [CuIIT2D] could be re-
formed through the cleavage and reunion of CuÀN bond
under oxygen, and ultimately, leading to the production of 3a
in higher yield than 50%; 3) the generation of the cross-cou-
pled product from a copper complex with whichever redox
state, for example, CuI to CuIII, but containing only one tetra-
zole anion is difficult. Otherwise, the yield of 3a should be also
higher than 50%. As such, a high yield reaction is conceived to
be carried out in such a system that is capable of generating
the [CuIIT2D] species sustainably during the reaction.
For the disproportionation of CuII, Tromp and co-workers[21]
have suggested that adventitious water was essential to pro-
mote the transfer of phenyl group from boronic acid to the
CuIII center. However, we demonstrated that the CuT2D-1-cata-
lyzed coupling of tetrazole 1a with 2a or its boroxin derivative
could proceed very smoothly in the scrupulously dried DMSO
solvent (Table 10, entries 6 and 7). Comparison studies showed
that external addition of water to the reaction system do not
influence the reaction (Table 10, entries 8 and 9). These results
clearly exemplify that water is not essential for our reaction.
On the other hand, since it has been proposed that the gener-
ation of phenyl radical is also possible through the homolytic
splitting of boronic acid,[21,27] we wondered whether the cou-
pling reaction proceeded through a radical pathway under our
conditions. However, the control experiment by adding one e-
quiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) into the
reaction system showed that the reaction proceeded unevent-
fully to give the product in 87% yield (Table 10, entry 10). The
result clearly demonstrates that the phenyl radical does not
participate in the reaction cycle.
Accordingly, we investigated the reaction of tetrazole 1a
and boronic acid 2a by using a catalytic amount of CuT2D-
1 or CuT2D-2 complexes as catalysts under oxygen. Based on
the reaction cycle illustrated in the B cycle in Scheme 1, such
a system could ensure a contiguous formation of the [CuIIT2D]
intermediate from a catalytic amount of [CuIT] species generat-
ed in the reaction cycle and excess 1a added initially through
the oxidative copper amination process. As expected, the cou-
pling reaction of tetrazole 1a and boronic acid 2a could really
proceed very efficiently in the presence of 5 mol% CuT2D-1 or
CuT2D-2 (Table 10, entries 1 and 2). A high yield was also ob-
tained when the reaction was carried out at 808C (Table 10,
entry 3). However, the reaction hardly takes place when the re-
action temperature was decreased to lower than 708C
(Table 10, entry 4), indicating that disproportionation of CuII
may be the rate-limiting step in the reaction cycle. In addition,
Consequently, a variety of spectroscopic analyses combined
with the comprehensive control experimental studies enable
us to propose a plausible mechanism for the copper (either
CuI or CuII)-catalyzed cross-coupling of tetrazole and boronic
acid (Scheme 2). The reaction initiates with the formation of
a CuII complex possessing a unit formula of [CuIIT2D] (step i,
T=tetrazole anions; D=DMSO) either from CuI or CuII salts. In-
terestingly, we have demonstrated that the CuI undergoes an
oxidative copper amination reaction with the presence of
oxygen to generate the CuII complex. Then, transmetalation of
the aryl group from boronic acid to [CuIIT2D] delivers
[CuIIT(Ar)D] through the intermediate [CuIIT2D·ArB(OH)2]
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achieved the reaction through the direct coupling of tetrazoles
and nontoxic boronic acids. Moreover, the reaction could be
carried out simply in the presence of only 5–10 mol% of
copper salts under oxygen in DMSO solvent. In addition, an
array of CuI and CuII salts were demonstrated to be effective
catalysts for this transformation. Thus, the new method offers
a rich range of apparent advantages in terms of efficiency, sim-
plicity, practicality, generality, and environmental impact. Most
significantly, through a comprehensive spectroscopic studies
and properly designed control experiments, we have clarified
the critical role played by each component in the reaction mix-
ture, which enabled us to establish a reasonable mechanism
for the reaction. The most key points involved in the reaction
cycle are the formation of a catalytically active CuII species
through the oxidative copper amination of CuI and the appar-
ent coordination effect of DMSO solvent. Furthermore, we
have also clearly demonstrated that the disproportionation of
CuII can proceed without the assistance of oxygen, and that
a free radical species does not participate in the cycle. We be-
lieve this unprecedented finding will be valuable for a clear un-
derstanding of CEL reaction as well as for the de novo design
and development of new methods for Cu-catalyzed coupling
reactions.
Scheme 2. Proposed reaction mechanism of CuI- and CuII-catalyzed direct-
coupling of terazole and boronic acid.
(Scheme 2, steps ii and iii). Disproportionation of [CuIIT(Ar)D]
with another equiv of CuII generates the [CuIIIT2(Ar)D] and
[CuITD] (step iv). Facile reductive elimination of [CuIIIT2(Ar)D]
yields the product 3 and [CuITD] (step v). Finally, re-oxidative
copper amination of [CuITD] generated in steps iv and v by
oxygen takes place to regenerate [CuIIT2D] (step vi). In the reac-
tion cycle, tetrazole can be supplied either by the initially
added materials or can be generated from TB(OH)2 formed in
step iii (step vii).
Acknowledgements
Financial support from Hundred Talent Program of CAS, Inno-
vation program of Jilin Province (20111802), and State Key Lab-
oratory of Fine Chemicals (KF1201) is acknowledged. We are
also grateful to Prof. Xiang Gao and Dr. Zong-Jun Li at CIAC for
generous help with the computational work.
The regiospecific formation of 2,5-disubstituted tetrazole
may be governed by the steric effect of the regioisomers of
[CuIIIT2(Ar)] intermediate. As illustrated in Scheme 2, three ap-
preciable regioisomers IN1, IN2, and IN3 may exist for
[CuIIIT2(Ar)]. Among these regioisomers, IN1, the CuÀN bond of
which is formed at the N2 position of tetrazole, should present
as the most favorable one due to having the smallest steric re-
pulsion. As a result, the 2,5-disubstituted product is afforded.
In comparison, IN2 and IN3, the CuÀN bonds of which are con-
nected at the N1 position of tetrazole, are unfavorable inter-
mediates owing to the larger sterical repulsion. Consequently,
the 1,5-disubstituted regioisomer cannot be formed. The hy-
pothesis is strongly supported by the results of a detailed com-
putational study,[28] which shows that the energy of IN1 is
about 3.5 kcalmolÀ1 lower than that of IN2, and about 7.3 kcal
molÀ1 lower than that of IN3.
Keywords: boronic acid · copper · CÀN bond formation ·
cross-coupling · tetrazole
[1] For selected reviews, see: a) D. A. Horton, G. T. Bourne, M. L. Smythe,
Chem. Rev. 2003, 103, 893; b) A. O. King, N. Yasuda, Top. Organomet.
Chem. 2004, 6, 205; c) A. Quintas-Cardama, H. Kantarjian, J. Cortes, Nat.
Rev. Drug Discovery 2007, 6, 834.
[2] For selected recent reviews and accounts, see: a) D. S. Surry, S. L. Buch-
wald, Chem. Sci. 2011, 2, 27; b) N. Marion, S. P. Nolan, Acc. Chem. Res.
2008, 41, 1440; c) D. Ma, Q. Cai, Acc. Chem. Res. 2008, 41, 1450; d) J. F.
Hartwig, Acc. Chem. Res. 2008, 41, 1534.
[3] For a recent extensive review on Chan–Evans–Lam coupling, see: J. X.
Qiao, P. Y. S. Lam, Synthesis 2011, 829; and references therein.
[4] a) H. C. Kolb, M. G. Finn, K. B. Sharpless, Angew. Chem. 2001, 113, 2056;
Angew. Chem. Int. Ed. 2001, 40, 2004; b) W. G. Lewis, L. G. Green, F.
Grynszpan, Z. Radic, P. R. Carlier, P. Taylor, M. G. Finn, K. B. Sharpless,
Angew. Chem. 2002, 114, 1095; Angew. Chem. Int. Ed. 2002, 41, 1053;
c) R. Huisgen, Angew. Chem. 1968, 80, 329; Angew. Chem. Int. Ed. Engl.
1968, 7, 321.
Conclusion
[5] For an example, see: Z. P. Demko, K. B. Sharpless, Org. Lett. 2001, 3,
4091.
Through a careful and patient study, we have developed
a copper-catalyzed protocol that allows for the diverse synthe-
sis of 2,5-disubstituted tetrazoles in a regiospecific manner. To
compare with the very few Cu- or Pd-catalyzed methods,[10] in
which metalated tetrazole and high-valent diaryliodonium salts
were used as coupling partners, the protocol presented herein
[6] a) Z. P. Demko, K. B. Sharpless, Angew. Chem. 2002, 114, 2214; Angew.
Chem. Int. Ed. 2002, 41, 2110; b) Z. P. Demko, K. B. Sharpless, Angew.
Chem. 2002, 114, 2217; Angew. Chem. Int. Ed. 2002, 41, 2113.
[7] F. Chen, C. Qin, Y. Cui, N. Jiao, Angew. Chem. 2011, 123, 11689; Angew.
Chem. Int. Ed. 2011, 50, 11487.
[8] a) L. E. Kaim, L. Grimaud, P. Patil, Org. Lett. 2011, 13, 1261; b) Q. Tang, R.
Gianatassio, Tetrahedron Lett. 2010, 51, 3473.
Chem. Eur. J. 2014, 20, 2373 – 2381
www.chemeurj.org
2380
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[9] a) Y. Wang, Q. Lin, Org. Lett. 2009, 11, 3570; b) S. Ito, Y. Tanaka, A.
Kakehi, K. Kondo, Bull. Chem. Soc. Jpn. 1976, 49, 1920.
[10] a) I. P. Beletskaya, D. V. Davydov, M. S. Gorovoy, Tetrahedron Lett. 2002,
43, 6221; b) D. V. Davydov, I. P. Beletskaya, B. B. Semenov, Y. I. Smushke-
vich, Tetrahedron Lett. 2002, 43, 6217.
[11] H. Singh, A. S. Chawla, V. K. Kapoor, D. Paul, R. K. Malhotra, Prog. Med.
Chem. 1980, 17, 151.
[12] For example: a) A. D. Bond, A. Fleming, F. Kelleher, J. McGinkley, V. Praja-
pati, Tetrahedron 2006, 62, 9577; b) R. J. Herr, Bioorg. Med. Chem. 2002,
10, 3379.
[23] N. A. Daugherty, Jr., C. H. Brubaker, J. Am. Chem. Soc. 1961, 83, 3779.
[24] L. M. Huffman, S. S. Stahl, J. Am. Chem. Soc. 2008, 130, 9196.
[25] a) X. Ribas, D. A. Jackson, B. Donnadieu, J. Mahꢁa, T. Parella, R. Xifra, B.
Hedman, K. O. Hodgson, A. Llobet, T. D. P. Stack, Angew. Chem. 2002,
114, 3117; Angew. Chem. Int. Ed. 2002, 41, 2991; b) R. Xifra, X. Ribas, A.
Llobet, A. Poater, M. Duran, M. Solꢂ, T. D. P. Stack, J. Benet-Buchholz, B.
Donnadieu, J. Mahꢁa, T. Parella, Chem. Eur. J. 2005, 11, 5146; c) X. Ribas,
C. Calle, A. Poater, A. Casitas, L. Gꢃmez, R. Xifra, T. Parella, J. Benet-Buch-
holz, A. Schweiger, G. Mitrikas, M. Solꢂ, A. Llobet, T. D. P. Stack, J. Am.
Chem. Soc. 2010, 132, 12299.
[13] R. N. Butler, in Comprehensive Heterocyclic Chemistry, Vol. 4 (Eds.: A. R.
Katritzky, C. W. Rees, E. F. V. Scriven), Pergamon, Oxford, 1996.
[14] M. Hiskey, D. E. Chavez, D. L. Naud, S. F. Son, H. L. Berghout, C. A. Bome,
Proc. Int. Pyrotech. Semin. 2000, 27, 3.
[15] For some recent examples, see: a) A. S. Gundugola, K. L. Chandra, E. M.
Perchellet, A. M. Waters, J.-P. H. Perchellet, S. Rayat, Bioorg. Med. Chem.
Lett. 2010, 20, 3920; and references cited therein; b) P. Srihari, P. Dutta,
R. S. Rao, J. S. Yadav, S. Chandrasekhar, P. Thombare, J. Mohapatra, A.
Chatterjee, M. R. Jain, Bioorg. Med. Chem. Lett. 2009, 19, 5569; and refer-
ences cited therein.
[16] a) Y. Wang, W. Song, W. J. Hu, Q. Lin, Angew. Chem. 2009, 121, 5434;
Angew. Chem. Int. Ed. 2009, 48, 5330; b) W. Song, Y. Wang, J. Qu, M. M.
Madden, Q. Lin, Angew. Chem. 2008, 120, 2874; Angew. Chem. Int. Ed.
2008, 47, 2832; c) W. Song, Y. Wang, J. Qu, Q. Lin, J. Am. Chem. Soc.
2008, 130, 9654; d) Y. Wang, W. J. Hu, W. Song, R. K. V. Lim, Q. Lin, Org.
Lett. 2008, 10, 3725.
[17] For the nickel-catalyzed cross-couplings, see: a) F.-S. Han, Chem. Soc.
Rev. 2013, 42, 5270. For the copper-catalyzed coupling reactions, see:
b) Y. Li, L.-X. Gao, F.-S. Han, Chem. Eur. J. 2010, 16, 7969; c) Y. Ye, Y.-H.
Wang, P.-T. Liu, F.-S. Han, Chin. J. Org. Chem. 2013, 31, 27.
[18] Y. Li, L.-X. Gao, F.-S. Han, Chem. Commun. 2012, 48, 2719.
[19] P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T.
Chan, A. Combs, Tetrahedron Lett. 1998, 39, 2941.
[26] For selected recent examples of aerobic oxidative cross-coupling, see:
a) H. Zhao, M. Wang, W. Su, M. Hong, Adv. Synth. Catal. 2010, 352, 1301;
b) A. N. Campbell, P. B. White, I. A. Guzei, S. S. Stahl, J. Am. Chem. Soc.
2010, 132, 15116; c) Y. Wei, H. Zhao, J. Kan, W. Su, M. Hong, J. Am.
Chem. Soc. 2010, 132, 2522; d) W. Wu, J. Xu, S. Huang, W. Su, Chem.
Commun. 2011, 47, 9660.
[27] C.-J. Li, Angew. Chem. 2003, 115, 5004; Angew. Chem. Int. Ed. 2003, 42,
4856.
[28] Gaussian 09, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Pe-
tersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J.
Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R.
Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bear-
park, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J.
Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J.
Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev,
A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Moro-
kuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dap-
prich, A. D. Daniels, ꢄ. Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski,
D. J. Fox, Gaussian, Inc. Wallingford CT, 2009. Structure optimization
and energy calculation of IN1, IN2, and IN3 were carried out by using
B3LYP/6-31G and B3LYP/6-311G(d) methods, respectively.
[20] A. E. King, T. C. Brunold, S. S. Stahl, J. Am. Chem. Soc. 2009, 131, 5044.
[21] M. Tromp, G. P. F. van Strijdonck, S. S. van Berkel, A. van den Hoogen-
band, M. C. Feiters, B. De Bruin, S. G. Fiddy, A. M. J. van der Eerden, J. A.
van Bokhoven, P. W. N. M. van Leeuwen, D. C. Koningsberger, Organo-
metallics 2010, 29, 3085.
Received: July 21, 2013
Revised: November 12, 2013
Published online on January 21, 2014
[22] E. Alessio, Chem. Rev. 2004, 104, 4203.
Chem. Eur. J. 2014, 20, 2373 – 2381
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