Palladium-Catalyzed One-Pot Synthesis of 5-(1-Arylvinyl)-1H-benzimidazoles: Overcoming the Limitation of Acetamide Partners

Article abstract of DOI:10.1002/adsc.201600173

A new one-pot palladium-catalyzed process between N-tosylhydrazones, N-(dihalophenyl)-imidates, and amines was designed. This reaction involves Barluenga cross-coupling and N-arylation followed by cyclization to produce functionalized benzimidazoles. Duri

Full text of DOI:10.1002/adsc.201600173

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DOI: 10.1002/adsc.201600173
Very Important Publication
Palladium-Catalyzed One-Pot Synthesis of 5-(1-Arylvinyl)-1H-
benzimidazoles: Overcoming the Limitation of Acetamide
Partners
TimothØe Naret,a Pascal Retailleau,b JØrôme Bignon,b Jean-Daniel Brion,a
Mouad Alami,a,* and Abdallah Hamzea,*
a
Univ. Paris-Sud, CNRS, BioCIS-UMR 8076, Laboratoire de Chimie ThØrapeutique, Equipe LabellisØe Ligue Contre Le
Cancer, LabEx LERMIT, FacultØ de Pharmacie, 5 rue J.-B. ClØment, 92296 Châtenay-Malabry, France
Fax: (+33)-1-46835828; Phone: (+33)-1-46835498; e-mail: mouad.alami@u-psud.fr or abdallah.hamze@u-psud.fr
Laboratoire des Institut de Chimie des Substances Naturelles, UPR 2301, CNRS, Avenue de la Terrasse, 91198
b
Gif-sur-Yvette, France
Received: February 10, 2016; Revised: March 25, 2016; Published online: May 25, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600173.
Abstract: A new one-pot palladium-catalyzed pro- benzimidazoles was synthesized. Among several aryl-
cess between N-tosylhydrazones, N-(dihalophenyl)- vinylbenzimidazole derivatives evaluated, one com-
imidates, and amines was designed. This reaction in- pound exhibits excellent antiproliferative activity in
volves Barluenga cross-coupling and N-arylation fol- the nanomolar concentration range against human
lowed by cyclization to produce functionalized benz- colon carcinoma cell lines (HCT-116) and human
À
imidazoles. During this transformation, one C C lung adenocarcinoma epithelial cell lines (A549).
bond and two C N bonds were created by a single
À
palladium-catalyzed reaction. Depending on the Keywords: benzimidazoles; hydrazones; olefination;
starting materials, a library of 5-(1-arylvinyl)-1H- one-pot reaction; palladium
Introduction
drug it suffers from some drawbacks. In particular,
CA-4 presents chemical instability, leading to the in-
In search of new biologically active molecules, the in- active trans-isomer.[6] In our efforts to discover non-
corporation of heterocycles appears as a priority. isomerizable CA-4 analogues,[7] we recently synthe-
Among the multitude of known heterocyclic com- sized a series of 1,1-diarylethylene derivatives among
pounds, benzimidazole is a privileged structure and which isoCA-4,[8] has emerged as a lead compound.
essential building block used in medicinal chemistry. This last compound has the particular feature of pos-
It belongs to the top five most commonly used het- sessing a 1,1-diarylethylene scaffold, which exhibits
erocycles in medicinal chemistry. Benzimidazoles are the same cytotoxic properties as the CA-4, but with-
found in 13 FDA approved pharmaceuticals,[1] among out the stability problem due to the isomerization of
them, a proton-pump inhibitor (esomeprazole), an an- the natural compound CA-4. In the aim of obtaining
giotensin II receptor antagonist (candesartan), and an a novel type of potent cytotoxic agents, and increase
oral anticoagulant from the class of the direct throm- the chemical diversity of our active compounds li-
bin inhibitors (dabigatran).[2]
brary in order to go further toward clinical develop-
Cancer is one of the major health challenges of the ment, we planned to associate the benzimidazole nu-
21st century.[3] Among the developed strategies used cleus with a 1,1-disubstituted ethylene link.
to counter this disease, the search of new molecules
Today, there is a growing interest in developing effi-
with a novel mechanism of action is very desirable. In cient chemical processes. In this context, a one-pot re-
this direction, Pettit and co-workers discovered a natu- action in which three or more bonds are formed in
ral compound, the combretastatin A-4 (CA-4), which a single vessel to obtain a final product is very desira-
presents a powerful activity against cancer.[4] This ble. This involves, among other advantages, important
product disrupts the polymerization of tubulin and energy, time, and materials savings. As an attractive
opens the way to a new therapeutic class, vascular dis- synthetic route, metal-catalyzed reactions by using N-
rupting agents.[5] Despite the great potential of this tosylhydrazone reagents constitute a powerful method
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[9]
À
À
for C C and C N bond formation. The synthetic Results and Discussion
method developed by Barluenga and co-workers[10]
provides access to polysubstituted olefins,[11] allenes,[12] First, we investigated the one-pot synthesis of 5-(1-ar-
and substituted amines.[13] This method can be used ylvinyl)-1H-benzoimidazole (Scheme 2, path A), by
for ring closing[14] and formation of other C hetero- using a model reaction, from N-tosylhydrazone 1a
À
atom bonds.[15] Despite these achievements, continu- (1.2 equiv.), N-(2-chloro-5-iodophenyl)-acetamide 2a
ous effort is required, especially for the generation of (1.0 equiv.) and p-anisidine 3a (1.2 equiv.). In the be-
versatile, and potential synthetic procedures to ach- ginning of this work, we used conditions close to
ieve complex molecules and libraries. In this way, the those of the protocol described by Buchwald and in
development of new methods to synthesize complex our previous work [Eq. (2)]: Pd2(dba)3·CHCl3, XPhos,
molecules containing benzimidazoles with remarkable LiO-t-Bu in dioxane. Under these conditions, no trace
biological activity using N-tosylhydrazones chemistry of compound 4a was observed, instead, we observed
becomes a priority.
mainly the formation of the Bamford–Stevens by-
Recently, Buchwald and co-workers developed an product due to the degradation of N-tosylhydra-
interesting method employing Pd2(dba)3 and XPhos zone.[19] To get some insight of what is going on, we
which permits the efficient synthesis of N-arylbenz- decided to run the two steps of this one-pot reaction
imidazoles
from
starting
ortho-haloanilides separately. Firstly, the formation of benzimidazole 5a
[Scheme 1, Eq. (1)].[16] On the other hand, a few cata- from ortho-haloanilide 2b and p-anisidine 3a was
lytic systems based on a Pd carbene migratory inser- studied (Scheme 2, path B). A screening of the reac-
tion process with other coupling reactions have been tion conditions was realized (Table 1S, in the Support-
reported for the construction of cyclic architectures.[17] ing Information). As a result, the precatalyst G3-Pd-
Very recently, we developed a catalytic three-compo- XPhos was more efficient than Pd2(dba)3·CHCl3,
nent one-pot reaction of hydrazones, dihaloarenes, K3PO4 gave the best yield of 5a, in comparison with
and amines [Eq. (2)].[18] We hypothesized that ortho- LiO-t-Bu and NaO-t-Bu as a base. Among many
haloanilides could be an appropriate substrate in tested solvents, t-BuOH was found as an appropriate
À
À
which a combination of C C [Eq. (3), a], C N [Eq. choice as a solvent for this coupling, and 5a was ob-
(3), b], and N C [Eq. (3), c] bond forming reactions tained in 70% yield.
À
may be applied for the synthesis of elaborated arylvi-
Next, we turned our effort to the second coupling
nylbenzimidazole derivatives. At first glance, this between benzimidazole derivative 5a and hydrazone
transformation seems to be a simple combination of 1a (Scheme 2, path C). We started our essay by using
conditions used in Eqs. (1) and (2). However, in this the optimal conditions for the first coupling: G3-Pd-
work, we will see that the elaboration of one-pot con- XPhos, XPhos, and K3PO4 in t-BuOH. Unfortunately,
ditions still represents a big challenge. Here we report after 12 h, a poor 22% yield of 4a was obtained
the process which led to the discovery and validation (Table 2S, in the Supporting Information). In view of
of our synthetic tool [Eq. (3)].
this result, several conditions were tested, and the
2
2
2
À
À
Scheme 1. Catalytic approaches for building Csp Csp and Csp N bonds.
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Scheme 2. Different strategies used for the formation of arylvinyl-benzimidazole derivatives 4.
best yield was obtained with Pd2(dba)3·CHCl3, XPhos, change drastically our strategy for the development of
LiO-t-Bu in dioxane. As a conclusion, if t-BuOH con- this one-pot reaction and to find other suitable elec-
stitutes the optimal solvent for the first coupling, it is trophilic partners for the coupling with hydrazone.
not suitable for the second coupling. This result is not
Recently, the group of Willis and co-workers devel-
surprising since Barluenga and co-workers have dem- oped a Pd-catalyzed synthesis of benzimidazoles from
onstrated that the basic metal-free C O bond forming the corresponding imidates.[21] We envisaged that imi-
À
reaction proceeds through decomposition of hydra- dates 7 could be used to synthesize arylvinylbenzimi-
zones in the presence of alcohols, and results in the dazole derivatives in a one-pot fashion. Accordingly,
insertion reaction of the carbene into the OH bond.[20] we studied first the benzimidazole synthesis from the
In the framework of this separate study, we decided model imidate 7a (Table 1). The reaction of imidate
to inverse the order of coupling partners to find 7a in the presence of Pd(OAc)2 and DavePhos with
a better solvent, suitable for both coupling reactions NaO-t-Bu as base and toluene afforded a low yield of
(Scheme 2, path D). The coupling between hydrazone benzimidazole 5a (entry 1). Increasing the reaction
1a and ortho-haloanilides 2a or 2c can be performed temperature from 120 to 1308C slightly increases the
effectively under several conditions: many sources of yield of product 5a (entry 2) but we observed the for-
bases can be used including K3PO4, LiO-t-Bu, and mation of by-product 5b resulting from dehalogena-
NaO-t-Bu in dioxane or fluorobenzene as the solvent. tion of benzimidazole 5a. The use of Pd2(dba)3·CHCl3
The cross-coupling product was synthesized with an instead of Pd(OAc)2 leads to a total conversion of
excellent yield >90% (Table 3S, in the Supporting In- imidate 7a (entry 4). DavePhos was found to be more
formation). The best conditions found for this step efficient as ligand than XPhos for this coupling (en-
were tested for the coupling between compound 6 tries 4 and 5). Subsequently, a range of bases, such as
and p-anisidine 3a (Scheme 2, path E). Unfortunately, K3PO4, Cs2CO3, and LiO-t-Bu was examined.
none of these new conditions afforded the desired
Among the studied bases, LiO-t-Bu produced the
product efficiently and, in the best case, the desired highest yield of 5a and reduced significantly the
product 4a was obtained with a low 19% yield amount of by-product 5b (Table 1, entries 5–8). De-
(Table 4S, in the Supporting Information).
creasing the amount of the amine 3a gave the product
Following these attempts, it seems that the ortho- 5a in a high yield (entries 9 and 10).
haloanilide partner is not suitable for the one-pot syn-
After optimization of the reaction conditions for
thesis of arylvinylbenzimidazoles 4. Screening experi- the benzimidazole formation (5a), next, we tried to
ments revealed that t-BuOH and K3PO4 constitute study the one-pot experiment, as mentioned in
the optimal combination of solvent and base for the Scheme 3, after the coupling between imidate 7a and
synthesis of N-arylbenzimidazoles from ortho-haloani- p-anisidine 3a for 3 h, hydrazone 1a, and LiO-t-Bu
lides. On the other hand, t-BuOH was found to be in- were added and the reaction was continued for 2 ad-
efficient as a solvent for the coupling between hydra- ditional hours. Again, to our great regret, the second
zone and aryl halide derivative, consequently, this coupling was unsuccessful, since no traces of arylvi-
makes impractical the realization of the one-pot reac- nylbenzimidazole 4 were isolated. One possible ex-
tion. This incompatibility of solvents pushes us to planation of this result can be due to the formation of
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Table 1. Optimization of the reaction conditions for Pd-catalyzed amination of imidates.[a]
[a]
Reaction onditions: imidate 7a (0.5 mmol), p-anisidine 3a (0.75 mmol), [Pd] source
(5 mol%), ligand (10 mol%), base (1.1 mmol), solvent (2.0 mL), sealed tube, 1308C,
3 h.
[b]
Reaction was performed at 1208C.
3a (1.3 equiv).
3a (1.1 equiv.).
[c]
[d]
Scheme 3. One-pot reaction optimization.
t-BuOH after the first coupling between imidate 7a overall yield of 72%. This represents an average of
and aniline 3a, which competes directly with the elec- ~90% yield for each step.
trophile 5a during the coupling with the hydrazone
Scale up of this coupling was also realized with op-
timized conditions with 1 g (3.3 mmol) of hydrazone
1a.[20]
At this stage, we still have a last possibility, which 1a and a 65% yield was isolated (634 mg, 1.80 mmol).
consists in carrying out the coupling first between the Using the established optimized conditions, we sub-
hydrazone 1a and imidate 7b, followed by formation sequently examined the scope of the one-pot reaction.
of the benzimidazole in the second step (Scheme 3, First, various N-tosylhydrazones were employed with
bottom part). Finally, we are pleased that this last imidate 7b and amine 3a. As presented in Table 2, the
path constitutes the best way to obtain the arylvinyl- reaction could be carried out with an array of N-tosyl-
benzimidazole 5a in a one-pot fashion and in a good hydrazones derived from acetophenones, phenylpro-
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Table 2. Palladium-catalyzed one-pot synthesis of arylvinylbenzimidazoles from imidates 7.[a]
panones, chromanones, diphenylethanones and cyclo- both hydrazones containing electron-withdrawing and
hexanones (4a–s). The reaction in general afforded electron-donating groups were coupled efficiently (4a,
the corresponding products in moderate to good 4e–g, and 4p). The reactions with para-, meta-, and
yields. The reaction was globally unaffected by elec- ortho-substituted hydrazones all proceeded efficiently
tronic effects of the substituents of hydrazones, since (4a–g, 4k, and 4p). In the cases where trisubstituted
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[a]
Yields are for the isolated products.
olefins were formed, the coupling only afforded the between N-arylacetamide 2a and n-butylamine under
product with E selectivity (compound 4p). However, the reaction conditions described in Buchwaldꢁs
when the steric hindrance was similar for the E and Z work,[16] in this case, no trace of benzimidazole 5 was
1
isomers, a mixture of the two isomers was obtained detected in the crude H NMR. In contrast, the de-
(compound 4r, Z/E=66/34). Interestingly, the cou- sired benzimidazole 5 was obtained with a moderate
pling reaction is also effective even with more chal- yield of 60% by using, N-arylimidate 7a and n-butyl-
lenging sterically hindered hydrazones. Accordingly, amine under our coupling conditions, this proves that
the expected olefins 4n and 4o were obtained in mod- the imidate is a more suitable partner for the forma-
erate yields of 52% and 48%. It is noteworthy that tion of benzimidazole since it tolerates both aromatic
the chloro substituent on the phenyl ring of the hy- and aliphatic amines. To study the selectivity issue, we
drazone was tolerated and compound 4g was obtained realized a coupling using our optimized conditions be-
in 35% yield, this will enable the realization further tween N-tosylhrazone 1a, imidate 7b and 4-chloroani-
metal-catalyzed functionalization processes. Next we line. In this case, the desired product 4ag was isolated
examined the efficiency of this one-pot reaction with with 32% yield.
respect to the nature of the amine. Reactions with
To broaden the substrate scope, we further investi-
para- and ortho-substituted anilines proceeded effi- gated the potential of this one-pot reaction with re-
ciently to form the expected products (4v–4aa) in spect to imidates 7. Fortunately, as depicted in
good yields. This demonstrates that steric factors have Table 2, the entire coupling proceeded cleanly and se-
À
little influence on the rate of C N bond formation. lectively in good to excellent yields.
The electronic nature of the substituents on the ani-
Depending on the used imidate, the molecular di-
lines did not have a significant effect on the reaction. versity can be obtained easily: (i) modification of the
Electron-donating or electron-withdrawing substrates connection position between aryl and benzimidazole
all reacted to give the corresponding products in good ring (compounds 4ah–ai), (ii) changing the methyl
yields (4x–4aa). Then, in the hope of further pushing group (R5) by an ethyl, or phenyl group (compounds
the limits of the scope of the reaction, we examined 4aj–am) and (iii) modification of the nature of the
the formation of arylvinylbenzimidazoles with aliphat- substituent (R4) on the aromatic ring (4an–as). Final-
ic and benzylic amines. Accordingly, under our stan- ly, for the trisubstituted olefin 4p, the E configuration
dard conditions, we found that the coupling proved to was unambiguously confirmed by X-ray diffraction.
be efficient, giving rise to the desired products 4ab–af, The structure of 4a is also presented (Figure 1, for
with good isolated yields. It should be noted that, in other X-ray structures of compounds 4t, 4ak, 4al and
the case of alkylamines derivatives, we realized a com- 4ao, see the Supporting Information).[22]
parative study of the reactivity between N-arylacet-
To evaluate the ability of the novel arylvinylbenz-
amide or N-arylimidate on one side, and n-butylamine imidazoles to inhibit the cellular proliferation of
on the other side. Thus, we performed the reaction tumor cells, synthesized compounds (4) were screened
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Figure 1. X-ray structures of 4p and 4a.
using the CellTiter-96 assay.[23] All arylvinylbenzimi- showed a remarkable nanomolar level of cytotoxicity
dazole 4 were tested at 1 mM concentration, in tripli- against two human cancer cell lines. We believe that
cate (Table 5, in the Supporting Information) against our method can be used to obtain other functional-
human colon carcinoma cell line (HCT116). Results ized benzimidazoles, and will contribute to the discov-
were expressed as a percentage of cell cytotoxicity, ery of new biologically active compounds.
comparing with 0.1% DMSO control. Among the
tested compounds, the best results were obtained with
compounds 4aj, 4an, and 4aq which have percentages
of cell cytotoxicity of 50%, 48%, and 98%, respective-
Experimental Section
ly. Following these encouraging results, a determina-
tion of IC50 was performed on these three molecules
on HCT-116 and human lung adenocarcinoma epithe-
General Procedure for the Synthesis of 1-Aryl-5-(1-
arylvinyl)-1H-benzimidazoles 4 from N-(Dihalo-
phenyl)-imidates 7, N-Tosylhydrazones 1 and N-
Nucleophiles 3
lial (A549) cells. The cytotoxic activity was initially
evaluated using isoCA-4 (IC50 =2 nM),[8b] and phen-
statin (IC50 =33 nM)[24] as reference compounds. Com-
A 6-mL microwave tube containing a stir bar was charged
with N-(dihalophenyl)-imidate (0.5 mmol, 1.0 equiv.), N-to-
pounds 4aj and 4an gave a moderate activity and in-
sylhydrazone (0.6 mmol, 1.2 equiv.), Pd2dba3·CHCl3 (13 mg,
hibited the growth of HCT-116 cell line with an IC50
2.5 mol%), DavePhos (20 mg, 10 mol%) and lithium tert-
butoxide (88 mg, 1.1 mmol, 2.2 equiv.). The tube was capped
and purged with argon three times, then distilled dioxane
was added via syringe. After sealing the tube, it was put into
a pre-heated oil bath at 1008C and stirred for 1.5 h. Then,
value of 2 mM and 3 mM, respectively.
The best result was obtained with compound 4aq
which retained potent growth inhibitory activity at
nanomolar concentrations against both HCT-116 and
A549 cancer cells, with an IC50 value of 30 and 35 nM, the tube was removed from the oil bath, degassed, and N-
nucleophile (0.55 mmol, 1.1 equiv.) and lithium tert-butoxide
(88 mg, 1.1 mmol, 2.2 equiv.) were added in one time. The
tube was sealed again and put in a pre-heated oil bath at
1308C. After stirring for 3 h, the reaction mixture was al-
lowed to cool to room temperature. EtOAc was added to
the mixture, which was filtered through Celiteꢂ. The sol-
vents were evaporated under reduce pressure and the crude
residue was purified by flash chromatography on silica gel.
1-(4-Methoxyphenyl)-2-methyl-5-(1-(p-tolyl)vinyl)-1H-
benzo[d]imidazole (4a): Flash chromatography on silica gel
respectively. Interestingly, compound 4aq presents an
original template for further study because it is still
active without the trimethoxyphenyl ring of our origi-
nal lead, isoCA-4.
Conclusions
In conclusion, we have developed the palladium-cata-
lyzed synthesis of a library of 5-(1-arylvinyl)-1H-benz- (cyclohexane/acetone, 10/0 to 7/3) afforded 4a as a yellow
solid: yield: 128 mg (0.36 mmol, 72%); mp 106–1088C;
TLC: Rf =0.25 (cyclohexane/acetone, 7/3, SiO2); IR (film):
n=1611, 1573, 1477, 1393, 1329, 1296, 1250, 1169, 1108,
imidazole derivatives. This one-pot reaction associates
Barluenga cross-coupling and N-arylation, followed
À
À
by cyclization to create one C C bond and two C N
bonds with the same catalytic species. Through this
work, we demonstrated that imidates constitute an
ideal partner for the cross-coupling with hydrazones
in comparison with acetamides. Our method, based
on simple starting materials, tolerates various func-
tional groups. From this new series of arylvinylbenzi-
1036 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.76 (s, 1H,
;
HAr), 7.30 (dd, J=8.6, 2.1 Hz, 4H, HAr), 7.19–7.02 (m, 6H,
HAr), 5.45 (d, J=2.3 Hz, 2H, =CH2), 3.92 (s, 3H, CH3), 2.50
(s, 3H, CH3), 2.38 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=159.9 (C), 152.6 (C), 150.5 (C), 142.7 (C), 139.2
(C), 137.5 (C), 136.7 (C), 136.6 (C), 128.9 (2CH), 128.4
(2CH), 128.3 (2CH), 123.4 (CH), 119.0 (CH), 115.2 (2CH),
midazoles, we have identified compound 4aq which 113.1 (CH2), 109.4 (CH), 55.7 (CH3), 21.3 (CH3), 14.5
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(CH3); HR-MS (ESI): m/z=355.1814, calculated for
C24H23N2O (M+H)+: 355.1810.
(d, J=9.9 Hz, 2H, HAr), 7.61 (s, 1H, HAr), 7.49 (d, J=
8.2 Hz, 2H, HAr), 7.30 (d, J=9.4 Hz, 2H, HAr), 7.18–7.01 (m,
4H, HAr), 5.59 (d, J=19.7 Hz, 2H, =CH2), 3.92 (s, 3H,
CH3), 2.50 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
160.0 (C), 153.1 (C), 149.3 (C), 147.3 (C), 142.8 (C), 137.0
(C), 135.0 (C), 132.1 (2CH), 129.1 (2CH), 128.5 (C), 128.4
(2CH), 123.1 (CH), 119.1 (C), 118.9 (CH), 116.4 (CH2),
115.3 (2CH), 111.3 (C), 109.8 (CH), 55.8 (CH3), 14.5 (CH3);
HR-MS (ESI): m/z=366.1614, calculated for C24H20N3O
(M+H)+: 366.1606.
1-(4-Methoxyphenyl)-2-methyl-5-(1-phenylvinyl)-1H-ben-
zo[d]imidazole (4b): Flash chromatography on silica gel (cy-
clohexane/acetone, 10/0 to 7/3) afforded 4b as a white solid:
yield: 90 mg (0.26 mmol, 53%); mp 89–918C; TLC: Rf =0.36
(cyclohexane/acetone, 7/3, SiO2). IR (film): n=1612, 1514,
1444, 1393, 1329, 1297, 1251, 1190, 1108, 1036 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.86 (s, 1H, HAr), 7.55–7.36
(m, 7H, HAr), 7.29 (d, J=9.3 Hz, 1H, HAr), 7.20 (d, J=
8.7 Hz, 2H, HAr), 7.15 (d, J=8.4 Hz, 1H, HAr), 5.60 (d, J=
6.1 Hz, 2H, =CH2), 4.03 (s, 3H, CH3), 2.61 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): d=159.9 (C), 152.7 (C), 150.6
(C), 142.68 (C), 142.1 (C), 136.7 (C), 136.4 (C), 128.7 (C),
128.5 (2CH), 128.4 (2CH), 128.2 (2CH), 127.7 (CH), 123.4
(CH), 119.0 (CH), 115.2 (2CH), 113.8 (CH2), 109.4 (CH),
55.7 (CH3), 14.5 (CH3); HR-MS (ESI): m/z=341.1667, cal-
culated for C23H21N2O (M+H)+: 341.1654.
5-[1-(4-Fluorophenyl)vinyl]-1-(4-methoxyphenyl)-2-meth-
yl-1H-benzo[d]imidazole (4f): Flash chromatography on
silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4f as
a white solçid; yield: 108 mg (0.30 mmol, 60%); mp 131–
1328C; TLC: Rf =0.31 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=1602, 1511, 1477, 1429, 1393, 1328, 1295, 1250,
1190, 1158, 1108, 1030 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=7.61 (d, J=1.2 Hz, 1H, HAr), 7.29–7.15 (m, 4H, HAr),
7.05 (dd, J=8.4, 1.6 Hz, 1H, HAr), 7.02–6.85 (m, 5H, HAr),
5.34 (d, J=14.3 Hz, 2H, =CH2), 3.80 (s, 3H, CH3), 2.39 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3): d=162.5 (d, J=
245.0 Hz, C), 159.9 (C), 152.8 (C), 149.6 (C), 142.7 (C),
138.2 (C), 136.7 (C), 136.1 (C), 130.0 (d, J=7.9 Hz, 2CH),
128.6 (C), 128.3 (2CH), 123.2 (CH), 118.8 (CH), 115.2
(2CH), 115.0 (d, J=21.8 Hz, 2CH), 113.6 (CH2), 109.5
(CH), 55.7 (CH3), 14.4 (CH3); 19F NMR (188 MHz, CDCl3):
d=À113.1 (s); HR-MS (ESI): m/z=359.1565, calculated for
C23H20N2OF (M+H)+: 359.1560.
1-(4-Methoxyphenyl)-5-[1-(4-methoxyphenyl)vinyl]-2-
methyl-1H-benzo[d]imidazole (4c): Flash chromatography
on silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4c
as a white solid; yield: 115 mg (0.31 mmol, 62%); mp 99–
1018C; TLC: Rf =0.31 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2961, 2836, 1607, 1512, 1462, 1393, 1298, 1248,
1
1171, 1109, 1034 cmÀ1; H NMR (300 MHz, CDCl3): d=7.87
(s, 1H, HAr), 7.43 (t, J=8.8 Hz, 4H, HAr), 7.30 (d, J=8.4 Hz,
1H, HAr), 7.20 (d, J=8.8 Hz, 2H, HAr), 7.15 (d, J=8.4 Hz,
1H, HAr), 6.99 (d, J=8.7 Hz, 2H, HAr), 5.52 (d, J=5.9 Hz,
2H, =CH2), 4.03 (s, 3H, CH3), 3.95 (s, 3H, CH3), 2.62 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.9 (C), 159.4
(C), 152.63 (C), 150.1 (C), 142.6 (C), 136.7 (C), 134.6 (C),
132.7 (CH), 129.6 (2CH), 128.7 (C), 128.4 (2CH), 123.5
(CH), 118.9 (CH), 115.2 (2CH), 113.6 (2CH), 112.4 (CH2),
109.4 (CH), 55.7 (CH3), 55.4 (CH3), 14.5 (CH3); HR-MS
(ESI): m/z=371.1771, calculated for C24H23N2O2 (M+H)+:
371.1760.
5-[1-(4-Chlorophenyl)vinyl]-1-(4-methoxyphenyl)-2-meth-
yl-1H-benzo[d]imidazole (4g): Flash chromatography on
silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4g as
a yellow oil; yield: 65 mg (0.175 mmol, 35%); TLC: Rf =
0.64 (cyclohexane/acetone, 7/3, SiO2); IR (film): n=2960,
1612, 1558, 1514, 1490, 1430, 1394, 1328, 1296, 1251, 1168,
1090, 1036 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.72 (s,
;
1H), 7.33–7.27 (m, 6H), 7.14 (dd, J=8.4, 1.3 Hz, 1H), 7.10
(d, J=8.9 Hz, 2H), 7.04 (d, J=8.5 Hz, 1H), 5.48 (d, J=
9.5 Hz, 2H), 3.93 (s, 3H), 2.51 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=160.0 (C), 149.5 (C), 140.6 (C), 136.1 (C), 133.6
(C), 130.1 (C), 129.7 (2CH), 128.6 (C), 128.4 (4CH), 123.4
(CH), 118.8 (CH), 115.3 (2CH), 114.3 (CH2), 109.7 (CH),
55.8 (CH3), 14.4 (CH3); HR-MS (ESI): m/z=375.1265, cal-
culated for C23H20ClN2O (M + H)+: 375.1264.
5-{1-([1,1’-Biphenyl]-4-yl)vinyl}-1-(4-methoxyphenyl)-2-
methyl-1H-benzo[d]imidazole (4d): Flash chromatography
on silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4d
as a white solid; yield: 83 mg (0.20 mmol, 40%); mp 181–
1838C; TLC: Rf =0.32 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=1611, 1513, 1486, 1428, 1394, 1330, 1298, 1251,
1
1169, 1108, 1036 cmÀ1; H NMR (300 MHz, CDCl3): d=7.69
(s, 1H, HAr), 7.53 (d, J=7.5 Hz, 2H, HAr), 7.47 (d, J=
8.1 Hz, 2H, HAr), 7.40–7.32 (m, 4H, HAr), 7.26 (d, J=7.5 Hz,
1H, HAr), 7.20 (d, J=8.8 Hz, 2H, HAr), 7.12 (dd, J=8.3,
1.3 Hz, 1H, HAr), 7.00 (s, 1H, HAr), 6.96 (d, J=9.1 Hz, 2H,
HAr), 5.43 (d, J=8.3 Hz, 2H, =CH2), 3.81 (s, 3H, CH3), 2.40
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.9 (C),
152.71 (C), 150.2 (2C), 142.7 (C), 141.1 (C), 141.0 (C), 140.6
(C), 136.73 (C), 136.3 (C), 128.9 (2CH), 128.8 (2CH), 128.4
(2CH), 127.4 (CH), 127.2 (2CH), 126.9 (2CH), 123.4 (CH),
119.0 (CH), 115.2 (2CH), 113.8 (CH2), 109.5 (CH), 55.7
(CH3), 14.5 (CH3); HR-MS (ESI): m/z=417.1970, calculated
for C29H25N2O (M+H)+: 417.1967.
1-(4-Methoxyphenyl)-2-methyl-5-[1-(3,4,5-trimethoxyphe-
nyl)vinyl]-1H-benzo[d]imidazole (4h): Flash chromatogra-
phy on silica gel (cyclohexane/acetone, 10/0 to 5/5) afforded
4h as a yellow solid; yield: 170 mg (0.395 mmol, 79%); mp
143–1458C; TLC: Rf =0.16 (cyclohexane/acetone, 7/3, SiO2);
IR (film): n=3000, 2936, 2836, 1613, 1513, 1463, 1393, 1344,
1296, 1236, 1188, 1125, 1036 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d=7.89 (s, 1H, HAr), 7.43 (d, J=8.8 Hz, 2H, HAr),
7.33 (d, J=8.4 Hz, 1H, HAr), 7.22 (d, J=8.9 Hz, 2H, HAr),
7.16 (d, J=8.4 Hz, 1H, HAr), 6.74 (s, 2H, HAr), 5.57 (d, J=
12.2 Hz, 2H, =CH2), 4.04 (s, 3H, CH3), 4.01 (s, 3H, CH3),
3.94 (s, 6H, 2 CH3), 2.63 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=159.9 (C), 152.9 (C), 152.9 (C), 150.6 (C), 142.5
(C), 137.9 (C), 137.6 (C), 137.0 (C), 136.3 (C), 128.6 (C),
128.4 (2CH), 124.9 (CH), 123.5 (CH), 118.4 (CH), 115.3
(2CH), 113.6 (CH2), 109.7 (CH), 105.8 (2CH), 61.0 (CH3),
56.2 (2CH3), 55.7 (CH3), 14.5 (CH3); HR-MS (ESI): m/z=
431.1960, calculated for C26H27N2O4 (M+H)+: 431.1971.
4-{1-[1-(4-Methoxyphenyl)-2-methyl-1H-benzo[d]imida-
zol-5-yl]vinyl}benzonitrile (4e): Flash chromatography on
silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4e as
a yellow solid; yield: 102 mg (0.28 mmol, 56%); mp:116–
1178C; TLC: Rf =0.28 (cyclohexane/acetone, 7/3, SiO2). IR
(film): n=2227, 1606, 1514, 1430, 1393, 1329, 1398, 1251,
1
1170, 1108, 1036 cmÀ1; H NMR (300 MHz, CDCl3): d=7.65
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FULL PAPERS
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5-[1-(3,5-Dimethoxyphenyl)vinyl]-1-(4-methoxyphenyl)-2-
methyl-1H-benzo[d]imidazole (4i): Flash chromatography
on silica gel (cyclohexane/acetone, 10/0 to 5/5) afforded 4i
as a yellow solid; yield: 131 mg (0.33 mmol, 66%); mp 134–
1368C; TLC: Rf =0.2 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=3001, 2933, 2836, 1589, 1513, 1455, 1424, 1395,
1H NMR (300 MHz, CDCl3): d=7.64 (s, 1H, HAr), 7.20 (d,
J=8.9 Hz, 2H, HAr), 7.08 (dd, J=8.4, 1.4 Hz, 1H, HAr), 6.99
(d, J=8.9 Hz, 2H, HAr), 6.93 (d, J=8.4 Hz, 1H, HAr), 6.82
(d, J=1.9 Hz, 1H, HAr), 6.78 (dd, J=8.3, 2.0 Hz, 1H, HAr),
6.72 (d, J=8.3 Hz, 1H, HAr), 5.30 (d, J=8.4 Hz, 2H, =CH2),
4.17 (s, 4H, 2 CH2), 3.82 (s, 3H, CH3), 2.40 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): d=159.9 (C), 152.60 (C), 149.9
(C), 143.41 (C), 143.2 (C), 142.6 (C), 136.7 (C), 136.5 (C),
135.7 (C), 128.8 (C), 128.4 (2CH), 123.5 (CH), 121.7 (CH),
119.0 (CH), 117.3 (CH), 116.9 (CH), 115.2 (2 CH), 112.7
(CH2), 109.4 (CH), 64.6 (CH2), 64.5 (CH2), 55.7 (CH3), 14.4
(CH3); HR-MS (ESI): m/z=399.1705, calculated for
C25H23N2O3 (M+H)+: 399.1709.
1350, 1297, 1250, 1205, 1155, 1108, 1064 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=7.66 (s, 1H, HAr), 7.20 (d, J=8.8 Hz,
2H, HAr), 7.08 (dd, J=8.4, 0.7 Hz, 1H, HAr), 6.99 (d, J=
8.8 Hz, 2H, HAr), 6.93 (d, J=8.4 Hz, 1H, HAr), 6.45 (d, J=
2.2 Hz, 2H, HAr), 6.35 (t, J=2.1 Hz, 1H, HAr), 5.38 (d, J=
4.9 Hz, 2H, =CH2), 3.82 (s, 3H, CH3), 3.67 (s, 6H, 2CH3),
2.40 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=160.6 (2
C), 159.9 (C), 152.6 (C), 150.6 (C), 144.3 (C), 142.6 (C),
136.7 (C), 136.1 (C), 128.7 (C), 128.4 (2CH), 123.4 (CH),
118.9 (CH), 115.2 (2CH), 113.9 (CH2), 109.4 (CH), 106.8
(2CH), 100.0 (CH), 55.7 (CH3), 55.5 (2CH3), 14.45 (CH3);
HR-MS (ESI): m/z=401.1856, calculated for C25H25N2O3
(M+H)+: 401.1865.
5-[1-(3-Fluoro-4-methoxyphenyl)vinyl]-1-(4-methoxy-
phenyl)-2-methyl-1H-benzo[d]imidazole (4m): Flash chro-
matography on silica gel (cyclohexane/acetone, 10/0 to 6/4)
afforded 4m as a white solid; yield: 118 mg (0.305 mmol,
61%); mp 114–1158C; TLC: Rf =0.19 (cyclohexane/acetone,
7/3, SiO2); IR (film): n=1613, 1576, 1514, 1429, 1394, 1321,
1
5-[1-(3,4-Dimethoxyphenyl)vinyl]-1-(4-methoxyphenyl)-2-
methyl-1H-benzo[d]imidazole (4j): Flash chromatography
on silica gel (cyclohexane/acetone, 10/0 to 5/5) afforded 4j
as a white solid; yield: 90 mg (0.225 mmol, 45%); mp 118–
1198C; TLC: Rf =0.13 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2963, 1613, 1513, 1463, 1399, 1321, 1299, 1253,
1300, 1251, 1181, 1138, 1101, 1021 cmÀ1; H NMR (300 MHz,
CDCl3): d=7.63 (s, 1H, HAr), 7.21 (d, J=8.9 Hz, 2H, HAr),
7.07 (d, J=8.3 Hz, 1H, HAr), 7.00 (m, 4H, HAr), 6.95 (d, J=
8.4 Hz, 1H, HAr), 6.82 (t, J=8.7 Hz, 1H, HAr), 5.33 (d, J=
2.2 Hz, 2H, =CH2), 3.82 (s, 6H, 2 CH3), 2.41 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): d=159.9 (C), 152.8 (C), 152.1
(d, J=243.0 Hz, C), 149.2 (C), 147.3 (d, J=10.8 Hz, C),
142.4 (C), 136.7 (C), 136.1 (C), 135.3 (d, J=6.1 Hz, C), 128.6
(s, C), 128.4 (s, 2CH), 124.2 (d, J=2.8 Hz, CH), 123.4 (CH),
118.9 (CH), 116.1 (d, J=18.8 Hz, CH), 115.2 (2CH), 113.4
(CH2), 113.0 (CH), 109.6 (CH), 56.4 (CH3), 55.7 (CH3), 14.4
(CH3); 19F NMR (188 MHz, CDCl3): d= À133.99 (s); HR-
MS (ESI): m/z=389.1668, calculated for C24H22N2O2F (M+
H)+: 389.1665.
1173, 1142, 1111, 1024 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=7.68 (s, 1H, HAr), 7.23 (s, 1H, HAr), 7.20 (d, J=3.8 Hz,
2H, HAr), 7.09 (dd, J=8.2, 1.1 Hz, 1H, HAr), 7.00 (d, J=
8.8 Hz, 2H, HAr), 6.94 (d, J=8.4 Hz, 1H, HAr), 6.85 (s, 1H,
HAr), 6.75 (d, J=7.9 Hz, 1H, HAr), 5.33 (s, 2H, =CH2), 3.83
(s, 3H, CH3), 3.82 (s, 3H, CH3), 3.75 (s, 3H, CH3), 2.41 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.9 (C), 152.7
(C), 150.4 (C), 148.9 (C), 148.7 (C), 142.7 (C), 136.7 (C),
136.5 (C), 135.1 (C), 128.8 (C), 128.4 (2CH), 123.5 (CH),
121.1 (CH), 119.0 (CH), 115.2 (2CH), 112.6 (CH2), 111.7
(CH), 110.9 (CH), 109.4 (CH), 56.1 (CH3), 56.0 (CH3), 55.8
(CH3), 14.5 (CH3); HR-MS (ESI): m/z=401.1876, calculated
for C25H25N2O3 (M+H)+: 401.1865.
1-(4-Methoxyphenyl)-2-methyl-5-(2-methyl-1-phenylprop-
1-en-1-yl)-1H-benzo[d]imidazole (4n): Flash chromatogra-
phy on silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded
4n as a yellow solid; yyield: 96 mg (0.26 mmol, 52%); mp
98–1008C; TLC: Rf =0.38 (cyclohexane/acetone, 7/3, SiO2);
IR (film): n=2964, 2844, 1613, 1512, 1475, 1142, 1393, 1323,
1-(4-Methoxyphenyl)-5-[1-(2-methoxyphenyl)vinyl]-2-
methyl-1H-benzo[d]imidazole (4k): Flash chromatography
on silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4k
as a yellow soldi; yield: 97 mg (0.26 mmol, 52%); mp 110–
1128C; TLC: Rf =0.28 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2960, 1669, 1515, 1470, 1374, 1295, 1258, 1235,
1295, 1248, 1169, 1107, 1035 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d=7.57 (s, 1H, HAr), 7.28–7.24 (m, 4H, HAr), 7.21–
7.12 (m, 3H, HAr), 7.06 (d, J=8.8 Hz, 2H, HAr), 6.97 (d, J=
8.3 Hz, 1H, HAr), 6.92 (d, J=8.3 Hz, 1H, HAr), 3.89 (s, 3H,
CH3), 2.47 (s, 3H, CH3), 1.85 (s, 6H, 2 CH3); 13C NMR
(75 MHz, CDCl3): d=159.8 (C), 152.2 (C), 143.9 (C), 142.4
(C), 138.0 (C), 137.5 (C), 135.4 (C), 130.8 (C), 130.0 (2CH),
129.0 (C), 128.4 (2CH), 127.9 (2CH), 126.0 (CH), 124.8
(CH), 120.2 (CH), 115.1 (2CH), 109.4 (CH), 55.7 (CH3),
22.7 (sCH3), 14.4 (CH3); HR-MS (ESI): m/z=369.1981, cal-
culated for C25H25N2O (M+H)+: 369.1967.
1082 1024 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.72 (s,
;
1H, HAr), 7.26–7.14 (m, 7H, HAr), 7.10 (d, J=8.4 Hz, 1H,
HAr), 6.99 (d, J=8.9 Hz, 2H, HAr), 6.95 (d, J=8.5 Hz, 1H,
HAr), 6.44 (s, 1H, HAr), 3.83 (s, 3H, CH3), 3.69 (s, 3H, CH3),
2.41 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.9
(C), 152.2 (C), 145.9 (CH2), 142.2 (C), 141.0 (C), 135.7 (C),
132.2 (C), 128.8 (C), 128.4 (2CH), 128.3 (2CH), 128.1
(2CH), 126.4 (CH), 125.0 (CH), 121.2 (C), 120.6 (CH),
115.2 (2CH), 109.5 (CH), 60.6 (CH3), 55.7 (CH3), 14.4
(CH3); HR-MS (ESI): m/z=371.1763, calculated for
C24H23N2O2 (M+H)+: 371.1760.
1-(4-Methoxyphenyl)-2-methyl-5-[2-methyl-1-(3,4,5-trime-
thoxyphenyl)prop-1-en-1-yl]-1H-benzo[d]imidazole
(4o):
Flash chromatography on silica gel (cyclohexane/acetone,
10/0 to 5/5) afforded 4o as a yellow solid; yield: 110 mg
(0.24 mmol, 48%); mp 151–1538C; TLC: Rf =0.15 (cyclo-
hexane/acetone, 7/3, SiO2); IR (film): n=2924, 1595, 1494,
5-[1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)vinyl]-1-(4-me-
thoxyphenyl)-2-methyl-1H-benzo[d]imidazole (4l): Flash
chromatography on silica gel (cyclohexane/acetone, 10/0 to
5/5) afforded 4l as a white solid; yield: 107 mg (0.27 mmol,
54%); mp 141–1438C; TLC: Rf =0.18 (cyclohexane/acetone,
7/3, SiO2); IR (film): n=2933, 2842, 1611, 1578, 1514, 1460,
1464, 1321, 1299, 1260, 1213, 1153, 1107, 1023 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.57 (s, 1H, HAr), 7.28 (d,
J=8.7 Hz, 2H, HAr), 7.06 (d, J=8.7 Hz, 2H, HAr), 6.99 (d,
J=8.3 Hz, 1H, HAr), 6.95 (d, J=8.4 Hz, 1H, HAr), 6.40 (s,
2H, HAr), 3.90 (s, 3H, CH3), 3.83 (s, 3H, CH3), 3.79 (s, 6H,
2 CH3), 2.48 (s, 3H, CH3), 1.85 (s, 3H, CH3), 1.83 (s, 3H,
1426, 1395, 1322, 1284, 1250, 1169, 1124, 1066 cmÀ1
;
Adv. Synth. Catal. 2016, 358, 1833 – 1847
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FULL PAPERS
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CH3); 13C NMR (75 MHz, CDCl3): d=159.9 (C), 152.8
(2C), 152.2 (C), 141.8 (C), 139.6 (C), 137.8 (C), 137.5 (C),
136.3 (C), 135.3 (C), 130.9 (C), 128.6 (C), 128.4 (2CH),
124.8 (CH), 119.7 (CH), 115.2 (2CH), 109.5 (CH), 107.0 (2
CH), 61.0 (CH3), 56.2 (2CH3), 55.7 (CH3), 22.8 (CH3), 22.6
(CH3), 14.4 (CH3); HR-MS (ESI): m/z=459.2290, calculated
for C28H31N2O4 (M+H)+: 459.2284.
(C), 130.7 (2CH), 128.7 (2CH), 128.3 (2CH, 2C), 125.9
(CH), 125.3 (CH), 120.8 (CH), 115.1 (2CH), 113.5 (2CH),
113.5 (2CH), 109.3 (CH), 55.6 (CH3), 55.3 (CH3), 55.1
1
(CH3), 14.4 (CH3); H NMR [minor compound (E isomer);
400 MHz, CDCl3]: d=7.71 (s, 1H, HAr), 7.33 (d, J=8.8 Hz,
2H, HAr), 7.17 (d, J=8.6 Hz, 3H, HAr), 7.09–7.07 (m, 2H,
HAr), 7.05–7.04 (m, 3H, HAr), 6.89–6.86 (m, 3H, CH, 2 HAr),
6.70 (d, J=8.8 Hz, 2H, HAr), 3.83 (s, 3H, CH3), 3.83 (s, 3H,
CH3), 3.75 (s, 3H, CH3), 2.48 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d=159.8 (C), 158.8 (C), 158.1 (C), 152.5
(C), 143.0 (C), 141.0 (C), 139.1 (C), 136.4 (C), 133.4 (C),
131.7 (2CH), 130.7 (2CH), 130.6 (C), 128.2 (2CH, C), 126.6
(CH), 122.7 (CH), 118.2 (CH), 115.1 (2CH), 114.1 (2CH),
113.5 (2CH), 110.1 (CH), 55.6 (CH3), 55.3 (CH3), 55.2
(CH3), 14.4 (CH3); HR-MS (ESI, mixture): m/z=477.2174,
calculated for C31H29N2O3 (M+H)+: 477.2178.
(E)-1-(4-Methoxyphenyl)-2-methyl-5-{1-[3-(trifluorome-
thyl)phenyl]prop-1-en-2-yl}-1H-benzo[d]imidazole
(4p):
Flash chromatography on silica gel (cyclohexane/acetone,
10/0 to 7/3) afforded 4p as a white solid; yield: 133 mg
(0.315 mmol, 63%); mp 122–1248C; TLC: Rf =0.25 (cyclo-
hexane/acetone, 7/3, SiO2); IR (film): n=1613, 1587, 1513,
1479, 1443, 1395, 1331, 1295, 1248, 1206, 1180, 1161, 1120,
1094, 1031 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.79 (s,
;
1H, HAr), 7.54 (s, 1H, HAr), 7.46 (d, J=3.8 Hz, 1H, HAr),
7.40 (d, J=4.7 Hz, 2H, HAr), 7.31 (dd, J=8.5, 1.5 Hz, 1H,
HAr), 7.20 (d, J=8.8 Hz, 2H, HAr), 7.01–6.98 (m, 3H, HAr),
6.77 (s, 1H, HAr), 3.82 (s, 3H, CH3), 2.41 (s, 3H, CH3), 2.26
(s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.9 (C),
152.79 (C), 142.8 (C), 139.9 (C), 139.4 (C), 138.4 (C), 136.5
(C), 132.5 (CH), 130.6 (q, J=31.8 Hz, CF3), 128.7 (CH),
128.3 (2CH), 126.2 (C), 125.9 (d, J=3.5 Hz, CH), 125.7
(CH), 123.0 (d, J=3.5 Hz, CH), 122.6 (C), 121.1 (CH), 116.6
(CH), 115.2 (2CH), 109.7 (CH), 55.7 (CH3), 18.2 (CH3), 14.5
(CH3); 19F NMR (188 MHz, CDCl3): d=À60.73 (s); HR-MS
(ESI): m/z=423.1681, calculated for C25H22N2OF3 (M+H)+:
423.1684.
5-(Cyclohex-1-en-1-yl)-1-(4-methoxyphenyl)-2-methyl-1H-
benzo[d]imidazole (4s): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 6/4) afforded 4s as a white
solid; yield: 68 mg (0.215 mmol, 43%); mp 112–1148C;
TLC: Rf =0.24 (cyclohexane/acetone, 7/3, SiO2); IR (film):
n=2930, 2834, 1513, 1478, 1430, 1395, 1321, 1298, 1211,
1
1171, 1108, 1037 cmÀ1; H NMR (300 MHz, CDCl3): d=7.64
(s, 1H, HAr), 7.21 (s, 1H, HAr), 7.19 (d, J=2.5 Hz, 2H, HAr),
6.99 (d, J=8.8 Hz, 2H, HAr), 6.93 (d, J=8.5 Hz, 1H, HAr),
6.09–5.93 (m, 1H, =CH-), 3.83 (s, 3H, CH3), 2.40 (s, 3H,
CH3), 2.15 (m, 2H, CH2), 1.79–1.70 (m, 2H, CH2), 1.68–1.57
(m, 4H, 2CH2); 13C NMR (75 MHz, CDCl3): d=159.8 (C),
152.2 (C), 142.7 (C), 137.9 (C), 137.1 (C), 135.8 (C), 128.8
(C), 128.3 (2 CH), 124.1 (CH), 120.3 (CH), 115.3 (CH),
115.1 (2CH), 109.4 (CH), 55.7 (CH3), 28.1 (CH2), 26.1
(CH2), 23.3 (CH2), 22.4 (CH2), 14.4 (CH3); HR-MS (ESI):
m/z=319.1801, calculated for C21H23N2O (M+H)+:
319.1810.
5-(2H-Chromen-4-yl)-1-(4-methoxyphenyl)-2-methyl-1H-
benzo[d]imidazole (4q): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 7/3) afforded 4q as a white
solid; yield: 131 mg (0.355 mmol, 71%); mp 178–1808C;
TLC: Rf =0.38 (cyclohexane/acetone, 7/3, SiO2); IR (film):
n=1720, 1603, 1512, 1477, 1446, 1394, 1318, 1297, 1246,
1222, 1186, 1107, 1065 cmÀ1
;
1H NMR (300 MHz, CDCl3):
5-[1-(4-Methoxyphenyl)vinyl]-2-methyl-1-phenyl-1H-ben-
zo[d]imidazole (4t): Flash chromatography on silica gel (cy-
clohexane/acetone, 10/0 to 7/3) afforded 4t as a yellow solid;
yield: 145 mg (0.425 mmol, 85%); mp 110–1128C; TLC:
Rf =0.34 (cyclohexane/acetone, 7/3, SiO2); IR (film): n=
2836, 1598, 1499, 1458, 1399, 1330, 1304, 1283, 1246, 1176,
d=7.62 (s, 1H, HAr), 7.19 (d, J=8.9 Hz, 2H, HAr), 7.09–7.02
(m, 2H, HAr), 7.02–6.93 (m, 4H, HAr), 6.79 (d, J=8.0 Hz,
1H, HAr), 6.71 (t, J=7.5 Hz, 1H, HAr), 5.72 (t, J=3.9 Hz,
1H, HAr), 4.76 (d, J=3.9 Hz, 2H, HAr), 3.79 (s, 3H, CH3),
2.39 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.9
(C), 154.8 (C), 152.7 (C), 142.7 (C), 137.5 (C), 136.6 (C),
132.7 (C), 129.2 (CH), 128.6 (C), 128.3 (2CH), 126.1 (CH),
124.2 (C), 123.5 (CH), 121.2 (CH), 119.8 (CH), 119.0 (CH),
116.2 (CH), 115.2 (2CH), 109.7 (CH), 65.4 (CH2), 55.7
(CH3), 14.4 (CH3); HR-MS (ESI): m/z=369.1599, calculated
for C24H21N2O2 (M+H)+: 369.1603.
1
1111, 1074, 1032 cmÀ1; H NMR (300 MHz, CDCl3): d=7.66
(s, 1H, HAr), 7.45 (m, 3H, HAr), 7.28 (d, J=7.4 Hz, 2H,
HAr), 7.22 (d, J=8.7 Hz, 2H, HAr), 7.08 (dd, J=8.4, 1.4 Hz,
1H, HAr), 6.96 (d, J=8.4 Hz, 1H, HAr), 6.76 (d, J=8.7 Hz,
2H, HAr), 5.30 (d, J=5.7 Hz, 2H, =CH2), 3.72 (s, 3H, CH3),
2.42 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.4
(C), 152.2 (C), 150.0 (C), 142.5 (C), 136.8 (C), 136.3 (C),
136.2 (C), 134.6 (C), 130.0 (2CH), 129.5 (2CH), 128.9 (CH),
127.1 (2CH), 123.5 (CH), 119.0 (CH), 113.6 (2CH), 112.4
(CH2), 109.4 (CH), 55.4 (CH3), 14.5 (CH3); HR-MS (ESI):
m/z=341.1649, calculated for C23H21N2O (M+H)+:
341.1654.
(Z/E)-1-(4-Methoxyphenyl)-5-[2-(3-methoxyphenyl)-1-(4-
methoxyphenyl)vinyl]-2-methyl-1H-benzo[d]imidazole (4r).
Flash chromatography on silica gel (cyclohexane/acetone,
10/0 to 7/3) afforded 4r as a mixture of two diastereoisomers
(Z:E, 66:34); white solid; yield: 204 mg (0.43 mmol, 86%);
mp 198–2008C; TLC: Rf =0.29/0.25 (cyclohexane/acetone, 7/
3, SiO2); IR (film, mixture): n=1605, 1511, 1462, 1394, 1320,
2-Methyl-1-phenyl-5-[1-(p-tolyl)vinyl]-1H-benzo[d]imida-
zole (4u): Flash chromatography on silica gel (cyclohexane/
acetone, 10/0 to 7/3) afforded 4u as a yellow solid; yield:
127 mg (0.39 mmol, 78%); mp 131–1338C; TLC: Rf =0.48
(cyclohexane/acetone, 7/3, SiO2); IR (film): n=1598, 1524,
1299, 1246, 1175, 1108, 1033 cmÀ1 1H NMR [major com-
;
pound (Z isomer); 400 MHz, CDCl3]: d=7.60 (s, 1H, HAr),
7.33 (d, J=8.8 Hz, 2H, HAr), 7.27 (d, J=8.0 Hz, 2H, HAr),
7.09–7.07 (m, 2H, HAr), 7.05–7.04 (m, 1H, HAr), 7.02–6.98
(m, 3H, HAr), 6.88 (s, 1H, CH), 6.82 (d, J=8.8 Hz, 2H,
HAr), 6.63 (d, J=8.8 Hz, 2H, HAr), 3.89 (s, 3H, CH3), 3.79 (s,
3H, CH3), 3.71 (s, 3H, CH3), 2.50 (s, 3H, CH3); 13C NMR
(100 MHz, CDCl3): d=159.8 (C), 158.99 (C), 158.1 (C),
152.3 (C), 142.7 (C), 140.6 (C), 136.9 (C), 136.2 (C), 135.0
1500, 1476, 1388, 1369, 1329, 1305, 1234, 1188, 1074 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=(ppm) 7.66 (s, 1H, HAr),
7.43 (m, 3H, HAr), 7.26 (d, J=7.6 Hz, 2H, HAr), 7.17 (d, J=
8.0 Hz, 2H, HAr), 7.06 (d, J=9.0 Hz, 1H, HAr), 7.02 (d, J=
8.0 Hz, 2H, HAr), 6.94 (d, J=8.4 Hz, 1H, HAr), 5.33 (d, J=
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2.4 Hz, 2H, CH2), 2.40 (s, 3H, CH3), 2.25 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): d=152.1 (C), 150.3 (C), 142.7
(C), 139.1 (C), 137.4 (C), 136.6 (C), 136.2 (C), 136.1 (C),
130.0 (2CH), 128.8 (3CH), 128.2 (2CH), 127.0 (2CH), 123.5
(CH), 118.9 (CH), 113.1 (CH2), 109.4 (CH), 21.2 (CH3), 14.5
(CH3); HR-MS (ESI): m/z=325.1709, calculated for
C23H21N2(M+H)+: 325.1705.
clohexane/µcetone, 10/0 to 7/3) afforded 4y as a white solid;
yield: 139 mg (0.405 mmol, 81%); mp 114–1168C; TLC:
Rf =0.0.49 (cyclohexane/acetone, 7/3, SiO2); IR (film): n=
1606, 1510, 1477, 1427, 1392, 1328, 1312, 1225, 1187, 1155,
1095 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.78 (s, 1H,
;
HAr), 7.38 (dd, J=8.7, 4.9 Hz, 2H, HAr), 7.31 (d, J=4.0 Hz,
2H, HAr), 7.28 (d, J=3.4 Hz, 2H, HAr), 7.20 (dd, J=8.4,
1.4 Hz, 1H, HAr), 7.15 (d, J=7.9 Hz, 2H, HAr), 7.03 (d, J=
8.4 Hz, 1H, HAr), 5.46 (d, J=4.6 Hz, 2H, =CH2), 2.51 (s,
3H, CH3), 2.38 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3):
d=162.5 (d, J=248.3 Hz, C), 152.2 (C), 150.3 (C), 142.6 (C),
139.1 (C), 137.5 (C), 136.8 (C), 136.3 (C), 132.1 (d, J=
2.9 Hz, C), 129.0 (d, J=9.0 Hz, 2CH), 128.8 (2CH), 128.3
(2CH), 123.7 (CH), 119.0 (CH), 117.1 (d, J=22.9 Hz, 2CH),
113.2 (CH2), 109.16 (CH), 21.2 (CH3), 14.4 (CH3); 19F NMR
(188 MHz, CDCl3): d=À109.78 (s); HR-MS (ESI): m/z=
343.1613, calculated for C23H20N2F (M+H)+: 343.1611.
5-[1-(4-Methoxyphenyl)vinyl]-2-methyl-1-(p-tolyl)-1H-
benzo[d]imidazole (4z): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 7/3) afforded 4z as a brown
solid; yield: 138 mg (0.39 mmol, 78%); mp 125–1278C;
TLC: Rf =0.47 (cyclohexane/acetone, 7/3, SiO2); IR (film):
n=1606, 1511, 1477, 1428, 1391, 1329, 1302, 1284, 1246,
1-(2-Methoxyphenyl)-5-[1-(4-methoxyphenyl)vinyl]-2-
methyl-1H-benzo[d]imidazole (4v): Flash chromatography
on silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4v
as a yellow solid; yield: 150 mg (0.405 mmol, 81%); mp 83–
858C; TLC: Rf =0.33 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2836, 1648, 1601, 1508, 1464, 1429, 1391, 1330,
1281, 1247, 1178, 1117, 1027 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d=7.64 (s, 1H, HAr), 7.38 (td, J=8.0, 1.3 Hz, 1H),
7.20 (m, 3H, HAr), 7.02 (m, 3H, HAr), 6.82 (d, J=8.3 Hz,
1H, HAr), 6.74 (d, J=8.7 Hz, 2H, HAr), 5.27 (d, J=3.2 Hz,
2H, =CH2), 3.69 (s, 3H, CH3), 3.63 (s, 3H, CH3), 2.31 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.3 (s), 155.2
(s), 153.3 (s), 150.0 (s), 142.6 (s), 136.3 (s), 134.6 (s), 130.7
(s), 129.5 (s), 129.1 (s), 124.3 (s), 123.2 (s), 121.1 (s), 118.7
(s), 113.5 (s), 112.5 (s), 112.2 (s), 109.3 (s), 55.6 (s), 55.3 (s),
14.0 (s); HR-MS (ESI): m/z=371.1754, calculated for
C24H23N2O2 (M+H)+: 371.1760.
1
1176, 1110, 1032 cmÀ1; H NMR (300 MHz, CDCl3): d=7.63
1-(2-Methoxyphenyl)-2-methyl-5-[1-(p-tolyl)vinyl]-1H-
benzo[d]imidazole (4w): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 7/3) afforded 4w as a brown
solid; yield: 152 mg (0.43 mmol, 86%); mp 92–948C; TLC:
Rf =0.40 (cyclohexane/acetone, 7/3, SiO2); IR (film): n=
2922, 1599, 1527, 1506, 1427, 1389, 1329, 1298, 1263, 1246,
(s, 1H, HAr), 7.20 (t, J=8.9 Hz, 4H, HAr), 7.09 (d, J=8.2 Hz,
2H, HAr), 7.03 (d, J=8.4 Hz, 1H, HAr), 6.91 (d, J=8.4 Hz,
1H, HAr), 6.71 (d, J=8.7 Hz, 2H, HAr), 5.25 (d, J=4.7 Hz,
2H, =CH2), 3.65 (s, 3H, CH3), 2.36 (s, 3H, CH3), 2.32 (s,
3H, CH3); 13C NMR (75 MHz, CDCl3): d=159.3 (C), 152.2
(C), 149.9 (C), 142.6 (C), 138.9 (C), 136.5 (C), 136.3 (C),
134.5 (C), 133.3 (C), 130.5 (2CH), 129.4 (2CH), 126.7
(2CH), 123.3 (CH), 118.8 (CH), 113.4 (2CH), 112.2 (C),
109.3 (CH), 55.2 (CH3), 21.2 (CH3), 14.3 (CH3); HR-MS
(ESI): m/z=355.1810, calculated for C24H23N2O (M+H)+:
355.1810.
1182, 1117, 1048, 1024 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=7.79 (s, 1H, HAr), 7.61–7.42 (m, 1H, HAr), 7.39–7.25 (m,
3H, HAr), 7.18–7.12 (m, 5H, HAr), 6.95 (d, J=8.3 Hz, 1H,
HAr), 5.46 (s, 2H, =CH2), 3.77 (s, 3H, CH3), 2.45 (s, 3H,
CH3), 2.38 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
155.2 (C), 153.3 (C), 150.5 (C), 142.8 (C), 139.2 (C), 137.3
(C), 136.4 (C), 136.2 (C), 130.7 (CH), 129.1 (CH), 128.8
(2CH), 128.3 (2 CH), 124.4 (C), 123.2 (CH), 121.2 (CH),
118.7 (CH), 112.9 (CH2), 112.5 (CH), 109.3 (CH), 55.7
(CH3), 21.2 (CH3), 14.0 (CH3); HR-MS (ESI): m/z=
355.1819, calculated for C24H23N2O (M+H)+: 355.1810.
1-(4-Fluorophenyl)-5-[1-(4-methoxyphenyl)vinyl]-2-
2-Methyl-1-(p-tolyl)-5-[1-(p-tolyl)vinyl]-1H-benzo[d]imi-
dazole (4aa): Flash chromatography on silica gel (cyclohex-
ane/acetone, 10/0 to 7/3) afforded 4aa as a white solid;
yield: 127 mg (0.375 mmol, 75%); mp 143–1458C; TLC:
Rf =0.52 (cyclohexane/acetone, 7/3, SiO2); IR (film): n=
1608, 1513, 1477, 1429, 1391, 1328, 1300, 1235, 1213, 1190,
1111, 1039 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.78 (s,
;
methyl-1H-benzo[d]imidazole (4x): Flash chromatography
on silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4x
as a brown solid; yield: 138 mg (0.385 mmol, 77%); mp 97–
998C; TLC: Rf =0.35 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=1605, 1511, 1430, 1393, 1329, 1248, 1225, 1177,
1H, HAr), 7.39 (d, J=8.3 Hz, 2H, HAr), 7.29 (t, J=8.8 Hz,
4H, HAr), 7.17 (m, 3H), 7.06 (d, J=8.4 Hz, 1H, HAr), 5.46
(d, J=2.1 Hz, 2H, =CH2), 2.52 (s, 3H, CH3), 2.50 (s, 3H),
2.39 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=152.3
(C), 150.4 (C), 142.6 (C), 139.2 (C), 139.0 (C), 137.5 (C),
136.6 (C), 136.4 (C), 133.5 (C), 130.6 (2CH), 128.9 (2CH),
128.3 (2CH), 126.9 (2CH), 123.5 (CH), 118.9 (CH), 113.1
(CH2), 109.4 (CH), 21.3 (CH3), 21.3 (CH3), 14.5 (CH3); HR-
MS (ESI): m/z=339.1844, calculated for C24H23N2 (M+
Na)+: 339.1861.
1155, 1033 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.76 (s,
;
1H, HAr), 7.43–7.25 (m, 6H, HAr), 7.20 (dd, J=8.4, 1.4 Hz,
1H, HAr), 7.03 (d, J=8.4 Hz, 1H, HAr), 6.87 (d, J=8.8 Hz,
2H, HAr), 5.41 (dd, J=8.8, 1.0 Hz, 2H, =CH2), 3.83 (s, 3H,
CH3), 2.51 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
162.7 (d, J=251.7 Hz, C), 159.4 (C), 152.2 (C), 149.9 (C),
142.7 (C), 137.0 (C), 136.4 (C), 134.3 (C), 132.2 (d, J=
1.5 Hz, C), 129.5 (s, 2CH), 129.0 (d, J=8.7 Hz, 2CH), 123.7
(CH), 119.1 (CH), 117.1 (d, J=22.9 Hz, 2 CH), 113.6
(2CH), 112.6 (CH2), 109.2 (CH), 55.4 (CH3), 14.5 (CH3);
19F NMR (188 MHz, CDCl3): d=À109.79 (s); HR-MS
(ESI): m/z=359.1563, calculated for C23H20FN2O (M+H)+:
359.1560.
1-Butyl-5-[1-(4-methoxyphenyl)vinyl]-2-methyl-1H-ben-
zo[d]imidazole (4ab): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 7/3) afforded 4ab as a viscous
oil; yield: 75 mg (0.235 mmol, 47%); TLC: Rf =0.15 (cyclo-
hexane/acetone, 6/4, SiO2); IR (film): n=2938, 2831, 1605,
1510, 1463, 1429, 1399, 1361, 1333, 1283, 1246, 1177, 1103,
1031 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.68 (s, 1H,
;
HAr), 7.30 (d, J=8.5 Hz, 2H, HAr), 7.20 (s, 2H, HAr), 6.85
(d, J=8.5 Hz, 2H, HAr), 5.37 (d, J=3.5 Hz, 2H, =CH2),
4.08 (t, J=7.3 Hz, 2H, CH2), 3.82 (s, 3H, CH3), 2.59 (s, 3H,
1-(4-Fluorophenyl)-2-methyl-5-[1-(p-tolyl)vinyl]-1H-ben-
zo[d]imidazole (4y): Flash chromatography on silica gel (cy-
Adv. Synth. Catal. 2016, 358, 1833 – 1847
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CH3), 1.79 (dt, J=15.1, 7.6 Hz, 2H, CH2), 1.45–1.32 (m, 2H,
CH2), 0.97 (t, J=7.3 Hz, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=159.4 (C), 152.1 (C), 150.1 (C), 142.8 (C), 136.1
(C), 135.0 (C), 134.7 (C), 129.6 (2 CH), 122.9 (CH), 119.0
(CH), 113.6 (2CH), 112.3 (CH2), 108.6 (CH), 55.4 (CH3),
43.9 (CH2), 32.0 (CH2), 20.3 (CH2), 14.1 (CH3), 13.9 (CH3);
HR-MS (ESI): m/z=321.1963, calculated for C21H25N2O
(M+H)+: 321.1967.
1481, 1454, 1428, 1395, 1354, 1331, 1247, 1160, 1113,
1031 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.77 (d, J=
;
0.5 Hz, 1H, HAr), 7.34–7.29 (m, 5H, HAr), 7.20–7.13 (m, 4H,
HAr), 7.12–7.05 (m, 2H, HAr), 5.46 (s, 2H, =CH2), 5.31 (s,
2H, CH2), 2.58 (s, 3H, CH3), 2.39 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d=152.5 (C), 150.4 (C), 142.8 (C), 139.2
(C), 137.4 (C), 136.2 (C), 135.9 (C), 135.3 (C), 129.1 (2CH),
128.9 (2CH), 128.3 (2CH), 128.0 (CH), 126.4 (2CH), 123.2
(CH), 119.1 (CH), 113.1 (CH2), 108.8 (CH), 47.3 (CH2), 21.2
(CH3), 14.1 (CH3); HR-MS (ESI): m/z=339.1839, calculated
for C24H23N2 (M+H)+: 339.1861.
1-Butyl-2-methyl-5-[1-(p-tolyl)vinyl]-1H-benzo[d]imida-
zole (4ac): Flash chromatography on silica gel (cyclohexane/
acetone, 10/0 to 7/3) afforded 4ac as acpolorless oil; yield:
81 mg (0.265 mmol, 53%); TLC: Rf =0.25 (cyclohexane/ace-
tone, 7/3, SiO2); IR (film): n=2958, 2929, 1607, 1512, 1483,
1-(4-Chlorophenyl)-2-methyl-5-[1-(p-tolyl)vinyl]-1H-ben-
zo[d]imidazole (4ag): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 6/4) afforded 4ag as a yellow
oil; yield: 57 mg (0.16 mmol, 32%); TLC: Rf =0.33 (cyclo-
hexane/acetone, 7/3, SiO2); IR (film): n=2924, 1596, 1558,
1513, 1495, 1430, 1390, 1328, 1312, 1259, 1189, 1092,
1429, 1398, 1361, 1322, 1290, 1165, 1113, 1034 cmÀ1
;
1H NMR (300 MHz, CDCl3): d=7.71 (s, 1H, HAr), 7.29 (d,
J=7.7 Hz, 2H, HAr), 7.22 (s, 2H, HAr), 7.15 (d, J=7.5 Hz,
2H, HAr), 5.44 (s, 2H, =CH2), 4.11 (t, J=7.3 Hz, 2H, CH2),
2.62 (s, 3H, CH3), 2.39 (s, 3H, CH3), 1.92–1.68 (m, 2H,
CH2), 1.43 (tt, J=14.7, 7.5 Hz, 2H, CH2), 0.99 (t, J=7.3 Hz,
3H, CH3); 13C NMR (75 MHz, CDCl3): d=152.1 (C), 150.5
(C), 142.8 (C), 139.3 (C), 137.5 (C), 136.0 (C), 135.0 (C),
128.9 (2CH), 128.4 (2CH), 122.9 (CH), 119.0 (CH), 113.0
(CH2), 108.6 (CH), 43.9 (CH2), 32.0 (CH2), 21.3 (CH3), 20.3
(CH2), 14.1 (CH3), 13.9 (CH3); HR-MS (ESI): m/z=
305.2012, calculated for C21H25N2 (M+H)+: 305.2018.
1010 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.77 (d, J=
;
1.1 Hz, 1H), 7.59 (d, J=8.7 Hz, 2H), 7.35 (d, J=8.7 Hz,
2H), 7.29 (d, J=8.0 Hz, 2H), 7.20 (dd, J=8.4, 1.6 Hz, 1H),
7.15 (d, J=7.9 Hz, 2H), 7.05 (d, J=8.4 Hz, 1H), 5.46 (d, J=
5.6 Hz, 2H), 2.53 (s, 3H), 2.39 (s, 3H); 13C NMR (75 MHz,
CDCl3): d=152.0 (C), 150.3 (C), 142.7 (C), 139.1 (C), 137.6
(C), 137.0 (C), 136.1 (C), 134.98 (C), 134.7 (C), 130.4
(2CH), 129.0 (2CH), 128.5 (2CH), 128.3 (2CH), 123.8
(CH), 119.1 (CH), 113.4 (CH2), 109.2 (CH), 21.3 (CH3), 14.6
(CH3); HR-MS (ESI): m/z=359.1308, calculated for
C23H20ClN2 (M+H)+: 359.1315.
1,2-Dimethyl-5-[1-(3,4,5-trimethoxyphenyl)vinyl]-1H-ben-
zo[d]imidazole (4ad): Flash chromatography on silica gel
(cyclohexane/acetone, 5/5 to 0/10) afforded 4ad as a colorless
oil; yield: 111 mg (0.33 mmol, 66%); TLC: Rf =0.35 (ace-
tone, SiO2); IR (film): n=2936, 1579, 1504, 1465, 1430, 1398,
1-(4-Methoxyphenyl)-2-methyl-6-[1-(p-tolyl)vinyl]-1H-
benzo[d]imidazole (4ah): Flash chromatography on silica
gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4ah as
a white solid; yield: 149 mg (0.42 mmol, 84%); mp 132–
1348C; TLC: Rf =0.26 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=1607, 1581, 1512, 1443, 1395, 1334, 1298, 1250,
1345, 1237, 1177, 1126 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=7.63 (s, 1H, HAr), 7.21–7.15 (m, 2H, HAr), 6.51 (s, 2H,
HAr), 5.36 (d, J=12.5 Hz, 2H, =CH2), 3.80 (s, 3H, CH3),
3.72 (s, 6H, 2 CH3), 3.67 (s, 3H, CH3), 2.54 (s, 3H, CH3);
13C NMR (75 MHz, CDCl3): d=153.0 (3C), 152.6 (C), 150.7
(C), 142.5 (C), 138.0 (C), 137.9 (C), 135.8 (C), 123.0 (CH),
119.0 (CH), 113.3 (CH2), 108.4 (CH), 105.9 (2CH), 61.0
(CH3), 56.2 (2CH3), 30.1 (CH3), 14.0 (CH3); HR-MS (ESI):
m/z=339.1703, calculated for C20H23N2O3 (M+H)+:
339.1708.
1
1168, 1108, 1035 cmÀ1; H NMR (300 MHz, CDCl3): d=7.79
(d, J=8.3 Hz, 1H, HAr), 7.40 (d, J=8.7 Hz, 2H, HAr), 7.34
(m, 3H, HAr), 7.24 (m, 3H, HAr), 7.18 (d, J=8.7 Hz, 2H,
HAr), 5.49 (d, J=19.8 Hz, 2H, =CH2), 4.01 (s, 3H, CH3),
2.61 (s, 3H, CH3), 2.48 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=159.8 (C), 152.7 (C), 150.8 (C), 142.4 (C), 139.0
(C), 137.5 (C), 137.0 (C), 136.8 (C), 128.9 (2CH), 128.6 (C),
128.4 (2CH), 128.2 (2CH), 123.6 (CH), 118.3 (CH), 115.2
(2CH), 113.4 (CH2), 109.7 (CH), 55.7 (CH3), 21.3 (CH3),
14.5 (CH3); HR-MS (ESI): m/z=355.1817, calculated for
C24H23N2O (M+H)+: 355.1810.
1-Benzyl-5-[1-(4-methoxyphenyl)vinyl]-2-methyl-1H-ben-
zo[d]imidazole (4ae): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 7/3) afforded 4ae as a yellow
solid; yield: 80 mg (0.225 mmol, 45%); mp 127–1298C;
TLC: Rf =0.25 (cyclohexane/acetone, 6/4, SiO2); IR (film):
n=1648, 1608, 1511, 1430, 1397, 1332, 1303, 1250, 1172,
4-{1-[1-(4-Fluorophenyl)-2-methyl-1H-benzo[d]imidazol-
6-yl]vinyl}benzonitrile (4ai): Flash chromatography on silica
gel (cyclohexane/acetone, 10/0 to 6/4) afforded 4ai as
a brown solid; yield: 131 mg (0.37 mmol, 74%); mp 138–
1408C; TLC: Rf =0.20 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2231, 1604, 1510, 1478, 1447, 1395, 1335, 1268,
1109, 1031 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.65 (s,
;
1H, HAr), 7.26–7.21 (m, 5H, HAr), 7.09 (d, J=2.5 Hz, 2H,
HAr), 7.00 (d, J=7.5 Hz, 2H, HAr), 6.78 (d, J=8.6 Hz, 2H,
HAr), 5.30 (d, J=3.7 Hz, 2H, CH2), 5.24 (s, 2H, CH2), 3.74
(s, 3H, CH3), 2.50 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=159.4 (C), 152.5 (C), 150.0 (C), 142.4 (C), 136.6
(C), 135.8 (C), 135.2 (C), 134.6 (C), 129.6 (2CH), 129.2
(2CH), 128.1 (CH), 126.4 (2CH), 123.4 (CH), 119.0 (CH),
113.6 (2CH), 112.6 (CH2), 108.9 (CH), 55.4 (CH3), 47.4
(CH2), 14.1 (CH3); HR-MS (ESI): m/z=355.1815, calculated
for C24H23N2O (M+H)+: 355.1810.
1
1225, 1155, 1095 cmÀ1; H NMR (300 MHz, CDCl3): d=7.60
(d, J=8.3 Hz, 1H, HAr), 7.51 (d, J=8.2 Hz, 2H, HAr), 7.34
(d, J=8.2 Hz, 2H, HAr), 7.29 (d, J=4.9 Hz, 1H, HAr), 7.26
(d, J=4.8 Hz, 1H, HAr), 7.23–7.15 (m, 2H, HAr), 7.06 (dd,
J=8.3, 1.5 Hz, 1H, HAr), 6.92 (s, 1H, HAr), 5.43 (d, J=
2.0 Hz, 2H, =CH2), 2.42 (s, 3H, CH3); 13C NMR (75 MHz,
CDCl3): d=162.6 (d, J=249.9 Hz, C), 152.7 (C), 149.2 (C),
146.4 (C), 142.7 (C), 136.8 (C), 135.5 (C), 132.1 (2CH) 131.8
(d, J=3.0 Hz, C), 129.0 (d, J=8.8 Hz, 2CH), 128.9 (2CH),
123.4 (CH), 118.9 (C), 118.9 (CH), 117.2 (d, J=22.9 Hz,
2CH), 116.7 (CH2), 111.4 (C), 109.4 (CH), 14.5 (CH3);
1-Benzyl-2-methyl-5-[1-(p-tolyl)vinyl]-1H-benzo[d]imida-
zole (4af): Flash chromatography on silica gel (cyclohexane/
acetone, 10/0 to 7/3) afforded 4af as a yellow solid; yield:
84 mg (0.25 mmol, 50%); mp 133–1358C; TLC: Rf =0.28
(cyclohexane/acetone, 7/3, SiO2). IR (film): n=1606, 1521,
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19F NMR (188 MHz, CDCl3): d=À109.45 (s); HR-MS
(ESI): m/z=354.1401, calculated for C23H17N3F (M+H)+:
354.1407.
silica gel (cyclohexane/acetone, 10/0 to 8/2) afforded 4am as
a yellow solid; yield: 147 mg (0.355 mmol, 71%); mp 155–
1568C; TLC: Rf =0.51 (cyclohexane/acetone, 95/5, SiO2); IR
(film): n=2227, 1604, 1510, 1474, 1448, 1429, 1383, 1326,
2-Ethyl-1-(4-methoxyphenyl)-5-[1-(p-tolyl)vinyl]-1H-ben-
zo[d]imidazole (4aj): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 7/3) afforded 4aj as a white
solid; yield: 145 mg (0.395 mmol, 79%); mp 140–1428C;
TLC: Rf =0.73 (cyclohexane/acetone, 7/3, SiO2); IR (film):
n=2972, 1612, 1518, 1464, 1421, 1377, 1340, 1289, 1236,
1
1267, 1225, 1155, 1112, 1094, 1075 cmÀ1; H NMR (300 MHz,
CDCl3): d=7.70 (s, 1H, HAr), 7.50 (d, J=8.1 Hz, 2H, HAr),
7.45 (d, J=6.8 Hz, 2H, HAr), 7.38 (d, J=8.2 Hz, 2H, HAr),
7.26–7.16 (m, 5H, HAr), 7.14–7.05 (m, 4H, HAr), 5.49 (d, J=
22.8 Hz, 2H, =CH2); 13C NMR (75 MHz, CDCl3): d=162.3
(d, J=248.3 Hz, C), 153.3 (C), 148.9 (C), 146.5 (C), 143.1
(C), 137.3 (C), 135.7 (C), 132.8 (d, J=2.9 Hz, C), 132.1
(2CH), 129.8 (CH), 129.5 (C), 129.4 (2CH), 129.1 (d, J=
8.7 Hz, 2CH), 129.0 (2CH), 128.5 (2CH), 124.0 (CH), 119.7
(CH), 118.9 (C), 117.1 (d, J=22.9 Hz, 2CH), 116.4 (CH2),
111.3 (C), 110.1 (CH); 19F NMR (188 MHz, CDCl3): d=
À109.62 (s); HR-MS (ESI): m/z=416.1562, calculated for
C28H19N3F (M+H)+: 416.1563.
1199, 1152, 1101, 1073 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=7.69 (s, 1H, HAr), 7.18 (s, 2H, HAr), 7.15 (d, J=2.0 Hz,
2H, HAr), 7.06 (d, J=9.3 Hz, 1H, HAr), 7.01 (d, J=7.9 Hz,
2H, HAr), 6.95 (d, J=8.8 Hz, 2H, HAr), 6.89 (d, J=8.4 Hz,
1H, HAr), 5.32 (s, 2H, =CH2), 3.78 (s, 3H, CH3), 2.67 (q, J=
7.5 Hz, 2H, CH2), 2.25 (s, 3H, CH3), 1.25 (t, J=7.5 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d=159.9 (C), 157.3 (C),
150.5 (C), 142.5 (C), 139.2 (C), 137.4 (C), 136.7 (C), 136.4
(C), 128.8 (2CH), 128.6 (C), 128.5 (2 CH), 128.3 (2CH),
123.3 (CH), 119.1 (CH), 115.1 (2CH), 113.0 (CH2), 109.3
(CH), 55.6 (CH3), 21.3 (CH2), 21.2 (CH3), 12.1 (CH3); HR-
MS (ESI): m/z=369.1965, calculated for C25H25N2O (M+
H)+: 369.1967.
1-(4-Methoxyphenyl)-2,4-dimethyl-5-[1-(p-tolyl)vinyl]-1H-
benzo[d]imidazole (4an): Flash chromatography on silica
gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4an as
a yellow solid; yield: 129 mg (0.35 mmol, 70%); mp 163–
1648C; TLC: Rf =0.57 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=1611, 1512, 1442, 1386, 1318, 1297, 1250, 1227,
4-{1-[2-Ethyl-1-(4-fluorophenyl)-1H-benzo[d]imidazol-5-
yl]vinyl}benzonitrile (4ak): Flash chromatography on silica
gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4ak as
a white solid; yield: 149 mg (0.405 mmol, 81%); mp 157–
1598C; TLC: Rf =0.78 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2976, 2228, 1604, 1511, 1450, 1418, 1377, 1338,
1183, 1169, 1107, 1034 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=7.19 (d, J=8.8 Hz, 2H, HAr), 7.11 (d, J=8.1 Hz, 2H,
HAr), 6.97 (m, 5H, HAr), 6.83 (d, J=8.2 Hz, 1H, HAr), 5.71
(s, 1H, =CH2), 5.07 (s, 1H, =CH2), 3.79 (s, 3H, CH3), 2.41 (s,
3H, CH3), 2.37 (s, 3H, CH3), 2.22 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d=159.8 (C), 151.6 (C), 149.2 (C), 142.1
(C), 138.5 (C), 137.3 (C), 135.8 (C), 135.7 (C), 129.0 (2CH),
128.9 (C), 128.4 (2CH), 127.1 (C), 126.6 (2CH), 125.0 (CH),
115.1 (2CH), 114.3 (CH2), 107.0 (CH), 55.7 (CH3), 21.2
1266, 1239, 1219, 1154, 1122, 1096, 1074 cmÀ1 1H NMR
;
(300 MHz, CDCl3): d=7.72 (s, 1H, HAr), 7.61 (d, J=8.1 Hz,
2H, HAr), 7.48 (d, J=8.2 Hz, 2H, HAr), 7.70–7.35 (m, 2H,
HAr), 7.32–7.27 (m, 2H, HAr), 7.13 (d, J=9.3 Hz, 1H, HAr),
7.03 (d, J=8.4 Hz, 1H, HAr), 5.58 (d, J=21.1 Hz, 2H, = (CH3), 14.4 (2CH3); HR-MS (ESI): m/z=369.1973, calculat-
CH2), 2.79 (q, J=7.5 Hz, 2H, CH2), 1.37 (t, J=7.5 Hz, 3H,
CH3); 13C NMR (75 MHz, CDCl3): d=162.7 (d, J=
249.8 Hz, C), 157.4 (C), 149.1 (C), 146.7 (C), 142.7 (C),
136.8 (C), 135.2 (C), 132.1 (2CH), 131.8 (d, J=2.8 Hz, C),
129.2 (d, J=8.7 Hz, 2CH), 129.0 (2CH), 123.3 (CH), 119.2
(CH), 119.0 (C), 117.2 (d, J=22.9 Hz, 2CH), 116.3 (CH2),
111.3 (C), 109.6 (CH), 21.3 (CH2), 11.9 (CH3); 19F NMR
(188 MHz, CDCl3): d=À109.44 (s); HR-MS (ESI): m/z=
368.1563, calculated for C24H19N3F (M+H)+: 368.1563.
1-(4-Methoxyphenyl)-2-phenyl-5-[1-(p-tolyl)vinyl]-1H-
benzo[d]imidazole (4al): Flash chromatography on silica gel
(cyclohexane/acetone, 10/0 to 8/2) afforded 4al as a white
solid; yield: 135 mg (0.325 mmol, 65%); mp 164–1668C;
TLC: Rf =0.55 (cyclohexane/acetone, 95/5, SiO2); IR (film):
n=1609, 1512, 1471, 1446, 1384, 1327, 1299, 1248, 1182,
ed for C25H25N2O (M+H)+: 369.1967.
4-{1-[1-(4-Fluorophenyl)-2,4-dimethyl-1H-benzo[d]imida-
zol-5-yl]vinyl}benzonitrile (4ao): Flash chromatography on
silica gel (cyclohexane/acetone, 10/0 to 6/4) afforded 4ao as
a white solid; yield: 150 mg (0.41 mmol, 82%); mp 170–
1728C; TLC: Rf =0.44 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2227, 1605, 1511, 1424, 1386, 1328, 1220, 1155,
1095, 1042 cmÀ1 1H NMR (300 MHz, CDCl3): d=7.46 (d,
;
J=8.2 Hz, 2H, HAr), 7.29 (m, 4H, HAr), 7.20 (m, 2H, HAr),
6.95 (d, J=8.2 Hz, 1H, HAr), 6.85 (d, J=8.2 Hz, 1H, HAr),
5.85 (s, 1H, =CH2), 5.31 (s, 1H, =CH2), 2.43 (s, 3H, CH3),
2.32 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=162.6 (d,
J=247.5 Hz, C), 151.6 (C), 148.0 (C), 145.8 (C), 142.3 (C),
135.9 (C), 134.3 (C), 132.2 (2CH), 132.1 (d, J=3.0 Hz, C),
129.0 (d, J=8.7 Hz, 2CH), 127.2 (2CH), 125.0 (CH), 119.0
(2C), 118.4 (CH2), 117.1 (d, J=22.9 Hz, 2CH), 111.0 (C),
107.2 (CH), 14.4 (2CH3); 19F NMR (188 MHz, CDCl3): d=
À109.67 (s); HR-MS (ESI): m/z=368.1559, calculated for
C24H19N3F (M+H)+: 368.1563.
1168, 1108, 1075, 1031 cmÀ1 1H NMR (300 MHz, CDCl3):
;
d=7.92 (s, 1H, HAr), 7.63 (dd, J=7.7, 1.6 Hz, 2H, HAr),
7.36–7.31 (m, 5H, HAr), 7.26 (d, J=9.2 Hz, 3H, HAr), 7.18
(d, J=3.1 Hz, 2H, HAr), 7.15 (d, J=3.7 Hz, 1H, HAr), 7.03
(d, J=8.8 Hz, 2H, HAr), 5.50 (s, 2H, =CH2), 3.90 (s, 3H,
CH3), 2.40 (s, 3H, CH3); 13C NMR (75 MHz, CDCl3): d=
159.6 (C), 153.1 (C), 150.4 (C), 143.0 (C), 139.2 (C), 137.5
(C), 137.4 (C), 137.2 (C), 130.1 (C), 129.7 (C), 129.5 (3CH),
128.9 (2CH), 128.6 (2CH), 128.4 (2CH), 128.3 (2CH), 124.2
(CH), 119.7 (CH), 115.2 (2CH), 113.3 (CH2), 110.0 (CH),
55.7 (CH3), 21.3 (CH3); HR-MS (ESI): m/z=417.1973, cal-
culated for C29H25N2O (M+H)+: 417.1967.
1-(4-Methoxyphenyl)-2,4-dimethyl-6-[1-(p-tolyl)vinyl]-1H-
benzo[d]imidazole (4ap): Flash chromatography on silica
gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4ap as
a white solid; yield: 147 mg (0.40 mmol, 80%); mp 180–
1828C; TLC: Rf =0.40 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=1612, 1590, 1513, 1442, 1416, 1337, 1300, 1251,
1222, 1183, 1169, 1109, 1035 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d=7.27 (dd, J=8.1, 5.0 Hz, 4H, HAr), 7.14 (s, 1H,
HAr), 7.12 (s, 1H, HAr), 7.06 (m, 3H, HAr), 6.97 (s, 1H, HAr),
5.37 (d, J=18.2 Hz, 2H, =CH2), 3.89 (s, 3H, CH3), 2.70 (s,
4-{1-[1-(4-Fluorophenyl)-2-phenyl-1H-benzo[d]imidazol-
5-yl]vinyl]benzonitrile (4am): Flash chromatography on
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3H, CH3), 2.53 (s, 3H, CH3), 2.37 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d=159.7 (C), 151.8 (C), 150.6 (C), 141.5
(C), 139.1 (C), 137.4 (C), 136.7 (C), 136.5 (C), 128.8 (2CH,
C), 128.4 (2CH), 128.1 (2CH, C), 123.9 (CH), 115.1 (2CH),
113.2 (CH2), 107.4 (CH), 55.6 (CH3), 21.2 (CH3), 16.8 (CH3),
14.4 (CH3); HR-MS (ESI): m/z=369.1968, calculated for
C25H25N2O (M+H)+: 369.1967.
19F NMR (188 MHz, CDCl3): d=À108.94 (s), À115.52 (s);
HR-MS (ESI): m/z=372.1312, calculated for C23H16N3F2
(M+H)+: 372.1312.
Acknowledgements
4-{1-[1-(4-Fluorophenyl)-2,4-dimethyl-1H-benzo[d]imida-
zol-6-yl]vinyl}benzonitrile (4aq): Flash chromatography on
silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4aq as
a brown solid; yield: 141 mg (0.385 mmol, 77%); mp 132–
1348C; TLC: Rf =0.40 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=2228, 1604, 1511, 1450, 1418, 1377, 1338, 1266,
The authors gratefully acknowledge support of this project by
CNRS, University Paris Sud and by “La LigueContre le
Cancer” through an “Equipe LabellisØe 2014” grant. BioCIS
UMR 8076 laboratory is a member of the Laboratory of Ex-
cellence LERMIT supported by a grant from ANR (ANR-
10-LABX-33).
1239, 1154, 1122, 1096, 1074 cmÀ1
;
1H NMR (300 MHz,
CDCl3): d=7.51 (d, J=8.2 Hz, 2H, HAr), 7.34 (d, J=8.3 Hz,
2H, HAr), 7.28–7.23 (m, 2H, HAr), 7.20–7.14 (m, 2H, HAr),
6.87 (s, 1H, HAr), 6.75 (s, 1H, HAr), 5.41 (d, J=3.9 Hz, 2H,
=CH2), 2.57 (s, 3H, CH3), 2.43 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d=162.6 (d, J=248.3 Hz, C), 151.9 (C),
149.3 (C), 146.6 (C), 141.9 (C), 136.4 (C), 135.4 (C), 132.1
(2CH), 132.0 (d, J=1.9 Hz, C), 129.0 (d, J=8.8 Hz, 2CH),
128.9 (2CH, C), 123.8 (CH), 119.0 (2C), 117.2 (d, J=
22.9 Hz, 2CH), 116.5 (C), 111.3 (C), 107.2 (CH), 16.8 (CH3),
14.5 (CH3); 19F NMR (188 MHz, CDCl3): d=À109.56 (s);
HR-MS (ESI): m/z=368.1558, calculated for C24H19N3F
(M+H)+: 368.1563.
References
[1] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem.
2014, 57, 10257–10274.
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2012, 29, 2943–2971.
6-Fluoro-1-(4-methoxyphenyl)-2-methyl-5-[1-(p-tolyl)vin-
yl]-1H-benzo[d]imidazole (4ar): Flash chromatography on
silica gel (cyclohexane/acetone, 10/0 to 7/3) afforded 4ar as
a white solid; yield: 123 mg (0.33 mmol, 66%); mp 204–
2068C; TLC: Rf =0.45 (cyclohexane/acetone, 7/3, SiO2); IR
(film): n=1629, 1608, 1512, 1469, 1442, 1396, 1324, 1300,
1
1250, 1184, 1169, 1146, 1111, 1035 cmÀ1; H NMR (300 MHz,
[6] S. L. Young, D. J. Chaplin, Expert Opin. Invest. Drugs
CDCl3): d=7.67 (d, J=6.6 Hz, 1H, HAr), 7.28 (t, J=8.9 Hz,
4H, HAr), 7.11 (t, J=8.2 Hz, 4H, HAr), 6.80 (d, J=9.7 Hz,
1H, HAr), 5.57 (d, J=103.2 Hz, 2H, =CH2), 3.92 (s, 3H,
CH3), 2.50 (s, 3H, CH3), 2.36 (s, 3H, CH3); 13C NMR
(75 MHz, CDCl3): d=160.0 (C), 157.2 (d, J=240.8 Hz, C),
152.9 (C), 144.9 (C), 138.6 (C), 138.1 (C), 137.5 (C), 136.6
(d, J=12.8 Hz, C), 128.9 (2CH), 128.3 (C), 128.1 (2CH),
126.6 (2CH), 125.0 (d, J=17.8 Hz, C), 120.9 (d, J=4.7 Hz,
CH), 115.71 (C), 115.2 (2CH), 97.0 (d, J=29.0 Hz, CH),
55.6 (CH3), 21.1 (CH3), 14.3 (CH3); 19F NMR (188 MHz,
CDCl3): d=À116.28 (s); HR-MS (ESI): m/z=373.1715, cal-
culated for C24H22N2OF (M+H)+: 373.1716.
2004, 13, 1171–1182.
[7] a) C. Mousset, A. Giraud, O. Provot, A. Hamze, J.
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