Triorganoindium reagents in selective palladium-catalyzed cross-coupling with iodoimidazoles: Synthesis of neurodazine

Article abstract of DOI:10.1021/jo501664p

Triorganoindium reagents (R₃In, R = aryl, heteroaryl, alkynyl) react selectively under palladium catalysis with N-benzyl-2,4,5-triiodoimidazole to afford the C-2 monocoupling products. The reaction proceeds efficiently for a variety of aryl- and heteroarylindium reagents with the transfer of all three organic groups attached to the metal. The coupling products can be used in a subsequent two-fold cross-coupling to give trisubstituted imidazoles in good yields. This approach was employed to synthesize neurodazine and analogues in good yields. (Chemical Equation Presented).

Full text of DOI:10.1021/jo501664p

Article
pubs.acs.org/joc
Triorganoindium Reagents in Selective Palladium-Catalyzed Cross-
Coupling with Iodoimidazoles: Synthesis of Neurodazine
Cristina Perez-Caaveiro, Jose Perez Sestelo, M. Montserrat Martínez,* and Luis A. Sarandeses*
́
́
́
Departamento de Química Fundamental and Centro de Investigaciones Científicas Avanzadas (CICA), Universidade da Coruna,
̃
E-15071 A Coruna, Spain
̃
S
* Supporting Information
ABSTRACT: Triorganoindium reagents (R3In, R = aryl,
heteroaryl, alkynyl) react selectively under palladium catalysis
with N-benzyl-2,4,5-triiodoimidazole to afford the C-2
monocoupling products. The reaction proceeds efficiently for
a variety of aryl- and heteroarylindium reagents with the
transfer of all three organic groups attached to the metal. The
coupling products can be used in a subsequent two-fold cross-
coupling to give trisubstituted imidazoles in good yields. This approach was employed to synthesize neurodazine and analogues
in good yields.
Another interesting example of the synthetic potential
pharmacophore imidazole, which has attracted significant
attention as a consequence of its potent biological activity, is
neurodazine (4). This compound is able to specifically induce
neurogenesis of nonpluripotent myoblasts and the cells derived
from mature human skeletal muscle.10 In fact, compounds such
as neurodazine have been proposed as a more convenient and
attractive approach to stem cell therapies in neurodegenerative
diseases.
The synthesis of substituted imidazoles has been carried out
by two main approaches: (a) a traditional linear synthetic
sequence based on the formation of the imidazole ring in the
final steps of the synthesis, which often provides limited access
to target compounds in terms of substituents and substitution
patterns,1a−c,11 and (b) functionalization of imidazoles by
successive metalation and reaction with electrophiles12 or by
transition metal-catalyzed cross-coupling reactions, a limited
methodology due to the π-excessive character of the hetero-
cycle. Nevertheless, the reactivity can be modulated by using
the appropriate catalyst, imidazole halide, and/or highly
reactive nucleophiles.13,14
INTRODUCTION
■
Imidazole is an important structural motif in natural and
synthetic organic compounds that are useful in pharmaceutical
and industrial applications.1 This unit is present in conjugated
molecules and polymers for organic electronics such as sensors,
lasers, and other semiconductor devices,2 as ligands in
metalloenzymes,3 in coordination complexes,4 and in environ-
mentally friendly ionic solvents.1c,5 Substituted imidazoles are
also present in a number of highly significant biomolecules with
interesting biological activities.1d,6 Among them, 4,5-diaryl-
imidazoles such as 1 (Figure 1) have been identified as a class
of compounds that show antimicrobial activity against bacteria,
yeast, and fungi.7 Furthermore, triarylimidazole 2 is a potent
nontoxic modulator of P-glycoprotein-mediated multidrug
resistance (MDR),8 and synthetic imidazole analogues such
as fenflumizole (3) have shown anti-inflammatory activity.9
In recent years we have shown that indium organometallics
are useful reagents in metal-catalyzed cross-coupling reac-
tions.15,16 Besides their high efficiency, versatility, and
selectivity in cross-coupling reactions, triorganoindium reagents
(R3In) are particularly effective for the synthesis of function-
alized heterocyclic compounds,17 and they exhibit high
selectivity in coupling reactions with 3,4-dihalomaleimides,
2,5-dibromothiophenes, and 4,6-dichloropyrimidines.18 As a
continuation of our studies into the application of R3In in
organic synthesis, we report herein an efficient approach to
trisubstituted imidazoles by selective and sequential palladium-
Received: July 23, 2014
Published: September 9, 2014
Figure 1. Biologically active imidazole compounds.
© 2014 American Chemical Society
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catalyzed cross-coupling reactions of triorganoindium reagents
with 2,4,5-trihaloimidazoles and the application of this
approach to the synthesis of neurodazine and analogues.
Table 1. Selective Cross-Coupling Reactions of
Triorganoindium Reagents with N-Benzyl-2,4,5-
triiodoimidazole (5)
RESULTS AND DISCUSSION
■
The relatively low reactivity of imidazole derivatives in coupling
reactions and the high selectivity shown by indium organo-
metallics led us to explore selective coupling processes. It was
envisaged that 2,4,5-trisubstituted imidazoles could be synthe-
sized by an initial C-2-selective palladium-catalyzed cross-
coupling reaction between a 2,4,5-trihaloimidazole and a
triorganoindium reagent, followed by a two-fold coupling
reaction with other different R3In species to provide the desired
2,4,5-trisubstituted imidazoles (Scheme 1).
Scheme 1. Synthetic Route to 2,4,5-Trisubstituted
Imidazoles
As stated above, the introduction of good leaving groups is a
common approach to increase the reactivity of electron-rich
heterocycles in coupling reactions.13,14 Accordingly, for this
study we selected N-benzyl-2,4,5-triiodoimidazole (5), which is
readily prepared from imidazole.19 We began by exploring the
reactions of 5 with tri(4-methoxyphenyl)indium using different
palladium sources and ligands such as Pd(PPh3)4, Pd-
(PPh3)2Cl2, Pd2dba3, and Pd(OAc)2 in the presence of SPhos
or XPhos as ligands. The best results in terms of conversion
and selectivity were obtained on using Pd(PPh3)4 (5 mol %) as
catalyst and 50 mol % of the indium reagent (corresponding to
1.5 equiv of R1) in THF under reflux to afford the
monocoupling product N-benzyl-2-(4-methoxyphenyl)-4,5-
diiodoimidazole (6a) in 78% yield (Table 1, entry 1) as the
only regioisomer detected by 1H NMR. Although the efficiency
of the indium reagents in transferring the three groups attached
to the metal in coupling reactions has been widely established,
the use of lower amounts of indium reagents afforded lower
yields of 6a.
The methodology was extended to the synthesis of new
biologically active compounds by studying the introduction of
other functional groups. In this way, the reaction of 5 with
tri(4-fluorophenyl)indium under the same conditions gave the
fluorinated compound 6b in 83% yield (entry 2). The
monocoupling reaction with triheteroarylindium reagents such
as tri(thiophen-2-yl)indium and tri(furan-2-yl)indium also gave
the cross-coupling products 6c and 6d regioselectively and in
high yield (entries 3 and 4). Analogously, the use of a
substituted thiophenylindium compound such as tri-
(phenylthiophen-2-yl)indium with 5 under the standard
conditions gave imidazole 6e in 79% yield (entry 5).
bromoimidazole also occur efficiently in the first selective C-2
coupling; however, coupling at C-4 and C-5 requires higher
amounts of the triorganoindium and harsh reaction conditions
to give moderate yields.
According to our synthetic route, a two-fold cross-coupling
reaction of monocoupled imidazoles (6) with R3In should
provide access to the desired analogues in a versatile and
efficient manner. As a consequence, we proposed the synthesis
of bioactive compound neurodazine.20 The methods reported
to date have involved the construction of the imidazole ring of
neurodazine by multistep sequences.10a
The synthesis of neurodazine was planned by following a
synthetic sequence of three sequential palladium-catalyzed
coupling reactions using organoindium reagents. Starting from
the commercially available 3-chloroiodobenzene, chemoselec-
tive cross-coupling using tri(furan-2-yl)indium (40 mol %)
under reflux with Pd(PPh3)4 as catalyst (5 mol %) afforded the
2-(3-chlorophenyl)furan (7) in 86% yield (Scheme 2). Prior to
the second coupling, lithiation of 7 with n-BuLi at low
temperature and subsequent transmetalation with InCl3 gave
the corresponding indium reagent in solution (50 mol %). The
reaction of this indium reagent with 2,4,5-triiodoimidazole 5 in
the presence of Pd(PPh3)4 (5 mol %) as catalyst afforded 8 in
69% yield and with high regioselectivity.
In general, these results show that the palladium-catalyzed
coupling reactions of aryl- and heteroarylindium organo-
metallics with trihalogenated imidazole 5 occurred with high
efficiency and complete regioselectivity to give the correspond-
ing C-2 monocoupling compounds in good yields. Alter-
natively, we found that coupling reactions with N-benzyltri-
Finally, the sequence was completed with a two-fold cross-
coupling reaction of 4,5-diiodoimidazole 8 with 100 mol % of
tri(4-methoxyphenyl)indium. On using the same catalytic
system and after 16 h under reflux, trisubstituted imidazole 9
was obtained in 91% yield. The final step in the synthesis
involved the removal of the benzyl group.21 Treatment of 9
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Scheme 2. Synthesis of Neurodazine
with DMSO and KOt-Bu in combination with oxygen at room
temperature afforded neurodazine (4) in 90% yield (Scheme
2). It is remarkable that the synthesis of this biologically active
compound has been achieved in 49% overall yield (four steps)
by a sequential triple cross-coupling strategy using organo-
indium reagents.
conditions, the coupling product 17a was obtained in 92% yield
(Scheme 3), and this is an attractive derivative of biologically
active neurodazine.10 Overall, these results demonstrate the
utility of R3In in the synthesis of neurodazine and analogues
through a two-fold coupling sequence.
Removal of the benzyl group from some N-benzyl-2,4,5-
trisusbtituted imidazoles 10a−17a was also carried out under
the previously described conditions to afford the corresponding
imidazoles 10b, 11b, 12b, 16b, and 17b in yields ranging from
84% to 96%. Interestingly, 11b has shown antiproliferative
activities against the growth of some cell lines.22
Finally, the synthetic utility of our strategy was expanded by
the introduction of different substituents in a one-pot
procedure via sequential reactions with various R3In reagents.
The reaction of 5 with tri(furan-2-yl)indium (50 mol %) under
the standard conditions followed by addition of tri(4-
methoxyphenyl)indium (100 mol %) afforded coupling product
11a in 74% yield (Scheme 4). We also tested our protocol
preparing 2-alkynyl-4,5-diarylimidazoles, which are of interest
in materials science.23 In this case, the same sequence was
performed with tris(trimethylsilylethynyl)indium (50 mol %)
and tri(4-methoxyphenyl)indium (100 mol %), and this proved
to be satisfactory in providing the trisubstituted product 18a in
40% yield.
Having established the efficiency of organoindium reagents
in the second coupling for the substitutions at the C-4 and C-5
positions of imidazole, we proceeded to examine the scope and
limitations of selected monocoupled products 6 in a new two-
fold Pd-catalyzed cross-coupling reaction to obtain 2,4,5-
trisusbtituted imidazoles of interest. On employing the
previously described conditions, the reaction of tri(4-methox-
yphenyl)indium (100 mol %) with 6b gave 10a in 87% yield
after 12 h (Scheme 3). Interestingly, compound 10a is
structurally related to fenflumizole (3, Figure 1), which has
been identified as an anti-inflammatory nonselective COX
enzyme inhibitor.9 In a similar manner, the aryl group was also
efficiently transferred from the indium reagent as shown in the
reaction of tri(4-methoxyphenyl)indium with imidazoles 6d
and 6e to give the corresponding 4,5-diarylimidazoles 11a and
12a in 90% and 80% yield, respectively (Scheme 3). While the
C-2 coupling reactions of triorganoindium reagents with 5
occur with complete regioselectivity, selective couplings at C-4
or C-5 in 2-substituted-4,5-diiodoimidazoles (6a−e) gave
mixtures of isomers.
The versatility of this two-fold coupling reaction was also
studied using heteroaryl indium organometallics. Thus, the
reaction of tri(benzo[b]thiophen-2-yl)indium with imidazole
6e, under standard conditions, afforded imidazole 13a in 89%
yield. Under the same conditions, the high efficiency of R3In in
this coupling was also evidenced by the reaction of tri(benzo-
[b]thiophen-2-yl)indium with the C-2 substituted imidazoles
6b and 6d, which provided derivatives 14a and 15a in good
yields (98% and 87%, respectively).
CONCLUSIONS
■
It has been demonstrated that triorganoindium reagents react
selectively with N-benzyl-2,4,5-triiodoimidazole under palla-
dium catalysis to afford monocoupling products at C-2 in good
yields. All three organic groups attached to the metal are
efficiently transferred. The reaction can be performed using
triaryl- or triheteroarylindium reagents. The monocoupling
products were subsequently used in a two-fold cross-coupling
process to afford a series of trisubstituted imidazoles. This
methodology was applied to the synthesis of the bioactive
compound neurodazine by three sequential palladium-catalyzed
cross-coupling reactions using organoindium compounds to
give the target compound in good yield. The biological
activities of the novel imidazoles are currently being evaluated,
and further applications of this method to other targets are now
underway.
Additionally, the reaction between tri(5-phenylthiophen-2-
yl)indium and imidazole 6a under the same conditions gave
compound 16a in a satisfactory 68% yield. We also found it of
interest to study the two-fold cross-coupling reaction of the
triorganoindium reagent derived from 7 (Scheme 2) with the
C-2 substituted imidazole 6a. Under the previously optimized
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Scheme 3. Synthesis of 2,4,5-Trisubtituted Imidazoles by
Two-Fold Cross-Coupling Reactions of N-Benzyl-2-
substituted-4,5-diiodoimidazoles with Triorganoindium
Reagents Followed by Deprotection
Scheme 4. One-Pot Cross-Coupling of 5 with Different R3In
Preparation of Triorganoindium Reagents. Triorganoindium
compounds were prepared according to previously published
methods15−18 by treatment of the corresponding organolithium
reagents (3 equiv., ∼0.5 M in dry THF) with a solution of InCl3
(1.1 equiv., ∼0.05 M in dry THF) at −78 or −20 °C and warming to
room temperature.
Synthesis of 1-Benzyl-2,4,5-triiodo-1H-imidazole (5). To a
solution of imidazole (1.80 g, 26.4 mmol) in aqueous NaOH (160 mL,
2 M) was added a solution of I2 (25.0 g, 98.5 mmol) and KI (35.0 g,
210.8 mmol) in water (75 mL). The mixture was stirred overnight and
then neutralized by the addition of HOAc. The resulting precipitate
was filtered off and dried in vacuo over P2O5 to give 7.1 g of a gray
crude solid, which was dissolved in dry THF (25 mL) and slowly
added to a mixture of NaH (0.45 g, 18.84 mmol) in dry THF (15 mL)
at 0 °C. After 30 min, BnBr (2.24 mL, 18.84 mmol) was added
dropwise and the mixture was stirred overnight at rt. Water (30 mL)
was added, and the mixture was extracted with EtOAc (3 × 40 mL).
The combined organic extracts were washed with brine (20 mL),
dried, and concentrated. The residue was purified by flash
chromatography (20% EtOAc/hexanes), to provide 1-benzyl-2,4,5-
1
triiodoimidazole (5) as a white solid (6.80 g, 48%). H NMR (300
MHz, CDCl3) δ 7.30−7.37 (m, 3H), 7.08 (d, J = 6.8 Hz, 2H), 5.31 (s,
2H); 13C{1H} NMR (75 MHz, CDCl3) δ 134.4 (C), 128.9 (2 × CH),
128.2 (CH), 126.6 (2 × CH), 97.9 (C), 90.5 (C), 85.0 (C), 55.2
(CH2); IR (ATR) νmax 2922, 1438, 1377, 1348, 1175 cm−1; MS (EI)
m/z 537 [M + H]+ (12), 536 [M]+ (100); HRMS (EI-ion trap) calcd
for C10H7N2I3 [M]+ 535.7743, found 535.7765.
General Procedure for the C-2 Selective Palladium-
Catalyzed Cross-Coupling Reactions. A solution of R3In (0.25
mmol, 0.05 M in dry THF) was added to a solution of 5 (0.5 mmol)
and Pd(PPh3)4 (0.025 mmol) in dry THF (2 mL) in a Schlenk tube
filled with argon. The reaction mixture was heated to 80 °C until the
starting material had been consumed (5−16 h). The mixture was
allowed to cool to rt and quenched by the addition of a few drops of
MeOH, and the solvent was removed. The residue was diluted with
EtOAc (25 mL), and the organic phase was washed with brine (20
mL), dried, and concentrated. The residue was purified by flash
chromatography (EtOAc/hexanes) to afford, after concentration and
high-vacuum drying, the corresponding cross-coupling products.
1-Benzyl-2-(4-methoxyphenyl)-4,5-diiodo-1H-imidazole
(6a). According to the general procedure, the reaction of 5 with tri(4-
methoxyphenyl)indium afforded, after purification by column
chromatography (50% EtOAc/hexanes), compound 6a as a pale
EXPERIMENTAL SECTION
■
General Methods. All reactions were carried out in flame-dried
glassware under an argon atmosphere using standard gas-tight
syringes, cannulae, and septa. Tetrahydrofuran (THF) was dried by
distillation from the sodium ketyl of benzophenone. Reaction
temperatures refer to external bath temperatures. Butyllithium and
4-methoxyphenylmagnesium bromide were titrated prior to use. Furan
was lithiated according to a previously reported method.24 All other
commercially available reagents were used as received. Organic extracts
were dried over anhydrous MgSO4, filtered, and concentrated using a
rotary evaporator at aspirator pressure. Reactions were monitored by
1
brown solid (201 mg, 78%): mp 129−131 °C; H NMR (300 MHz,
CDCl3) δ 7.36−7.39 (m, 3H), 7.31−7.34 (m, 2H), 6.98−7.01 (m,
2H), 6.84−6.89 (m, 2H), 5.30 (s, 2H), 3.80 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 160.7 (C), 153.3 (C), 135.9 (C), 130.1 (2 ×
CH), 129.0 (2 × CH), 127.9 (CH), 126.0 (2 × CH), 122.0 (C), 114.0
(2 × CH), 96.3 (C), 83.9 (C), 55.3 (CH3), 52.4 (CH2); IR (ATR)
νmax 2931, 1610, 1468, 1254 cm−1; MS (EI) m/z 517 [M + H]+ (17),
516 [M]+ (98), 425 [M − C7H7]+ (100); HRMS (EI-ion trap) calcd
for C17H14N2I2O [M]+ 515.9190, found 515.9180.
TLC using precoated silica gel plates (Alugram Xtra SIL G/UV254
,
1-Benzyl-2-(4-fluorophenyl)-4,5-diiodo-1H-imidazole (6b).
According to the general procedure, the reaction of 5 with tri(4-
fluorophenyl)indium afforded, after purification by column chroma-
tography (30% EtOAc/hexanes), compound 6b as a pale brown solid
(193 mg, 83%): mp 96−98 °C; 1H NMR (300 MHz, CDCl3) δ 7.39−
7.49 (m, 3H), 7.32−7.37 (m, 2H), 7.09−7.05 (m, 2H), 6.97−7.02 (m,
2H), 5.30 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.2 (C),
161.9 (C), 152.2 (C), 135.7 (C), 130.7 (CH), 130.6 (CH), 129.1 (2 ×
CH), 128.0 (CH), 125.9 (2 × CH), 115.9 (CH), 115.6 (CH), 96.5
0.20 mm thick) with UV light as a visualizing agent and ethanolic
phosphomolybdic acid as a developing agent. Flash column
chromatography was performed using 230−400 mesh silica gel packed
1
in glass columns. H and 13C NMR spectra were recorded in CDCl3
and DMSO-d6 at 300 MHz for 1H and 75 MHz for 13C, at 300 K, and
calibrated to the solvent peak. DEPT data were used to assign carbon
types. Mass spectra were obtained with EI ionization at 70 eV. Melting
points are uncorrected.
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(C), 84.8 (C), 52.5 (CH2); IR (ATR) νmax 3033, 2926, 1468, 1224
cm−1; MS (EI) m/z 505 [M + H]+ (24), 504 [M]+ (87), 413 [M −
C7H7]+ (12); HRMS (EI-ion trap) calcd for C16H11N2I2F [M]+
503.8990, found 503.8980.
2921, 1412, 1304, 1257 cm−1; MS (EI) m/z 587 [M + H]+ (23), 586
[M]+ (100), 495 [M − C7H7]+ (100); HRMS (EI-ion trap) calcd for
C20H13N2OI2Cl [M]+ 585.8806, found 585.8816.
General Procedure for the Multiple Palladium-Catalyzed
Cross-Coupling Reactions. A solution of R3In (0.5 mmol, 0.05 M in
dry THF) was added to a solution of protected 2-substituted 4,5-
diiodo-1H-imidazole (0.5 mmol) and Pd(PPh3)4 (0.025 mmol) in dry
THF (2 mL) in a Schlenk tube filled with argon. The reaction mixture
was heated to 80 °C until the starting material had been consumed
(4−12 h). The mixture was allowed to cool to rt and quenched by the
addition of a few drops of MeOH, and the solvent was removed. The
residue was diluted with EtOAc (25 mL), and the organic phase was
washed with brine (20 mL), dried, and concentrated. The residue was
purified by flash chromatography (EtOAc/hexanes) to afford, after
concentration and high-vacuum drying, the corresponding cross-
coupling products.
1-Benzyl-2-(thiopen-2-yl)-4,5-diiodo-1H-imidazole (6c). Ac-
cording to the general procedure, the reaction of 5 with tri(thiophen-
2-yl)indium afforded, after purification by column chromatography
(30% EtOAc/hexanes), compound 6c as a pale brown oil (170 mg,
84%): 1H NMR (300 MHz, CDCl3) δ 7.29−7.40 (m, 4H), 6.96−7.11
(m, 4H), 5.45 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 135.3 (2 ×
C), 131.0 (C), 129.1 (2 × CH), 128.0 (CH), 127.9 (CH), 127.5
(CH), 127.1 (CH), 125.9 (2 × CH), 125.9 (2 × CH), 96.7 (C), 85.1
(C), 52.7 (CH2); IR (ATR) νmax 2924, 1443, 1156 cm−1; MS (EI) m/z
493 [M + H]+ (10), 492 [M]+ (65), 401 [M − C7H7]+ (18); HRMS
(EI-ion trap) calcd for C14H10N2I2S [M]+ 491.8654, found 491.8647.
1-Benzyl-2-(furan-2-yl)-4,5-diiodo-1H-imidazole (6d). Accord-
ing to the general procedure, the reaction of 5 with tri(furan-2-yl)
indium afforded, after purification by column chromatography (40%
EtOAc/hexanes), compound 6d as a white solid (197 mg, 83%): mp
154−156 °C; 1H NMR (300 MHz, CDCl3) δ 7.43 (s, 1H), 7.27−7.34
(m, 3H), 7.04 (d, J = 7.4 Hz, 2H), 6.78 (d, J = 2.7 Hz, 1H), 6.44−6.47
(m, 1H), 5.54 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 144.0 (C),
143.3 (CH), 135.5 (2 × C), 128.9 (2 × CH), 127.9 (CH), 126.3 (2 ×
CH), 111.6 (CH), 110.9 (CH), 96.9 (C), 85.0 (C), 52.9 (CH2); IR
(ATR) νmax 3030, 2362, 1446, 1387, 1224 cm−1; MS (EI) m/z 477 [M
+ H]+ (27), 476 [M]+ (100), 385 [M − C7H7]+ (25); HRMS (EI-ion
trap) calcd for C14H10N2I2O [M]+ 475.8882, found 475.8863.
1-Benzyl-2-(5-phenylthiophen-2-yl)-4,5-diiodo-1H-imida-
zole (6e). According to the general procedure, the reaction of 5 with
tri(5-phenylthiophen-2-yl)indium afforded, after purification by
column chromatography (30% EtOAc/hexanes), compound 6e as a
1-Benzyl-2-(5-(3-chlorophenyl)furan-2-yl)-4,5-bis(4-methox-
yphenyl)-1H-imidazole (9).20 According to the general procedure,
the reaction of 8 with tri(4-methoxyphenyl)indium afforded, after
purification by column chromatography (50% EtOAc/hexanes),
1
compound 9 as a yellow solid (249 mg, 91%): mp 68−70 °C; H
NMR (300 MHz, CDCl3) δ 7.51 (dt, J = 8.9, 2.5 Hz, 2H), 7.27−7.35
(m, 4H), 7.22−7.25 (m, 2H), 7.13−7.20 (m, 3H), 6.99−7.05 (m, 3H),
6.87 (dt, J = 8.8, 2.5 Hz, 2H), 6.79 (dt, J = 8.9, 2.5 Hz, 2H), 6.73 (d, J
= 3.6 Hz, 1H), 5.32 (s, 2H), 3.83 (s, 3H), 3.78 (s, 3H); 13C{1H} NMR
(75 MHz, CDCl3) δ 159.9 (C), 158.4 (C), 152.4 (C), 145.7 (C),
138.6 (C), 138.5 (C), 137.9 (C), 134.7 (C), 132.3 (2 × CH), 131.8
(C), 129.9 (CH), 129.5 (C), 128.8 (2 × CH), 128.1 (2 × CH), 127.4
(CH), 127.3 (CH), 127.1 (C), 125.6 (2 × CH), 123.6 (CH), 122.4
(C), 121.8 (CH), 114.4 (2 × CH), 113.6 (2 × CH), 112.1 (CH),
108.0 (CH), 55.2 (2 × CH3), 48.5 (CH2); IR (ATR) νmax 2933, 1519,
1494, 1249 cm−1; MS (EI) m/z 547 [M + H]+ (6), 546 [M]+ (19),
455 [M − C7H7]+ (49); HRMS (EI-ion trap) calcd for C34H27N2O3Cl
[M]+ 546.1705, found 546.1702.
1
yellow solid (224 mg, 79%): mp 126−128 °C; H NMR (300 MHz,
CDCl3) δ 7.56 (d, J = 7.1 Hz, 2H), 7.35−7.41 (m, 4H), 7.29−7.32 (m,
2H), 7.16 (d, J = 3.9 Hz, 1H), 7.06 (d, J = 7.0 Hz, 2H), 7.00 (d, J = 3.9
Hz, 1H), 5.49 (s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 147.0 (C),
146.6 (C), 135.3 (C), 133.5 (C), 130.1 (C), 129.2 (2 × CH), 129.0 (2
× CH), 128.2 (CH), 128.0 (CH), 127.7 (CH), 126.0 (2 × CH), 125.9
(2 × CH), 123.4 (CH), 96.8 (C), 85.2 (C), 52.8 (CH2); IR (ATR)
νmax 3063, 2925, 1496, 1478, 1207 cm−1; MS (EI) m/z 569 [M + H]+
(6), 568 [M]+ (20), 477 [M − C7H7]+ (42); HRMS (EI-ion trap)
calcd for C20H14N2I2S 567.8962, found 567.8954.
1-Benzyl-2-(4-fluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-
imidazole (10a). According to the general procedure, the reaction of
6b with tri(4-methoxyphenyl)indium afforded, after purification by
column chromatography (30% EtOAc/hexanes), compound 10a as a
pale yellow solid (202 mg, 87%): mp 53−56 °C; 1H NMR (300 MHz,
CDCl3) δ 7.58−7.62 (m, 2H), 7.52 (dt, J = 8.9, 2.4 Hz, 2H), 7.20−
7.23 (m, 3H), 7.13 (dt, J = 8.7, 2.4 Hz, 2H), 7.03−7.09 (m, 2H),
6.82−6.86 (m, 4H), 6.78 (dt, J = 8.9, 2.5 Hz, 2H), 5.05 (s, 2H), 3.81
(s, 3H), 3.76 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 164.7 (C),
161.4 (C), 159.8 (C), 158.3 (C), 146.6 (C), 137.9 (C), 137.6 (C),
132.4 (2 × CH), 130.9 (CH), 130.8 (CH), 128.9 (C), 128.7 (2 ×
CH), 127.9 (2 × CH), 127.4 (CH), 127.3 (C), 125.9 (2 × CH), 123.1
(C), 115.7 (CH), 115.4 (CH), 114.3 (2 × CH), 113.6 (2 × CH), 55.2
(2 × CH3), 48.1 (CH2); IR (ATR) νmax 2933, 1518, 1494, 1247 cm−1;
MS (EI) m/z 465 [M + H]+ (59), 464 [M]+ (93), 373 [M − C7H7]+
(100); HRMS (EI-ion trap) calcd for C30H25N2O2F [M]+ 464.1895,
found 464.1881.
2-(3-Chlorophenyl)furan (7).25 A solution of tri(2-furyl)indium
(6.7 mL, 1.01 mmol, 0.15 M in dry THF) was added to a solution of 3-
chloroiodobenzene (600 mg, 2.52 mmol) and Pd(PPh3)2Cl2 (88 mg,
0.13 mmol) in dry THF (2 mL) in a Schlenk tube filled with argon.
The reaction mixture was heated to 80 °C for 20 h. The mixture was
allowed to cool to rt and quenched by the addition of a few drops of
MeOH, and the solvent was removed. The residue was diluted with
EtOAc (40 mL), and the organic phase was washed with brine (30
mL), dried, and concentrated. The residue was purified by flash
chromatography (10% EtOAc/hexanes) to afford, after concentration
and high-vacuum drying, compound 7 as a yellowish oil (387 mg,
1-Benzyl-2-(furan-2-yl)-4,5-(4-methoxyphenyl)-1H-imida-
zole (11a).20 According to the general procedure, the reaction of 6d
with tri(4-methoxyphenyl)indium afforded, after purification by
column chromatography (50% EtOAc/hexanes), compound 11a as a
1
86%): H NMR (300 MHz, CDCl3) δ 7.68 (t, J = 1.7 Hz, 1H), 7.56
(dt, J = 6.3, 1.4 Hz, 1H), 7.49 (d, J = 1.7 Hz, 1H), 7.34−7.21 (m, 2H),
6.68 (d, J = 3.4 Hz, 1H), 6.48 (dd, J = 3.4, 1.7 Hz, 1H); 13C{1H} NMR
(75 MHz, CDCl3) δ 152.5 (C), 142.6 (CH), 134.7 (C), 132.5 (C),
129.9 (CH), 127.2 (CH), 123.8 (CH), 121.8 (CH), 111.8 (CH),
106.1 (CH); IR (ATR) νmax 2925, 1727, 1603, 1582, 1563, 1499, 1471
cm−1.
1-Benzyl-2-(5-(3-chlorophenyl)furan-2-yl)-4,5-diiodo-1H-
imidazole (8). According to the general procedure, the reaction of 5
with tri(2-(3-chlorophenyl)furan-2-yl)indium afforded, after purifica-
tion by column chromatography (30% EtOAc/hexanes), compound 8
as a dark yellow solid (202 mg, 69%): mp 135−137 °C; 1H NMR (300
MHz, CDCl3) δ 7.31−7.41 (m, 4H), 7.20−7.24 (m, 3H), 7.09 (d, J =
6.8 Hz, 2H), 6.96 (d, J = 3.6 Hz, 1H), 6.73 (d, J = 3.6 Hz, 1H), 5.62 (s,
2H); 13C{1H} NMR (75 MHz, CDCl3) δ 153.2 (C), 143.9 (C), 143.8
(C), 135.6 (C), 134.8 (C), 131.4 (C), 130.0 (CH), 129.1 (2 × CH),
127.9 (2 × CH), 125.8 (2 × CH), 123.8 (CH), 122.0 (CH), 113.0
(CH), 108.0 (CH), 97.1 (C), 85.6 (C), 53.2 (CH2); IR (ATR) νmax
1
yellow solid (196 mg, 90%): mp 66−68 °C; H NMR (300 MHz,
CDCl3) δ 7.51 (dt, J = 8.9, 2.5 Hz, 2H), 7.45 (d, J = 1.2 Hz, 1H),
7.21−7.26 (m, 3H), 7.11 (dt, J = 8.8, 2.4 Hz, 2H), 6.93 (m, 2H), 6.86
(dt, J = 8.8, 2.4 Hz, 2H), 6.76 (dt, J = 8.9, 2.5 Hz, 2H), 6.71 (d, J = 3.4
Hz, 1H), 6.43 (dd, J = 1.8, 3.4 Hz, 1H), 5.23 (s, 2H), 3.82 (s, 3H),
3.76 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3) δ 159.9 (C), 158.3
(C), 145.5 (C), 142.7 (CH), 138.9 (C), 138.3 (C), 137.6 (C), 132.4
(2 × CH), 129.1 (C), 128.6 (2 × CH), 128.0 (2 × CH), 127.2 (CH),
127.3 (C), 126.0 (2 × CH), 122.6 (C), 114.3 (2 × CH), 113.5 (2 ×
CH), 111.4 (CH), 109.7 (CH), 55.2 (2 × CH3), 48.2 (CH2); IR
(ATR) νmax 2933, 1517, 1493, 1245 cm−1; MS (EI) m/z 437 [M + H]+
(54), 436 [M]+ (100), 345 [M − C7H7]+ (100); HRMS (IE) calcd for
C28H24N2O3 [M]+ 436.1781, found 436.1778.
1-Benzyl-2-(5-phenylthiophen-2-yl)-4,5-bis(4-methoxy-
phenyl)-1H-imidazole (12a). According to the general procedure,
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the reaction of 6e with tri(4-methoxyphenyl)indium afforded, after
purification by column chromatography (30% EtOAc/hexanes),
compound 12a as a pale yellow solid (211 mg, 80%): mp 206−208
°C; 1H NMR (300 MHz, CDCl3) δ 7.61 (d, J = 7.2 Hz, 2H), 7.52 (dt,
J = 8.8, 2.5 Hz, 2H), 7.37−7.40 (m, 2H), 7.30 (dd, J = 7.4 Hz, 4H),
7.10−7.17 (m, 3H), 6.99−7.04 (m, 3H), 6.85 (dt, J = 8.8, 2.3 Hz, 2H),
6.78 (dt, J = 8.8, 2.5 Hz, 2H), 5.21 (s, 2H), 3.82 (s, 3H), 3.78 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 159.9 (C), 158.3 (C), 145.2 (C),
141.6 (C), 138.2 (C), 137.4 (2 × C), 134.0 (C), 132.3 (2 × CH),
129.6 (C), 129.0 (2 × CH), 128.9 (2 × CH), 128.0 (2 × CH), 127.7
(CH), 127.5 (CH), 127.2 (C), 126.3 (CH), 125.8 (2 × CH), 125.7 (2
× CH), 123.4 (CH), 122.7 (C), 114.3 (2 × CH), 113.6 (2 × CH),
55.2 (2 × CH3), 48.2 (CH2); IR (ATR) νmax 2932, 1518, 1493, 1249
cm−1; MS (EI) m/z 529 [M + H]+ (32), 528 [M]+ (71), 437 [M −
C7H7]+ (100); HRMS (EI-ion trap) calcd for C34H28N2O2S [M]+
528.1866, found 528.1857.
1-Benzyl-2-(4-methoxyphenyl)-4,5-bis(5-phenylthiophen-2-
yl)-1H-imidazole (16a). According to the general procedure, the
reaction of 6a with tri(5-phenylthiophen-2-yl)indium afforded, after
purification by column chromatography (20% EtOAc/hexanes),
compound 16a as a pale green solid (197 mg, 68%): mp 83−86 °C;
1H NMR (300 MHz, CDCl3) δ 7.55−7.60 (m, 7H), 7.35−7.41 (m,
2H), 7.24−7.33 (m, 6H), 7.13 (dd, J = 3.8, 10.4 Hz, 2H), 6.90−6.96
(m, 6H), 5.18 (s, 2H), 3.82 (s, 3H); 13C{1H} NMR (75 MHz, CDCl3)
δ 160.4 (C), 149.0 (C), 147.7 (C), 142.5 (C), 137.6 (2 × C), 137.1
(C), 136.3 (C), 134.7 (C), 133.9 (C), 132.3 (CH), 130.4 (2 × CH),
129.0 (2 × CH), 128.8 (4 × CH), 128.0 (CH), 127.5 (CH), 127.0
(CH), 126.0 (2 × CH), 125.8 (2 × CH), 125.5 (2 × CH), 124.3
(CH), 123.4 (CH), 123.3 (CH), 122.8 (C), 120.7 (C), 114.1 (2 ×
CH), 55.3 (CH3), 48.4 (CH2); IR (ATR) νmax 2929, 1610, 1476, 1251
cm−1; MS (EI) m/z 581 [M + H]+ (23), 580 [M]+ (60), 489 [M −
C7H7]+ (100); HRMS (EI-ion trap) calcd for C37H28N2S2O [M]+
580.1638, found 580.1615.
1-Benzyl-2-(4-methoxyphenyl)-4,5-bis(5-(3-chlorophenyl)-
furan-2-yl)-1H-imidazole (17a). According to the general proce-
dure, the reaction of 6a with tri(5-(3-chlorophenyl)furan-2-yl)indium
afforded, after purification by column chromatography (40% EtOAc/
hexanes), compound 17a as a yellow-orange solid (284 mg, 92%): mp
64−66 °C; 1H NMR (300 MHz, CDCl3) δ 7.51−7.57 (m, 3H), 7.26−
7.42 (m, 7H), 7.04−7.20 (m, 4H), 6.90−6.94 (m, 4H), 6.79 (d, J = 3.4
Hz, 1H), 6.72 (dd, J = 3.5, 8.0 Hz, 2H), 5.28 (s, 2H), 3.83 (s, 3H);
13C{1H} NMR (75 MHz, CDCl3) δ 160.6 (C), 153.1 (C), 151.3 (C),
1-Benzyl-2-(5-phenylthiophen-2-yl)-4,5-bis(benzo[b]-
thiophen-2-yl)-1H-imidazole (13a). According to the general
procedure, the reaction of 6e with tri(benzo[b]thiophen-2-yl)indium
afforded, after purification by column chromatography (20% EtOAc/
hexanes), compound 13a as a lemon-yellow solid (261 mg, 89%): mp
1
225−227 °C; H NMR (300 MHz, CDCl3) δ 7.84−7.87 (m, 1H),
7.76−7.80 (m, 1H), 7.70−7.73 (m, 1H), 7.62 (d, J = 7.6 Hz, 4H), 7.47
(s, 1H), 7.37−7.43 (m, 4H), 7.23−7.33 (m, 6H), 7.19 (d, J = 3.9 Hz,
1H), 7.11 (d, J = 3.9 Hz, 1H), 7.04 (d, J = 6.3 Hz, 2H), 5.35 (s, 2H);
13C{1H} NMR (75 MHz, CDCl3) δ 146.3 (C), 143.5 (C), 141.7 (C),
150.1 (C), 149.8 (C), 143.2 (C), 137.6 (C), 134.7 (C), 134.6 (C),
133.0 (C), 132.3 (C), 131.9 (C), 130.5 (2 × CH), 129.9 (CH), 129.7
(CH), 128.9 (2 × CH), 127.7 (CH), 127.5 (CH), 126.8 (CH), 125.8
(2 × CH), 123.7 (CH), 123.5 (CH), 122.4 (C), 121.8 (CH), 121.5
(CH), 119.9 (C), 115.0 (CH), 114.2 (2 × CH), 109.1 (CH), 107.9
(CH), 107.4 (CH), 55.3 (CH3), 49.3 (CH2); IR (ATR) νmax 2933,
2836, 1594, 1480, 1250 cm−1; MS (EI) m/z 617 [M + H]+ (19), 616
[M]+ (50), 525 [M − C7H7]+ (100); HRMS (EI-ion trap) calcd for
C37H26N2O3Cl2 [M]+ 616.1315, found 616.1306.
140.2 (C), 139.6 (C), 139.4 (C), 137.0 (C), 136.8 (C), 136.6 (C),
133.8 (C), 131.0 (C), 129.6 (C), 129.1 (2 × CH), 129.0 (2 × CH),
128.8 (CH), 128.0 (CH), 127.8 (CH), 127.4 (CH), 125.9 (2 × CH),
125.7 (2 × CH), 125.3 (CH), 124.6 (CH), 124.3 (CH), 124.1 (CH),
123.9 (CH), 123.5 (CH), 123.4 (CH), 123.0 (C), 122.4 (CH), 122.1
(CH), 120.3 (CH), 48.7 (CH2); IR (ATR) νmax 2921, 1594, 1479
cm−1; MS (EI) m/z 581 [M + H]+ (18), 580 [M]+ (48), 489 [M −
C7H7]+ (100); HRMS (EI-ion trap) calcd for C36H24N2S3 [M]+
580.1096, found 580.1090.
Benzyl-2-((trimethylsilyl)ethynyl)-4,5-bis(4-methoxyphen-
yl)-1H-imidazole (18a). Compound 18a was prepared by sequential
cross-coupling reactions in a one-pot procedure: a solution of
tris(trimethylsilylethynyl)indium (5 mL, 0.05 M in THF, 0.3 mmol)
was added slowly to a solution of 5 (268 mg, 0.5 mmol) and
Pd(PPh3)4 (29 mg, 0.025 mmol) in dry THF (2 mL) in an argon-filled
Schlenk tube. The mixture was heated at 80 °C for 20 h, and the
starting material was consumed (TLC monitoring). A solution of tri(4-
methoxyphenyl)indium (5 mL, 0.05 M in THF, 0.5 mmol) was added,
and the mixture was heated at 80 °C until the intermediate
monocoupling product had been consumed (21 h). The reaction
mixture was quenched and treated according to the general procedure
to afford, after purification by column chromatography (20% EtOAc/
hexanes), compound 18a as a pale yellow oil (70 mg, 40%): 1H NMR
(300 MHz, CDCl3) δ 7.44 (dt, J = 8.9, 2.3 Hz, 2H), 7.22−7.25 (m,
3H), 7.06 (dt, J = 8.7, 2.2 Hz, 2H), 6.95−6.99 (m, 2H), 6.88 (dt, J =
8.9, 2.3 Hz, 2H), 6.74 (dt, J = 8.9, 2.5 Hz, 2H), 5.08 (s, 2H), 3.83 (s,
3H), 3.74 (s, 3H), 0.19 (s, 9H); 13C{1H} NMR (75 MHz, CDCl3) δ
160.0 (C), 158.4 (C), 138.4 (C), 136.1 (C), 132.2 (2 × CH), 131.2
(C), 128.9 (C), 128.5 (2 × CH), 128.0 (2 × CH), 127.6 (CH), 127.1
(2 × CH), 126.7 (C), 122.4 (C), 114.4 (2 × CH), 113.5 (2 × CH),
100.1 (C), 94.2 (C), 55.1 (2 × CH3), 48.5 (CH2), −0.4 (3 × CH3); IR
(ATR) νmax 2964, 2164, 1495, 1248 cm−1; MS (EI) m/z 467 [M + H]+
(38), 466 [M]+ (100), 375 [M − C7H7]+ (30); HRMS (EI-ion trap)
m/z calcd for C29H30N2O2Si [M]+ 466.2071, found 466.2070.
1-Benzyl-2-(4-fluorophenyl)-4,5-bis(benzo[b]thiophen-2-yl)-
1H-imidazole (14a). According to the general procedure, the
reaction of 6b with tri(benzo[b]thiophen-2-yl)indium afforded, after
purification by column chromatography (30% EtOAc/hexanes),
compound 14a as a pale yellow solid (253 mg, 98%): mp 202−205
1
°C; H NMR (300 MHz, CDCl3) δ 7.81−7.88 (m, 1H), 7.76−7.79
(m, 1H), 7.69−7.72 (m, 1H), 7.59−7.64 (m, 3H), 7.36−7.43 (m, 3H),
7.20−7.28 (m, 6H), 7.09 (t, J = 8.6 Hz, 2H), 6.90−6.93 (m, 2H), 5.19
(s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 165.0 (C), 161.6 (C),
148.5 (C), 141.7 (C), 140.2 (C), 139.5 (C), 139.5 (C), 137.2 (C),
137.1 (C), 136.4 (C), 131.1 (CH), 131.0 (CH), 129.9 (C), 128.9 (2 ×
CH), 128.7 (CH), 127.7 (CH), 125.8 (2 × CH), 125.2 (CH), 124.6
(CH), 124.3 (CH), 123.9 (CH), 123.4 (CH), 122.6 (C), 122.4 (CH),
122.1 (CH), 120.0 (CH), 115.9 (CH), 115.6 (CH), 48.6 (CH2); IR
(ATR) νmax 2922, 1454, 1225 cm−1; MS (EI) m/z 517 [M + H]+ (30),
516 [M]+ (90), 425 [M − C7H7]+ (100); HRMS (EI-ion trap) calcd
for C32H21N2S2F [M]+ 516.1125, found 516.1121.
1-Benzyl-2-(furan-2-yl)-4,5-bis(benzo[b]thiophen-2-yl)-1H-
imidazole (15a). According to the general procedure, the reaction of
6d with tri(benzo[b]thiophen-2-yl)indium afforded, after purification
by column chromatography (30% EtOAc/hexanes), compound 15a as
1
a pale yellow solid (211 mg, 87%): mp 192−194 °C; H NMR (300
MHz, CDCl3) δ 7.85−7.88 (m, 1H), 7.78−7.82 (m, 1H), 7.69−7.72
(m, 1H), 7.59−7.62 (m, 1H), 7.48−7.49 (m, 4H), 7.46 (d, J = 1.0 Hz,
1H), 7.39−7.45 (m, 2H), 7.29 (d, J = 1.0 Hz, 1H), 7.20−7.27 (m,
5H), 6.84 (dd, J = 1.0, 3.5 Hz, 1H), 6.48 (q, J = 3.5, 1.8 Hz, 1H), 5.39
(s, 2H); 13C{1H} NMR (75 MHz, CDCl3) δ 144.6 (C), 143.3 (CH),
141.8 (C), 140.6 (C), 140.2 (C), 139.5 (C), 139.4 (C), 137.0 (2 × C),
136.7 (C), 129.5 (C), 128.9 (CH), 128.8 (2 × CH), 127.6 (CH),
125.9 (2 × CH), 125.3 (CH), 124.6 (CH), 124.3 (CH), 124.1 (CH),
123.9 (CH), 123.4 (CH), 122.6 (C), 122.5 (CH), 122.0 (CH), 120.3
(CH), 111.6 (CH), 111.0 (CH), 48.7 (CH2); IR (ATR) νmax 2921,
1454, 1354, 1155 cm−1; MS (EI) m/z 489 [M + H]+ (34), 488 [M]+
(100), 397 [M − C7H7]+ (100), 331 [M − C4H3O]+ (33); HRMS
(EI-ion trap) calcd for C30H20N2OS2 [M]+ 488.1012, found 488.1003.
General Procedure for Deprotection of the Benzyl Group.21
1-Benzyl-2,4,5-trisubstituted-1H-imidazole (0.06 mmol) and anhy-
drous DMSO (5 mL) were placed in a dry 25 mL two-necked flask.
KOt-Bu (1.0 M in THF, 0.47 mmol) was slowly added, and O2 was
bubbled through the solution for 10 min. The reaction mixture was
stirred at rt, and the reaction was monitored by TLC. After completion
of the reaction, the solution was poured into sat. aq NH4Cl (20 mL)
and extracted with EtOAc (3 × 20 mL). The combined organic layers
were washed with H2O (20 mL), dried, and concentrated. The residue
was purified by flash chromatography (50% EtOAc/hexanes) to afford,
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after concentration and high-vacuum drying, the corresponding N-
debenzylation products.
CH), 125.8 (2 × CH), 125.5 (2 × CH), 124.9 (CH), 124.6 (CH),
124.4 (CH), 122.7 (C), 120.8 (C), 114.7 (2 × CH), 55.7 (CH3); IR
(ATR) νmax 2924, 2854, 1599, 1440, 1254 cm1; MS (EI) m/z 491 [M
+ H]+ (35), 490 [M]+ (100); HRMS (EI-ion trap) calcd for
C30H22N2OS2 [M]+ 490.1168, found 490.1157.
2-(5-(3-Chlorophenyl)furan-2-yl)-4,5-bis(4-methoxyphenyl)-
1H-imidazole (Neurodazine, 4).20 According to the general
procedure, the reaction of 9 with KOt-Bu afforded, after purification
by column chromatography (20% EtOAc/hexanes), compound 4 as a
2-(4-Methoxyphenyl)-4,5-bis(5-(3-chlorophenyl)furan-2-yl)-
1H-imidazole (17b). According to the general procedure, the
reaction of 17a with KOt-Bu afforded, after purification by column
chromatography (20% EtOAc/hexanes), compound 17b as an orange
1
yellow solid (24 mg, 90%): mp 86−88 °C; H NMR (300 MHz,
DMSO-d6) δ 12.79 (s, 1H), 7.98 (t, J = 1.7 Hz, 1H), 7.84 (d, J = 7.9
Hz, 1H), 7.41−7.49 (m, 5H), 7.32−7.37 (m, 1H), 7.23 (d, J = 3.4 Hz,
1H), 7.03 (dd, J = 2.4, 6.0 Hz, 3H), 6.87 (d, J = 8.8 Hz, 2H), 3.81 (s,
3H), 3.75 (s, 3H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 159.4 (C),
158.5 (C), 151.4 (C), 146.3 (C), 138.0 (C), 137.3 (C), 134.3 (C),
132.4 (C), 131.2 (CH), 130.4 (2 × CH), 128.7 (2 × CH), 127.9 (C),
127.7 (CH), 127.4 (C), 123.7 (C), 123.5 (CH), 122.7 (CH), 114.6 (2
× CH), 114.1 (2 × CH), 109.9 (CH), 109.4 (CH), 55.7 (CH3), 55.5
(CH3); IR (ATR) νmax 2921, 2835, 1500, 1244 cm−1; MS (EI) m/z
457 [M + H]+ (32), 456 [M]+ (100), 441 [M − CH3]+ (27); HRMS
(EI-ion trap) calcd for C27H21N2O3Cl [M]+ 456.1235, found
456.1232.
1
oil (30 mg, 96%): H NMR (300 MHz, DMSO-d6) δ 12.78 (s, 1H),
8.06 (d, J = 8.7 Hz, 2H), 7.90 (s, 1H), 7.65−7.80 (m, 3H), 7.27−7.43
(m, 5H), 7.23 (d, J = 3.4 Hz, 1H), 7.14 (d, J = 3.5 Hz, 1H), 7.10 (d, J
= 8.8 Hz, 2H), 6.93 (d, J = 3.4 Hz, 1H), 3.84 (s, 3H); 13C{1H} NMR
(75 MHz, DMSO-d6) δ 160.4 (C), 151.5 (C), 150.9 (C), 150.5 (C),
147.6 (C), 145.3 (C), 134.3 (2 × C), 132.6 (C), 132.3 (C), 131.2
(CH), 131.1 (C), 130.1 (C), 127.9 (2 × CH), 127.7 (CH), 127.4
(CH), 123.5 (CH), 123.1 (CH), 122.7 (C), 122.6 (CH), 122.0 (CH),
119.5 (CH), 114.7 (2 × CH), 110.9 (CH), 109.9 (CH), 109.8 (2 ×
CH), 55.8 (CH3); IR (ATR) νmax 2923, 2852, 1595, 1500, 1252 cm−1;
MS (EI) m/z 527 [M + H]+ (34), 526 [M]+ (100); HRMS (EI-ion
trap) calcd for C30H20N2O3Cl2 [M]+ 526.0845, found 526.0836.
2-(4-Fluorophenyl)-4,5-bis(4-methoxyphenyl)-1H-imidazole
(10b).26 According to the general procedure, the reaction of 10a with
KOt-Bu afforded, after purification by column chromatography (30%
EtOAc/hexanes), compound 10b as a yellow solid (20 mg, 92%): mp
ASSOCIATED CONTENT
■
1
194−197 °C; H NMR (300 MHz, CDCl3) δ 7.78−7.82 (m, 2H),
S
* Supporting Information
7.41 (d, J = 8.7 Hz, 4H), 7.01−7.07 (m, 2H), 6.83 (d, J = 8.7 Hz, 4H),
3.80 (s, 6H); 13C{1H} NMR (75 MHz, DMSO-d6) δ 164.6 (C), 164.0
(C), 161.3 (C), 159.0 (2 × C), 144.7 (C), 129.1 (4 × CH), 127.3
(CH), 127.2 (CH), 126.3 (C), 126.2 (C), 115.9 (CH), 115.6 (CH),
114.0 (4 × CH), 55.2 (2 × CH3); IR (ATR) νmax 2927, 2837, 1498,
1243 cm−1; MS (EI) m/z 375 [M + H]+ (25), 374 [M]+ (100), 359
[M − CH3]+ (29); HRMS (EI-ion trap) calcd for C23H19N2O2F [M]+
374.1425, found 374.1415.
Copies of 1H and 13C{1H} NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: mmartinezc@udc.es.
*E-mail: qfsarand@udc.es.
2-(Furan-2-yl)-4,5-bis(4-methoxyphenyl)-1H-imidazole
(11b).22 According to the general procedure, the reaction of 11a with
KOt-Bu afforded, after purification by column chromatography (30%
EtOAc/hexanes), compound 11b as a pale brown solid (20 mg, 96%):
mp 169−172 °C; 1H NMR (300 MHz, CDCl3) δ 7.40−7.43 (m, 5H),
6.95 (d, J = 3.3 Hz, 1H), 6.85 (dt, J = 8.8, 2.4 Hz, 4H), 6.48 (dd, J =
3.4, 1.8 Hz, 1H), 3.82 (s, 6H); 13C{1H} NMR (75 MHz, DMSO-d6) δ
159.0 (4 × C), 145.5 (2 × C), 142.2 (CH), 138.3 (2 × C), 129.1 (4 ×
CH), 114.0 (4 × CH), 112.0 (CH), 107.4 (CH), 55.3 (2 × CH3); IR
(ATR) νmax 2956, 2835, 1518, 1497, 1248 cm−1; MS(EI) m/z 347 [M
+ H]+ (20), 346 [M]+ (100), 331 [M − CH3]+ (29); HRMS (EI-ion
trap) calcd for C21H18N2O3 [M]+ 346.1312, found 346.1307.
2-(5-Phenylthiophen-2-yl)-4,5-bis(4-methoxyphenyl)-1H-
imidazole (12b). According to the general procedure, the reaction of
12a with KOt-Bu afforded, after purification by column chromatog-
raphy (30% EtOAc/hexanes), compound 12b as a lemon-yellow solid
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We are grateful to the Ministerio de Economia y Competividad
for financial support (CTQ2012-31200) and the EDRF funds
for financial support.
■
́
REFERENCES
■
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(24 mg, 92%): mp 58−60 °C; H NMR (300 MHz, DMSO-d6) δ
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(24 mg, 84%): H NMR (300 MHz, CDCl3) δ 8.02 (dt, J = 8.9, 2.4
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