Selective sequential cross-coupling reactions on imidazole towards neurodazine and analogues

Article abstract of DOI:10.1055/s-0032-1316906

Polysubstituted imidazoles represent a common structural motif in bioactive molecules. A modular and flexible strategy towards 2,4,5-triarylated imidazoles is reported applying a Suzuki-Miyaura cross-coupling protocol. Employing 1-protected 2,4,5-tribromoimidazole as starting material, both stepwise and one-pot protocols towards the title compounds are disclosed. The utility of the approach was demonstrated by synthesizing neurodazine, a biologically active molecule affecting neuronal cell differentiation.

Full text of DOI:10.1055/s-0032-1316906

PAPER
▌1387
paper
Selective Sequential Cross-Coupling Reactions on Imidazole towards
Neurodazine and Analogues
Triarylated Imidazoles via Sequential Cross-Coupling
Lisa-Maria Recnik,a Mohammed Abd El Hameid,b Maximilian Haider,a Michael Schnürch,*a Marko D. Mihovilovic*a
a
Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria
Fax +43(1)58801163616; E-mail: michael.schnuerch@tuwien.ac.at; E-mail: marko.mihovilovic@tuwien.ac.at
b
Faculty of Pharmacy, Cairo University, 33 Kasr El-Aini Street, P.O. Box 11562, Cairo, Egypt
Received: 03.12.2012; Accepted after revision: 20.03.2013
MeO
Abstract: Polysubstituted imidazoles represent a common structur-
al motif in bioactive molecules. A modular and flexible strategy to-
wards 2,4,5-triarylated imidazoles is reported applying a Suzuki–
Cl
Miyaura cross-coupling protocol. Employing 1-protected 2,4,5-tri-
bromoimidazole as starting material, both stepwise and one-pot pro-
tocols towards the title compounds are disclosed. The utility of the
approach was demonstrated by synthesizing neurodazine, a biolog-
ically active molecule affecting neuronal cell differentiation.
N
O
N
H
MeO
Figure 1 Neurodazine
Key words: heterocycles, cross-coupling, palladium, regioselectiv-
ity, homogeneous catalysis
method applied remains problematic since several genes
have to be introduced into the cell genome in order to get
the desired de-differentiation of a specialized to a plurip-
otent cell. A retrovirus is required for the insertion of the
genes, which reduces the probability for the method of ob-
taining authority approval to be used in patient treatment.
As an alternative, inducing differentiation processes by
using synthetic small molecules is highly attractive since
protocols for toxicological testing are long established. In
several recent studies, a number of small molecules were
identified capable to trigger differentiation processes en
route to cardiac as well as skeletal muscle, pancreatic, or
neuronal tissue, as is the case for neurodazine.6,8
Heterocyclic compounds and especially their arylated an-
alogues are important compounds for a number of appli-
cations. Numerous examples of pharmaceuticals,1 plant
protection agents,2 and organic materials3 have been re-
ported. Amongst heterocycles, nitrogen-containing sys-
tems represent a privileged compound class due to their
frequent occurrence in natural products (e.g., alkaloids).4
Polyfunctionally decorated imidazoles are encountered as
common structural core motif in several bioactive mole-
cules.5 Therefore, the synthesis of such products is an im-
portant as well as competitive research area requiring
novel versatile synthetic methods for the preparation of Due to these reasons, the synthesis of neurodazine ana-
these target compounds.
logues for structure activity relationship studies is highly
interesting in order to improve this initially found activity.
For this purpose an efficient, modular, and rapid synthetic
strategy would be required in order to synthesize a com-
pound library of triarylated imidazoles.
A very interesting example of a bioactive imidazole deriv-
ative is neurodazine (Figure 1), a molecule with cell-dif-
ferentiating properties. Recent reports demonstrated that
treatment of C2C12 mouse myoblasts with neurodazine
resulted in the development of cells, which display neuron A common strategy for the synthesis of substituted imid-
like properties.6 Neuronal marker proteins were found to azoles is the cyclocondensation of 1,2-dicarbonyl com-
be upregulated; however, also skeletal muscle specific pounds with ammonia and an aldehyde.9 This is definitely
markers remained highly expressed. This suggests that an an attractive method for the synthesis of single com-
incomplete transformation from a muscle cell to a neuron pounds or a small collection of products as well as for pro-
was observed. Still, this initial finding indicates that trans- duction in large scale. Recently, Singh et al.10 synthesized
formation of certain cell types into a neuronal phenotype various 2,4,5-trisubstituted and 1,2,4,5-tetrasubstituted
is possible potentially opening up new opportunities for compounds using this well established method. In this
the treatment of neurodegenerative diseases.
publication easily available benzil was mainly used as
1,2-diketone. However, employing this strategy towards a
library of differently substituted imidazoles quickly be-
comes quite elaborate: For each substitution pattern the
corresponding 1,2-dicarbonyl compounds and aldehydes
have to be prepared separately. Alternatively, the prepara-
tion of trisubstituted imidazoles from N-protected tribro-
moimidazole was reported by Lipshutz employing
sequential bromine–lithium exchange followed by elec-
trophilic quenching.11
Generally, influencing cell differentiation to form certain
cell types from easily available tissue received significant
attention due to the potential benefits of such therapies.
Lately, the transformation of somatic cells to pluripotent
stem cells has stirred up much attention.7 However, the
SYNTHESIS 2013, 45, 1387–1405
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DOI: 10.1055/s-0032-1316906; Art ID: SS-2012-Z0934-OP
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One way to overcome the limitations of cyclization strat- [2-(trimethylsilyl)ethoxy]methyl (SEM), and p-methoxy-
egies is the use of a common imidazole building block to benzyl (PMB) proceeded well using a common protocol
be functionally decorated with the desired substituents in (Scheme 1). Attempts to install the common N-protecting
subsequent steps, for example, via transition metal-cata- group BOC, however, failed most probably due to steric
lyzed cross-coupling reactions.12 Employing suitably hindrance of the bromine substituents.
functionalized precursors, sequential coupling processes
have been demonstrated utilizing the well-established in-
Br
Br
dividual coupling protocols.12b,13 Recently, the synthesis
of triarylated imidazoles starting from 5-aryl-N-methyl-
imidazole via direct arylation was reported.13k
N
N
NaH, PG-X
THF, reflux
Br
Br
Br
Br
N
N
H
PG
1
2a: PG = Bn; 58%
2b: PG = SEM; 90%
2c: PG = PMB; 53%
In the present contribution, we investigated site selective
cross-coupling reactions of 2,4,5-tribromoimidazole.
Since the goal was to develop a method for facile library
synthesis of triarylated imidazoles the protocol should
meet the following criteria: (1) a cheap and readily avail-
able catalyst should be used, ideally Pd(PPh3)4; (2) reac-
Scheme 1 Introducing protecting groups on 2,4,5-tribromoimid-
azole (1)
tion conditions for all coupling steps should ideally be Next, selective cross-coupling at position 2 was investi-
identical in order to carry out all steps in one-pot; (3) over- gated using substrates 2a–c and (het)arylboronic acids as
all reaction conditions should be environmentally benign; coupling partners (Scheme 2). The group of Ohta reported
and (4) a readily available substrate should be used.
selective cross-coupling at position 2 of MOM-protected
tribromoimidazole using 5 mol% Pd(PPh3)4 as catalyst, 1
equivalent of 2 M aqueous Na2CO3, 1.1 equivalents of
phenylboronic acid, and a mixture of benzene–methanol
(5:1) as solvent.16b In our hands it was found that benzene
can very well be replaced by more benign toluene and ad-
ditionally, higher yields were obtained by using 2 M aque-
ous K2CO3 instead of Na2CO3 as the base.
Our aim was to synthesize 2,4,5-triarylated imidazoles
starting from the easily accessible and commercially
available substrate tribromoimidazole (1) by selective se-
quential Suzuki–Miyaura cross-coupling reactions. The
Suzuki–Miyaura14 protocol was chosen since a large num-
ber of boronic acids are commercially available and tox-
icity problems often encountered when employing tin
organyls in particular in a medicinal chemistry context
can be avoided. Additionally, inert conditions are not re-
quired further facilitating development of an operational-
ly simple protocol.
Br
Br
Pd(PPh3)4, aq 2 M K2CO3,
ArB(OH)2, toluene–MeOH
N
N
Br
Br
reflux
Br
N
N
PG
PG
The Suzuki–Miyaura cross-coupling reaction is a com-
mon and well-established tool in the arylation of monoha-
logenated imidazoles.15 Moreover, selective cross-
coupling reactions at positions 2 and 4/5 could be
achieved on dihalogenated imidazoles.16 Additionally,
Ohta et al. reported selective coupling at position 2 of
MOM-protected tribromoimidazole as well as a subse-
quent selective cross-coupling reaction at position 5 of
4,5-dibromo-1-MOM-2-phenylimidazole.16b The authors
do not report a final coupling at position 4. Huang et al.
published another protocol for the cross-coupling on
SEM-protected tribromoimidazole.17 To the best of our
knowledge, the synthesis of triarylated imidazoles starting
from tribromoimidazole has not been reported, so far.
Consequently, no one-pot procedure has been reported to-
wards the title compounds, as well. The modular combi-
nation of a sequence of iterative and methodologically
related steps offers the prospect of reaction automation,
ultimately. This is a highly appealing aspect in modern
medicinal chemistry and drug discovery, as access to
large compound libraries is enabled.13
Scheme 2 Cross-coupling at 2 position
All protecting groups were suitable for the coupling reac-
tion and a variety of protected 2-aryl-4,5-dibromo-1H-im-
idazoles were synthesized with high regioselectivity
(Table 1).
All reactions using arylboronic acids were over within a
few hours (reaction monitoring by TLC). In some cases
(compounds 3, 7, 11), a slightly larger excess of boronic
acid had to be added to complete consumption of imidaz-
ole starting material. Yields are usually good for coupling
with arylboronic acids (55–82%). The protecting group
had no major influence on the yields of the cross-coupling
process; for example, cross-coupling using phenylboronic
acid yielded 81% using benzyl (Table 1, entry 1, com-
pound 3), 82% using SEM (entry 7, compound 9), and
74% using PMB (entry 13, compound 15) as protecting
groups, respectively. Both electron-donating (OMe, en-
tries 2, 8, 14) and electron-withdrawing substituents
(NO2, entries 3, 4, 9, 10, 15) on the phenyl ring were well
accepted in the cross-coupling reaction. Sterically chal-
lenging o-tolylboronic acid gave a good yield of 7 using
benzyl (entry 5, 79%) or SEM (entry 11, 74%) as protect-
ing group, whereas with PMB a somewhat lower yield
was obtained (entry 16, 59%).
Our initial experiments confirmed that the free NH group
of imidazole was not well tolerated under general Suzuki
coupling conditions. Hence, 1-protected tribromoimid-
azoles were prepared using different protecting groups
with orthogonal properties. Introduction of benzyl (Bn),
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Triarylated Imidazoles via Sequential Cross-Coupling
1389
Table 1 Substrate Scope of Suzuki–Miyaura Cross-Coupling at Position 2 of 2,4,5-Tribromoimidazolea
Entry
Substrate
Boronic acid
Product
Yield (%)
81b
Br
Br
B(OH)2
N
1
2a
3
Br
Br
N
Bn
B(OH)2
N
2
3
2a
2a
2a
2a
2a
2b
2b
2b
2b
2b
4
5
78
55
64
79c
43d
82
74
65b
68
74
N
MeO
O2N
OMe
Bn
Br
Br
Br
Br
Br
Br
Br
Br
B(OH)2
B(OH)2
N
NO2
Br
Br
Br
Br
Br
Br
Br
Br
N
Bn
N
4
6
N
O2N
NO2
Bn
B(OH)2
N
5
7
N
Bn
N
O
O
B(OH)2
B(OH)2
6
8
N
Bn
N
7
9
N
SEM
B(OH)2
N
8
10
11
12
13
N
MeO
O2N
OMe
SEM
B(OH)2
B(OH)2
N
NO2
9
N
SEM
N
10
11
N
O2N
NO2
SEM
Br
Br
B(OH)2
N
Br
Br
N
SEM
N
O
31e
O
12
2b
14
B(OH)2
N
SEM
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L.-M. Recnik et al.
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Table 1 Substrate Scope of Suzuki–Miyaura Cross-Coupling at Position 2 of 2,4,5-Tribromoimidazolea (continued)
Entry
13
Substrate
Boronic acid
Product
Yield (%)
74
Br
Br
Br
Br
Br
B(OH)2
N
2c
15
Br
Br
Br
Br
Br
N
PMB
B(OH)2
B(OH)2
N
14
15
16
17
2c
2c
2c
2c
16
17
18
19
77
63
59
35e
N
MeO
O2N
OMe
PMB
N
NO2
N
PMB
B(OH)2
N
N
PMB
N
O
O
B(OH)2
N
PMB
a Reaction conditions: Pd(PPh3)4 (5 mol%), 2 M aq K2CO3 (1 equiv), boronic acid (1.1 equiv), toluene–MeOH (5:1) as solvent.
b Boronic acid used: 1.2 equiv.
c Boronic acid used: 1.3 equiv.
d Boronic acid used: 4.1 equiv in total.
e Boronic acid used: 3.6 equiv in total.
The cross-coupling of 2-furylboronic acid with N-protect-
ed 2,4,5-tribromoimidazole – the first step in the synthesis
Br
Br
Ar2
Ar1 Ar2
Pd catalyst, base,
aryl donor, solvent
N
N
N
+
Br
Ar1
of neurodazine – was more complicated. It is known that,
generally, heterocyclic boronic acids are less stable than
their carbocyclic counterparts and 2-furylboronic acid
represents a particularly troublesome case.18 As the reac-
tion had to be performed at 120 °C, 2-furylboronic acid
decomposed very quickly. Hence, more equivalents of bo-
ronic acid had to be added in portions to drive the reaction
to completion. However, even after adding up to 4.1
equivalents of 2-furylboronic acid conversion was not
complete and a larger excess was not considered based on
economics. Still, coupling products were obtained in only
43% using Bn (entry 6), 31% with SEM (entry 12), and
35% in case of PMB (entry 17).
Ar2
Ar1
N
N
temperature
N
PG
PG
PG
Scheme 3 Cross-coupling at positions 4 and 5
pected to have quite similar reactivity. Additionally, the
steric effect of nitrogen PGs disfavors position 5 and,
hence, only limited selectivity was expected. Indeed,
when using the benzyl protected analogue, we could not
obtain comparable selectivity as Ohta et al.16b did and only
30% of impure 5-coupled product could be obtained.
Even after extensively screening of reaction parameters
such as temperature, base, solvent, catalyst, and aryl do-
nor (boronic acid, boronic acid ester, and PhSnBu3) only
low selectivity could be achieved with 2,5-diarylated im-
idazole as major product and overarylation as competitive
process (Scheme 3, maximum selectivity 2:1 in favor of
the 2,5-diaryl over the 2,4,5-triaryl product).
As the next logical extension, cross-coupling at 5-position
was attempted, eventually elaborating selectivity relative
to position 4. In the literature only the report by Ohta et
al.16b can be found where a selective coupling at position
5 was obtained without compromising position 4: When
coupling phenylboronic acid with 1-methoxymethyl-2-
phenyl-4,5-dibromo-1H-imidazole they obtained 1-meth-
oxymethyl-2,5-diphenyl-4-bromo-1H-imidazole in 70%
yield after 10 hours.
Since selective cross-coupling could not be achieved in 5-
position and, hence, formation of 2,4,5-triarylated imidaz-
oles with three different substituents was not possible in
good yields, conversion of N-protected 2-aryl-4,5-dibro-
moimidazoles to triarylated compounds was studied in a
one-step protocol with identical aryl substituents in posi-
In our case, the protecting groups (PGs) have a negligible
electronic influence and hence positions 5 and 4 were ex-
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Triarylated Imidazoles via Sequential Cross-Coupling
1391
Ar2
Ar2
tions 4 and 5. Thus, N-protected 2-aryl-4,5-dibromoimid-
azoles were reacted with 3 equivalents of boronic acid.
The same conditions [2 M aq K2CO3, Pd(PPh3)4, toluene–
MeOH, 5:1] as for the first coupling step were employed
(Scheme 4). The results of this coupling step are summa-
rized in Table 2; in case arylation was not complete after
a few hours, more equivalents of boronic acid were added.
Br
Pd catalyst, base,
aryl donor, solvent
N
N
Ar1
Br
Ar1
N
N
temperature
PG
PG
Scheme 4 Cross-coupling at positions 4 and 5
Table 2 Substrate Scope of Suzuki–Miyaura Cross-Coupling at Positions 4 and 5 of 2-Aryl-4,5-dibromoimidazolea
Entry Substrate
Boronic acid
Product
Yield (%)
Br
B(OH)2
N
N
1
2
3
3
20
79
Br
N
N
Bn
Bn
MeO
Br
B(OH)2
N
21
85
N
Br
N
MeO
O2N
Bn
N
MeO
Bn
Br
Br
Br
Br
O2N
O2N
B(OH)2
N
N
3
4
5
6
3
3
4
4
22
23
24
25
55
37
60
32
Br
Br
Br
Br
N
N
Bn
Bn
B(OH)2
N
N
N
N
Bn
Bn
O2N
O2N
O2N
B(OH)2
N
N
N
OMe
OMe
N
Bn
OMe
Bn
B(OH)2
N
N
N
N
Bn
OMe
Bn
Br
B(OH)2
N
NO2
N
7
5
26
85
NO2
Br
N
N
Bn
Bn
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Table 2 Substrate Scope of Suzuki–Miyaura Cross-Coupling at Positions 4 and 5 of 2-Aryl-4,5-dibromoimidazolea (continued)
Entry Substrate
Boronic acid
Product
Yield (%)
Br
Br
Br
Br
B(OH)2
N
N
8
9
6
7
7
8
27
79
68
39b
81
Br
Br
Br
Br
N
NO2
N
Bn
NO2
Bn
MeO
B(OH)2
N
28
29
30
N
N
MeO
O2N
Bn
N
MeO
Bn
O2N
N
B(OH)2
N
O2N
10
11
N
N
Bn
Bn
MeO
B(OH)2
N
O
N
N
MeO
O
Bn
N
MeO
Bn
Br
Br
Br
N
B(OH)2
N
12
13
14
9
10
10
31
32
33
91
80
11c
Br
Br
Br
N
N
SEM
SEM
B(OH)2
N
N
N
OMe
N
SEM
OMe
OMe
SEM
N
B(OH)2
N
N
OMe
N
SEM
SEM
MeO
Br
B(OH)2
N
NO2
15
11
34
53
N
Br
NO2
N
MeO
SEM
N
MeO
SEM
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Triarylated Imidazoles via Sequential Cross-Coupling
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Table 2 Substrate Scope of Suzuki–Miyaura Cross-Coupling at Positions 4 and 5 of 2-Aryl-4,5-dibromoimidazolea (continued)
Entry Substrate
Boronic acid
Product
Yield (%)
MeO
Br
Br
Br
B(OH)2
N
16
17
18
12
13
14
35
21
N
Br
Br
Br
N
MeO
O2N
NO2
SEM
N
MeO
NO2
SEM
O2N
B(OH)2
N
74d
N
O2N
36
37
N
N
SEM
SEM
MeO
B(OH)2
N
O
96
N
N
MeO
O
SEM
N
MeO
SEM
MeO
Br
Br
Br
B(OH)2
N
NO2
19
20
21
17
18
19
38
39
40
92
42
53
N
Br
Br
Br
NO2
N
MeO
O2N
PMB
N
MeO
PMB
O2N
N
B(OH)2
N
O2N
N
N
PMB
PMB
MeO
B(OH)2
N
O
N
N
MeO
O
PMB
N
MeO
PMB
a Reaction conditions: Pd(PPh3)4 (5 mol%), 2 M aq K2CO3 (3 equiv), boronic acid (3.0 equiv), toluene–MeOH (5:1) as solvent.
b Boronic acid used: 3.5 equiv.
c Boronic acid used: 5 equiv.
d Boronic acid used: 6 equiv.
The yields of this two-fold coupling step were generally lower yields (39–60%) in the coupling step (entries 3, 5,
good. The nature of the N-protecting group did not impose 10, 20). Only within the synthesis of compound 36, start-
a major influence. The highest yields were obtained when ing from the substrate 13 having the sterically demanding
using phenylboronic acid (Table 2, entries 1, 7, 8, 12, 13) o-tolyl group as the substituent, a more pronounced PG ef-
or 4-methoxyphenylboronic acid as coupling partner (Ta- fect was observed with SEM (74%, entry 17) giving supe-
ble 2, entries 2, 9, 11, 18, 19). The neurodazine precursors rior results compared to Bn and PMB (entries 9, 10, 20).
30, 37, and 40 were synthesized in 81% (30, entry 11), Use of o-tolylboronic acid in the second coupling step re-
96% (37, entry 18), and 53% (40, entry 21), respectively. sulted in the lowest yields for the two-fold coupling reac-
Hence, the SEM group gave the best result in the coupling tion (entries 4, 6, 14). This is not surprising and can be
step. 3-Nitrophenylboronic acid usually gave somewhat explained by steric hindrance.
© Georg Thieme Verlag Stuttgart · New York
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L.-M. Recnik et al.
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two-step protocol (Table 3, entry 1). Also 24 (entry 2,
73% one pot vs. 46% stepwise), and 34 (entry 4, 58% one
pot vs. 34% stepwise) gave significantly higher yield
demonstrating the great utility of this approach. The only
exception was the synthesis of the neurodazine precursor
37 where a similar yield was obtained for both processes
(entry 3, 25% one pot vs. 29% stepwise). The overall low
yield is again caused by the instability of the heterocyclic
boronic acid and, hence, the overall challenge of handling
this specific transformation. Still, the one-pot process is
superior to the stepwise protocol in cases where such sta-
bility problems are not an issue.
Br
Br
Ar2
Ar2
N
N
N
a
b
Br
Br
Br
Ar1
Ar1
N
N
N
PG
2a: PG = Bn
2b: PG = SEM
PG
PG
21, 24, 34, 37
not isolated
Scheme 5 One-pot synthesis of triarylated imidazoles. Reagents and
conditions: a) Pd(PPh3)4 (5 mol%), 2 M aq K2CO3 (4 equiv), toluene–
MeOH (5:1); b) 3 equiv of second boronic acid added.
Based on identical reaction conditions for all coupling
steps, synthesis of triarylated imidazoles in a single one-
pot process was attempted. Reactions were conducted us-
ing 5 mol% of Pd(PPh3)4 and 4 equivalents of 2 M aque-
ous potassium carbonate solution in toluene–methanol
(5:1) as solvent. In the first step, 1.1 equivalents of boron-
ic acid reacted with the protected tribromoimidazole 2a or
2b. When consumption of the substrate was complete ac-
cording to TLC, 3 equivalents of another boronic acid
were added to the reaction solution (Scheme 5). On select-
ed examples, this one-pot process was compared to se-
quential-step preparation (Table 3). In general, yields
were higher in the one-pot procedure (3 out of 4 cases).
Compound 21 was synthesized in 89% yield starting from
2a in the one-pot process as compared to 68% over the
If neurodazine (50) should be synthesized via this cou-
pling sequence, deprotection of the protecting group is
mandatory (Scheme 6). Hence, possibilities to cleave the
different protecting groups were investigated. Standard
reductive cleavage of the benzyl group did not give a pos-
itive result under several reaction conditions frequently
applied (e.g., MeOH–formic acid, 10% Pd/C, 5 bar H2;19
transfer hydrogenation using anhydrous EtOH, 10% of
Pd/C, cyclohexa-1,4-diene20).
Gratifyingly, the benzyl group was cleaved by the oxida-
tive deprotection protocol of Deaton-Rewoliski et al.21
This protocol uses DMSO and potassium tert-butoxide in
combination with oxygen to obtain the unprotected prod-
Table 3 One-Pot Synthesis of 2,4,5-Triarylated Imidazoles
Entry
Substrate Boronic acid 1
Boronic acid 2
Product
Yield (%)
89 (68)a
MeO
B(OH)2
B(OH)2
1
2a
21
N
MeO
O2N
N
MeO
Bn
O2N
B(OH)2
B(OH)2
N
O2N
2
3
2a
24
37
73 (46)a
MeO
N
OMe
Bn
MeO
B(OH)2
O
2b
2b
B(OH)2
25 (29)a
N
MeO
O
N
MeO
SEM
MeO
B(OH)2
O2N
B(OH)2
4
34
58 (34)a
N
NO2
MeO
N
MeO
SEM
a The overall yields for the two-step process are given in parentheses.
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Triarylated Imidazoles via Sequential Cross-Coupling
1395
Ar2
Ar2
Ar2
equiv) in excellent yields in all cases investigated (Table
4, entries 4, 5).
N
N
a or b
Ar2
N
Ar1
Ar1
Several conditions were investigated for cleavage of the
PMB group (trifluoroacetic acid at 65–80 °C; 2.2 equiv of
DDQ toluene/H2O, 80 °C); however, none of them led to
the formation of the required product. Since the other two
protecting groups could be removed efficiently and the
PMB group does not provide an advantage in the previous
coupling steps, this is only a minor drawback.
N
H
PG
PG = Bn, SEM
41–45
Scheme 6 Deprotection protocols. Reagents and conditions: a) ben-
zyl deprotection: DMSO, oxygen, t-BuOK; b) SEM deprotection: 1
M Bu4NF (5 equiv) in THF, reflux.
To demonstrate the utility of the developed cross-cou-
pling chemistry in the synthesis of an interesting target
molecule, the synthesis of neurodazine (50) (Scheme 7)
was completed starting from benzyl and SEM protected
precursors 30 and 37 based on the above developed suc-
cessful deprotection conditions. The furan ring was bro-
minated by NBS in position 5 in 73% (46, PG = Bn) and
75% yield (47, PG = SEM), respectively. Suzuki–Miyaura
coupling with 3-chlorophenylboronic acid was performed
using Pd(PPh3)4 as catalyst and cesium carbonate as base.
uct. Although all tested substrates could be deprotected,
only in the case of compound 21 an excellent yield of 92%
could be obtained (Table 4, entry 2). In the other two cases
the yields were significantly lower (Table 4, entries 1, 3);
the reason for this is not quite clear.
The cleavage of SEM protected 2,4,5-triarylated imidaz-
oles was performed according to a procedure by Whitten
et al.22 employing Bu4NF (TBAF). This protocol enabled
access to unprotected 2,4,5-triaryl-1H-imidazoles (1
Table 4 Deprotection of 2,4,5-Triarylated Imidazoles
Entry
Substrate
Product
Yield (%)
N
1
20
41
42
25a
N
N
N
H
Bn
MeO
MeO
2
21
92a
N
N
N
N
H
MeO
MeO
Bn
N
N
N
3
4
27
32
43
44
30a
N
N
H
NO2
NO2
Bn
94b
N
N
N
H
OMe
OMe
SEM
MeO
MeO
5
35
45
90b
N
N
N
N
H
MeO
NO2
MeO
NO2
SEM
a Benzyl deprotection: DMSO, O2, t-BuOK.
b SEM deprotection: 1 M Bu4NF (5 equiv), THF, reflux.
© Georg Thieme Verlag Stuttgart · New York
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L.-M. Recnik et al.
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MeO
MeO
B(OH)2
Cs2CO3
Pd(PPh3)4
N
N
NBS
O
O
Br
+
N
N
anhyd toluene, 120 °C
DMF, r.t.
MeO
MeO
Cl
PG
30: PG = Bn
37: PG = SEM
PG
46: PG = Bn; 73%
47: PG = SEM; 75%
MeO
MeO
Cl
Cl
a or b
N
N
O
O
N
N
H
MeO
MeO
PG
48: PG = Bn; 69%
49: PG = SEM; 37%
50 via Bn deprotection 51%
via SEM deprotection 74%
Scheme 7 Synthesis of neurodazine. Reagents and conditions: a) benzyl deprotection: DMSO, oxygen, t-BuOK; b) SEM deprotection: 1 M
Bu4NF (5 equiv), THF, reflux.
While the SEM protected precursor gave only a moderate low-yielding step due to the instability of this boronic ac-
37% yield (Scheme 7, 49), satisfying results were ob- id.
tained in the benzyl protecting series (Scheme 7, 48,
69%). Deprotection of the imidazole ring led to neuroda-
Light petroleum (LP) used refers to the fraction boiling in the 40–
zine (50) in 74% yield (SEM deprotection) and 51% (ben-
zyl cleavage). Comparing both protecting groups in the
neurodazine total synthesis starting from tribromoimid-
azole (1), overall better results were obtained in the SEM
series due to higher yields in the protection and deprotec-
tion steps as well as in the furyl coupling step (precursor
37). Only the coupling step with 3-chlorophenylboronic
acid gives a higher yield for the benzyl protecting group.
65 °C range. Flash column chromatography was performed on silica
gel 60 (Merck, 40–63 μm). Separations were carried out using a Bü-
chi SepacoreTM MPLC system. Aluminum backed silica gel was
used for TLC. TLC plates (20 × 20 cm, 1000 μm silica layer thick-
ness) were used for preparative TLC; signals were visualized by UV
light (254 nm). Melting points were determined using a Stanford
Research Systems OptiMelt MPA100 or a Kofler-type Leica Galen
III micro hot stage microscope and are uncorrected. NMR spectra
were recorded from either CDCl3 (solvent peak referenced to 77.16
ppm), DMSO-d6 (solvent peak referenced to 39.52 ppm), or CD3OD
(solvent peak referenced to 49.00 ppm) solutions on a Bruker AC
200 (200 MHz) or a Bruker Avance Ultrashield (400MHz) spec-
trometer (as indicated). Chemical shifts are reported in ppm relative
to the nominal residual solvent signals. HRMS measurements were
carried out by E. Rosenberg at the Vienna University of Technolo-
gy, Institute for Chemical Technologies and Analytics. All samples
were analyzed by LC-IT-TOF-MS in only positive ion detection
mode upon recording of MS and MS/MS spectra. For the evaluation
in the following, only positive ionization spectra were used (where
the quasi-molecular ion is the one of [M + H]+), and further data or
information were not taken into consideration. Shimadzu Promi-
nence HPLC: solvent degassing unit (DGU-20 A3), binary gradient
Pump (2 × LC-20AD), auto-injector (SIL-20A), column oven
(CTO-20AC), control module (CBM-20A), and diode array detec-
tor (SPD-M20A). MS System: Shimadzu IT-TOF-MS with electro-
spray interface. Column: Phenomenex Prodigy ODS (3), 30 mm ×
In conclusion tribromoimidazole (1) was used as a cheap
and easily accessible starting material for three subse-
quent selective Suzuki–Miyaura cross-coupling steps.
Three different protecting groups were investigated for
their influence on the cross-coupling reaction. Selective
cross-coupling at 2-position generally gave good yields
and a broad range of arylboronic acids were tolerated (as
long as boronic acid reaction partners are sufficiently sta-
ble under reaction conditions; see results with 2-furylbo-
ronic acid). Preparatively insufficient selectivity was
observed for cross-coupling at 5-position even after an
elaborate condition screening. On the other hand, the
cross-couplings at 4- and 5-positions of the 4,5-dibro-
moimidazole substrates were performed simultaneously
in good yields and with good substrate scope. An excep- 4.6 mm, 3 μm particles, operated at 40 °C; Gradient: 0 min: 70% A,
30% B (1 min); linear gradient to 5 min to 10% A, 90% B (hold 2
min); at 7.01 min back to 70% A, 30% B, hold until 8.0 min). A:
MeCN + 0.1% formic acid, B: H2O + 0.1% formic acid. Column
flow: 0.5 mL/min; injection volume: 2 μL. MS parameters as in au-
tion is the use of 2-tolylboronic acid as aryl donor, which
is too sterically demanding. Deprotection of the SEM and
benzyl groups was also realized. With this method, a crit-
ical neurodazine precursor could be obtained, which was
totune. Data recorded with detector voltage at autotune value. Scan
converted into the bioactive target within three linear
steps. Starting from N-protected 2,4,5-tribromoimidazole
neurodazine (50) was synthesized in 8.9% overall yield
using benzyl as protecting group and 5.1% in the case of
SEM. In both cases, coupling with furanboronic acid is a
range: 50–1000 amu for both, MS and MS/MS (PI) detection, ES
ionization.
1-Benzyl-2,4,5-tribromo-1H-imidazole (2a)
A dry 500 mL three-necked flask equipped with a thermometer, a
reflux condenser, a magnetic stir bar, and a septum was flushed with
argon. Anhyd THF (200 mL) was placed in the flask and NaH (2.16
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Triarylated Imidazoles via Sequential Cross-Coupling
1397
g, 90 mmol, 3 equiv) was added and suspended. The mixture was
cooled to 0 °C. Then, 2,4,5-tribromoimidazole (1; 9.15 g, 30 mmol,
1 equiv) was added in portions. The solution was warmed to r.t. and
stirred for 30 min. Benzyl bromide (3.92 mL, 33 mmol, 1.1 equiv,
ρ = 1.438 g/cm3) was added dropwise and then the reaction solution
was heated to reflux for 5 h. Subsequently, the reaction mixture was
poured into H2O (100 mL). The aqueous solution was extracted
with CH2Cl2 (3 × 70 mL). The combined organic layers were
washed with H2O (70 mL) and dried (Na2SO4). The solvent was
evaporated and the crude product was purified by flash column
chromatography (100 g silica gel, LP–EtOAc, 30:1); yield: 6.83 g
(58%, 17.30 mmol); colorless solid; mp 68–69 °C (Lit.23 mp 58–
59 °C).
for 5 min. Then, the septum screw cap was exchanged for a closed
cap under argon flow, since caps with septum did not withstand the
pressure built up during the reaction. The mixture was heated to
120 °C in a heating block. The reaction was monitored by TLC and
stopped when reaction control showed complete consumption of the
starting material. If the reaction showed no further progress, addi-
tional equivalents of boronic acid were added until the reaction was
complete. The reaction mixture was cooled to r.t., filtered through a
pad of Celite, and the solvent was evaporated. The residue was di-
luted with H2O and extracted with CH2Cl2. The combined organic
layers were washed with H2O and dried (Na2SO4). The solvent was
evaporated and the desired product was obtained by flash column
chromatography.
1H NMR (200 MHz, CDCl3): δ = 5.22 (s, 2 H), 7.09–7.19 (m, 2 H),
7.31–7.41 (m, 3 H).
13C NMR (50 MHz, CDCl3): δ = 51.2 (t), 105.6 (s), 117.0 (s), 118.6
(s), 126.7 (d), 128.3 (d), 128.9 (d), 133.9 (s).
Cross-Coupling of 2a–c with 2-Furylboronic Acid; General
Procedure B
Protected 2,4,5-tribromo-1H-imidazole (1 equiv), 2-furylboronic
acid (1.1 equiv), NaHCO3 (2.5 equiv), Pd(PPh3)4 (5 mol%), and
DME–H2O (3:1) were placed in a 8 mL vial with a magnetic stirring
bar and a screw cap with septum. The solution was purged with ar-
gon for 5 min. Then the septum screw cap was exchanged for a
closed cap under argon flow, since caps with septum did not with-
stand the pressure built up during the reaction. The mixture was
heated to 100 °C in a heating block. If the reaction showed no fur-
ther progress by TLC, additional equivalents of boronic acid were
added. The addition of boronic acid was stopped when about 4
equiv were already added. The reaction mixture was cooled to r.t.,
filtered through a pad of Celite, and the solvent was evaporated. The
residue was diluted with H2O and extracted with CH2Cl2. The com-
bined organic layers were washed with H2O and dried (Na2SO4).
The solvent was evaporated and the desired product was obtained
by flash column chromatography.
2,4,5-Tribromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imid-
azole (2b)24
A dry 500 mL three-necked flask equipped with a thermometer, a
reflux condenser, a magnetic stirring bar, and a septum was flushed
with argon. Anhyd THF (200 mL) was placed in the flask and NaH
(0.72 g, 30 mmol, 2 equiv) was added and suspended. The mixture
was cooled to 0 °C before 2,4,5-tribromoimidazole (1; 4.58 g, 15
mmol, 1 equiv) was added in portions. The mixture was warmed to
r.t. and stirred for 2 h. 2-(Trimethylsilyl)ethoxymethyl chloride
(2.93 mL, 17 mmol, 1.1 equiv) was added dropwise and the mixture
was stirred at r.t. After 1 h, the reaction was complete according to
TLC. The mixture was poured into H2O (100 mL) and the aqueous
solution was extracted with Et2O (3 × 70 mL). The combined organ-
ic layers were washed with H2O (70 mL) and dried (Na2SO4). The
solvent was evaporated and the yellow oil obtained was purified by
flash column chromatography (50 g silica gel, LP–EtOAc, 10:1);
yield: 5.85 g (90%, 13.45 mmol); colorless solid; mp 58–60 °C.
Cross-Coupling of Substrates 3–19 Towards Triarylated Imid-
azoles 20–40; General Procedure C
Protected 2-aryl-4,5-tribromo-1H-imidazole (1 equiv), boronic acid
(3 equiv), 2 M aq K2CO3 (3 equiv), Pd(PPh3)4 (5 mol%), and
MeOH–toluene (5:1) were placed in a 4 mL vial with a magnetic
stirring bar and a screw cap with septum. The solution was purged
with argon for 5 min. Then the septum screw cap was exchanged for
a closed cap under argon flow, since caps with septum did not with-
stand the pressure built up during the reaction. The mixture was
heated to 120 °C in a heating block. The reaction was monitored by
TLC and stopped when reaction control showed complete con-
sumption of the starting material. If the reaction showed no further
progress, additional equivalents of boronic acid were added until
the reaction was complete. The reaction mixture was cooled to r.t.,
filtered through a pad of Celite, and the solvent was evaporated. The
residue was diluted with H2O and extracted with CH2Cl2. The com-
bined organic layers were washed with H2O and dried (Na2SO4).
The solvent was evaporated and the desired product was obtained
by flash column chromatography.
1H NMR (200 MHz, CDCl3): δ = 0.00 (s, 9 H), 0.93 (t, 3J = 8.2 Hz,
2 H), 3.61 (t, 3J = 8.2 Hz, 2 H), 5.33 (s, 2 H).
13C NMR (50 MHz, CDCl3): δ = 1.3 (q), 17.9 (t), 67.4 (t), 76.0 (t),
105.8 (s), 117.7 (s), 119.2 (s).
2,4,5-Tribromo-1-(4-methoxybenzyl)-1H-imidazole (2c)
A dry 50 mL three-necked flask equipped with a thermometer, a re-
flux condenser, a magnetic stir bar, and a septum was flushed with
argon. Anhyd THF (12.5 mL) was placed in the flask and NaH (0.12
g, 4.8 mmol, 3 equiv) was added and suspended. The mixture was
cooled to 0 °C before 2,4,5-tribromoimidazole (1; 0.5 g, 1.6 mmol,
1 equiv) was added in portions. The mixture was warmed to r.t. and
stirred for 30 min. 4-Methoxybenzyl chloride (0.24 mL, 1.8 mmol,
1.1 equiv, ρ = 1.154 g/cm3) was added dropwise and then the mix-
ture was heated under reflux for 6 h. The mixture was poured into
H2O (20 mL) and the aqueous solution was extracted with CH2Cl2
(3 × 10 mL). The combined organic layers were washed with H2O
(15 mL) and dried (Na2SO4). The solvent was evaporated and the
crude product was purified by flash column chromatography (50 g
silica gel, LP–EtOAc, 30:1); yield: 0.37 g (53%, 0.87 mmol); color-
less solid; mp 58–59 °C (Lit.23 mp 69–70 °C).
One-Pot Protocol for the Formation of 2,4,5-Triarylated Imid-
azoles; General Procedure D
Protected 2,4,5-tribromo-1H-imidazole (1 equiv), boronic acid (1.1
equiv), 2 M aq K2CO3 (4 equiv), Pd(PPh3)4 (5 mol%), and MeOH–
toluene (5:1) were placed in a 4 mL vial with a magnetic stirring bar
and a screw cap with septum. The solution was purged with argon
for 5 min. Then the septum screw cap was exchanged for a closed
cap under argon flow, since caps with septum did not withstand the
pressure built up during the reaction. The mixture was heated to
120 °C in a heating block. The reaction was monitored by TLC. If
the reaction showed no further progress, additional equivalents of
boronic acid were added until the reaction was complete. After
complete consumption of the starting material, the second boronic
acid (3 equiv) was added, and the subsequent cross-coupling steps
were carried out again at 120 °C. The reaction was stopped when re-
action control showed complete consumption of the starting materi-
al. The reaction mixture was cooled to r.t., filtered through a pad of
1H NMR (200 MHz, CDCl3): δ = 3.79 (s, 3 H), 5.14 (s, 2 H), 6.87
(d, 3J = 8.6 Hz, 2 H), 7.14 (d, 3J = 8.6 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = 51.0 (t), 55.4 (q), 105.6 (s), 114.4
(d), 117.1 (s), 118.5 (s), 126.2 (s), 128.6 (d), 159.7 (s).
Suzuki–Miyaura Cross-Coupling Reaction
Cross-Coupling at Position 2 of 2a–c; General Procedure A
Protected 2,4,5-tribromo-1H-imidazole (1 equiv), boronic acid (1.1
equiv), 2 M aq K2CO3 (1 equiv), Pd(PPh3)4 (5 mol%), and MeOH–
toluene (5:1) were placed in a 8 mL vial with a magnetic stirring bar
and a screw cap with septum. The solution was purged with argon
© Georg Thieme Verlag Stuttgart · New York
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1398
L.-M. Recnik et al.
PAPER
Celite, and the solvent was evaporated. The residue was diluted
with H2O and extracted with CH2Cl2. The combined organic layers
were washed with H2O and dried (Na2SO4). The solvent was evap-
orated and the desired product was obtained by flash column chro-
matography.
1-Benzyl-4,5-dibromo-2-(2-tolyl)-1H-imidazole (7)
Prepared according to general procedure A starting from compound
2a (500 mg, 1.27 mmol) and 2-tolylboronic acid (223 mg, 1.64
mmol, 1.3 equiv); 1.1 equiv added at the beginning, 0.2 equiv added
after 4 h; toluene–MeOH (5:1, 3 mL); 6 h. Flash column chroma-
tography (150 g silica gel, CH2Cl2–MeOH, 200:1); yield: 403 mg
(79%, 0.99 mmol); yellow solid; mp 105–106 °C.
1-Benzyl-4,5-dibromo-2-phenyl-1H-imidazole (3)
Prepared according to general procedure A starting from compound
2a (1 g, 2.53 mmol) and phenylboronic acid (0.37 g, 3.04 mmol, 1.2
equiv); 1.1 equiv added at the beginning, 0.1 equiv added after 4 h;
toluene–MeOH (5:1, 6 mL); 5 h. Flash column chromatography
(150 g silica gel, CH2Cl2–MeOH, 200:1); yield: 0.8 g (81%, 2.05
mmol); pale yellow solid; mp 91–92 °C (Lit.25 mp 91–93 °C).
1H NMR (200 MHz, CDCl3): δ = 2.11 (s, 3 H), 5.06 (s, 2 H), 6.83–
6.94 (m, 2 H), 7.13–7.42 (m, 7 H).
13C NMR (50 MHz, CDCl3): δ = 19.7 (q), 50.0 (t), 104.1 (s), 116.8
(s), 125.8 (d), 126.8 (d), 128.1 (d), 128.8 (d), 129.3 (s), 130.2 (d),
130.3 (d), 130.7 (d), 135.4 (s), 138.7 (s), 148.5 (s).
1H NMR (200 MHz, CDCl3): δ = 5.29 (s, 2 H), 6.97–7.07 (m, 2 H),
7.29–7.53 (m, 8 H).
13C NMR (50 MHz, CDCl3): δ = 50.1 (t), 105.3 (s), 117.4 (s), 125.7
(d), 127.8 (d), 128.4 (d), 128.6 (d), 129.0 (d), 129.2 (s), 129.6 (d),
135.4 (s), 149.0 (s).
1-Benzyl-4,5-dibromo-2-(2-furyl)-1H-imidazole (8)
Prepared according to general procedure B starting from compound
2a (500 mg, 1.27 mmol) and 2-furylboronic acid (586 mg, 5.23
mmol, 4.1 equiv); 1.1 equiv added at the beginning, 1 equiv added
after 0.5 h, 1 equiv after 2 h, 1 equiv after 1 h; toluene–MeOH (5:1,
4 mL); 4 h. Flash column chromatography (50 g silica gel, LP–
EtOAc, 6:1); yield: 210 mg (43%, 0.55 mmol); brown solid; mp
109–116 °C.
1H NMR (200 MHz, CDCl3): δ = 5.52 (s, 2 H), 6.63 (dd, 3J = 3.3 Hz,
4J = 1.7 Hz, 1 H), 6.85 (d, 3J = 3.5 Hz, 1 H), 7.05 (d, 3J = 6.5 Hz, 2
H), 7.23–7.43 (m, 3 H), 7.79–7.86 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 50.9 (t), 107.1 (s), 111.8 (d), 112.7
(d), 117.8 (s), 126.9 (d), 128.6 (d), 129.8 (d), 136.6 (s), 140.5 (s),
144.2 (s), 145.2 (d).
HRMS: m/z calcd for [M + H]+: 380.9233; found: 380.9252, differ-
ence = 4.99 ppm.
1-Benzyl-4,5-dibromo-2-(4-methoxyphenyl)-1H-imidazole (4)
Prepared according to general procedure A starting from compound
2a (250 mg, 0.63 mmol) and 4-methoxyphenylboronic acid (105.8
mg, 0.70 mmol, 1.1 equiv) in toluene–MeOH (5:1, 1.5 mL) for 6 h.
Flash column chromatography (50 g silica gel, LP–EtOAc, 10:1);
yield: 209 mg (78%, 0.50 mmol); colorless solid; mp 117–121 °C.
1H NMR (200 MHz, CDCl3): δ = 3.81 (s, 3 H), 5.26 (s, 2 H), 6.82–
6.92 (m, 2 H), 6.97–7.07 (m, 2 H), 7.29–7.45 (m, 5 H).
13C NMR (50 MHz, CDCl3): δ = 50.3 (t), 55.4 (q), 105.1 (s), 114.2
(d), 117.1 (s), 121.7 (s), 125.9(d), 128.2 (d), 129.2 (d), 130.2 (d),
135.7 (s), 149.3 (s), 160.8 (s).
HRMS: m/z calcd for [M + H]+: 420.9546; found: 420.9553, differ-
ence = 1.66 ppm.
4,5-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2-phenyl-
1H-imidazole (9)17
Prepared according to general procedure A starting from compound
2b (500 mg, 1.15 mmol) and phenylboronic acid (154 mg, 1.26
mmol, 1.1 equiv) in toluene–MeOH (5:1, 3 mL) for 5 h. Flash col-
umn chromatography (75 g silica gel, LP–EtOAc, 20:1); yield: 409
mg (82%, 0.94 mmol); colorless solid: mp 76–79 °C.
1H NMR (200 MHz, CDCl3): δ = 0.08 (s, 9 H), 0.95 (t, 3J = 8.2 Hz,
2 H), 3.65 (t, 3J = 8.2 Hz, 2 H), 5.31 (s, 2 H), 7.41–7.51 (m, 3 H),
7.72–7.83 (m, 2 H).
1-Benzyl-4,5-dibromo-2-(3-nitrophenyl)-1H-imidazole (5)
Prepared according to general procedure A starting from compound
2a (592.5 mg, 1.5 mmol) and 3-nitrophenylboronic acid (275 mg,
1.65 mmol, 1.1 equiv) in toluene–MeOH (5:1, 3.6 mL) for 3.5 h.
Flash column chromatography (100 g silica gel, CH2Cl2–MeOH,
200:1); yield: 357 mg (55%, 0.82 mmol); yellow solid; mp 96–
100 °C.
1H NMR (200 MHz, DMSO-d6): δ = 5.44 (s, 2 H), 7.02 (d, 3J = 6.4
Hz, 2 H), 7.24–7.43 (m, 3 H), 7.70–7.81 (m, 1 H), 7.99 (d, 3J = 7.8
Hz, 1 H), 8.24–8.34 (m, 2 H).
13C NMR (50 MHz, DMSO-d6): δ = 50.1 (t), 107.5 (s), 117.1 (s),
122.9 (d), 124.2 (d), 125.8 (d), 127.8 (d), 129.0 (d), 130.4 (s), 130.6
(d), 134.4 (d), 135.6 (s), 146.2 (s), 147.9 (s).
HRMS: m/z calcd for [M + H]+: 435.9291; found: 435.9301, differ-
ence = 2.29 ppm.
13C NMR (50 MHz, CDCl3): δ = –1.3 (q), 18.0 (t), 67.1 (t), 74.8 (t),
105.4 (s), 117.9 (s), 128.8 (d), 129.1 (d), 129.3 (s), 130.0 (d), 149.9
(s).
LCMS: m/z (%) = 455 (12), 433 (82, MH+), 403 (17), 375 (100).
4,5-Dibromo-2-(4-methoxyphenyl)-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1H-imidazole (10)26
Prepared according to general procedure A starting from compound
2b (500 mg, 1.15 mmol) and 4-methoxyphenylboronic acid (192
mg, 1.26 mmol, 1.1 equiv) in toluene–MeOH (5:1, 3 mL) for 6.5 h.
Flash column chromatography (100 g silica gel, LP–EtOAc, 7:1);
yield: 393 mg (74%, 0.85 mmol); red brown solid; mp 95–97 °C.
1-Benzyl-4,5-dibromo-2-(4-nitrophenyl)-1H-imidazole (6)
Prepared according to general procedure A starting from compound
2a (250 mg, 0.63 mmol) and 4-nitrophenylboronic acid (116.3 mg,
0.70 mmol, 1.1 equiv) in toluene–MeOH (5:1, 1.5 mL) for 6 h. Flash
column chromatography (50 g silica gel, LP–EtOAc, 10:1); yield:
176.3 mg (64%, 0.40 mmol); yellow solid; mp 153–155 °C.
1H NMR (200 MHz, CDCl3): δ = 5.26 (s, 2 H), 6.88–7.04 (m, 2 H),
7.22–7.40 (m, 3 H), 7.60 (d, 3J = 8.7 Hz, 2 H), 8.13 (d, 3J = 8.7 Hz,
1 H).
13C NMR (50 MHz, CDCl3): δ = 50.7 (t), 107.9 (s), 118.7 (s), 124.1
(d), 125.7 (d), 128.5 (d), 129.2 (d), 129.6 (d), 134.9 (s), 135.2 (s),
146.7 (s), 148.2 (s).
HRMS: m/z calcd for [M + H]+: 435.9296; found: 435.9291, differ-
ence = 1.15 ppm.
1H NMR (200 MHz, CDCl3): δ = 0.00 (s, 9 H), 0.94 (t, 3J = 8.3 Hz,
2 H), 3.65 (t, 3J = 8.3 Hz, 2 H), 3.83 (s, 3 H), 5.26 (s, 2 H), 6.94 (d,
3J = 8.7 Hz, 2 H), 7.79 (d, 3J = 8.7 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = –1.6 (q), 17.7 (t), 55.2 (q), 66.8 (t),
74.5 (t), 104.7 (s), 114.0 (s), 116.7 (d), 120.9 (s), 130.3 (d), 149.6
(s), 160.8 (s).
4,5-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2-(3-nitro-
phenyl)-1H-imidazole (11)
Prepared according to general procedure A starting from compound
2b (500 mg, 1.15 mmol) and 3-nitrophenylboronic acid (230 mg,
1.38 mmol, 1.2 equiv.); 1.1 equiv added at the beginning, 0.1 equiv
added after 5 h; toluene–MeOH (5:1, 3 mL); 6.5 h. Flash column
chromatography (100 g silica gel, LP–EtOAc, 10:1); yield: 355 mg
(65%, 0.74 mmol); yellow solid; mp 102–105 °C.
Synthesis 2013, 45, 1387–1405
© Georg Thieme Verlag Stuttgart · New York

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Triarylated Imidazoles via Sequential Cross-Coupling
1399
1H NMR (200 MHz, CDCl3): δ = 0.03 (s, 9 H), 1.05 (t, 3J = 8.3 Hz,
2 H), 3.78 (t, 3J = 8.3 Hz, 2 H), 5.33 (s, 2 H), 7.65 (t, 3J = 8.0 Hz, 1
H), 8.17–8.33 (m, 2 H), 8.77 (t, 3J = 1.8 Hz, 1 H).
13C NMR (50 MHz, CDCl3): δ = 49.8 (t), 55.3 (q), 105.3 (s), 114.4
(d), 117.4 (s), 127.3 (d), 127.5 (s), 128.6 (d), 128.7 (d), 129.5 (s),
129.7 (d), 149.1 (s), 159.2 (s).
13C NMR (50 MHz, CDCl3): δ = –1.6 (q), 17.8 (t), 67.1 (t), 74.4 (t),
106.6 (s), 118.1 (s), 123.3 (d), 124.2 (d), 129.7 (d), 130.5 (s), 134.3
(d), 147.0 (s), 148.2 (s).
HRMS: m/z calcd for [M + H]+: 420.9546; found: 420.9547, differ-
ence = 0.24 ppm.
4,5-Dibromo-2-(4-methoxyphenyl)-1-(4-methoxybenzyl)-1H-
imidazole (16)
4,5-Dibromo-1-{[2-(trimethylsilyl)ethoxy]methyl}-2-(4-nitro-
phenyl)-1H-imidazole (12)
Prepared according to general procedure A starting from compound
2c (100 mg, 0.24 mmol) and 4-methoxyphenylboronic acid (39 mg,
0.26 mmol, 1.1 equiv) in toluene–MeOH (5:1, 0.6 mL) for 5 h. Flash
column chromatography (50 g silica gel, LP–EtOAc, 10:1); yield:
82 mg (77%, 0.18 mmol); yellow oil.
Prepared according to general procedure A starting from compound
2b (250 mg, 0.58 mmol) and 4-nitrophenylboronic acid (106 mg,
0.63 mmol, 1.1 equiv) in toluene–MeOH (5:1, 1.5 mL) for 5 h. Flash
column chromatography (50 g silica gel, LP–EtOAc, 15:1); yield:
188 mg (68%, 0.39 mmol); yellow solid; mp 133–136 °C.
1H NMR (200 MHz, CDCl3): δ = 3.79 (s, 3 H), 3.80 (s, 3 H), 5.18
(s, 2 H), 6.79–7.00 (m, 6 H), 7.33–7.45 (m, 2 H).
13C NMR (50 MHz, CDCl3): δ = 49.6 (t), 55.18 (q), 55.22 (q), 104.6
(s), 114.0 (d), 114.3 (d), 117.0 (s), 121.8 (s), 127.1 (d), 127.6 (s),
130.0 (d), 149.0 (s), 159.1 (s), 160.5 (s).
1H NMR (200 MHz, CDCl3): δ = 0.04 (s, 9 H), 1.00 (t, 3J = 8.3 Hz,
2 H), 3.79 (t, 3J = 8.3 Hz, 2 H), 5.34 (s, 2 H), 8.08 (d, 3J = 8.9 Hz, 2
H), 8.31 (d, 3J = 8.9 Hz, 2 H).
13C NMR (50 MHz, CDCl3): δ = –1.2 (q), 18.2 (t), 67.7 (t), 74.8 (t),
107.5 (s), 118.9 (s), 124.1 (d), 129.6 (d), 135.0 (s), 147.4 (s), 148.4
(s)
HRMS: m/z calcd for [M + H]+: 475.9635; found: 475.9645, differ-
HRMS: m/z calcd for [M + H]+: 450.9651; found: 450.9670, differ-
ence = 4.21 ppm.
4,5-Dibromo-1-(4-methoxybenzyl)-2-(3-nitrophenyl)-1H-imid-
azole (17)
ence = 2.10 ppm.
Prepared according to general procedure A starting from compound
2c (200 mg, 0.47 mmol) and 3-nitrophenylboronic acid (86 mg,
0.52 mmol, 1.1 equiv) in toluene–MeOH (5:1, 1.2 mL) for 6 h. Flash
column chromatography (75 g silica gel, LP–EtOAc, 10:1); yield:
138 mg (63%, 0.29 mmol); beige oil.
1H NMR (200 MHz, CDCl3): δ = 3.80 (s, 3 H), 5.27 (s, 2 H), 6.82–
7.01 (m, 4 H), 7.57 (t, 3J = 8.2 Hz, 1 H), 7.85 (d, 3J = 7.7 Hz, 1 H),
8.25 (d, 3J = 8.2 Hz, 1 H), 8.32–8.39 (m, 1 H).
13C NMR (50 MHz, CDCl3): δ = 50.1 (t), 55.3 (q), 107.1 (s), 114.6
(d), 118.1 (s), 123.3 (d), 124.2 (d), 126.6 (s), 127.1 (d), 129.9 (d),
130.9 (s), 134.2 (d), 146.3 (s), 148.2 (s), 159.5 (s).
HRMS: m/z calcd for [M + Na]+: 487.9216; found: 487.9229, dif-
ference = 2.66 ppm.
4,5-Dibromo-1-((2-(trimethylsilyl)ethoxy)methyl)-2-(2-tolyl)-
1H-imidazole (13)
Prepared according to general procedure A starting from compound
2b (250 mg, 0.58 mmol) and 2-tolylboronic acid (86 mg, 0.63
mmol, 1.1 equiv) in toluene–MeOH (5:1, 1.5 mL) for 5 h. Flash col-
umn chromatography (50 g silica gel, LP–EtOAc, 15:1); yield: 190
mg (74%, 0.43 mmol); beige oil.
1H NMR (200 MHz, CDCl3): δ = 0.00 (s, 9 H), 0.85 (t, 3J = 8.3 Hz,
2 H), 2.29 (s, 3 H), 3.41 (t, 3J = 8.3 Hz, 2 H), 5.16 (s, 2 H), 7.24–
7.48 (m, 4 H).
13C NMR (50 MHz, CDCl3): δ = –1.7 (q), 17.5 (t), 19.6 (q), 66.4 (t),
74.2 (t), 103.6 (s), 117.0 (s), 125.4 (d), 128.5 (s), 129.9 (d), 130.34
(d), 130.38 (d), 138.2 (s), 148.5 (s)
HRMS: m/z calcd for [M + H]+: 444.9941; found: 444.9956, differ-
ence = 2.10 ppm.
4,5-Dibromo-1-(4-methoxybenzyl)-2-(2-tolyl)-1H-imidazole
(18)
Prepared according to general procedure A starting from compound
2c (200 mg, 0.47 mmol) and 2-tolylboronic acid (70 mg, 0.52
mmol, 1.1 equiv) in toluene–MeOH (5:1, 1.2 mL) for 6 h. Flash col-
umn chromatography (75 g silica gel, LP–EtOAc, 10:1); yield: 121
mg (59%, 0.28 mmol); beige oil.
1H NMR (200 MHz, CDCl3): δ = 1.97 (s, 3 H), 3.73 (s, 3 H), 5.03
(s, 2 H), 6.72–6.79 (m, 4 H), 7.14–7.49 (m).
13C NMR (50 MHz, CDCl3): δ = 20.3 (q), 51.3 (t), 56.5 (q), 106.6
(s), 115.9 (d), 117.4 (s), 127.8 (d), 129.4 (s), 130.2 (d), 131.1 (s),
132.2 (d), 132.4 (d), 132.5 (d), 140.7 (s), 150.7 (s), 161.7 (s).
HRMS: m/z calcd for [M + H]+: 434.9702; found: 434.9707, differ-
ence = 1.15 ppm.
4,5-Dibromo-2-(2-furyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-
1H-imidazole (14)
Prepared according to general procedure B starting from compound
2b (500 mg, 1.15 mmol) and 2-furylboronic acid (463 mg, 4.14
mmol, 3.6 equiv); 1.1 equiv added at the beginning, 0.5 equiv added
after 1 h, 1 equiv after 30 min, 1 equiv after 15 min; toluene–MeOH
(5:1, 3 mL); 2 h. Flash column chromatography (100 g silica gel,
LP–EtOAc, 10:1); yield: 149 mg (31%, 0.35 mmol); brown solid;
mp 73–76 °C.
1H NMR (200 MHz, CDCl3): δ = –0.04 (s, 9 H), 0.90 (t, 3J = 8.2 Hz,
2 H), 3.60 (t, 3J = 8.2 Hz, 2 H), 5.56 (s, 2 H), 6.53 (dd, 3J = 3.5 Hz,
4J = 1.8 Hz, 1 H), 7.02 (d, 3J = 3.5 Hz, 1 H), 7.53 (d, 3J = 1.8 Hz, 1
H).
13C NMR (50 MHz, CDCl3): δ = –1.3 (q), 17.9 (t), 66.9 (t), 75.0 (t),
105.4 (s), 111.8 (d), 111.9 (d), 118.2 (s), 140.9 (s), 143.7 (d), 144.0
(s).
HRMS: m/z calcd for [M + H]+: 420.9577; found: 420.9579, differ-
ence = 0.48 ppm.
4,5-Dibromo-2-(2-furyl)-1-(4-methoxybenzyl)-1H-imidazole
(19)
Prepared according to general procedure B starting from compound
2c (400 mg, 0.94 mmol) and 2-furylboronic acid (379 mg, 3.39
mmol, 3.6 equiv); 1.1 equiv added at the beginning, 0.5 equiv added
after 1 h, 1 equiv after 30 min, 1 equiv after 15 min; toluene–MeOH
(5:1, 2.4 mL); 2 h. Flash column chromatography (200 g silica gel,
LP–EtOAc, 9:1); yield: 136 mg (35%, 0.33 mmol); dark beige oil.
4,5-Dibromo-1-(4-methoxybenzyl)-2-phenyl-1H-imidazole (15)
Prepared according to general procedure A starting from compound
2c (100 mg, 0.24 mmol) and phenylboronic acid (32 mg, 0.26
mmol, 1.1 equiv) in toluene–MeOH (5:1, 0.6 mL) for 5 h. Flash col-
umn chromatography (50 g silica gel, LP–EtOAc, 10:1); yield: 74
mg (74%, 0.17 mmol); pale yellow solid; mp 98–102 °C.
1H NMR (200 MHz, CDCl3): δ = 3.75 (s, 3H), 5.42 (s, 2 H), 6.42–
6.52 (m, 1 H), 6.77–6.87 (m, 3 H), 7.02 (d, 3J = 8.7 Hz, 2 H), 7.42–
7.52 (m, 1 H).
13C NMR (50 MHz CDCl3,): δ = 49.9 (t), 55.1 (q), 105.4 (s), 110.8
(d), 111.6 (d), 114.1 (d), 117.6 (s), 127.2 (s), 127.8 (d), 139.9 (s),
143.1 (d), 144.1 (s), 159.2 (s).
1H NMR (200 MHz, CDCl3): δ = 3.79 (s, 3 H), 5.22 (s, 2 H), 6.81–
6.99 (m, 4 H), 7.31–7.54 (m, 5 H).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1387–1405

1400
L.-M. Recnik et al.
PAPER
HRMS: m/z calcd for [M + H]+: 410.9338; found: 410.9326, differ-
ence = –2.92 ppm.
13C NMR (50 MHz CD3OD): δ = 19.8 (q), 20.7 (q), 49.7 (t), 126.3
(d), 126.8 (d), 127.5 (d), 128.5 (d), 128.7 (d), 129.4 (d), 129.9 (d),
130.0 (d), 130.4 (d), 130.5 (s), 131.3 (d), 131.4 (d), 131.6 (d), 131.7
(s), 131.8 (s), 132.8 (d), 135.1 (s), 139.8 (s), 140.3 (s), 149.6 (s).
HRMS: m/z calcd for [M + H]+: 415.2169; found: 415.2176, differ-
ence = 1.69 ppm.
1-Benzyl-2,4,5-triphenyl-1H-imidazole (20)27
Prepared according to general procedure C starting from compound
3 (100 mg, 0.26 mmol) and phenylboronic acid (93 mg, 0.77 mmol,
3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 3 h. Flash column
chromatography (50 g silica gel, LP–EtOAc, 5:1); yield: 79 mg
(79%, 0.20 mmol); colorless solid; mp 157–160 °C (Lit.27 mp 157–
159 °C).
1-Benzyl-2-(4-methoxyphenyl)-4,5-di(3-nitrophenyl)-1H-imid-
azole (24)
Prepared according to general procedure C starting from compound
4 (100 mg, 0.24 mmol) and 3-nitrophenylboronic acid (119 mg,
0.71 mmol, 3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 5 h. Flash
column chromatography (20 g silica gel, LP–EtOAc, 5:1); yield: 73
mg (60%, 0.14 mmol).
1H NMR (200 MHz, DMSO-d6): δ = 5.15 (s, 2 H), 6.63–6.85 (m, 2
H), 6.97–7.94 (m, 18 H).
13C NMR (50 MHz, DMSO-d6): δ = 47.6 (t), 125.6 (d), 126.1 (d),
126.2 (d), 126.4 (d), 127.1 (d), 128.1 (d), 128.48 (d), 128.53 (d),
128.8 (d), 128.9 (d), 130.1 (s), 130.5 (s), 130.7 (s), 130.8 (d), 134.5
(s), 136.8 (s), 137.3 (s), 147.0 (s).
Alternatively prepared according to general procedure D starting
from compound 2a (100 mg, 0.26 mmol); boronic acid 1: 4-meth-
oxyphenylboronic acid (42 mg, 0.28 mmol, 1.1 equiv); boronic acid
2: 3-nitrophenylboronic acid (254 mg, 1.52 mmol, 6 equiv); tolu-
ene–MeOH (5:1, 0.6 mL); 6 h for the first coupling step, 3 h for the
second coupling step. Flash column chromatography (50 g silica
gel, LP–EtOAc, 10:1); yield: 94 mg (73%, 0.18 mmol); yellow sol-
id; mp 149–151 °C.
1H NMR (200 MHz, DMSO-d6): δ = 3.80 (s, 3 H), 5.20 (s, 2 H),
6.71–6.84 (m, 2 H), 7.06 (d, 3J = 8.7 Hz, 2 H), 7.12–7.28 (m, 3 H),
7.50 (t, 3J = 8.1 Hz, 1 H), 7.59–7.81 (m, 5 H), 8.01 (dd, 3J = 7.83
Hz, 4J = 1.76 Hz, 1 H), 8.13 (s, 1 H), 8.23–8.38 (m, 2 H).
13C NMR (50 MHz DMSO-d6): δ = 48.2 (t), 55.3 (q), 114.2 (d),
120.3 (d), 121.1 (d), 122.3 (s), 124.0 (d), 125.4 (d), 125.8 (d), 127.4
(d), 128.6 (d), 130.0 (d), 130.2 (d), 130.8 (d), 131.6 (s), 131.9 (d),
135.4 (d), 135.7 (s), 136.8 (s), 137.5 (d), 148.0 (s), 148.1 (s), 148.5
(s), 160.0 (s).
1-Benzyl-4,5-di(4-methoxyphenyl)-2-phenyl-1H-imidazole (21)
Prepared according to general procedure C starting from compound
3 (100 mg, 0.26 mmol) and 4-methoxyphenylboronic acid (116 mg,
0.77 mmol, 3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 4 h. Flash
column chromatography (50 g silica gel, LP–EtOAc, = 4:1); yield:
97 mg (85%, 0.22 mmol).
Alternatively prepared according to general procedure D starting
from compound 2a (100 mg, 0.26 mmol); boronic acid 1: phenylbo-
ronic acid (34 mg, 0.28 mmol, 1.1 equiv); boronic acid 2: 4-meth-
oxyphenylboronic acid (115 mg, 0.76 mmol, 3 equiv); toluene–
MeOH (5:1, 0.6 mL); 3 h for the first coupling step, 4.5 h for the sec-
ond coupling step. Flash column chromatography (50 g silica gel,
LP–EtOAc, 7:1); yield: 102 mg (89%, 0.23 mmol); beige oil.
1H NMR (200 MHz, CD3OD): δ = 3.65 (s, 3 H), 3.69 (s, 3 H), 5.05
(s, 2 H), 6.60–7.65 (m, 18 H).
13C NMR (50 MHz, CD3OD): δ = 49.1 (t), 55.6 (q), 55.7 (q), 114.6
(d), 115.3 (d), 123.7 (s), 127.0 (d), 128.0 (s), 128.4 (d), 129.4 (d),
129.6 (d), 129.7 (d), 130.3 (d), 130.4 (d), 130.7 (s), 131.8 (s), 133.5
(d), 138.8 (s), 138.9 (s), 149.2 (s), 160.0 (s), 161.4 (s).
HRMS: m/z calcd for [M + H]+: 507.1663; found: 507.1686, differ-
ence = 4.53 ppm.
1-Benzyl-2-(4-methoxyphenyl)-4,5-di(2-tolyl)-1H-imidazole
(25)
Prepared according to general procedure C starting from compound
4 (100 mg, 0.24 mmol) and 2-tolylboronic acid (97 mg, 0.71 mmol,
3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 4 h. Flash column
chromatography (50 g silica gel, LP–EtOAc, 4:1), followed by pre-
parative HPLC; yield: 66 mg (63%, 0.15 mmol); colorless oil.
HRMS: m/z calcd for [M + H]+: 447.2067; found: 447.2085, differ-
ence = 4.02 ppm.
1-Benzyl-4,5-di(3-nitrophenyl)-2-phenyl-1H-imidazole (22)
Prepared according to general procedure C starting from compound
3 (100 mg, 0.26 mmol) and 3-nitrophenylboronic acid (128 mg,
0.77 mmol, 3. equiv) in toluene–MeOH (5:1, 0.6 mL) for 3 h. Flash
column chromatography (15 g silica gel, CH2Cl2–MeOH, 200:1);
yield: 68 mg (56%, 0.14 mmol); yellow solid; mp 159–161 °C.
1H NMR (200 MHz, DMSO-d6): δ = 5.23 (s, 2 H), 6.68–6.87 (m, 2
H), 7.08–7.27 (m, 3 H), 7.43–7.61 (m, 4 H), 7.64–7.84 (m, 5 H),
8.03 (d, 3J = 8.10 Hz, 1 H), 8.15 (s, 1 H), 8.26–8.41 (m, 2 H).
13C NMR (50 MHz, DMSO-d6): δ = 48.2 (t), 120.3 (d), 121.2 (d),
124.0 (d), 125.4 (d), 125.9 (d), 127.4 (d), 128.6 (d), 128.8 (d), 128.9
(s), 129.3 (d), 129.9 (d), 130.0 (s), 130.8 (d), 131.4 (s), 131.9 (d),
135.5 (s), 135.6 (s), 136.7 (s), 137.5 (d), 148.1 (s), 148.5 (s).
1H NMR (200 MHz, CD3OD): δ = 1.72 (s, 3 H), 2.29 (s, 3 H), 3.82
3
3
(s, 3 H), 5.08 (d, J = 16.1 Hz, 1 H), 5.18 (d, J = 16.1 Hz, 1 H),
6.55–6.68 (m, 2 H), 6.91–7.23 (m, 13 H), 7.62 (d, 3J = 8.9 Hz, 2 H).
13C NMR (50 MHz, CD3OD): δ = 19.8 (q), 20.7 (q), 49.6 (t), 55.8
(q), 115.3 (d), 124.0 (s), 126.3 (d), 126.8 (d), 127.5 (d), 128.5 (d),
128.6 (d), 129.4 (d), 123.0 (d), 130.7 (s), 131.26 (d), 131.30 (s),
131.4 (d), 131.6 (d), 131.8 (d), 132.8 (d), 135.3 (s), 138.2 (s), 138.4
(s), 139.8 (s), 140.1 (s), 149.6 (s), 162.0 (s).
HRMS: m/z calcd for [M + H]+: 445.2274; found: 445.2282, differ-
ence = 1.80 ppm.
1-Benzyl-2-(3-nitrophenyl)-4,5-diphenyl-1H-imidazole (26)27
Prepared according to general procedure C starting from compound
5 (100 mg, 0.23 equiv) and phenylboronic acid (84 mg, 0.69 mmol,
3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 3 h. Flash column
chromatography (50 g silica gel, LP–EtOAc, 4:1); yield: 84 mg
(85%, 0.20 mmol); yellow solid; mp 126–128 °C.
1H NMR (200 MHz, DMSO-d6): δ = 5.23 (s, 2 H), 6.73–6.89 (m, 2
H), 7.07–7.54 (m, 13 H), 7.71 (t, 3J = 8.0 Hz, 1 H), 8.13 (d, 3J = 8.0
Hz, 1 H), 8.23 (dd, 3J = 8.0 Hz, 4J = 2.0 Hz, 1 H), 8.42–8.53 (m, 1
H).
13C NMR (50 MHz, DMSO-d6): δ = 47.9 (t), 122.8 (d), 123.4 (d),
125.7 (d), 126.2 (d), 126.5 (d), 127.3 (d), 128.2 (d), 128.6 (d), 129.0
(d), 130.1 (s), 130.3 (d), 130.8 (d), 131.3 (s), 132.0 (s), 134.1 (s),
134.4 (d), 136.9 (s), 137.4 (s), 144.7 (s), 147.8 (s).
HRMS: m/z calcd for [M + Na]+: 499.1377; found: 499.1398, dif-
ference = 4.21 ppm.
1-Benzyl-2-phenyl-4,5-di(2-tolyl)-1H-imidazole (23)
Prepared according to general procedure C starting from compound
3 (100 mg, 0.26 mmol) and 2-tolylboronic acid (104.1 mg, 0.77
mmol, 3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 4 h. Flash col-
umn chromatography (50 g silica gel, LP–EtOAc, 4:1), followed by
preparative HPLC; yield: 39 mg (37%, 0.09 mmol); beige oil.
1H NMR (200 MHz, CD3OD): δ = 1.73 (s, 3 H), 2.30 (s, 3 H), 5.21
(d, 3J = 16.0 Hz, 1 H), 5.11 (d, 3J = 16.0 Hz, 1 H), 6.51–6.70 (m, 2
H), 6.90–7.32 (m, 11 H), 7.39–7.58 (m, 3 H), 7.61–7.79 (m, 2 H).
Synthesis 2013, 45, 1387–1405
© Georg Thieme Verlag Stuttgart · New York

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Triarylated Imidazoles via Sequential Cross-Coupling
1401
1-Benzyl-2-(4-nitrophenyl)-4,5-diphenyl-1H-imidazole (27)28
Prepared according to general procedure C starting from compound
6 (135 mg, 0.31 equiv) and phenylboronic acid (126 mg, 1.03
mmol, 3 equiv) in toluene–MeOH (5:1, 0.9 mL) for 1.5 h. Flash col-
umn chromatography (75 g silica gel, LP–EtOAc, 4:1); yield: 106
mg (79%, 0.25 mmol); yellow solid: mp 171–173 °C (Lit.28 mp
168–171 °C).
1H NMR (200 MHz DMSO-d6): δ = 5.25 (s, 2 H), 6.68–6.87 (m, 2
H), 7.04–7.57 (m, 13 H), 7.98 (d, 3J = 8.8 Hz, 2 H), 8.27 (d, 3J = 8.8
Hz, 2 H).
1-{[2-(Trimethylsilyl)ethoxy]methyl}-2,4,5-triphenyl-1H-imid-
azole (31)
Prepared according to general procedure C starting from compound
9 (100 mg, 0.23 mmol) and phenylboronic acid (85 mg, 0.69 mmol,
3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 4 h. Flash column
chromatography (50 g silica gel, LP–EtOAc, 6:1); yield: 90 mg
(91%, 0.21 mmol); colorless solid, mp 67–70 °C.
1H NMR (200 MHz, DMSO-d6): δ = –0.10 (s, 9 H), 0.73 (t, 3J = 8.2
Hz, 2 H), 3.20 (t, 3J = 8.2 Hz, 2 H), 5.06 (s, 2 H), 7.12–7.28 (m, 3
H), 7.36–7.65 (m, 10 H), 7.79–7.93 (m, 2 H).
13C NMR (50 MHz, DMSO-d6): δ = –1.4 (q), 18.7 (t), 67.0 (t), 74.3
(t), 128.0 (d), 128.6 (d), 129.2 (d), 129.8 (d), 130.0 (d), 130.5 (d),
130.7 (d), 131.3 (s), 131.5 (s), 131.7 (s), 132.4 (d), 135.2 (s), 138.9
(s), 150.2 (s).
13C NMR (50 MHz, DMSO-d6): δ = 47.9 (t), 123.8 (d), 125.7 (d),
126.2 (d), 126.6 (d), 127.4 (d), 128.2 (d), 128.7 (d), 129.1 (d), 129.3
(d), 130.0 (s), 130.8 (d), 131.9 (s), 134.0 (s), 136.7 (s), 136.8 (s),
137.8 (s), 144.8 (s), 147.0 (s).
HRMS: m/z calcd for [M + H]+: 427.2202; found: 427.2209, differ-
ence = –0.54 ppm.
HRMS: m/z [M + H]+: 432.1707; found: 432.1711, difference =
0.93 ppm.
2-(4-Methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-4,5-
diphenyl-1H-imidazole (32)
1-Benzyl-4,5-di(4-methoxyphenyl)- 2-(2-tolyl)-1H-imidazole
(28)
Prepared according to general procedure C starting from compound
10 (150 mg, 0.33 mmol) and phenylboronic acid (119 mg, 0.97
mmol, 3 equiv) in toluene–MeOH (5:1, 0.9 mL) for 2.5 h. Flash col-
umn chromatography (75 g silica gel, LP–EtOAc, 3:1); yield: 119
mg (80%, 0.26 mmol); colorless oil.
Prepared according to general procedure C starting from compound
7 (115 mg, 0.28 mmol) and 4-methoxyphenylboronic acid (169 mg,
1.11 mmol, 3 equiv) in toluene–MeOH (5:1, 0.9 mL) for 1.5 h. Flash
column chromatography (75 g silica gel, LP–EtOAc, 2:1); yield: 89
mg (68%, 0.19 mmol); beige oil.
1H NMR (200 MHz, CD3OD): δ = –0.04 (s, 9 H), 0.81 (t, 3J = 8.3
Hz, 2 H), 3.25 (t, 3J = 8.3 Hz, 2 H), 3.83 (s, 3 H), 4.97 (s, 2 H) 6.97–
7.11 (m, 2 H), 7.12–7.25 (m, 3 H), 7.30–7.48 (m, 7 H), 7.75 (d, 3J =
8.8 Hz, 2 H).
13C NMR (50 MHz, CD3OD): δ = –1.3 (q), 18.8 (t), 55.9 (q), 67.0
(t), 74.2 (t), 115.2 (d), 123.4 (s), 127.9 (d), 128.6 (d), 129.2 (d),
130.0 (d), 131.3 (s), 131.5 (s), 131.8 (d), 132.3 (d), 135.2 (s), 138.6
(s), 150.2 (s), 162.2 (s).
1H NMR (200 MHz, DMSO-d6): δ = 2.18 (s, 3 H), 3.68 (s, 3 H), 3.75
(s, 3 H), 4.91 (s, 2 H), 6.55–6.67 (m, 2 H), 6.69–6.80 (m, 2 H), 6.86–
6.97 (m, 2 H), 7.02–7.13 (m, 3 H), 7.14–7.45 (m, 8 H).
13C NMR (50 MHz, DMSO-d6): δ = 19.9 (q), 48.9 (t), 55.6 (q), 55.7
(q), 114.6 (d), 115.5 (d), 123.9 (s), 126.8 (d), 127.6 (d), 128.1 (s),
128.4 (d), 129.3 (d), 129.4 (d), 129.6 (s), 130.9 (d), 131.5 (d), 131.6
(d), 133.6 (d), 138.2 (s), 139.9 (s), 148.5 (s), 159.9 (s), 161.5 (s).
HRMS: m/z calcd for [M + H]+: 461.2224; found: 461.2237, differ-
ence = 2.82 ppm.
HRMS: m/z calcd for [M + H]+: 457.2306; found: 457.2319, differ-
ence = 2.84 ppm.
1-Benzyl-4,5-di(3-nitrophenyl)-2-(2-tolyl)-1H-imidazole (29)
Prepared according to general procedure C starting from compound
7 (100 mg, 0.25 mmol) and 3-nitrophenylboronic acid (144 mg,
0.86 mmol, 3.5 equiv); 3 equiv added at the beginning, 0.5 equiv
added after 4 h; toluene–MeOH (5:1, 0.6 mL) for 7 h. Flash column
chromatography (50 g silica gel, LP–EtOAc, 5:1); yield: 48 mg
(39%, 0.10 mmol); yellow oil.
1H NMR (200 MHz, DMSO-d6): δ = 2.29 (s, 3 H), 5.01 (s, 2 H),
6.59–6.72 (m, 2 H), 7.02–7.18 (m, 3 H), 7.23–7.82 (m, 8 H), 7.97–
8.07 (m, 1 H), 8.10–8.15 (m, 1 H), 8.22–8.34 (m, 2 H).
13C NMR (50 MHz, DMSO-d6): δ = 20.0 (q), 49.6 (t), 122.5 (d),
122.6 (d), 125.1 (d), 126.9 (d), 127.1 (d), 127.7 (d), 128.8 (d), 129.6
(d), 130.6 (s), 130.8 (d), 131.4 (d), 131.68 (d), 131.74 (d), 131.8 (d),
133.0 (s), 133.8 (d), 136.6 (s), 137.4 (s), 138.5 (d), 139.9 (s), 149.7
(s), 150.0 (s), 150.6 (s).
2-(4-Methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-4,5-
di(2-tolyl)-1H-imidazole (33)
Prepared according to general procedure C starting from compound
10 (100 mg, 0.22 mmol) and 2-tolylboronic acid (147 mg, 1.08
mmol, 5 equiv); 3 equiv added at the beginning, 2 equiv added after
4 h; toluene–MeOH (5:1, 0.6 mL); 6 h. Flash column chromatogra-
phy (50 g silica gel, LP–EtOAc, 5:1), followed by preparative
HPLC; yield: 28 mg (11%, 0.04 mmol); yellow-beige oil.
1H NMR (200 MHz, CD3OD): δ = –0.07 (s, 9 H), 0.76 (t, 3J = 8.2
Hz, 2 H), 1.99 (s, 3 H), 2.28 (s, 3 H), 3.20 (t, 3J = 8.2 Hz, 2 H), 3.86
3
3
(s, 3 H), 5.00 (d, J = 10.5 Hz, 1 H), 5.19 (d, J = 10.5 Hz, 1 H),
6.93–7.45 (m, 10 H), 7.71–7.83 (m, 2 H).
13C NMR (50 MHz, CD3OD): δ = –1.4 (q), 18.7 (t), 20.2 (q), 20.7
(q), 55.9 (q), 67.0 (t), 74.6 (t), 115.2 (d), 123.6 (s), 126.3 (d), 126.8
(d), 128.8 (d), 130.2 (d), 130.5 (s), 131.2 (s), 131.3 (d), 131.4 (d),
131.6 (d), 131.8 (d), 133.3 (d), 135.1 (s), 138.3 (s), 139.8 (s), 140.0
(s), 150.0 (s), 162.2 (s).
HRMS: m/z calcd for [M + H]+: 491.1714; found: 491.1731, differ-
ence = 3.46 ppm.
1-Benzyl-2-(2-furyl)-4,5-di(4-methoxyphenyl)-1H-imidazole
(30)
HRMS: m/z calcd for [M + H]+: 485.2619; found: 485.2641, differ-
ence = 4.53 ppm.
Prepared according to general procedure C starting from compound
8 (200 mg, 0.52 mmol) and 4-methoxyphenylboronic acid (238 mg,
1.57 mmol, 3 equiv) in toluene–MeOH (5:1, 1.2 mL) for 4 h. Flash
column chromatography (100 g silica gel, LP–EtOAc, 2:1); yield:
184 mg (81%, 0.42 mmol); brown solid; mp 67–70 °C.
1H NMR (200 MHz, CD3OD): δ = 3.70 (s, 3 H), 3.75 (s, 3 H), 5.26
(s, 2 H), 6.47–6.54 (m, 1 H), 6.65–7.45 (m, 14 H), 7.54–7.61 (m, 1
H).
4,5-Di(4-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-
2-(3-nitrophenyl)-1H-imidazole (34)
Prepared according to general procedure C starting from compound
11 (50 mg, 0.11 mmol) and 4-methoxyphenylboronic acid (48 mg,
0.31 mmol, 3 equiv) in toluene–MeOH (5:1, 0.3 mL) for 4 h. Flash
column chromatography (50 g silica gel, LP–EtOAc, 5:1); yield: 30
mg (53%, 0.07 mmol).
Alternatively prepared according to general procedure D starting
from compound 2b (100 mg, 0.23 mmol); boronic acid 1: 3-nitro-
phenylboronic acid (42 mg, 0.25 mmol, 1.1 equiv), boronic acid 2:
4-methoxyphenylboronic acid (105 mg, 0.69 mmol, 3 equiv); tolu-
13C NMR (50 MHz, CD3OD): δ = 49.2 (t), 55.6 (q), 55.7 (q), 111.5
(d), 112.6 (d), 114.6 (d), 115.4 (d), 123.0 (s), 126.9 (d), 127.7 (s),
128.4 (d), 129.5 (d), 129.7 (d), 130.9 (s), 133.5 (d), 138.6 (s), 139.3
(s), 140.2 (s), 144.5 (d), 145.9 (s), 160.1 (s), 161.5 (s).
© Georg Thieme Verlag Stuttgart · New York
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1402
L.-M. Recnik et al.
PAPER
ene–MeOH (5:1, 0.6 mL); 6 h for the first coupling step, 2 h for the
second coupling step. Flash column chromatography (50 g silica
gel, LP–EtOAc, 4:1); yield: 71 mg (58%, 0.13 mmol); yellow-beige
oil.
1H NMR (200 MHz, CD3OD): δ = –0.01 (s, 9 H), 0.96 (t, 3J = 8.3
Hz, 2 H), 3.41 (t, 3J = 8.3 Hz, 2 H), 3.74 (s, 3 H), 3.84 (s, 3 H), 5.01
(s, 2 H), 6.74 (d, 3J = 8.6 Hz, 2 H), 7.01 (d, 3J = 8.6 Hz, 2 H), 7.28–
7.40 (m, 4 H), 7.76 (t, 3J = 8.1 Hz, 1 H), 8.20–8.39 (m, 2 H), 8.74–
8.81 (m, 1 H).
13C NMR (50 MHz, CD3OD): δ = –1.4 (q), 18.8 (t), 55.6 (q), 55.8
(q), 67.0 (t), 74.2 (t), 114.7 (d), 115.5 (d), 123.0 (s), 124.4 (d), 124.9
(d), 127.5 (s), 129.7 (d), 131.2 (d), 131.7 (s), 132.9 (s), 133.6 (d),
136.0 (d), 139.1 (s), 147.1 (s), 149.8 (s), 160.3 (s), 161.8 (s).
MeOH (5:1, 1.2 mL); 6 h for the first coupling step, 2 h for the sec-
ond coupling step. Flash column chromatography (50 g silica gel,
LP–EtOAc, 4:1); yield: 54 mg (58 %, 0.11 mmol); yellow beige oil.
1H NMR (200 MHz, CD3OD): δ = –0.07 (s, 9 H), 0.78 (t, 3J = 8.1
Hz, 2 H), 3.35 (t, 3J = 8.1 Hz, 2 H), 3.75 (s, 3 H), 3.85 (s, 3 H), 5.34
(s, 2 H), 6.61–6.67 (m, 1 H), 6.74–6.83 (m, 2 H), 6.97–6.06 (m, 3
H), 7.26–7.38 (m, 4 H, ArH), 7.70–7.75 (m, 1 H).
13C NMR (50 MHz, CD3OD): δ = –1.4 (q), 18.6 (t), 55.6 (q), 55.8
(q), 67.1 (t), 74.1 (t), 112.2 (d), 112.7 (d), 114.6 (d), 115.5 (d), 122.9
(s), 127.5 (s), 129.8 (d), 130.7 (s), 133.9 (d), 139.0 (s), 140.6 (s),
144.8 (s), 145.8 (d), 160.2 (s), 161.7 (s).
HRMS: m/z calcd for [M + H]+: 477.2204; found: 477.2223, differ-
ence = 3.98 ppm.
HRMS: m/z calcd for [M + H]+: 532.2262; found: 532.2284, differ-
ence = 4.13 ppm.
4,5-Di(4-methoxyphenyl)-1-(4-methoxybenzyl)-2-(3-nitrophe-
nyl)-1H-imidazole (38)
Prepared according to general procedure C starting from compound
17 (130 mg, 0.28 mmol) and 4-methoxyphenylboronic acid (127
mg, 0.84 mmol, 3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 3.5 h.
Flash column chromatography (50 g silica gel, LP–EtOAc, 5:1);
yield: 62 mg (43%, 0.12 mmol); yellow oil.
1H NMR (200 MHz, CD3OD): δ = 3.68 (s, 3 H), 3.72 (s, 3 H), 3.78
(s, 3 H), 5.08 (s, 2 H), 6.63–6.84 (m, 6 H), 6.91 (d, 3J = 8.7 Hz, 2
H), 7.18 (d, 3J = 8.7 Hz, 2 H), 7.38 (d, 3J = 8.8 Hz, 2 H), 7.64 (t, 3J =
8.0 Hz, 1 H), 7.94–8.04 (m, 1 H), 8.18–8.32 (m, 1 H), 8.43 (t, 3J =
1.8 Hz, 1 H).
13C NMR (50 MHz, CD3OD): δ = 48.8 (t), 55.6 (q), 55.7 (q), 55.8
(q), 114.6 (d), 115.2 (d), 115.5 (d), 123.4 (s), 124.7 (d), 124.8 (d),
127.8 (s), 128.3 (d), 129.5 (d), 130.2 (s), 131.1 (d), 131.8 (s), 133.5
(s), 133.6 (d), 135.9 (d), 139.5 (s), 146.6 (s), 149.6 (s), 160.2 (s),
160.5 (s), 161.7 (s).
4,5-Di(4-methoxyphenyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-
2-(4-nitrophenyl)-1H-imidazole (35)
Prepared according to general procedure C starting from compound
12 (100 mg, 0.21 mmol) and 4-methoxyphenylboronic acid (96 mg,
0.63 mmol, 3 equiv) in toluene–MeOH (5:1, 0.6 mL) for 5 h. Flash
column chromatography (50 g silica gel, LP–EtOAc, 4:1); yield: 24
mg (21%, 0.04 mmol); yellow oil.
1H NMR (200 MHz, DMSO-d6): δ = –0.08 (s, 9 H), 0.76 (t, 3J = 8.3
Hz, 2 H), 3.27 (t, 3J = 8.3 Hz, 2 H), 3.71 (s, 3 H), 3.83 (s, 3 H), 5.10
(s, 2 H), 6.83 (d, 3J = 8.5 Hz, 2 H), 7.10 (d, 3J = 9.0 Hz, 2 H), 7.30–
7.45 (m, 4 H), 8.15 (d, 3J = 9.0 Hz, 2 H), 8.38 (d, 3J = 9.0 Hz, 2 H).
13C NMR (50 MHz DMSO-d6): δ = –1.5 (q), 17.3 (t), 55.0 (q), 55.2
(q), 65.5 (t), 72.6 (t), 113.7 (d), 114.5 (d), 121.7 (s), 124.0 (d), 126.6
(s), 127.6 (d), 129.1 (d), 130.5 (s), 132.4 (d), 136.5 (s), 137.5 (s),
144.8 (s), 147.1 (s), 158.2 (s), 159.8 (s).
HRMS: m/z calcd for [M + H]+: 522.2023; found: 522.2043, differ-
ence = 3.83 ppm.
HRMS: m/z calcd for [M + H]+: 532.2262; found: 532.2298, differ-
ence = 6.76 ppm.
1-(4-Methoxybenzyl)-4,5-di(3-nitrophenyl)-2-(2-tolyl)-1H-im-
idazole (39)
1-{[2-(Trimethylsilyl)ethoxy]methyl}-4,5-di(3-nitrophenyl)-2-
(2-tolyl)-1H-imidazole (36)
Prepared according to general procedure C starting from compound
18 (30 mg, 0.07 mmol) and 3-nitrophenylboronic acid (35 mg, 0.21
mmol, 3 equiv) in toluene–MeOH (5:1, 0.3 mL) for 5 h. Purification
via preparative TLC (LP–EtOAc, 3:1); yield: 33 mg (92%, 0.06
mmol); beige oil.
Prepared according to general procedure C starting from compound
13 (50 mg, 0.11 mmol) and 3-nitrophenylboronic acid (112 mg,
0.67 mmol, 6 equiv); 3 equiv added at the beginning, 3 equiv added
after 4 h in toluene–MeOH (5:1, 0.3 mL) for 5 h. Flash column chro-
matography (50 g silica gel, LP–EtOAc, 7:1); yield: 44 mg (74%,
0.08 mmol); yellow oil.
1H NMR (400 MHz, DMSO-d6): δ = 2.27 (s, 3 H), 3.62 (s, 3 H), 4.89
(s, 2 H), 6.51 (d, 3J = 8.5 Hz, 2 H), 6.66 (d, 3J = 8.5 Hz, 2 H), 7.26–
7.57 (m, 5 H), 7.65–7.85 (m, 3 H), 7.97–8.05 (m, 1 H), 8.16 (s, 1 H),
8.27–8.37 (m, 2 H).
13C NMR (100 MHz, DMSO-d6): δ = 19.5 (q), 47.4 (t), 55.0 (q),
113.8 (d), 120.2 (d), 121.0 (d), 123.9 (d), 125.4 (d), 125.8 (d), 127.6
(d), 127.8 (s), 128.2 (s), 129.6 (d), 129.8 (s), 130.0 (d), 130.3 (d),
130.5 (d), 130.8 (d), 131.7 (s), 131.8 (d), 135.0 (s), 135.8 (s), 137.5
(d), 138.0 (s), 148.0 (s), 148.1 (s), 158.4 (s).
1H NMR (200 MHz, CD3OD): δ = –0.08 (s, 9 H), 0.78 (t, 3J = 8.3
Hz, 2 H), 2.38 (s, 3 H), 3.25 (t, 3J = 8.3 Hz, 2 H), 5.01 (s, 2 H), 7.27–
7.59 (m, 5 H), 7.70–7.82 (m, 2 H), 7.85–7.94 (m, 1 H), 7.99–8.12
(m, 1 H), 8.21–8.31 (m, 1 H), 8.32–8.43 (m, 1 H), 8.44–8.53 (m, 1
H).
13C NMR (50 MHz, CD3OD): δ = –1.5 (q), 18.6 (t), 20.2 (q), 67.2
(t), 74.5 (t), 122.9 (d), 123.0 (s), 125.1 (d), 126.9 (d), 127.0 (d),
129.6 (s), 130.2 (d), 130.8 (d), 131.5 (d), 131.7 (d), 131.8 (d), 132.6
(d), 134.2 (d), 136.5 (s), 137.5 (s), 138.5 (d), 140.1 (s), 149.8 (s),
150.1 (s), 150.7 (s).
2-(2-Furyl)-4,5-di(4-methoxyphenyl)-1-(4-methoxybenzyl)-1H-
imidazole (40)
HRMS: m/z calcd for [M + H]+: 531.2058; found: 531.2071, differ-
ence = 2.45 ppm.
Prepared according to general procedure C starting from compound
19 (40 mg, 0.11 mmol) and 4-methoxyphenylboronic acid (88 mg,
0.58 mmol, 6 equiv); 3 equiv added at the beginning, 3 equiv added
after 6 h; toluene–MeOH (5:1, 0.3 mL); 7 h. Flash column chroma-
tography (25 g silica gel, LP–EtOAc, 2:1); yield: 24 mg (53%, 0.05
mmol); yellow oil.
2-(2-Furyl)-4,5-di(4-methoxyphenyl)-1-{[2-(trimethylsilyl)eth-
oxy]methyl}-1H-imidazole (37)
Prepared according to general procedure C starting from compound
14 (300 mg, 0.71 mmol) and 4-methoxyphenylboronic acid (324
mg, 2.13 mmol, 3 equiv) in toluene–MeOH (5:1, 1.8 mL) for 4 h.
Flash column chromatography (80 g silica gel, LP–EtOAc, 3:1);
yield: 325 mg (96%, 0.68 mmol); yellow beige oil.
1H NMR (200 MHz, CD3OD): δ = 3.71 (s, 3 H), 3.73 (s, 3 H), 3.80
(s, 3 H), 5.22 (s, 2 H), 6.50–6.60 (m, 1 H), 6.69–6.83 (m, 7 H), 6.92
(d, 3J = 8.7 Hz, 2 H), 7.11 (d, 3J = 8.7 Hz, 2 H), 7.34 (d, 3J = 8.7 Hz,
2 H), 7.58–7.62 (m, 1 H).
13C NMR (50 MHz, CD3OD): δ = 48.8 (t), 55.6 (q), 55.8 (q), 111.6
(d), 112.6 (d), 114.6 (d), 115.0 (d), 115.4 (d), 123.2 (s), 127.8 (s),
Alternatively prepared according to general procedure D starting
from compound 2b (200 mg, 0.46 mmol); boronic acid 1: 2-furyl-
boronic acid (160 mg, 1.43 mmol, 3.1 equiv); boronic acid 2: 4-me-
thoxyphenylboronic acid (210 mg, 1.38 mmol, 3 equiv); toluene–
Synthesis 2013, 45, 1387–1405
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Triarylated Imidazoles via Sequential Cross-Coupling
1403
128.4 (d), 129.6 (d), 130.5 (s), 133.5 (d), 133.6 (d), 144.6 (d), 146.0
(s), 160.2 (s), 160.5 (s), 161.7 (s).
HRMS: m/z calcd for [M + H]+: 467.1965; found: 467.1977, differ-
mmol); 7 equiv added at the beginning, 1.5 equiv added after 6 h.
The overall reaction time was 24 h. Flash column chromatography
(50 g silica gel, LP–EtOAc, 3:1); yield: 94 mg (94%, 0.29 mmol);
colorless solid; mp 229–230 °C (Lit.32 mp 226–227 °C).
1H NMR (200 MHz, DMSO-d6): δ = 3.81 (s, 3 H), 7.05 (d, 3J = 8.7
Hz, 2 H), 7.14–7.63 (m, 10 H), 8.04 (d, 3J = 8.7 Hz, 2 H), 12.53 (s,
1 H).
13C NMR (50 MHz, DMSO-d6): δ = 55.2 (q), 114.1 (d), 123.1 (s),
126.4 (d), 126.7 (d), 127.1 (d), 127.6 (d), 127.7 (s), 128.1 (d), 128.4
(d), 128.6 (d), 131.2 (s), 135.3 (s), 136.8 (s), 145.7 (s), 159.4 (s).
ence = 2.57 ppm.
Cleavage of the Benzyl Group; General Procedure E
1-Benzyl-2,4,5-triaryl-1H-imidazole (1 equiv) was dissolved in
DMSO in a 8 mL vial with stir bar and a screw cap with septum. A
1 M t-BuOK solution in THF (7 equiv) was added with a syringe.
The solution changed the color immediately. O2 was bubbled
through the solution for 10 min. The reaction mixture was stirred at
r.t. and the reaction was monitored by TLC. After the completion of
the reaction, the solution was poured into sat. aq NH4Cl and extract-
ed with EtOAc (3 ×). The combined organic layers were washed
with H2O and dried (Na2SO4). The solvent was evaporated and the
desired product was obtained by flash column chromatography.
HRMS: m/z calcd for [M + H]+: 327.1492; found: 327.1482, differ-
ence = –3.06 ppm.
4,5-Di(4-methoxyphenyl)-2-(4-nitrophenyl)-1H-imidazole
(45)33
Prepared according to general procedure F starting from compound
35 (33 mg, 0.06 mmol). TBAF: (0.31 mL, 1 M solution in THF, 0.31
mmol), 6 h reaction time. Flash column chromatography (50 g silica
gel, LP–EtOAc, 3:1); yield: 22 mg (90%, 0.06 mmol); orange solid;
mp 119–121 °C (Lit.33 mp 217–219 °C).
2,4,5-Triphenyl-1H-imidazole (41)29
Prepared according to general procedure E starting from compound
20 (91 mg, 0.24 mmol) using t-BuOK (1.6 mL, 1 M solution in
THF, 1.6 mmol) in THF (2 mL) for 16 h. Flash column chromatog-
raphy (50 g silica gel, LP–EtOAc, 6:1); yield: 17 mg (25%, 0.06
mmol); colorless solid; mp 270–272 °C (Lit.29 mp 269 °C).
1H NMR (200 MHz, DMSO-d6): δ = 3.75 (s, 3 H), 3.81 (s, 3 H), 6.90
(d, 3J = 8.5 Hz, 2 H), 7.03 (d, 3J = 8.4 Hz, 2 H), 7.35–7.57 (m, 4 H),
8.21–8.40 (m, 4 H), 12.97 (s, 1 H).
1H NMR (200 MHz, DMSO-d6): δ = 7.14–7.60 (m, 13 H), 8.01–
8.13 (m, 2 H), 12.69 (s, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 55.1 (q), 55.2 (q), 113.7 (d),
114.2 (d), 122.9 (s), 124.3 (d), 125.5 (d), 127.3 (s), 128.3 (d), 129.2
(s), 129.8 (d), 136.3 (s), 137.9 (s), 142.7 (s), 146.3 (s), 158.2 (s),
159.2 (s).
13C NMR (50 MHz DMSO-d6): δ = 125.2 (d), 126.5 (d), 127.1 (d),
127.8 (d), 128.2 (d), 128.3 (d), 128.5 (d), 128.69 (d), 128.71 (d),
130.3 (s), 131.1 (s), 135.2 (s), 137.1 (s), 145.5 (s).
HRMS: m/z calcd for [M + H]+: 532.2302; found: 532.2298, differ-
ence = –3.06 ppm.
4,5-Di(4-methoxyphenyl)-2-phenyl-1H-imidazole (42)30
Prepared according to general procedure E starting from compound
21 (99 mg, 0.22 mmol) using t-BuOK (1.5 mL, 1 M solution in
THF, 1.5 mmol) in THF (2 mL) for 16 h. Flash column chromatog-
raphy (50 g silica gel, LP–EtOAc, 3:1); yield: 72 mg (92%, 0.20
mmol); yellow oil.
1H NMR (200 MHz, DMSO-d6): δ = 3.77 (s, 6 H), 6.95 (d, 3J = 8.4
Hz, 4 H), 7.33–7.53 (m, 7 H), 8.08 (d, 3J = 7.6 Hz, 2 H), 12.53 (s, 1
H, NH).
13C NMR (50 MHz, DMSO-d6): δ = 55.1 (q), 113.9 (d), 125.1 (d),
128.0 (d), 128.7 (d), 128.9 (d), 130.6 (s), 144.8 (s), 158.4 (s).
HRMS: m/z calcd for [M + H]+: 357.1598, found: 357.1592, differ-
ence = –1.68 ppm.
1-Benzyl-2-(5-bromofuran-2-yl)-4,5-di(4-methoxyphenyl)-1H-
imidazole (46)
Substrate 30 (110 mg, 0.25 mmol, 1 equiv) was dissolved in DMF
(6 mL) in a 8 mL vial with a magnetic stirring bar and a screw cap.
The solution was cooled to 0 °C. N-Bromosuccinimide (49 mg, 0.28
mmol, 1.1 equiv) was added in portions and the reaction was
warmed to r.t. The reaction mixture was stirred for 4 h at r.t. The
mixture was poured into sat. aq NH4Cl (10 mL) and was extracted
with EtOAc (3 × 5 mL). The combined organic phases were washed
with H2O (5 mL) and dried (Na2SO4). The solvent was evaporated
and the pure product was obtained by flash column chromatography
(130 g silica gel, LP–EtOAc, 3:1); yield: 95 mg (73%, 0.18 mmol);
yellow solid; mp 95–99 °C.
2-(4-Nitrophenyl)-4,5-diphenyl-1H-imidazole (43)31
1H NMR (200 MHz, DMSO-d6): δ = 3.70 (s, 3 H), 3.77 (s, 3 H), 5.18
(s, 2 H), 6.60–7.05 (m, 8 H), 7.13–7.48 (m, 7 H).
13C NMR (50 MHz, DMSO-d6): δ = 47.4 (t), 55.9 (q), 56.1 (q),
112.8 (d), 114.5 (d), 115.5 (d), 122.6 (s), 122.9 (s), 126.5 (d), 127.6
(s), 128.2 (d), 128.3 (d), 129.6 (d), 130.3 (s), 133.2 (d), 137.8 (s),
138.1 (s), 147.7 (s), 158.9 (s), 160.6 (s).
Prepared according to general procedure E starting from compound
27 (109 mg, 0.25 mmol) using t-BuOK (1.7 mL, 1 M solution in
THF, 1.7 mmol) in THF (3 mL) for 16 h. Flash column chromatog-
raphy (50 g silica gel, LP–EtOAc, 4:1); yield: 26 mg (30%, 0.08
mmol); yellow solid; mp 233–236 °C (Lit.31 mp 235–237 °C).
1H NMR (200 MHz, DMSO-d6): δ = 7.21–7.63 (m, 10 H), 8.34 (s,
4 H).
HRMS: m/z calcd for [M + H]+: 515.0965; found: 515.0974, differ-
13C NMR (50 MHz, DMSO-d6): δ = 124.3 (d), 125.8 (d), 126.9 (d),
127.2 (d), 128.3 (d), 128.6 (d), 128.8 (d), 130.1 (s), 130.5 (s), 134.6
(s), 136.1 (s), 138.5 (s), 143.4 (s), 146.6 (s).
HRMS: m/z calcd for [M + H]+: 342.1237; found: 342.1227, differ-
ence = –2.92 ppm.
ence = 1.75 ppm.
2-(5-Bromofuran-2-yl)-4,5-di(4-methoxyphenyl)-1-{[2-(tri-
methylsilyl)ethoxy]methyl}-1H-imidazole (47)
Substrate 37 (288 mg, 0.61 mmol, 1 equiv) was dissolved in DMF
(15 mL) in a 25 mL flask with a thermometer, a condenser, and a
magnetic stirring bar. The solution was cooled to 0 °C. N-Bromo-
succinimide (118 mg, 0.67 mmol, 1.1 equiv) was added in portions
and the reaction was warmed to r.t. and stirred for 24 h. The mixture
was poured into sat. aq NH4Cl (30 mL) and extracted with EtOAc
(3 × 10 mL). The combined organic phases were washed with H2O
(15 mL) and dried (Na2SO4). The solvent was evaporated and the
product was obtained by flash column chromatography (150 g silica
gel, LP–EtOAc, 5:1); yield: 254 mg (75%, 0.46 mmol); orange oil.
Cleavage of the SEM Group; General Procedure F
The corresponding 1-SEM-2,4,5-triaryl-1H-imidazole was dis-
solved in 1 M Bu4NF (5 equiv) in THF in a 4 mL vial with stirring
bar and a screw cap. The reaction was heated to reflux and moni-
tored by TLC. After workup and purification by preparative TLC,
the pure product was obtained.
2-(4-Methoxyphenyl)-4,5-diphenyl-1H-imidazole (44)32
Prepared according to general procedure F starting from compound
32 (140 mg, 0.31 mmol). TBAF: (2.0 mL, 1 M solution in THF, 2.0
1H NMR (200 MHz, CD3OD): δ = –0.06 (s, 9 H), 0.81 (t, 3J = 8.2
Hz, 2 H), 3.38 (t, 3J = 8.2 Hz, 2 H), 3.74 (s, 3 H), 3.85 (s, 3 H), 5.29
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 1387–1405

1404
L.-M. Recnik et al.
PAPER
(s, 2 H), 6.63 (d, 3J = 3.6 Hz, 1 H), 6.78 (d, 3J = 8.8 Hz, 2 H), 6.97–
7.11 (m, 3 H), 7.22–7.39 (m, 4 H).
2-[5-(3-Chlorophenyl)furan-2-yl]-4,5-di(4-methoxyphenyl)-1H-
imidazole (Neurodazine, 50)6
Substrate 49 (62 mg, 0.11 mmol, 1 equiv) was dissolved in 1 M
Bu4NF in THF (0.53 mL, 0.53 mmol, 5 equiv) in a 4 mL vial with
stir bar and a screw cap with septum. The mixture was heated to
80 °C and the reaction progress was monitored by TLC (LP–
EtOAc, 3:1). After completion of the reaction (4 h), the mixture was
poured into H2O (20 mL) and extracted with CH2Cl2 (3 × 10 mL).
The combined organic layers were washed with H2O (15 mL) and
dried (Na2SO4). The solvent was evaporated and the product was
obtained by flash column chromatography (50 g silica gel, LP–
EtOAc, 3:1); yield: 36 mg (74%, 0.08 mmol); yellow oil.
1H NMR (400 MHz, DMSO-d6): δ = 3.75 (s, 3 H), 3.81 (s, 3 H), 6.88
(d, 3J = 8.9 Hz, 2 H), 7.00–7.07 (m, 3 H), 7.25 (d, 3J = 3.7 Hz, 1 H),
7.35–7.52 (m, 6 H), 7.85 (d, 3J = 8.2 Hz, 1 H), 7.98–8.01 (m, 1 H).
13C NMR (100 MHz, DMSO-d6): δ = 55.5 (q), 55.7 (q), 109.4 (d),
109.9 (d), 114.1 (d), 114.6 (d), 122.7 (d), 123.5 (d), 123.6 (s), 127.3
(s), 127.7 (d), 127.9 (s), 128.6 (d), 130.4 (d), 131.2 (d), 132.6 (s),
134.3 (s), 137.2 (s), 137.9 (s), 146.4 (s), 151.3 (s), 158.5 (s), 159.4
(s).
13C NMR (50 MHz, CD3OD): δ = –1.4 (q), 18.6 (t), 55.6 (q), 55.8
(q), 67.2 (t), 74.1 (t), 114.57 (d), 114.61 (d), 114.8 (d), 115.5 (d),
122.7 (s), 124.4 (s), 127.3 (s), 129.8 (d), 131.1 (s), 133.8 (d), 139.2
(s), 139.5 (s), 147.7 (s), 160.3 (s), 161.8 (s).
HRMS: m/z calcd for [M + H]+: 555.1309; found: 555.1355, differ-
ence = 8.29 ppm.
1-Benzyl-2-[5-(3-chlorophenyl)furan-2-yl]-4,5-di(4-methoxy-
phenyl)-1H-imidazole (48)
Substrate 46 (60 mg, 0.12 mmol, 1 equiv), 3-chlorphenylboronic
acid (20 mg, 0.13 mmol, 1.1 equiv), Cs2CO3 (76 mg, 0.23 mmol, 2
equiv), Pd(PPh3)4 (6.7 mg, 5 mol%), and anhyd toluene (1.5 mL)
were placed in a 4 ml vial with a magnetic stirring bar and a screw
cap with septum. The solution was purged with argon for 5 min.
Then, the septum screw cap was exchanged for a closed cap under
argon flow. The mixture was heated to 120 °C and the reaction was
monitored by TLC (LP–EtOAc, 3:1) and stopped after 4 h when the
reaction control showed complete consumption of the starting ma-
terial. The reaction mixture was cooled to r.t., filtered through a pad
of Celite, and the solvent was evaporated. The residue was diluted
with H2O (10 mL) and extracted with CH2Cl2 (3 × 5 mL). The com-
bined organic layers were washed with H2O (5 mL) and dried
(Na2SO4). The solvent was evaporated and the desired product was
obtained by flash column chromatography (50 g silica gel, LP–
EtOAc, 3:1); yield: 44 mg (69%, 0.08 mmol); yellow solid, mp 67–
69 °C.
Acknowledgment
The authors would like to thank Vienna University of Technology
for supporting this work via the innovative project grant BACARA.
References
1H NMR (200 MHz, DMSO-d6): δ = 3.70 (s, 3 H), 3.77 (s, 3 H), 5.33
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13C NMR (50 MHz, DMSO-d6): δ = 47.8 (t), 55.0 (q), 55.2 (q),
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2-[5-(3-Chlorophenyl)furan-2-yl]-4,5-di(4-methoxyphenyl)-1-
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Synthesis 2013, 45, 1387–1405
© Georg Thieme Verlag Stuttgart · New York

PAPER
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Synthesis 2013, 45, 1387–1405