Tunable Triazole-Phosphine-Copper Catalysts for the Synthesis of 2-Aryl-1H-benzo[d]imidazoles from Benzyl Alcohols and Diamines by Acceptorless Dehydrogenation and Borrowing Hydrogen Reactions

Article abstract of DOI:10.1002/adsc.201700179

Triazole-phosphine-copper complexes (TAP?Cu) have been synthesized and applied as tunable and efficient catalysts for the selective synthesis of fluoro-substituted 2-aryl-1H-benzo[d]imidazole and 1-benzyl-2-aryl-1H-benzo[d]imidazole derivatives from simple alcohols in only one step. TAP?Cu exhibited excellent and tunable catalytic activity for both dehydrogenation and borrowing hydrogen reactions with more than 80 examples being demonstrated for the first time. It was observed that the ligand played a critical role in catalyst activity. Mechanistic studies and deuterium labeling experiments indicated that the reactions proceeded by an initial and reversible alcohol dehydrogenation resulting in a copper hydride intermediate. This was also supported by the direct observation of a diagnostic copper hydride signal by solid-state infrared spectroscopy. The TAP?Cu-H complex showed absorptions at 912 cm^?1 that could be assigned to copper?hydride stretches. Furthermore, the direct trapping of an intermediate bisimine was also successfully performed. (Figure presented.).

Full text of DOI:10.1002/adsc.201700179

Title: Tunable Triazole-Phosphine-Copper Catalysts for the Synthesis
of 2-Aryl-1H-benzo[d]imidazoles from Benzyl Alcohols and
Diamines by Acceptorless Dehydrogenation and Borrowing
Hydrogen Reactions
Authors: Zhaojun Xu, Duo-Sheng Wang, Xiaoli Yu, Yongchun Yang,
and Dawei Wang
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201700179
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.200((will be filled in by the editorial staff))
Tunable Triazole-Phosphine-Copper Catalysts for the Synthesis of 2-
Aryl-1H-benzo[d]imidazoles from Benzyl Alcohols and Diamines by
Acceptorless Dehydrogenation and Borrowing Hydrogen Reactions
Zhaojun Xu,a Duo-Sheng Wang,b Xiaoli Yu,a Yongchun Yang,a Dawei Wang*a
a
Key Laboratory of Synthetic and Biological Colloids, Ministry of Education, School of Chemical and Material
Engineering, Jiangnan University, Wuxi 214122, Jiangsu Province, China. E-mail: wangdw@jiangnan.edu.cn
Department of Chemistry, University of Chicago, 5735 S. Ellis Avenue, Chicago, IL 60637, USA.
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.200######.((Please
delete if not appropriate))
Saito,[18] Feringa and Barta,[19] Wills[20] and Zhao[21]
Abstract. Triazole-phosphine-copper complexes (TAP-Cu)
have been synthesized and applied as tunable and efficient
catalysts for the selective synthesis of fluoro-substituted 2-
reported that iron is effective for the classical borrowing
hydrogen strategy. In 2009, Beller and Shi successfully
performed the copper-catalyzed alkylation of sulfonamides
with alcohols in excellent yields. They revealed that bis-
sulfonylated amidines served as novel and highly
influential ligands.[22] Li, Xu, Yus and Ramón have also
disclosed some important results in this area.[23] Recently,
Liu and Huang revealed that potassium tert-butoxide is
necessary for the generation of the active catalyst using
Cu(OAc)2, which suggested that ligand or additive plays an
important role in copper-catalyzed borrowing hydrogen
reactions.[24]
aryl-1H-benzo[d]imidazole
and
1-benzyl-2-aryl-1H-
benzo[d]imidazole derivatives from simple alcohols in only
one step. TAP-Cu exhibited excellent and tunable catalytic
activity for both dehydrogenation and borrowing hydrogen
reactions with more than 80 examples being demonstrated
for the first time. It was observed that the ligand played a
critical role in catalyst activity. Mechanistic studies and
deuterium labeling experiments indicated that the reactions
proceeded by an initial and reversible alcohol
dehydrogenation resulting in a copper hydride intermediate.
This was also supported by the direct observation of a
diagnostic copper hydride signal by solid-state infrared
spectroscopy. The TAP-Cu-H complex showed absorptions
at 912 cm−1 that could be assigned to copper–hydride
stretches. Furthermore, the direct trapping of an
intermediate bisimine was also successfully performed.
Figure 1. Inexpensive metal catalysts for the borrowing hydrogen
reaction
Keywords: triazole; copper; alcohols; dehydrogenation;
borrowing hydrogen
Borrowing hydrogen and dehydrogenation reactions
have become an effective tool in organic synthesis and
medicinal chemistry. Moreover, this strategy can provide
an easy and convenient route to an abundance of natural
compounds and pharmaceuticals from simple alcohols and
amines.[1] It has been demonstrated that catalysts such as
palladium, ruthenium, iridium and rhodium can perform a
host of dehydrogenation and borrowing hydrogen reactions.
Beller,[2] Milstein,[3] Williams,[4] Krische,[5] Li,[6] Zhang,[7]
Xu,[8] Yu[9] and Shi[10] et al. have greatly expanded and
advanced this area of research.[11,12] Recently, Kirchner and
co-workers[13] concluded that inexpensive metals, such as
Fe, Co, Cu, Mn (Figure 1), which are highly economic and
promising catalysts, were much less developed.[14] In 2015,
Kempe and co-workers described the alkylation of
aromatic amines through a borrowing hydrogen reaction
with a new Co-catalyst containing a PNP pincer ligand.[15a]
Hanson,[16] Zhang[17] and Kirchner also proved that cobalt
could catalyze borrowing hydrogen reactions. Meanwhile,
During the past several years, we found that triazole
oxazole and thiazole are effective ligands to adjust reaction
activity at a metal center.[25,26] It was observed that the
reactivity and chemoselectivity of catalysts were
dramatically changed and often enhanced through the use
of azole ligands. Recently, we developed several iridium
complexes based on benzoxazoles and benzothiazoles,
which were effective catalysts for the borrowing hydrogen
reaction.[26] However, for the synthesis of biologically
active benzimidazole derivatives,[27,28] we found that these
iridium catalysts couldn’t be used for a dehydrogenative
approach. Furthermore, benzimidazole derivatives exhibit
excellent biological activity (Figure 2), such as antifungal,
antiallergenic, insecticidal, herbicidal, anti-inflammatory,
1
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
anti-histaminic and potential anthelmintic activities.[28]
Therefore, we turned our focus to searching for an
effective approach to realize their synthesis through the
implementation of triazole ligands within economic metal-
complexes.
Figure 3. Synthesis of phosphine-triazole-copper complexes 2.
With these TAP-Cu complexes in hand, the reaction of
o-phenylenediamine (3a) and (3,5-difluorophenyl)meth-
anol (4a) was first explored. To our pleasure, the desired
product was smoothly obtained in 81% yield (Table 1,
entry 11). Other simple copper salts were also tested and
could not catalyze this reaction (Table 1, entries 4-8). The
effects of catalysts on the reactivity can be seen in the
results shown in Table 1. Several solvents were screened
including CH3CN, DCE, DMF, EtOAc, DCM, THF,
toluene and xylene (Table 1), with toluene producing the
best result (Table 1, entry 11). As expected, no desired
product was achieved in the absence of TAP-Cu catalyst
(Table 1, entry 25).
Figure 2. The biological benzoimidazole derivatives.
In the outset, several triazole copper complexes were
synthesized in good yields from triazole and simple copper
salts. When these triazole-copper complexes were used to
catalyze
the
synthesis
of
1-benzyl-2-aryl-1H-
benzo[d]imidazole, no desired product was achieved,
which might be caused by the strong coordinating ability
and strong electron withdrawing properties of the triazole.
Meanwhile, control reactions revealed that the simple
copper salts couldn’t catalyze this reaction (Scheme 1).
Table 1. Screening of reaction conditions a
Entry
1
Catalyst
Base
-
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
THF
Yield[%]b
<5
-
-
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
K2CO3
NEt3
Cs2CO3
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
tBuOK
<5
23
<5
<5
<5
<5
<5
<5
<5
81
64
73
32
<5
48
68
CuCl
CuBr
CuI
Cu(OTf)2
CuCl2
Cu(PPh3)2I
1a
Scheme 1. Cu-catalyzed borrowing hydrogen reaction.
As described in a plethora of reports,[22-24] ancillary
ligands can play an important role in copper-catalyzed
dehydrogenation and borrowing hydrogen reactions. With
this in mind, phosphines were assessed as ancillary ligands
to further adjust the reactivity of the Cu. It was pleasing to
see that triazole-phosphine-copper complexes (TAP-Cu)
could be synthesized in good yields. To better define and
validate the structure of TAP-Cu, single crystal X-ray
diffraction analysis was conducted (Figure 3). As depicted,
the structure of 2a was unambiguously confirmed by
single-crystal analysis.[29]
1b
2a
2b
2c
2a
2a
2a
2a
2a
2a
2a
2a
Xylene
Dioxane
DMF
DCM
DCE
65
32
<5
<5
2a
<5
2
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
23
24
25
2a
2a
-
tBuOK
tBuOK
tBuOK
EtOAc
CH3CN
Toluene
<5
21
<5
aReagents and conditions: 3a (0.5 mmol), 4a (1.5 mmol), [Cu]
loading (2 mol%, 0.02 mmol), base (0.75 mmol), solvent (3 mL),
reflux, 24 h. b Isolated yield.
To better explain this transformation, the reaction profiles
were also studied. As illustrated in Figure 4, 75% yield of
desired product was obtained when the reaction was run
for 8 hours.
Figure 4. Reaction process profile.
Table 2. Substrate expansion of 1-benzyl-2-aryl-1H-
a,b
benzo[d]imidazole derivatives
aConditions: 3 (0.5 mmol), 4 (1.5 mmol), TAP-Cu (2a) (2 mol%),
tBuOK (0.75 mmol), toluene (3 mL), 24 h, reflux. bIsolated yields
based on 3.
Following optimization, we then explored the substrate
tolerance by utilizing other diamines and alcohols. As
shown in Table 2, a wide range of diamines and alcohols
were smoothly transformed into the corresponding 1-
3
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
benzyl-2-aryl-1H-benzo[d]imidazole products in moderate
to good yields. For thiophen-2-ylmethanol, the desired 2-
(thiophen-2-yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imid-
azole was isolated in 88% yield. It was observed that
fluoro-substituted benzyl alcohols were converted into
tetrafluoro and difluoro substituted-1H-benzo[d]imidazole
in good yields.
obtained in toluene with TAP-Cu (2a) as the catalyst. The
results are summarized in Table 4. The experiments
showed that different N-alkylated anilines could be
obtained with good to excellent yields. Additionally, the
effect of substituents on the aromatic ring of amine was
explored (Table 4).
Table 4. Substrate expansion of the borrowing hydrogen reaction
of alcohols with amines a,b
Table 3. Substrate expansion of 2-aryl-1H-benzo[d]imidazole
derivatives a,b
aConditions: 3 (0.5 mmol), 4 (0.6 mmol), TAP-Cu(2a) (2 mol%),
KOH (0.75 mmol), CH3CN (3 mL), 24 h, 80 oC. bIsolated yields
based on 3.
aConditions: 7 (0.75 mmol), 8 (0.5 mmol), TAP-Cu(2a) (2 mol%),
base (0.75 mmol), Toluene (3 mL), 24 h, reflux. bIsolated yields
based on 8.
Interestingly, 2-aryl-1H-benzo[d]imidazole derivatives
could also be reached in excellent yields by tuning reaction
conditions. TAP-Cu (2a) was then investigated as the
catalyst, for the synthesis of 2-aryl-1H-benzo[d]imidazole
derivatives. The results of those investigations are
summarized in Table 3. It can be seen that diamines were
reacted with alcohols smoothly and 2-aryl-1H-
benzo[d]imidazole derivatives were achieved with good to
excellent yields in most cases (Table 3).
Following the studies on functional group tolerance, a
preliminary mechanistic investigation was performed. The
key intermediate for this borrowing hydrogen reaction is a
copper hydride species, which we wanted to intercept or
verify in some way. First, the transfer hydrogenation
control experiment between imine and alcohol was set up.
As described in Scheme 2, the result showed that benzyl
alcohol could serve as the hydrogen donor for this
Given these interesting results, we further employed this
method to the borrowing hydrogen reaction of amines and
alcohols. We were pleased that the N-alkylated amine was
4
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
transformation and the corresponding amine and aldehyde
were all obtained in moderate or good yields.
Scheme 2. Control experiment.
For a better mechanistic understanding of this method, a
deuterium labeling experiment using 1-methoxy-4-
vinylbenzene and d7-benzyl alcohol was set up and the
corresponding 1-ethyl-4-methoxybenzene and aldehyde
were all obtained with full conversion of starting material.
The results showed a mixture of H/D products was
obtained in the reduced styrene product. This further
indicated that a copper hydride species was formed and
served as a catalytic intermediate (Scheme 3).
Scheme 5. The proposed possible mechanism for the synthesis of
1H-benzo[d]imidazoles.
Additionally, a possible reaction mechanism for the
synthesis of 1H-benzo[d]imidazoles is also proposed,
although the exact mechanism for this reaction is not clear
at this moment (Scheme 5). Initially, the formation of the
aldehyde should occur under the assistance of TAP-Cu.
After the condensation of aldehyde with amine, the product
6a was easily formed from ring closure and
dehydrogenation. However, there are two possible
pathways for the formation of 6a. In this methodology, we
believe pathway I might be possible (bisimine formation
from condensation, cyclization and rearrangement), as
intermediate D was detected via MS analysis, while
intermediate F was not observed during this transformation.
In addition, the bisimine could also be isolated and
confirmed (Scheme 6). Therefore, pathway I may take
place through a bisimine intermediate, which has been
supported by related reactions.[26d]
Scheme 3. Deuterium labeling experiment.
Spectroscopic analysis of a copper hydride intermediate
was then performed to further confirm its intermediacy in
this copper-catalyzed borrowing hydrogen reaction. TAP-
Cu (2a) was reacted with sodium tert-butoxide and then
treated with benzyl alcohol. The solid-state infrared spectra
of 2a showed absorptions at 912 cm−1, which could be
assigned to copper-hydride stretches based on previously
reported
absorption
profiles
for
other
Cu-H
intermediates.[30]
Scheme 6. The capture of intermediate D.
To exclude the possibility of a radical pathway based on a
single electron transfer (SET),[31] we carried out several
control experiments (Scheme 7). Control reactions
revealed that the yield of the desired product remained
almost unchanged when using BHT (1.0 eq) and TEMPO
(1.0 eq) with TAP-Cu (2a) as the catalyst. As expected, the
reaction is not based on a single electron transfer (SET).
Scheme 4. The proposed possible mechanism for TAP-Cu
catalyzed borrowing hydrogen reaction.
With data obtained through mechanistic studies, a
possible reaction pathway for the present transformation
was proposed (Scheme 4). Initially, the hydrido-copper
species would be formed by the reaction of alcohol at the
cationic Cu(I). The copper hydride intermediate is
produced by a β-hydrogen elimination of a Cu-alkoxy
moiety to form the aldehyde. After the condensation of
aldehyde and amine, the intermediate imine was reduced
using the borrowed H2 from one molecule of alcohol while
water was produced as the only byproduct.
5
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
performed. It was observed that ligands played a key role
in promoting copper-catalyzed dehydrogenation and
borrowing hydrogen reactions. In addition, mechanism
studies and deuterium labeling experiments revealed that
this transformation proceeds by an initial reversible alcohol
dehydrogenation step involving
a
copper hydride
intermediate, which provided concrete evidence for a
copper-catalyzed dehydrogenation reaction. Importantly,
biological activity tests revealed that fluoro-substituted 2-
aryl-1H-benzo[d] imidazole and fluoro-substituted 1-
benzyl-2-aryl-1H-benzo[d]imidazole derivatives are potent
compounds against Penicillium digitatum and Penicillium
italicum.
Scheme 7. Control experiments with radical scavengers.
Importantly, the fungicidal activity of the 1-benzyl-
2-aryl-1H-benzo[d]imidazole
benzo[d]imid-azole derivatives was tested against
Fusaium graminearum, Magnaporthe grisea,
and
2-aryl-1H-
Penicillium digitatum, Penicillium italicum and
Rhizoctonia solani at 100 mg/L concentration (Table
5).[32] The initial results show that compounds 5a, 5b
and 5c exhibited quite good inhibitory activities on
Penicillium digitatum and Penicillium italicum. The
compound 5b had 83% inhibition rate on Penicillium
digitatum, which is superior to that of the agricultural
fungicide triadimefon.
Experimental Section
Typical experimental procedure for 2a
The triazole-phosphine-copper complexes (TAP-Cu) were
synthesized from the reaction of [Cu(PAr3)2I](1.0 mmol)
with triazole ligand (1.1 mmol) in a dry CH2Cl2 solution
o
(10 mL) at 40 C for 48 h. The precipitate was isolated by
Table 5. Fungicidal activities of compounds against five
kinds of funguses.
vacuum filtration and washed with CH2Cl2 and diethyl
ether 3 times. The solvent was removed under a reduced
pressure, and the yellow solid was obtained with 78% yield
of TAP-Cu (2a) through recrystallization.
P.
P.
F.
M.
R.
Compd.
digitatum italicum graminearum grisea solani
(%)
(%)
(%)
(%
(%)
Representative procedure for the preparation of 5a
5a
5b
5c
5g
5i
5i
6a
6b
6e
74
83
69
24
31
44
46
53
42
34
76
100
63
71
62
31
26
17
25
0
38
20
78
100
31
32
27
0
0
0
28
37
34
0
19
14
22
0
0
0
49
98
33
31
19
21
0
33
20
38
26
0
To 20 mL colorimetric tube was added TAP-Cu (2 mol%),
dry toluene (3 mL), alcohol (1.5 mmol), amine (0.5 mmol)
and potassium tert-butoxide (0.75 mmol) was added. The
mixture was heated under 120 oC for 24 h and then cooled
to room temperature. After removing the solvent, the
resulting mixture was directly purified by column
chromatography with petroleum ether/ethyl acetate as
eluent to give the desired product (5a).
0
24
33
0
45
93
6m
Triadimefon
Diniconazole
63
100
Representative procedure for the preparation of 6a
Finally, to further extend the application of this new
methodology and the TAP-Cu catalyst, the gram scale
To 20 mL colorimetric tube was added TAP-Cu (2 mol%),
MeCN (3 mL), alcohol (0.6 mmol), amine (0.5 mmol) and
KOH (0.75 mmol) was added. The mixture was heated
under 80 oC for 24 h and then cooled to room temperature.
fter removing the solvent, the resulting mixture was
directly purified by column chromatography with
petroleum ether/ethyl acetate as eluent to give the desired
product (6a).
synthesis
of
1-(3,5-difluorobenzyl)-2-(3,5-
difluorophenyl)-1H-benzo[d]imidazole,
which had
better anti P. digitatum activity, was performed. Good
yield and good selectivity were achieved for a reaction
scale exceeding 10 grams (Scheme 8).
Representative procedure for the preparation of 9a
To 20 mL colorimetric tube was added TAP-Cu (2 mol%),
dry toluene (3 mL), alcohol (0.75 mmol), amine (0.5
mmol) and potassium tert-butoxide (0.75 mmol) was
Scheme 8. The synthesis of 1-(3,5-difluorobenzyl)-2-(3,5-
difluorophenyl)-1H-benzo[d]imidazole in large scale.
o
added. The mixture was heated under 120 C for 24 h and
then cooled to room temperature. After removing the
solvent, the resulting mixture was directly purified by
column chromatography with petroleum ether/ethyl acetate
as eluent to give the desired product (9a).
In conclusion, we reported the synthesis and
unambiguous characterization of TAP-Cu through X-ray
crystallography. TAP-Cu was demonstrated to be an
effective and tunable catalyst for the synthesis of fluoro-
substituted 2-aryl-1H-benzo[d] imidazole and fluoro-
substituted
1-benzyl-2-aryl-1H-benzo[d]
imidazole
Acknowledgements
derivatives with more than 80 examples being successfully
6
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
We gratefully acknowledge financial support of this work
by the National Natural Science Foundation of China (No.
21401080), the Natural Science Foundation of Jiangsu
Province (BK20130125), Jiangsu Talents Project (2013-
JNHB-027), Fundamental Research Funds for the Central
Universities (JUSRP 51627B) and MOE & SAFEA for the
111 Project (B13025).
[9] a) W. He, L. Wang, C. Sun, K. Wu, S. He, J. Chen, P. Wu, Z.
Yu, Chem. Eur. J. 2011, 17, 13308; b) L. Wang, W. He, K.
Wu, S. He, C. Sun, Z. Yu, Tetrahedron Lett. 2011, 52, 7103;
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
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8
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10.1002/adsc.201700179
Advanced Synthesis & Catalysis
COMMUNICATION
Tunable Triazole-Phosphine-Copper
Catalysts for the Synthesis of 2-Aryl-1H-
benzo[d]imidazoles from Benzyl Alcohols
and Diamines by Acceptorless
Dehydrogenation and Borrowing Hydrogen
Reactions
Adv. Synth. Catal. Year, Volume, Page – Page
Zhaojun Xu,a Duo-Sheng Wang,b Xiaoli Yu,a
Yongchun Yang,a Dawei Wang*a
Triazole-phosphine-copper complexes (TAP-Cu) have been
synthesized and applied as tunable and efficient catalysts for
the selective synthesis of fluoro-substituted 2-aryl-1H-benzo[d]
imidazole
and
1-benzyl-2-aryl-1H-benzo[d]imidazole
derivatives from simple alcohols in only one step. TAP-Cu
exhibited excellent and tunable catalytic activity for both
dehydrogenation and borrowing hydrogen reactions with more
than 80 examples being demonstrated for the first time. It was
observed that the ligand played a critical role in catalyst
activity. Mechanistic studies and deuterium labeling
experiments indicated that the reactions proceeded by an initial
and reversible alcohol dehydrogenation resulting in a copper
hydride intermediate. This was also supported by the direct
observation of a diagnostic copper hydride signal by solid-state
infrared spectroscopy. The TAP-Cu-H showed absorptions at
912 cm−1 that could be assigned to copper-hydride stretches.
Furthermore, the direct trapping of an intermediate bisimine
was also successfully performed.
9
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