Improved Synthesis of Symmetrical 2,5-Diarylimidazoles by One-Pot Palladium-Catalyzed Direct Arylation Tailored on the Electronic Features of the Aryl Halide

Article abstract of DOI:10.1055/s-0036-1589071

Two methods for the one-pot synthesis of 2,5-diarylimidazoles by palladium-catalyzed direct C-H arylation of 1-substituted imidazoles with aryl bromides have been devised. The first method, promoted by copper(I) iodide, is best suited for electron-poor ar

Full text of DOI:10.1055/s-0036-1589071

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
special topic
A
en
M. Lessi et al.
Special Topic
Synthesis
Improved Synthesis of Symmetrical 2,5-Diarylimidazoles by
One-Pot Palladium-Catalyzed Direct Arylation Tailored on the
Electronic Features of the Aryl Halide
Marco Lessia
Gianmarco Panzettaa
Giulia Marianettib
Ar
Br
1)
Ar
Br
Pd(OAc)2 (5 mol%)
P(2-furyl)3 (10 mol%)
K2CO3 (2.0 equiv)
Pd(OAc)2 (5 mol%)
CsOAc (2.0 equiv)
DMA, 110 °C, 24 h
N
N
N
N
N
N
Fabio Bellina*a
0
0
0
0
0-
0
0
2
4-
9
3
9
7-
0
0
8
Ar
Ar
H
Ar
Ar
R
H
R
a Dipartimento di Chimica e Chimica Industriale, Università di
Pisa, Via G. Moruzzi 13, 56124 Pisa, Italy
fabio.bellina@unipi.it
b Scuola Normale Superiore, Piazza dei Cavalieri 7, 56126
Pisa, Italy
xylene, 140 °C, 24 h
2) CuI (2.0 equiv)
R
140 °C, 24 h
(67–71%)
(22–77%)
Method B
Method A
Dedicated to Prof. Renzo Rossi on the occasion of his 80th
birthday
Ar Electron-rich
Ar Electron-poor
Published as part of the Special Topic Modern Strategies for
Heterocycles Synthesis
Received: 22.05.2017
Accepted after revision: 19.06.2017
Published online: 31.07.2017
imidazole (2) and 4-bromobenzaldehyde (3a) were reacted
under the experimental conditions for the selective palladi-
um/copper-mediated C-2 direct arylation promoted by n-
Bu4NOAc, previously developed by us.7 However, in contrast
to our expectations, the main product of this coupling was
not 1a, but a sparingly soluble yellow solid, which was sub-
sequently identified as the symmetrical 2,5-diarylated im-
idazole 4a (Scheme 1).
DOI: 10.1055/s-0036-1589071; Art ID: ss-2017-c0347-st
Abstract Two methods for the one-pot synthesis of 2,5-diarylimidaz-
oles by palladium-catalyzed direct C–H arylation of 1-substituted imid-
azoles with aryl bromides have been devised. The first method, promot-
ed by copper(I) iodide, is best suited for electron-poor aryl bromides,
and also allows the 2,5-diarylation of thiazole and oxazole. The use of
xylene instead of DMA is the key for the efficiency of the second meth-
od, which gives the best results with electron-rich aryl bromides.
Imidazole 4a showed interesting optical properties, dis-
playing a very bright yellow-green fluorescence which is
also retained in the solid state (Figure 1).
Key words direct arylation, imidazoles, palladium, C–C coupling,
Intrigued by the fluorescence properties of this other-
wise simple molecule, and after an extensive survey of the
literature which provided no evidence of studies reporting
the optical properties of this class of symmetrical push–
pull fluorophores, we decided to focus our synthetic efforts
regioselectivity, C–H bond activation, catalysis, aryl halides
Aryl-substituted imidazoles represent a significant sub-
class of azoles found as the main structural core in several
important families of compounds, including bioactive de-
rivatives1 and organic functional materials.2 In this last
field, imidazoles and, more generally, heteroaromatic com-
pounds have emerged as privileged scaffolds for the devel-
opment of organic fluorescent push–pull dyes.2b,3 The pres-
ence of one or more heteroaromatic moieties in the skele-
ton of the fluorophore usually increases polarizability, due
to the lower aromatic character when compared to ben-
zene,4 stability, and thermal and chemical robustness re-
quired for fabrication processes. Since the discovery in 1877
of the yellow chemiluminescence of lophine (2,4,5-triphe-
nyl-1H-imidazole),5 arylimidazoles have been used as syn-
thetic scaffolds in charge-transfer fluorophores.2b
N
+
Br
CHO
N
Me
2
3a
(2.5 mmol)
(1.5 equiv)
Pd(OAc)2 (5 mol%), CuI (2.0 equiv)
n-Bu4NOAc (2.0 equiv)
DMA, 110 °C, 24 h
N
N
N
During our recent studies on the development of new
imidazole-based organic fluorophores via palladium-cata-
lyzed C–C bond-forming reactions,6 we planned the prepa-
ration of 2-(4-formylphenyl)-1-methyl-1H-imidazole (1a)
to be used as the electrophilic partner in Knoevenagel-type
condensations.6d With this target in mind, 1-methyl-1H-
CHO
CHO
+
N
Me
Me
OHC
4a
1a
(41% isolated yield)
(11% isolated yield)
Scheme 1 First preparation of imidazole 4a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
M. Lessi et al.
Special Topic
Synthesis
mobenzaldehyde (3a) in the presence of 5 mol% Pd(OAc)2
and 4.0 equivalents of CsOAc in DMA for 48 hours at 150 °C.
In our hands, the coupling gave rise to the required 4a too,
but in a low 18% GLC yield, along with a large amount of the
corresponding 5-monoarylated azole in a 40:60 GLC ratio
with 4a. Moreover, a byproduct, subsequently identified by
GLC/MS analyses as likely an aldol-type condensation ad-
duct between 4-bromobenzaldehyde (3a) and DMA, was
also found in the reaction mixture.
Due to this unexpected negative result, we elected to set
up a brief screening of the reaction conditions, starting
from those of our serendipitous discovery depicted in
Scheme 1. The results of this screening, which involved
1-methyl-1H-imidazole (2) and 4-bromobenzaldehyde (3a)
as model reactants, are summarized in Table 1. In general,
the data obtained confirm, on the one hand, that the pres-
ence of an inorganic base improves the yield and that, in
agreement with Doucet and co-workers,13 CsOAc is the best
base among those examined. On the other hand, however,
the results provide evidence that the presence of at least 2.0
Figure 1 (a) Experimental spectroscopic data for imidazole 4a as a
10–5 M THF solution. Fluorescence quantum yield was determined rela-
tive to quinine sulfate 0.1 M in H2SO4 (Φ = 0.54), λexc = 363 nm. (b)
Bright fluorescent powder of 4a under a UV lamp at 366 nm.
on the development of a viable procedure for the prepara-
tion of this class of compounds. In this paper, we summa-
rize the results of our studies, which led us to develop two
different one-pot direct C–H arylation protocols for the
synthesis of 2,5-diarylated 1-substituted imidazoles 4. The
first protocol (Method A), best suited for electron-poor and
electron-neutral bromides, consists of a two-step sequence
involving at first the direct arylation of a 1-substituted im-
idazole with 3.0 equivalents of the appropriate aryl bro-
mide in the presence of 5 mol% Pd(OAc)2 and 2.0 equiva-
lents of CsOAc in DMA at 110 °C for 24 hours, followed by
the addition of 2.0 equivalents of CuI and a further 24 hours
at 140 °C. On the contrary, the second protocol (Method B),
a double arylation of a 1-substituted imidazole which re-
quires 5 mol% Pd(OAc)2 and 10 mol% P(2-furyl)3 as the cata-
lyst system in the presence of 3.0 equivalents of an aryl bro-
mide and 2.0 equivalents of K2CO3 in xylene at 140 °C for 24
hours, fits better for electron-rich bromides.
Table 1 Screening of the Reaction Conditions for the Double Direct
Arylation of 1-Methyl-1H-imidazole (2) with 4-Bromobenzaldehyde
(3a)a
CHO
N
CHO
N
N
Pd(OAc)2, CuI
base, DMA
N
+
Me
Me
OHC
Br
2
3a
4a
Entry
Base
Time (h)
Temp (°C)
Yield of 4a (%)b
The direct arylation reaction applied to the synthesis of
aryl-substituted imidazoles represents one of the best pro-
cedures for obtaining this class of heteroaromatics.8 Howev-
er, despite several reported synthetic protocols for the regio-
selective palladium-catalyzed C-57,9 or C-27,9b,c,10 direct
arylation of imidazoles, symmetrical 2,5-diaryl-substituted
imidazoles 4 have been, in general, obtained in one-pot re-
actions only as unwanted byproducts during screenings de-
voted to establishing the best conditions for individual regio-
selective monoarylations9b,d–g,10a,11 or aimed at the complete
arylation of the imidazole nucleus.12 In 2014, Doucet and
co-workers reported the first intentional synthesis of sever-
al 2,5-diarylated 1-methylimidazoles 4 by a one-pot palla-
dium-catalyzed direct arylation involving 1-methyl-1H-im-
idazole (2) and aryl bromides 3.13 These authors reported
that the selection of the base appeared crucial for the reac-
tion pattern, and the use of 4.0 equivalents of CsOAc in
DMA along with a reaction temperature of 150 °C gave the
best results in terms of chemical yield.
1
2
n-Bu4NOAc
K2CO3
24
110
110
110
110
110
110
110
110
90
46 (44)
50
24
3
Cs2CO3
KOAc
24
56
4
24
56
5
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
24
58 (55)
32
6c
7d
8e
9
24
24
22
24
46
24
28
10
11
12f
24
140
110
64
48
59
24 + 24
110 to 140
82 (77)
a Unless otherwise mentioned, reaction conditions: 2 (1.0 mmol), 3a (3.0
equiv), Pd(OAc)2 (5 mol%), CuI (2.0 equiv), base (2.0 equiv), DMA (5 mL),
110 °C, 24 h.
b GC yield. Isolated yield is given in parentheses.
c With CuI (1.0 equiv).
d With Pd(OAc)2 (2 mol%).
e With P(t-Bu)3 (10 mol%).
Taking into account that recent paper, we decided to
start our survey by trying to replicate Doucet’s results.
Thus, we reacted 1-methyl-1H-imidazole (2) with 4-bro-
f This reaction was carried out for 24 h at 110 °C in the absence of CuI;
then, CuI (2.0 equiv) was added, the temperature was raised to 140 °C, and
the reaction mixture was stirred at this temperature for a further 24 h.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
M. Lessi et al.
Special Topic
Synthesis
equivalents of CuI are mandatory to force the reaction to-
wards the double C-5/C-2 arylation under ligandless condi-
tions and using DMA as the solvent.
In detail, a fine tuning of the cationic and anionic moi-
eties of the added base allowed an increase in the yield of
4a (up to 55% isolated yield) when CsOAc was employed
(Table 1, entry 5). In agreement with Doucet and co-work-
ers,13 better yields were obtained when cesium salts (Table
1, entries 3 and 5) were used instead of the corresponding
potassium salts (Table 1, entries 2 and 4).
faster than the formation of the 5-monoarylated regioiso-
mer. But, as stated before, the C-5 arylation of a 2-arylated
imidazole is slower than the C-2 arylation of a 5-arylated
imidazole. As a consequence, starting from 1-methyl-1H-
imidazole, we thought it appropriate to promote first the
regioselective formation of the 5-monoarylated imidazole
by working with palladium alone, and to subsequently add
the copper salt to push the reaction to completion by C-2
arylation of the 5-arylated intermediate.9g,10f
Next, we evaluated the scope and the limitations of this
one-pot palladium/copper-mediated double direct aryla-
tion by applying the reaction conditions of Table 1, entry 12
(Method A) to the preparation of several 2,5-diarylimidaz-
oles 4 starting from 1-methyl-1H-imidazole (2) and (hete-
ro)aryl bromides 3 (Scheme 2).
Regarding the anionic part of the base, acetates (Table 1,
entries 4 and 5) resulted in a slightly higher efficiency than
the corresponding carbonates (Table 1, entries 2 and 3). The
use of n-Bu4NOAc, which efficiently promotes the palladi-
um-catalyzed C-5 direct arylation of oxazole, thiazole, and
1-methyl-1H-imidazole,7 was in this case less effective than
inorganic bases (Table 1, entry 1). A decreased loading of
Pd(OAc)2 or of CuI resulted in a serious decrease in the reac-
tion yield (Table 1, entries 6 and 7). Finally, the use of 10
mol% P(t-Bu)3, which has been reported to promote the 2,5-
diarylation,10a,12a seems instead to have had a slight nega-
tive influence on the reaction yield when compared to the
ligandless conditions (Table 1, entry 8).
Aiming to further improve the yield of 4a, we examined
the effect of temperature on the outcome of the coupling.
While no formation of the desired product was observed af-
ter 24 hours at 70 °C, a progressive raising of the tempera-
ture from 90 °C to 110 °C increased the GLC yield of 4a from
28% to 58% (Table 1, entries 9 and 5, respectively), while a
further increment from 110 °C to 140 °C resulted in only a
slight improvement to 64% yield (Table 1, entry 10). Given
these results, we decided to test the potential benefit of in-
creasing the reaction time from 24 to 48 hours (Table 1, en-
try 11); however, this last attempt left the reaction yield
practically unaltered. Finally, we succeeded in enhancing
the formation of 4a by stirring the reaction mixture at
110 °C for 24 hours in the absence of CuI, then continuing
for another 24 hours at 140 °C after the addition of 2.0
equivalents of CuI. With this last modification of the reac-
tion procedure we were able to isolate 4a in 77% yield (Table
1, entry 12).
This last improvement may be explained taking into ac-
count our previous results on the direct palladium- and
copper-mediated arylation of 1,2- and 1,5-diarylimidaz-
oles.10a In those studies, we found that the rate of the C-2
arylation of a typical 1,5-diaryl-1H-imidazole is higher than
that of the C-5 arylation involving the corresponding 1,2-di-
aryl-1H-imidazole, and that the palladium- and copper-
mediated direct C-2 arylation of 1-arylimidazoles is faster
than the corresponding palladium-catalyzed direct C-5 ary-
lation. Hence, when the reaction involving 1-methyl-1H-
imidazole (2) is carried out in the presence of palladium
and copper, the diarylated imidazole 4a has to arise mainly
from the C-5 arylation of the intermediate 2-aryl-1-me-
thylimidazole, because the formation of that compound is
1) Pd(OAc)2 (5 mol%)
N
N
N
N
CsOAc (2.0 equiv)
DMA, 110 °C, 24 h
2) CuI (2.0 equiv)
140 °C, 24 h
Ar
Ar–Br
+
Ar
Me
Me
2
4
3
(3.0 equiv)
Method A
Scheme 2 Palladium- and copper-mediated one-pot synthesis of 2,5-
diarylimidazoles 4 (Method A)
In detail, the direct arylation involving 4- or 3-substitut-
ed electron-poor aryl bromides 3a–j proved to be clean and
furnished the required imidazoles 4a–j in 42–77% isolated
yield (Table 2, entries 1–10). The reactions performed using
Method A proved to be influenced by steric hindrance on
the aryl bromide. In fact, 2-bromobenzonitrile (3k), a typi-
cal 2-substituted electron-poor aryl bromide, gave the cor-
responding 2,5-diarylated imidazole 4k in only 30% isolated
yield (Table 2, entry 11). Moreover, yields lower than 40%
were obtained when two arbitrarily selected electron-poor
heteroaryl bromides, 5-bromopyrimidine (3q) and 3-bro-
mopyridine (3r), were used as the reaction partner (Table 2,
entries 21 and 22).
Regarding electron-rich aryl bromides, the results using
Method A were not completely satisfactory. The reaction of
4-bromotoluene (3l), 3-bromotoluene (3m), 2-bromotolu-
ene (3n), and 4-bromoanisole (3o) gave the 2,5-diarylimid-
azoles 4l, 4m, 4n, and 4o, in 49%, 47%, 23%, and 33% isolated
yield, respectively (Table 2, entries 12 and 14–16).
However, we found to our great delight that the use of
xylene as solvent at 140 °C for 24 hours, in the presence of
2.0 equivalents of K2CO3 as the base and a combination of 5
mol% Pd(OAc)2 and 10 mol% P(2-furyl)3 as the catalyst sys-
tem (Method B), allowed us to improve the efficiency of the
one-pot double direct arylation when electron-rich bro-
mides are used (Scheme 3).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
M. Lessi et al.
Special Topic
Synthesis
The reaction conditions of Method B arose from a
screening of solvents and bases that was set up during our
research, published in 2008, on the direct C-5 arylation of
1-methyl-1H-imidazole (2) with 4-bromoanisole (3o).9h In
that screening, we found that when xylene was used as a
solvent, instead of the more polar DMF or DMSO, at a reac-
tion temperature of 140 °C, the coupling was particularly
unselective, giving rise to a significant amount of the unre-
quired (at that time) 2,5-diarylimidazole 4o. In the same
study, we observed that an increase in the reaction tem-
perature from 110 °C to 140 °C significantly favored the for-
mation of 4o. In fact, the GLC molar ratio between 4o and
the corresponding monosubstituted (at C-5 or C-2) imidaz-
oles went from 1:99, when the reaction was carried out in
toluene at 110 °C, to 87:13 when the same coupling was
performed in xylene at 140 °C.9h
Disappointingly, when the reaction between 1-methyl-
1H-imidazole (2) and 4-bromoanisole (3o) was carried out
under Doucet’s conditions13 [i.e., CsOAc (4 equiv), Pd(OAc)2
(5 mol%), DMA, 150 °C], we recorded an 11% GLC yield of
the disubstituted imidazole 4o vs an isolated yield of 78%
reported by Doucet and co-workers. Even in this case, a sig-
nificant amount of a monosubstituted imidazole was ob-
served, very probably that arylated at C-5, in an 87:13 GLC
ratio with the double 2,5-arylated imidazole 4o.
Using the reaction conditions of Method B, we were also
able to prepare 2,5-diarylimidazole 4p, bearing the strong
electron-donor dimethylamino group on both the C-2 and
C-5 aromatic moieties. The preparation of 4p was unsuc-
cessful when Method A was tried for its synthesis (result
not shown). Indeed, we proved that the two methods are
complementary due to the fact that imidazoles 4a and 4g,
bearing electron-poor aromatic moieties, were obtained in
27% and 29% isolated yield when Method B was applied (Ta-
ble 2, entries 19 and 20), while the same compounds were
isolated in 77% and 37% yield when Method A was used (Ta-
ble 2, entries 1 and 7).
At present, we do not have sufficient data to fully ex-
plain the interesting role of xylene, which is particularly ef-
ficient but only when electron-rich aryl bromides are react-
ed with 2 as the electrophilic partner. However, the higher
reactivity displayed by electron-rich bromides when com-
pared with the electron-poor analogues points towards the
possibility of a potential Pd(II)/Pd(IV) catalytic cycle,14 in-
stead of the well-established SEAr or CMD (concerted meta-
lation–deprotonation) mechanisms15 which, on the con-
trary, both rely on Pd(0)/Pd(II) redox pathways. Our results
are in fact similar, for example, to those very recently re-
ported for the direct arylation of azoles in the presence of a
pincer-ligated palladium complex.16 In that study, the high
reactivity observed when electron-rich aryl halides are the
coupling partners was attributed to a better stabilization of
Pd(IV) intermediates resulting from the oxidative addition
of the aryl halide to a Pd(II) species.
Pd(OAc)2 (5 mol%)
P(2-furyl)3 (10 mol%)
K2CO3 (2.0 equiv)
N
N
N
Ar
Ar–Br
+
N
Ar
Me
Me
xylene, 140 °C, 24 h
2
4
3
(3.0 equiv)
Method B
Scheme 3 Palladium-catalyzed one-pot synthesis of electron-rich 2,5-
diarylimidazoles 4 (Method B)
When Method B was applied, imidazoles 4l and 4o were
actually isolated in 71% and 53% chemical yield (Table 2, en-
tries 13 and 17).
Table 2 Synthesis of 2,5-Diaryl-1-methyl-1H-imidazoles 4 by One-Pot
Double Direct Arylation of 1-Methyl-1H-imidazole (2) with Aryl Bro-
mides 3
N
N
Method A or B
"one pot"
Ar
+
Ar–Br
N
N
Ar
Me
Me
2
3
4
Entry
3
Ar
Methoda
4
Yield of 4 (%)b
1
2
3a
3b
3c
3d
3e
3f
4-OHCC6H4
4-NCC6H4
4-F3CC6H4
4-AcC6H4
A
A
A
A
A
A
A
A
A
A
A
A
B
A
A
A
B
B
B
B
A
A
4a
77
70
51
63
59
48
37
52
60
42
30
49
71
47
23
33
53
67
27
29
22
36
4b
4c
4d
4e
4f
3
4
5
4-EtO2CC6H4
4-ClC6H4
6
7
3g
3h
3i
4-O2NC6H4
3-F3CC6H4
3-OHCC6H4
3-FC6H4
4g
4h
4i
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
3j
4j
3k
3l
2-NCC6H4
4-MeC6H4
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-Me2NC6H4
4-OHCC6H4
4-O2NC6H4
5-pyrimidyl
3-pyridyl
4k
4l
3l
4l
3m
3n
3o
3o
3p
3a
3g
3q
3r
4m
4n
4o
4o
4p
4a
4g
4q
4r
a Method A: 1) 2 (1.0 mmol), 3 (3.0 equiv), Pd(OAc)2 (5 mol%), CsOAc (2.0
equiv), DMA (5 mL), 110 °C, 24 h; 2) CuI (2.0 equiv), 140 °C, 24 h. Method
B: 2 (1.0 mmol), 3 (3.0 equiv), Pd(OAc)2 (5 mol%), P(2-furyl)3 (10 mol%),
K2CO3 (2.0 equiv), xylene (5 mL), 140 °C, 24 h.
b Isolated yield.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

E
M. Lessi et al.
Special Topic
Synthesis
Having obtained satisfactory results in the preparation
of 1-methyl-1H-imidazoles 4 decorated at their positions 2
and 5 with electron-poor aryl groups via Method A, or bear-
ing electron-rich aryl groups at the same positions via
Method B, we decided to verify the feasibility of both meth-
ods for the synthesis of 2,5-diaryl-substituted azoles other
than 4. We were pleased to find that 1-phenyl-, 1-benzyl-,
and 1-n-butyl-1H-imidazole (5, 6, and 7; Figure 2) are able
to react with 3.0 equivalents of electron-poor aryl bromides
3 under the experimental conditions of Method A, giving
rise to the required 2,5-diarylated 1-substituted imidazoles
8, 9, and 10 (Figure 2) in moderate to good yields (Table 3).
The experimental conditions of Method A also allowed
the double C-2/C-5 arylation of thiazole (11) and oxazole
(12). In fact, two typical 2,5-diaryl-substituted thiazole and
oxazole compounds, 13 and 14 (Ar = 4-OHCC6H4), were iso-
lated in 76% and 62% yield, respectively (Table 3, entries 9
and 10).
Concluding, in this study we developed two comple-
mentary methods for the efficient one-pot synthesis of 2,5-
diarylimidazoles 4 by palladium-catalyzed direct arylation
reactions. The first method requires a copper(I) salt as pro-
moter, to force the C-2 arylation, under ligandless condi-
tions. It gives good results when electron-poor aryl bro-
mides are employed as the coupling partner. This protocol
allows the 2,5-diarylation of 1-substituted imidazoles other
than 1-methyl-1H-imidazole (2), and also of thiazole (11)
and oxazole (12). The second method is copper-free, but
employs tri(2-furyl)phosphine as palladium ligand and xy-
lene as the solvent. This latter protocol works well with
electron-rich aryl bromides, but was ineffective when imid-
azoles other than 2 were used, and gave unsatisfactory
yields with electron-poor aryl bromides. The observed dif-
ferences between the two methods can probably be at-
tributed to diverse mechanistic pathways, namely CMD vs
Pd(IV) intermediates.
N
S
N
S
N
N
N
N
Ar
Ar
Ar
Ar
Ar
11
13
R
R
N
N
5: R = Ph
6: R = Bn
7: R = n-Bu
8: R = Ph
9: R = Bn
10: R = n-Bu
O
12
O
14
Ar
Figure 2 Chemical structures of azoles 5, 6, 7, 11, 12, and of the cor-
responding 2,5-diarylated azoles 8, 9, 10, 13, 14
Table 3 Synthesis of 2,5-Diaryl-Substituted Azoles by One-Pot Double
Direct Arylation with Aryl Bromides 3a
The application of both methods to the efficient synthe-
sis of new, thermally and photochemically stable, fluores-
cent push–pull fluorophores with large Stokes shifts and
high fluorescence quantum yields is still in progress, and
the results will be published in due course.
N
N
Method A
Ar
+
Ar–Br
Y
Y
Ar
3
Entry
Product
Y
Ar
Yield (%)b
Melting points were recorded on a hot-stage microscope (Reichert
Thermovar). Precoated silica gel PET foils (Sigma-Aldrich) were used
for TLC analyses. GLC-FID analyses were performed on a Dani GC 1000
instrument equipped with a PTV injector and recorded with a Dani
DDS 1000 data station. Three types of capillary columns were used:
Agilent J&W HP-5ms column (30 m × 0.25 mm i.d. × 0.25 μm), Agilent
J&W DB-5 column (30 m × 0.25 mm i.d. × 1 μm) and J&W DB-1 col-
umn (15 m × 0.25 mm i.d. × 0.25 μm). EIMS spectra were recorded at
70 eV by GLC/MS. GLC/MS analyses were performed on an Agilent
6890N gas chromatograph interfaced with an Agilent 5973N mass de-
tector. 1H NMR spectra were recorded on a Bruker 400 MHz spec-
trometer using TMS as an internal standard. 13C NMR spectra were re-
corded on a Bruker 400 MHz spectrometer, operating at 100 MHz us-
ing the solvent signal as a reference. Standard abbreviations are used
in reporting the NMR splitting patterns. Unless otherwise stated, all
the reactions were performed under a positive atmosphere of argon
by standard syringe, cannula, and septa techniques. 1-Methyl-1H-im-
idazole (2) was distilled under reduced pressure over CaH2. CsOAc was
stored in a desiccator. All the other reagents and solvents were pur-
chased from Aldrich and used without further purification.
1
2
8a
8b
N-Ph
4-OHCC6H4
4-F3CC6H4
4-OHCC6H4
4-F3CC6H4
4-ClC6H4
38
44
76
55
44
55
45
31
76
62
N-Ph
N-Bn
N-Bn
N-Bn
N-Bn
N-n-Bu
N-n-Bu
S
3
9a
4
9b
5
9c
6
9d
4-NCC6H4
4-NCC6H4
4-ClC6H4
7
10a
10b
13
8
9
4-OHCC6H4
4-OHCC6H4
10
14
O
a Method A: 1) azole (1.0 mmol), 3 (3.0 equiv), Pd(OAc)2 (5 mol%), CsOAc
(2.0 equiv), DMA (5 mL), 110 °C, 24 h; 2) CuI (2.0 equiv), 140 °C, 24 h.
b Isolated yield.
In contrast, there was no formation of the expected 2,5-
diarylated imidazoles, but significant amounts of the corre-
sponding monoarylated derivatives were observed, when
1-phenyl-, 1-benzyl-, or 1-n-butyl-1H-imidazole (5, 6, and
7) was reacted with 3.0 equivalents of 4-bromoanisole (3o)
or 4-bromotoluene (3l) under the reaction conditions of ei-
ther Method A or Method B.
One-Pot Palladium/Copper-Mediated Synthesis of 2,5-Diarylimid-
azoles 4, 8, 9, 10, and of 2,5-Diarylthiazole 13 and 2,5-Diaryloxaz-
ole 14; General Procedure (Method A)
In a flame-dried reaction vessel were placed the appropriate aryl bro-
mide 3 (3.0 mmol) and azole (1.0 mmol) if solid, Pd(OAc)2 (11.2 mg,
0.050 mmol), and CsOAc (0.384 g, 2.00 mmol). The reaction vessel
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

F
M. Lessi et al.
Special Topic
Synthesis
was fitted with a silicon septum, evacuated, and back-filled with ar-
gon. This sequence was repeated twice. DMA (5 mL), the aryl bromide
3 (3.0 mmol) and the appropriate azole (1.0 mmol), if liquid, were
then added successively under a stream of argon by syringe at room
temperature. The resulting mixture was stirred at 110 °C under argon
for 24 h. CuI (0.380 g, 2.0 mmol) was then added to the resulting pale
yellow mixture under a stream of argon. The reaction mixture was
heated to 140 °C and stirred at this temperature for 24 h. After cooling
to room temperature, the reaction mixture was diluted with EtOAc
and poured into a saturated aqueous NH4Cl solution. The resulting
mixture was basified with a few drops of aqueous NH4OH, stirred in
the open air for 0.5 h, and then extracted with EtOAc. The organic ex-
tract was washed with water, dried with anhydrous Na2SO4, and con-
centrated under reduced pressure, and the residue was purified by
flash chromatography on silica gel or by crystallization. The chro-
matographic fractions containing the required compound were col-
lected and concentrated. This procedure was employed to prepare
2,5-diaryl-1-methyl-1H-imidazoles 4a–o,q,r (Table 2, entries 1–12,
14–16, 21, and 22), 2,5-diaryl-1-phenyl-1H-imidazoles 8a,b (Table 3,
entries 1 and 2), 2,5-diaryl-1-benzyl-1H-imidazoles 9a–d (Table 3,
entries 3–6), 2,5-diaryl-1-n-butyl-1H-imidazoles 10a,b (Table 3, en-
tries 7 and 8), 4,4′-(thiazole-2,5-diyl)dibenzaldehyde (13) (Table 3,
entry 9), and 4,4′-(oxazole-2,5-diyl)dibenzaldehyde (14) (Table 3, en-
try 10).
4,4′-(1-Methyl-1H-imidazole-2,5-diyl)dibenzonitrile (4b)
The crude reaction product obtained from 2 and aryl bromide 3b ac-
cording to Method A was purified by crystallization (toluene) to give
4b (0.200 g, 70%) as a yellow solid. GLC analysis showed that 4b had
chemical purity higher than 98%. The NMR spectroscopic data of this
compound were in agreement with those previously reported.13
Mp 208–210 °C.
1H NMR (400 MHz, CDCl3): δ = 7.88 (m, 6 H), 7.65 (m, 2 H), 7.42 (s, 1
H), 3.82 (s, 3 H).
EIMS: m/z (%) = 285 (21), 284 (100) [M+], 283 (89), 207 (10), 155 (18),
128 (13).
Anal. Calcd for C18H12N4: C, 76.04; H, 4.25; N, 19.71. Found: C, 76.34;
H, 4.26; N, 19.70.
1-Methyl-2,5-bis(4-(trifluoromethyl)phenyl)-1H-imidazole (4c)
The crude reaction product obtained from 2 and aryl bromide 3c ac-
cording to Method A was purified by crystallization (hexane) to give
4c (0.189 g, 51%) as a yellow solid. GLC analysis showed that 4c had
chemical purity higher than 98%. The NMR spectroscopic data of this
compound were in agreement with those previously reported.12a
Mp 156–158 °C.
1H NMR (400 MHz, CDCl3): δ = 7.85 (m, 2 H), 7.75 (m, 4 H), 7.59 (m, 2
H), 7.32 (s, 1 H), 3.73 (s, 3 H).
EIMS: m/z (%) = 370 (100) [M+], 369 (82), 351 (12), 198 (13), 171 (7).
One-Pot Palladium-Catalyzed Synthesis of 2,5-Diarylimidazoles 4
in Xylene; General Procedure (Method B)
Anal. Calcd for C18H12F6N2: C, 58.38; H, 3.27; N, 7.57. Found: C, 58.60;
H, 3.28; N, 7.59.
In a flame-dried reaction vessel were placed the appropriate aryl bro-
mide 3 (3.0 mmol), Pd(OAc)2 (11.2 mg, 0.050 mmol), P(2-furyl)3 (23.2
mg, 0.1 mmol), and K2CO3 (0.276 g, 2.0 mmol). The reaction vessel
was fitted with a silicon septum, evacuated, and back-filled with ar-
gon. This sequence was repeated twice. Xylene (5 mL) and 1-methyl-
1H-imidazole (2; 80.0 μL, 82.1 mg, 1.0 mmol) were then added suc-
cessively under a stream of argon by syringe at room temperature.
The resulting mixture was stirred at 140 °C under argon for 24 h. Af-
ter cooling to room temperature, the reaction mixture was diluted
with EtOAc/CH2Cl2 (1:1, 20 mL) and filtered through Celite. The fil-
trate was concentrated under reduced pressure and the residue was
purified by flash chromatography on silica gel. The chromatographic
fractions containing the required compound were collected and con-
centrated. This procedure was employed to prepare 2,5-diaryl-1-
methyl-1H-imidazoles 4a, 4g, 4l, 4o, and 4p (Table 2, entries 19, 20,
13, 17, and 18, respectively).
1,1′-((1-Methyl-1H-imidazole-2,5-diyl)bis(4,1-phenyl-
ene))bis(ethan-1-one) (4d)
The crude reaction product obtained from 2 and aryl bromide 3d ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 90:10) (Rf = 0.35) to give 4d (0.201 g, 63%) as a
pale yellow solid. GLC analysis showed that 4d had chemical purity
higher than 98%. The NMR spectroscopic data of this compound were
in agreement with those previously reported.13
Mp 212–214 °C.
1H NMR (400 MHz, CDCl3): δ = 8.07 (m, 4 H), 7.84 (m, 2 H), 7.58 (m, 2
H), 7.35 (s, 1 H), 3.77 (s, 3 H), 2.65 (s, 6 H).
EIMS: m/z (%) = 319 (22), 318 (100) [M+], 317 (33), 303 (49), 275 (13).
Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80. Found: C, 75.74;
H, 5.71; N, 8.77.
4,4′-(1-Methyl-1H-imidazole-2,5-diyl)dibenzaldehyde (4a)
The crude reaction product obtained from imidazole 2 and aryl bro-
mide 3a according to Method A was purified by flash chromatography
on silica gel (EtOAc) (Rf = 0.34) to give 4a (0.226 g, 77%) as a bright
yellow solid. GLC analysis showed that 4a had chemical purity higher
than 98%. The NMR spectroscopic data of this compound were in
agreement with those previously reported.13
Diethyl 4,4′-(1-Methyl-1H-imidazole-2,5-diyl)dibenzoate (4e)
The crude reaction product obtained from 2 and aryl bromide 3e ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 30:70) (Rf = 0.35) to give 4e (0.223 g, 59%) as a
white solid. GLC analysis showed that 4e had chemical purity higher
than 98%. The NMR spectroscopic data of this compound were in
agreement with those previously reported.13
Mp 164–165 °C.
1H NMR (400 MHz, CDCl3): δ = 10.12 (s, 1 H), 10.10 (s, 1 H), 8.05 (m, 2
Mp 168–170 °C.
H), 8.03 (m, 2 H), 7.94 (m, 2 H), 7.68 (m, 2 H), 7.28 (s, 1 H), 3.85 (s, 3
H).
EIMS: m/z (%) = 290 (100) [M+], 289 (66), 158 (11), 130 (8), 103 (7), 89
1H NMR (400 MHz, CDCl3): δ = 8.16 (m, 4 H), 7.81 (m, 2 H), 7.55 (m, 2
H), 7.33 (s, 1 H), 4.42 (q, J = 6.9 Hz, 4 H), 3.75 (s, 3 H), 1.43 (t, J = 6.9 Hz,
6 H).
(7).
EIMS: m/z (%) = 379 (25), 378 (100) [M+], 377 (21), 349 (11), 321 (10).
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.75;
H, 4.87; N, 9.68.
Anal. Calcd for C22H22N2O4: C, 69.83; H, 5.86; N, 7.40. Found: C, 70.09;
H, 5.88; N, 7.38.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

G
M. Lessi et al.
Special Topic
Synthesis
2,5-Bis(4-chlorophenyl)-1-methyl-1H-imidazole (4f)
Anal. Calcd for C18H14N2O2: C, 74.47; H, 4.86; N, 9.65. Found: C, 74.76;
H, 4.87; N, 9.68.
The crude reaction product obtained from 2 and aryl bromide 3f ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 30:70) (Rf = 0.37) to give 4f (0.146 g, 48%) as a pale
brown solid. GLC analysis showed that 4f had chemical purity higher
than 98%. The NMR spectroscopic data of this compound were in
agreement with those previously reported.13
2,5-Bis(3-fluorophenyl)-1-methyl-1H-imidazole (4j)
The crude reaction product obtained from 2 and aryl bromide 3j ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 30:70) (Rf = 0.33) to give 4j (0.114 g, 42%) as a pale
brown solid. GLC analysis showed that 4j had chemical purity higher
than 98%.
Mp 154–155 °C.
1H NMR (400 MHz, CDCl3): δ = 7.62 (m, 2 H), 7.41 (m, 6 H), 7.19 (s, 1
Mp 117–119 °C.
H), 3.64 (s, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.45 (m, 4 H), 7.17 (m, 5 H), 3.69 (s, 3
EIMS: m/z (%) = 306 (11), 305 (18), 304 (65), 303 (59), 302 (100) [M+],
H).
164 (19).
13C NMR (100 MHz, CDCl3): δ = 162.8 (d, J = 246 Hz), 162.7 (d, J = 246
Hz), 148.5 (d, J = 2.4 Hz), 134.6 (d, J = 2.1 Hz), 132.7 (d, J = 8.2 Hz),
132.1 (d, J = 8.3 Hz), 130.5 (d, J = 8.5 Hz), 130.3 (d, J = 8.3 Hz), 128.3,
124.4 (d, J = 2.9 Hz), 124.3 (d, J = 2.9 Hz), 115.8 (d, J = 22.1 Hz, 2 C),
115.4 (d, J = 22.3 Hz), 114.9 (d, J = 21.0 Hz), 33.8.
Anal. Calcd for C16H12Cl2N2: C, 63.38; H, 3.99; N, 9.24. Found: C, 63.61;
H, 4.00; N, 9.25.
1-Methyl-2,5-bis(4-nitrophenyl)-1H-imidazole (4g)
The crude reaction product obtained from 2 and aryl bromide 3g ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 40:60) (Rf = 0.38) to give 4g (0.120 g, 37%) as a
pale orange solid. GLC analysis showed that 4g had chemical purity
higher than 98%. The NMR spectroscopic data of this compound were
in agreement with those previously reported.13
EIMS: m/z (%) = 271 (17), 270 (100) [M+], 269 (79), 148 (24), 107 (10).
Anal. Calcd for C16H12F2N2: C, 71.10; H, 4.48; N, 10.36. Found: C,
71.37; H, 4.49; N, 10.40.
2,2′-(1-Methyl-1H-imidazole-2,5-diyl)dibenzonitrile (4k)
Mp 218–220 °C.
The crude reaction product obtained from 2 and aryl bromide 3k ac-
cording to Method A was purified by flash chromatography on silica
gel (CH2Cl2/MeOH, 99:1) (Rf = 0.31) to give 4k (0.085 g, 30%) as a pale
brown solid. GLC analysis showed that 4k had chemical purity higher
than 98%. The NMR spectroscopic data of this compound were in
agreement with those previously reported.13
1H NMR (400 MHz, DMSO-d6): δ = 8.43 (m, 4 H), 8.13–8.11 (m, 2 H),
7.93 (m, 2 H), 7.60 (s, 1 H), 3.88 (s, 3 H).
EIMS: m/z (%) = 325 (20), 324 (100) [M+], 323 (32), 294 (28), 232 (16),
89 (11).
Anal. Calcd for C16H12N4O2: C, 59.26; H, 3.73; N, 17.28. Found: C,
59.40; H, 3.74; N, 17.34.
Mp 190–192 °C.
1H NMR (400 MHz, CDCl3): δ = 7.84 (m, 2 H), 7.73 (m, 3 H), 7.55 (m, 3
H), 7.44 (s, 1 H), 3.60 (s, 3 H).
EIMS: m/z (%) = 285 (19), 284 (100) [M+], 283 (88), 258 (11), 155 (10),
114 (10).
1-Methyl-2,5-bis(3-(trifluoromethyl)phenyl)-1H-imidazole (4h)
The crude reaction product obtained from 2 and aryl bromide 3h ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 40:60) (Rf = 0.37) to give 4h (0.193 g, 52%) as a
pale yellow solid. GLC analysis showed that 4h had chemical purity
higher than 98%. The NMR spectroscopic data of this compound were
in agreement with those previously reported.13
Anal. Calcd for C18H12N4: C, 76.04; H, 4.25; N, 19.71. Found: C, 76.35;
H, 4.26; N, 19.78.
1-Methyl-2,5-di-p-tolyl-1H-imidazole (4l)
Mp 156–158 °C.
The crude reaction product obtained from 2 and aryl bromide 3l ac-
cording to Method B was purified by flash chromatography on silica
gel (EtOAc/toluene, 40:60) (Rf = 0.35) to give 4l (0.186 g, 71%) as a pale
yellow solid. GLC analysis showed that 4l had chemical purity higher
than 98%. The NMR spectroscopic data of this compound were in
agreement with those previously reported.13
1H NMR (400 MHz, CDCl3): δ = 8.01 (s, 1 H), 7.91 (d, J = 7.6 Hz, 1 H),
7.66 (m, 6 H), 7.29 (s, 1 H), 3.72 (s, 3 H).
EIMS: m/z (%) = 371 (20), 370 (100) [M+], 369 (80), 351 (12), 198 (13).
Anal. Calcd for C18H12F6N2: C, 58.38; H, 3.57; N, 7.57. Found: C, 58.15;
H, 3.58; N, 7.60.
Mp 163–165 °C.
1H NMR (400 MHz, CDCl3): δ = 7.58 (m, 2 H), 7.34 (m, 2 H), 7.26 (m, 4
H), 7.16 (s, 1 H), 3.64 (s, 3 H), 2.40 (s, 6 H).
EIMS: m/z (%) = 263 (20), 262 (100) [M+], 261 (68), 144 (14), 117 (7).
3,3′-(1-Methyl-1H-imidazole-2,5-diyl)dibenzaldehyde (4i)
The crude reaction product obtained from 2 and aryl bromide 3i ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc) (Rf = 0.40) to give 4i (0.174 g, 60%) as a pale orange solid.
GLC analysis showed that 4i had chemical purity higher than 98%.
Anal. Calcd for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.21;
H, 6.94; N, 10.65.
Mp 108–110 °C.
1-Methyl-2,5-di-m-tolyl-1H-imidazole (4m)
1H NMR (400 MHz, CDCl3): δ = 10.16 (s, 1 H), 10.05 (s, 1 H), 8.23 (s, 1
The crude reaction product obtained from 2 and aryl bromide 3m ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 30:70) (Rf = 0.32) to give 4m (0.123 g, 47%) as a
pale yellow solid. GLC analysis showed that 4m had chemical purity
higher than 98%. The NMR spectroscopic data of this compound were
in agreement with those previously reported.13
H), 7.97 (m, 4 H), 7.72 (m, 3 H), 7.32 (s, 1 H), 3.77 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.8, 191.7, 148.6, 137.0, 136.7,
134.7, 134.5, 134.3, 131.7, 131.1, 129.9, 129.8 (2 C), 129.6, 129.5,
129.2, 128.7, 34.0.
EIMS: m/z (%) = 291 (19), 290 (100) [M+], 289 (57), 261 (8), 158 (9).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

H
M. Lessi et al.
Special Topic
Synthesis
Mp 80–83 °C.
5,5′-(1-Methyl-1H-imidazole-2,5-diyl)dipyrimidine (4q)
1H NMR (400 MHz, CDCl3): δ = 7.37 (m, 9 H), 3.66 (s, 3 H), 2.41 (s, 6 H).
EIMS: m/z (%) = 263 (19), 262 (100) [M+], 261 (79), 144 (14), 117 (7).
The crude reaction product obtained from 2 and aryl bromide 3q ac-
cording to Method A was purified by flash chromatography on silica
gel (CH2Cl2/MeOH, 95:5) (Rf = 0.40) to give 4q (0.052 g, 22%) as a yel-
low solid. GLC analysis showed that 4q had chemical purity higher
than 98%.
Anal. Calcd for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.73;
H, 6.93; N, 10.71.
Mp 200–202 °C.
1-Methyl-2,5-di-o-tolyl-1H-imidazole (4n)
1H NMR (400 MHz, CDCl3): δ = 9.31 (s, 1 H), 9.28 (s, 1 H), 9.13 (s, 2 H),
8.90 (s, 2 H), 7.43 (s, 1 H), 3.80 (s, 3 H).
13C NMR (100 MHz, DMSO-d6 + CD3OD): δ = 158.6, 158.1, 156.7 (2 C),
156.41, 156.35 (2 C), 145.2, 130.2, 125.6, 124.9, 33.9.
EIMS: m/z (%) = 239 (15), 238 (100) [M+], 237 (90), 211 (17), 210 (59),
184 (16), 183 (21).
The crude reaction product obtained from 2 and aryl bromide 3n ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 40:60) (Rf = 0.37) to give 4n (0.060 g, 23%) as a
pale yellow solid. GLC analysis showed that 4n had chemical purity
higher than 98%. The NMR spectroscopic data of this compound were
in agreement with those previously reported.13
Mp 56–58 °C.
Anal. Calcd for C12H10N6: C, 60.50; H, 4.23; N, 35.27. Found: C, 60.73;
H, 4.24; N, 35.40.
1H NMR (400 MHz, CDCl3): δ = 7.33 (m, 8 H), 7.08 (s, 1 H), 3.18 (s, 3 H),
2.28 (s, 3 H), 2.25 (s, 3 H).
3,3′-(1-Methyl-1H-imidazole-2,5-diyl)dipyridine (4r)
EIMS: m/z (%) = 263 (18), 262 (100) [M+], 261 (96), 248 (14), 247 (69),
The crude reaction product obtained from 2 and aryl bromide 3r ac-
cording to Method A was purified by flash chromatography on silica
gel (CH2Cl2/MeOH, 93:7) (Rf = 0.50) to give 4r (0.085 g, 36%) as a pale
yellow solid. GLC analysis showed that 4r had chemical purity higher
than 98%. The NMR spectroscopic data of this compound were in
agreement with those previously reported.13
144 (27), 130 (26).
Anal. Calcd for C18H18N2: C, 82.41; H, 6.92; N, 10.68. Found: C, 82.73;
H, 6.94; N, 10.72.
2,5-Bis(4-methoxyphenyl)-1-methyl-1H-imidazole (4o)
The crude reaction product obtained from 2 and aryl bromide 3o ac-
cording to Method B was purified by flash chromatography on silica
gel (EtOAc/toluene, 80:20) (Rf = 0.36) to give 4o (0.156 g, 53%) as a
pale yellow solid. GLC analysis showed that 4o had chemical purity
higher than 98%. The NMR spectroscopic data of this compound were
in agreement with those previously reported.9h
Mp 137–139 °C.
1H NMR (400 MHz, CDCl3): δ = 8.97 (s, 1 H), 8.76 (s, 1 H), 8.65 (m, 2 H),
8.06 (d, J = 8.1 Hz, 1 H), 7.79 (d, J = 8.0 Hz, 1 H), 7.44 (m, 2 H), 7.31 (s, 1
H), 3.73 (s, 3 H).
EIMS: m/z (%) = 237 (13), 236 (100) [M+], 235 (100), 131 (20), 104 (9).
Mp 218–220 °C.
Anal. Calcd for C14H12N4: C, 71.17; H, 5.12; N, 23.71. Found: C, 71.44;
H, 5.14; N, 23.79.
1H NMR (400 MHz, CDCl3): δ = 7.70 (m, 2 H), 7.42 (m, 2 H), 7.22 (s, 1
H), 6.89 (m, 4 H), 3.72 (s, 3 H), 3.09 (s, 3 H), 3.08 (s, 3 H).
4,4′-(1-Phenyl-1H-imidazole-2,5-diyl)dibenzaldehyde (8a)
EIMS: m/z (%) = 295 (20), 294 (100) [M+], 293 (31), 279 (37), 147 (7).
The crude reaction product obtained from 5 and aryl bromide 3a ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 50:50) (Rf = 0.33) to give 8a (0.127 g, 38%) as a
pale yellow solid. GLC analysis showed that 8a had chemical purity
higher than 98%.
Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52. Found: C, 73.74;
H, 6.18; N, 9.55.
4,4′-(1-Methyl-1H-imidazole-2,5-diyl)bis(N,N-dimethylaniline)
(4p)
Mp 240–241 °C.
The crude reaction product obtained from 2 and aryl bromide 3p ac-
cording to Method B was purified by flash chromatography on silica
gel (CH2Cl2/MeOH, 95:5) (Rf = 0.41) to give 4p (0.215 g, 67%) as a pale
brown solid. GLC analysis showed that 4p had chemical purity higher
than 98%.
1H NMR (400 MHz, CDCl3): δ = 9.97 (s, 1 H), 9.95 (s, 1 H), 7.75 (m, 4 H),
7.48 (m, 6 H), 7.24 (m, 2 H), 7.17 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 191.7, 191.6, 147.8, 136.7, 135.9,
135.8, 135.4, 135.2, 134.9, 130.6, 130.2 (2 C), 129.9 (2 C), 129.6 (3 C),
129.2 (2 C), 128.5 (2 C), 128.2 (2 C).
Mp 180–182 °C.
EIMS: m/z (%) = 353 (24), 352 (100) [M+], 351 (56), 165 (11), 77 (8).
1H NMR (400 MHz, CDCl3): δ = 7.58 (m, 2 H), 7.31 (m, 2 H), 7.10 (s, 1
H), 6.83–6.73 (m, 4 H), 3.61 (s, 3 H), 2.98–2.97 (m, 12 H).
13C NMR (100 MHz, CDCl3): δ = 150.2, 149.8, 149.1, 135.0, 129.4 (4 C),
Anal. Calcd for C23H16N2O2: C, 78.39; H, 4.58; N, 7.95. Found: C, 78.70;
H, 4.59; N, 7.97.
125.6, 118.8, 118.1, 112.2 (2 C), 111.8 (2 C), 40.2 (2 C), 40.1 (2 C), 33.5.
1-Phenyl-2,5-bis(4-(trifluoromethyl)phenyl)-1H-imidazole (8b)
EIMS: m/z (%) = 321 (22), 320 (100) [M+], 319 (33), 306 (13), 305 (23),
The crude reaction product obtained from 5 and aryl bromide 3c ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 20:80) (Rf = 0.40) to give 8b (0.190 g, 44%) as a
pale pink solid. GLC analysis showed that 8b had chemical purity
higher than 98%.
159 (14), 158 (11).
Anal. Calcd for C20H24N4: C, 74.97; H, 7.55; N, 17.48. Found: C, 75.26;
H, 7.58; N, 17.54.
Mp 174–176 °C.
1H NMR (400 MHz, CDCl3): δ = 7.45 (m, 10 H), 7.19 (m, 2 H), 7.14 (m, 2
H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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M. Lessi et al.
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13C NMR (100 MHz, CDCl3): δ = 147.4, 136.6, 134.5, 133.8, 133.1,
130.3 (q, J = 32 Hz), 130.1 (2 C), 129.8, 129.5 (q, J = 31 Hz), 129.4,
129.0 (2 C), 128.4 (2 C), 128.2 (2 C), 125.5 (q, J = 3.8 Hz, 2 C), 125.2 (q,
J = 3.8 Hz, 2 C), 124.1 (q, J = 269 Hz), 124.0 (q, J = 270 Hz).
EIMS: m/z (%) = 380 (49), 379 (18) [M+], 378 (74), 289 (25), 287 (38),
123 (24), 91 (100).
Anal. Calcd for C22H16Cl2N2: C, 69.67; H, 4.25; N, 7.39. Found: C, 69.94;
H, 4.46; N, 7.41.
EIMS: m/z (%) = 433 (24), 432 (100) [M+], 431 (66), 261 (4), 165 (4).
4,4′-(1-Benzyl-1H-imidazole-2,5-diyl)dibenzonitrile (9d)
Anal. Calcd for C23H14F6N2: C, 63.89; H, 3.26; N, 6.48. Found: C, 64.14;
H, 3.27; N, 6.50.
The crude reaction product obtained from 6 and aryl bromide 3b ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 30:70) (Rf = 0.36) to give 9d (0.198 g, 55%) as a
pale yellow solid. GLC analysis showed that 9d had chemical purity
higher than 98%.
4,4′-(1-Benzyl-1H-imidazole-2,5-diyl)dibenzaldehyde (9a)
The crude reaction product obtained from 6 and aryl bromide 3a ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 70:30) (Rf = 0.40) to give 9a (0.278 g, 76%) as a
pale orange solid. GLC analysis showed that 9a had chemical purity
higher than 98%.
Mp 129–131 °C.
1H NMR (400 MHz, CDCl3): δ = 7.73 (m, 2 H), 7.63 (m, 4 H), 7.43 (m, 3
H), 7.30 (m, 3 H), 6.88 (s, 2 H), 5.33 (s, 2 H).
Mp 124–126 °C.
13C NMR (100 MHz, CDCl3): δ = 148.7, 136.6, 134.7, 134.5, 134.2,
132.6 (2 C), 132.5 (2 C), 130.5, 129.4 (2 C), 129.1 (2 C), 129.0 (2 C),
128.3, 125.5 (2 C), 118.41, 118.38, 112.7, 112.0, 49.1.
1H NMR (400 MHz, CDCl3): δ = 9.94 (s, 1 H), 9.92 (s, 1 H), 7.79 (m, 6 H),
7.44 (m, 3 H), 7.21 (m, 3 H), 6.84 (m, 2 H), 5.35 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 191.4, 191.3, 149.1, 136.7, 136.0,
135.9, 135.5, 135.5, 134.9, 130.2, 129.9 (2 C), 129.8 (2 C), 129.0 (2 C),
129.0 (2 C), 128.8 (2 C), 127.8, 125.5 (2 C), 48.9.
EIMS: m/z (%) = 361 (8), 360 (29) [M+], 269 (2), 114 (9), 91 (100), 65
(7).
Anal. Calcd for C24H16N4: C, 79.98; H, 4.47; N, 15.55. Found: C, 80.29;
H, 4.47; N, 15.61.
EIMS: m/z (%) = 367 (14), 366 (50) [M+], 207 (8), 92 (8), 91 (100).
Anal. Calcd for C24H18N2O2: C, 78.67; H, 4.95; N, 7.65. Found: C, 78.98;
H, 4.96; N, 7.68.
4,4′-(1-Butyl-1H-imidazole-2,5-diyl)dibenzonitrile (10a)
The crude reaction product obtained from 7 and aryl bromide 3b ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 30:70) (Rf = 0.38) to give 10a (0.147 g, 45%) as a
pale brown solid. GLC analysis showed that 10a had chemical purity
higher than 98%.
1-Benzyl-2,5-bis(4-(trifluoromethyl)phenyl)-1H-imidazole (9b)
The crude reaction product obtained from 6 and aryl bromide 3c ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 20:80) (Rf = 0.38) to give 9b (0.245 g, 55%) as a
pale yellow solid. GLC analysis showed that 9b had chemical purity
higher than 98%.
Mp 141–142 °C.
1H NMR (400 MHz, CDCl3): δ = 7.79 (m, 6 H), 7.60 (m, 2 H), 7.29 (s, 1
H), 4.18 (t, J = 7.4 Hz, 2 H), 1.31 (m, 2 H), 0.96 (m, 2 H), 0.64 (t, J = 7.3
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 135.2, 134.6, 133.7, 132.6 (2 C),
132.3 (2 C), 130.1, 129.2 (2 C), 128.8 (2 C), 118.3, 118.2, 112.3, 111.7,
45.2, 32.1, 19.0, 13.0.
Mp 107–109 °C.
1H NMR (400 MHz, CDCl3): δ = 7.72 (m, 2 H), 7.62 (m, 4 H), 7.41 (m, 3
H), 7.28 (m, 3 H), 6.88 (m, 2 H), 5.29 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.8, 137.1, 134.6, 134.1, 133.5,
131.0 (q, J = 33 Hz), 130.3 (q, J = 32 Hz), 129.7, 129.2 (2 C), 129.0 (4 C),
128.1, 125.8 (q, J = 3.7 Hz, 2 C), 125.73 (q, J = 3.7 Hz, 2 C), 125.67 (2 C),
124.02 (q, J = 272 Hz), 123.99 (q, J = 272 Hz), 48.9.
EIMS: m/z (%) = 327 (25), 326 (100) [M+], 283 (14), 271 (12), 270 (59),
114 (14).
EIMS: m/z (%) = 447 (19), 446 (67) [M+], 427 (10), 157 (10), 91 (100).
Anal. Calcd for C21H18N4: C, 77.28; H, 5.56; N, 17.17. Found: C, 77.58;
H, 5.58; N, 17.20.
Anal. Calcd for C24H16F6N2: C, 64.58; H, 3.61; N, 6.28. Found: C, 64.83;
H, 3.62; N, 6.30.
1-Butyl-2,5-bis(4-chlorophenyl)-1H-imidazole (10b)
The crude reaction product obtained from 7 and aryl bromide 3f ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 20:80) (Rf = 0.40) to give 10b (0.107 g, 31%) as a
pale brown solid. GLC analysis showed that 10b had chemical purity
higher than 98%. The NMR spectroscopic data of this compound were
in agreement with those previously reported.13
1-Benzyl-2,5-bis(4-chlorophenyl)-1H-imidazole (9c)
The crude reaction product obtained from 6 and aryl bromide 3f ac-
cording to Method A was purified by flash chromatography on silica
gel (EtOAc/toluene, 20:80) (Rf = 0.44) to give 9c (0.167 g, 44%) as a
pale yellow solid. GLC analysis showed that 9c had chemical purity
higher than 98%.
Mp 125–127 °C.
Mp 166–168 °C.
1H NMR (400 MHz, CDCl3): δ = 7.58 (m, 2 H), 7.45 (m, 4 H), 7.36 (m, 2
H), 7.13 (s, 1 H), 4.05 (t, J = 7.4 Hz, 2 H), 1.28 (m, 2 H), 0.95 (m, 2 H),
0.63 (t, J = 7.3 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 7.50 (m, 2 H), 7.28 (m, 10 H), 6.84 (m, 2
H), 5.22 (s, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.6, 137.3, 135.1, 134.3, 134.3,
130.2 (2 C), 130.0 (2 C), 129.3, 129.0 (2 C), 129.0 (2 C), 128.9 (2 C),
128.8, 128.5, 127.8, 125.7 (2 C), 48.6.
EIMS: m/z (%) = 346 (66), 345 (24), 344 (100) [M+], 288 (42), 123 (19).
Anal. Calcd for C19H18Cl2N2: C, 66.09; H, 5.25; N, 8.11. Found: C, 66.34;
H, 5.27; N, 8.14.
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M. Lessi et al.
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Synthesis
4,4′-(Thiazole-2,5-diyl)dibenzaldehyde (13)
X.-M.; Damu, G. L. V.; Geng, R.-X.; Zhou, C.-H. Med. Res. Rev.
2014, 34, 340. (d) Rossi, R.; Lessi, M.; Manzini, C.; Marianetti, G.;
Bellina, F. Synthesis 2016, 48, 3821.
The crude reaction product obtained from thiazole (11) and aryl bro-
mide 3a according to Method A was purified by crystallization (EtO-
Ac) to give 13 (0.223 g, 76%) as an orange solid. GLC analysis showed
that 13 had chemical purity higher than 98%.
(2) (a) Fridman, N.; Speiser, S.; Kafrory, M. Cryst. Growth Des. 2006,
6, 1653. (b) Kulkánek, J.; Burês, F. Beilstein J. Org. Chem. 2012, 8,
25. (c) Liu, H.-H.; Chen, Y. Tetrahedron 2013, 69, 1872.
(3) Klikar, M.; Solanke, P.; Tydlitát, J.; Burês, F. Chem. Rec. 2016, 16,
1886.
(4) (a) Krygowski, T. M.; Szatylowicz, H.; Stasyuk, O. A.;
Dominikowska, J.; Palusiak, M. Chem. Rev. 2014, 114, 6383.
(b) Pandey, S. K.; Manogaran, D.; Manogaran, S.; Schaefer, H. F.
III. J. Phys. Chem. A 2016, 120, 2894.
Mp 155–157 °C.
1H NMR (400 MHz, CDCl3): δ = 10.08 (s, 1 H), 10.05 (s, 1 H), 8.23 (s, 1
H), 8.16 (m, 2 H), 7.98 (m, 4 H), 7.79 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 191.4, 191.2, 166.8, 141.5, 139.4,
138.3, 137.3, 136.8, 136.1, 130.7 (2 C), 130.5 (2 C), 127.1 (2 C), 127.0
(2 C).
(5) (a) Radziszewski, B. Ber. Dtsch. Chem. Ges. 1877, 10, 70.
(b) Yanover, D.; Kaftory, M. Acta Crystallogr., Sect. E 2009, 65,
o711.
EIMS: m/z (%) = 294 (22), 293 (100) [M+], 292 (19), 162 (25), 161 (54).
Anal. Calcd for C17H11NO2S: C, 69.61; H, 3.78; N, 4.77. Found: C, 69.87;
H, 3.79; N, 4.78.
(6) (a) Minei, P.; Battisti, A.; Barondi, S.; Lessi, M.; Bellina, F.;
Ruggeri, G.; Pucci, A. ACS Macro Lett. 2013, 2, 317. (b) Lessi, M.;
Manzini, C.; Minei, P.; Perego, L. A.; Bloino, J.; Egidi, F.; Barone,
V.; Pucci, A.; Bellina, F. ChemPlusChem 2014, 79, 366. (c) Barone,
V.; Bellina, F.; Biczysko, M.; Bloino, J.; Fornaro, T.; Latouche, C.;
Lessi, M.; Marianetti, G.; Minei, P.; Panattoni, A.; Pucci, A. Phys.
Chem. Chem. Phys. 2015, 17, 26710. (d) Bellina, F.; Manzini, C.;
Marianetti, G.; Pezzetta, C.; Fanizza, E.; Lessi, M.; Minei, P.;
Barone, V.; Pucci, A. Dyes Pigm. 2016, 134, 118.
4,4′-(Oxazole-2,5-diyl)dibenzaldehyde (14)
The crude reaction product obtained from oxazole (12) and aryl bro-
mide 3a according to Method A was purified by crystallization (EtO-
Ac) to give 14 (0.172 g, 62%) as an orange solid. GLC analysis showed
that 14 had chemical purity higher than 98%.
Mp 194–196 °C.
1H NMR (400 MHz, DMSO-d6): δ = 10.09 (s, 1 H), 10.03 (s, 1 H), 8.29
(7) Bellina, F.; Manzini, C.; Lessi, M. Eur. J. Org. Chem. 2013, 5621.
(8) For selected representative reviews on the direct C–H arylation
of imidazoles, see: (a) Satoh, T.; Miura, M. Chem. Lett. 2007, 36,
200. (b) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (c) Bellina, F.; Rossi, R. Tetrahedron 2009, 65, 10269.
(d) Roger, J.; Gottumukkala, A. L.; Doucet, H. ChemCatChem
2010, 2, 20. (e) Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.;
Perego, L. A. Synthesis 2014, 46, 2833. (f) Rossi, R.; Lessi, M.;
Manzini, C.; Marianetti, G.; Bellina, F. Synthesis 2016, 48, 3821.
(9) (a) Aoyagi, Y.; Inoue, A.; Koizumi, I.; Hashimoto, R.; Tokunaga,
K.; Gohma, K.; Komatsu, J.; Sekine, K.; Miyafuji, A.; Kunoh, J.;
Homma, R.; Akita, Y.; Ohta, A. Heterocycles 1992, 33, 257.
(b) Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M.
Bull. Chem. Soc. Jpn. 1998, 71, 467. (c) Kondo, Y.; Komine, T.;
Sakamoto, T. Org. Lett. 2000, 2, 3111. (d) Bellina, F.; Cauteruccio,
S.; Mannina, L.; Rossi, R.; Viel, S. J. Org. Chem. 2005, 70, 3997.
(e) Touré, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979.
(f) Chiong, H. A.; Daugulis, O. Org. Lett. 2007, 9, 1449. (g) Bellina,
F.; Cauteruccio, S.; Di Fiore, A.; Marchetti, C.; Rossi, R. Tetrahe-
dron 2008, 64, 6060. (h) Bellina, F.; Cauteruccio, S.; Di Fiore, A.;
Rossi, R. Eur. J. Org. Chem. 2008, 5436. (i) Roger, J.; Doucet, H.
Tetrahedron 2009, 65, 9772. (j) Joo, J. M.; Touré, B. B.; Sames, D.
J. Org. Chem. 2010, 75, 4911. (k) Kumar, P. V.; Lin, W.-S.; Shen, J.-
S.; Nandi, D.; Lee, H. M. Organometallics 2011, 30, 5160.
(l) Shinahara, F.; Yamauchi, T.; Yamaguchi, E.; Murai, T. J. Org.
Chem. 2012, 77, 8815. (m) Skogh, A.; Fransson, R.; Sköld, C.;
Larhed, M.; Sandström, A. J. Org. Chem. 2013, 78, 12251. (n) He,
X.-X.; Li, Y.; Ma, B.-B.; Ke, Z.; Liu, F.-S. Organometallics 2016, 35,
2655.
(m, 2 H), 8.01 (m, 4 H), 7.91 (m, 2 H), 7.69 (s, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 192.1, 191.9, 160.0, 150.4, 137.1,
135.7, 132.0, 130.9, 130.0 (2 C), 129.8 (2 C), 127.1, 126.5 (2 C), 124.4
(2 C).
EIMS: m/z (%) = 278 (18), 277 (100) [M+], 276 (32), 165 (16), 89 (10).
Anal. Calcd for C17H11NO3: C, 73.64; H, 4.00; N, 5.05. Found: C, 73.93;
H, 3.99; N, 5.07.
Funding Information
This work was supported by the Università di Pisa under the projects
PRA 2015 (project no. 2015_0038) and PRA 2017 (project no.
2017_28).
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Acknowledgment
The authors wish to thank Prof. Andrea Pucci and Dr. Pierpaolo Minei
of the Dipartimento di Chimica e Chimica Industriale, Università di
Pisa for the experimental measurements of the optical properties of
compound 4a in solution.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1589071
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(10) (a) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.; Viel, S. Eur.
J. Org. Chem. 2006, 693. (b) Bellina, F.; Cauteruccio, S.; Rossi, R.
Eur. J. Org. Chem. 2006, 1379. (c) Bellina, F.; Calandri, C.;
Cauteruccio, S.; Rossi, R. Tetrahedron 2007, 63, 1970. (d) Bellina,
F.; Cauteruccio, S.; Rossi, R. J. Org. Chem. 2007, 72, 8543.
(e) Yamauchi, T.; Shibahara, F.; Murai, T. J. Org. Chem. 2014, 79,
7185. (f) Bellina, F.; Guazzelli, N.; Lessi, M.; Manzini, C. Tetrahe-
dron 2015, 71, 2298.
References
(1) For selected reviews on the biological activities of aryl-substi-
tuted imidazoles, see: (a) Bellina, F.; Cauteruccio, S.; Rossi, R.
Tetrahedron 2007, 63, 4571. (b) Shalini, K.; Kumar Sharma, P.;
Kumar, N. Der Chimica Sinica 2010, 1,03 : 36. (c) Zhang, L.; Peng,
(11) Arai, N.; Takahashi, M.; Mitani, M.; Mori, A. Synlett 2006, 3170.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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M. Lessi et al.
Special Topic
Synthesis
(12) (a) Shibahara, F.; Yamaguchi, E.; Murai, T. Chem. Commun. 2010,
46, 2471. (b) Shibahara, F.; Yamagichi, E.; Murai, T. J. Org. Chem.
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(14) For an interesting study on acetate-assisted C–H activation at
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K