Synthesis of N-(α-fluorovinyl)azoles by the reaction of difluoroalkenes with azoles

Article abstract of DOI:10.1021/jo5005845

A mild and versatile method for the construction of C-N bonds by the reaction of (2,2-difluorovinyl)arenes with various N-H-containing heterocycles in the presence of K₃PO₄ has been developed. The reaction proceeded efficiently at room temperature (25 °C) affording the (E)-N-α-fluorovinyl derivatives of azoles 3 in good to excellent yields with relatively high stereoselectivity.

Full text of DOI:10.1021/jo5005845

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pubs.acs.org/joc
Synthesis of N‑(α-Fluorovinyl)azoles by the Reaction of
Difluoroalkenes with Azoles
Yang Xiong, Xuxue Zhang, Tao Huang, and Song Cao*
Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Shanghai
200237, China
S
* Supporting Information
ABSTRACT: A mild and versatile method for the construction of C−N bonds by the reaction of (2,2-difluorovinyl)arenes with
various N−H-containing heterocycles in the presence of K3PO4 has been developed. The reaction proceeded efficiently at room
temperature (25 °C) affording the (E)-N-α-fluorovinyl derivatives of azoles 3 in good to excellent yields with relatively high
stereoselectivity.
undergo vinylic nucleophilic substitution reaction (SNV) to
form α-substituted fluoroalkenes.10 Ichikawa and co-workers
have extensively investigated the reactivity and potential
application of the difluoroalkene building blocks, and developed
several methods to synthesize the ring-fluorinated heterocyclic
compounds.11
INTRODUCTION
■
The Cu-catalyzed Ullmann cross-coupling reaction of nitrogen-
containing heterocycles with aryl halides is an important and
widely used strategy for the synthesis of N-arylazoles.1 N-
Vinylazoles such as N-vinylimidazole and N-vinylpyrazole are
useful building blocks and intermediates in organic syntheses.2
Up to now, most of the research has been focused on the
synthesis and application of N-arylazoles,3 and only a few
methods for the synthesis of N-vinylazoles have been reported.
The most common and efficient tool for the construction of the
N-vinylazole (for example N-vinylimidazole) framework is the
Cu-catalyzed Ullmann-type coupling reaction of vinyl iodides,
bromides, or chlorides with azoles at relatively high temper-
atures (e.g., 100−120 °C) or in the presence of complicated
ligand.4 However, the use of vinyl fluorides as reactants or
coupling partners has rarely been reported.
The introduction of a α-fluorovinyl functionality into organic
molecules has attracted much attention due to its specific
properties and significant effects on their reactivity and
biological activity.5 Nowadays, vinyl fluorides have found
many applications in pharmaceuticals,6 agrochemicals,7 espe-
cially in peptide chemistry,8 but only a limited number of
methods are available for the synthesis of substituted
monofluoroalkenes.9
Based on the above-mentioned considerations, we envisioned
that the direct nucleophilic attack of the polarized double bond
of the difluoroalkenes by azoles might also take place easily. A
literature survey revealed that there are only two examples
involving the nucleophilic substitution reaction of difluor-
oalkene with azoles. In 2004, Yagupolski reported that the
reaction of chlorotrifluoroethylene with azoles in the presence
of potassium metal could afford a mixture of fluorine
substitution and alkene addition products. However, the yields
and ratios of two types of products were not satisfactory.12 In
2000, Shi reported the reaction of ethyl 3,3-difluoro-2-
[(trimethylsilyl)methyl]propenoate with indole via nucleophilic
substitution of vinylic fluorine using n-BuLi as base at −78 °C
(only one example). They proposed a possible C−F···Si-type
coordinative interaction to explain the observed stereochemical
outcome.13 In this paper, we report an efficient and
stereoselective synthesis of (E)-N-(α-fluorovinyl)azoles 3 by
N-α-fluorovinylation of 1H-azoles 2a−i with 1-aryl-2,2-
Terminal gem-difluoroalkenes exhibit unusual reactivity
toward nucleophiles because of their high electron-deficient
and strong polar nature of the double bond. They easily
Received: March 12, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo5005845 | J. Org. Chem. XXXX, XXX, XXX−XXX

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difluoroethenes 1a−i in the presence of K3PO4 at room
make the reaction proceed readily (entry 9), whereas the
decrease in the amount of K3PO4 (e.g., 1 equiv; entry 10) led to
an obvious decrease in the yields. Thus, the optimized reaction
conditions are as follows: 1H-imidazole 2a (1 mmol), 1-(2,2-
difluorovinyl)-4-methoxybenzene 1a (1.2 equiv), K3PO4 (2
equiv), and DMF (2 mL), stirring for 12 h at 25 °C (entry 9).
The scope and limitations of this fluorovinylation were
investigated by treatment of 1-(2,2-difluorovinyl)-4-methox-
ybenzene 1a with various nitrogen-containing heterocycles
under the aforementioned optimized reaction conditions
(Table 2). The results indicated that the reactions of 1a with
imidazole (2a), pyrazole (2b), substituted 1H-benzo[d]-
imidazole (2c), 1H-indole (2d), 1H-benzo[d][1,2,3]triazole
(2e), and 1H-1,2,4-triazole (2f) proceeded well to afford the
expected N-vinylazoles in good to excellent yields as the pure
E-isomers. The vinylation of 5-(thiophene-2-yl)-1H-pyrazole
(2g) also provided pure E-isomer with excellent regioselectivity
(N-1 versus N-2) due to the presence of a bulky 3-thienyl
group on the pyrazole ring, and no 2-regioisomer was
observed.14 The reaction of 1H-indazole (2h) with 1a afforded
two regioisomers, (E)-1-(1-fluoro-2-(4-methoxyphenyl)vinyl)-
1H- indazole (3ah) and (E)-2-(1-fluoro-2-(4-methoxyphenyl)-
vinyl)-2H-indazole (3ah′), in relatively lower yield and
selectivity. We also employed 1H-benzo[d]imidazole (2i) as a
nucleophilic substrate; it only gave a mixture of E and Z
isomers 3ai which could be separated by column chromatog-
raphy (E/Z = 86:14).
temperature without any additional metal catalyst (Scheme 1).
Scheme 1. N-α-Fluorovinylation of 1H-Azoles 2a−i with 1-
Aryl-2,2-difluoroethenes 1a−i
RESULTS AND DISCUSSION
■
More recently, Diness and Fairlie developed a novel and
straightforward catalyst-free method for N-arylation of azole
with halogenated fluorobenzenes at high temperatures, typically
120−190 °C with the assistance of microwave.14 Therefore, in
the beginning, we carried out the reaction of 1-(2,2-
difluorovinyl)-4-methoxybenzene 1a with 1H-imidazole 2a at
120 °C in the presence of K3PO4 using DMF as a solvent
(Table 1). We observed that the vinylation reaction took place
Table 1. Fluorovinylation of 2a with 1a under Different
a
Reaction Conditions
To examine the applicability of this novel vinylation reaction,
the reactions of benzimidazole 2i with various 1-aryl-2,2-
difluoroethenes 1b−i were carried out under the above-
optimized conditions. The results were summarized in Table
3. It was found that for those difluoroethenes with electron-
donating substituents such as CH3 (1b) and OCH2O (1c) on
the aromatic ring could afford the corresponding products in
high yields and moderate stereoselectivity. 1-Aryl-2,2-difluor-
oethenes having naphthyl group or halide (Cl, Br and I) atoms
on the aryl ring have been converted into the corresponding N-
vinylbenzimidazoles in excellent yields; however, the E/Z
selectivity of the reaction decreased, furnishing a chromato-
graphically separable mixture of two E and Z isomers.
Furthermore, the stereoselectivity is also not satisfactory
when 1H-imidazole 2a was used as substrate to react with 1-
aryl-2,2-difluoroethenes having halide atom (such as Br) on the
aryl ring. Unfortunately, attempts to prepare difluoroethenes
having a strong electron-withdrawing group such as NO2
according to the method described in the literature failed.15
In addition, when symmetrical gem-difluoroalkenes were
employed as the substrates, the reactions proceeded well and
gave the desired products in excellent yields (Scheme 2).
To expand the application of this method, we further
examined the reactivity of the second C−F bond in alkenes
toward nitrogen-containing heterocycles (Scheme 3). First, the
model substrate 1a (1.2 mmol) was allowed to react with
imidazole 2a (2 equiv, 2.4 mmol) for 12 h at 25 °C. However,
the reaction could not proceed to completion, and a mixture of
monoamination and diamination product was observed. We
were delighted to find that the reaction proceeded smoothly at
elevated temperature (80 °C) and resulted in the formation of
diamination product 4 in nearly quantitative yield, no trace of
the monoamination product was detected. This might be due
to the fact that the cleavage of the second C−F bond in
difluoroalkenes is more difficult.
amt of 1a
temp
yield of
b
b
entry
(equiv)
(°C)
base (equiv) solvent 3aa (%)
E/Z
1
2
3
4
5
6
7
8
9
10
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
1.2
120
60
25
25
25
25
25
25
25
25
K3PO4(3)
K3PO4(3)
K3PO4(3)
none
DMF
DMF
DMF
DMF
DMF
DMF
>99
>99
>99
0
99:1
97:3
98:2
Cs2CO3(3)
DBU(3)
>99
>99
93
97:3
96:4
96:4
96:4
98:2
96:4
NaO-t-Bu(3) DMF
KO-t-Bu (3)
K3PO4(2)
K3PO4(1)
DMF
DMF
DMF
91
>99
80
a
Reaction conditions: 1H-imidazole 2a (1 mmol), solvent (2 mL), 12
b
h. DBU (1,8-diazabicyclo[5.4.0]undec-7-ene). The ratios of E/Z
isomers in the crude reaction mixture were determined by 19F NMR or
GC. Yields determined by GC analysis and based on 2a. The
configuration of the E-isomer 3aa (after purification) was determined
3
1
by its JH−F coupling constant in the H NMR spectrum.
smoothly to give the corresponding product 3aa in almost
quantitative yield with excellent stereoselectivity (E/Z = 99:1)
(entry 1). We were pleased to find that the reaction also
proceeded very efficiently at lower temperatures even if the
temperature decreased to 25 °C (entries 2 and 3).
The effect of base on the reaction of 1a with 2a was studied.
In the absence of the base, the reaction hardly proceeded and
no desired product 3aa was observed (entry 4). When Cs2CO3,
DBU, NaO-t-Bu, KO-t-Bu were employed, the yields and E/Z
selectivity were nearly the same as that of K3PO4 (entries 5−8).
Furthermore, addition of 2 equiv of K3PO4 was enough to
B
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a,b
Table 2. Reactions of 1a with Various Azoles
a
b
Reaction conditions: azoles 2a−i (1 mmol), 1a (1.2 mmol), K3PO4 1(2 mmol), DMF (2 mL), 12 h, 25 °C. The configurations of the E- and Z-
3
isomers 3 were determined by their JH−F coupling constants in the H NMR spectra.
Encouraged by this result, we also used 1a (1.2 mmol) as a
representative reactant to react sequentially with imidazole 2a
and pyrazole 2b, respectively, and two α,α′-dihetaryl-
substituted alkenes, (E)-5 and (Z)-5, could be obtained in
excellent yields by changing the addition sequence of 2a and 2b
(Scheme 3). It is very interesting that the configuration of α,α′-
dihetaryl substituted alkenes (E or Z) could be also controlled
by the selection of different azoles. In order to get satisfactory
results, the amination of N-(α-fluorovinyl)azoles, (E)-3aa and
(E)-3ab was performed at a higher temperature (80 °C). It is
noteworthy to mention here that the monoamination products
such as (E)-3aa and (E)-3ab should be isolated and then
reacted with another azole to yield diamination products.
However, attempts to synthesize diamination products, (E)-5
and (Z)-5, using the one-pot sequence without isolation of (E)-
3aa and (E)-3ab were unsuccessful, and a mixture of Z and E
diamination products was obtained. The configuration of the
compound (E)-5 was confirmed by X-ray crystallographic
analysis (see the Supporting Information, Figure 1 and the
CIF).
In summary, we have described a facile and straightforward
method for the stereoselective synthesis of (E)-N-(α-
fluorovinyl)azoles by the reaction of (2,2-difluorovinyl)arenes
with various N−H-containing heterocycles in the absence of
metal catalyst under very mild reaction conditions via vinylic
nucleophilic substitution reaction (SNV). Notably, the α-
hetaryl-substituted monofluoroalkenes could further react
with another π-electron-rich nitrogen heterocycle, affording
the N,N′-α,α′-dihetaryl-substituted alkenes in excellent yields
and tunable stereoselectivities. This method can be considered
as a valuable strategy for direct access to various N-
functionalized fluoroolefins and polysubstituted olefins.
EXPERIMENTAL SECTION
■
General Comments. All reagents were of analytical grade,
obtained from commercial suppliers, and used without further
purification. All solvents were dried by standard methods prior to
1
use. H NMR and 13C{1H} NMR spectra were recorded on a 400
1
spectrometer (400 MHz for H and 100 MHz for 13C) using TMS as
internal standard. The 19F NMR spectra were obtained using a 400
spectrometer (376 MHz). CDCl3 was used as the NMR solvent in all
cases. The GC and GC−MS were calibrated by authentic standards.
High-resolution mass spectra (HRMS) were acquired in the electron-
impact mode (EI) using a TOF mass analyzer.
Preparation of 1,1-Difluoroalkenes 1a−i and Symmetrical
gem-Difluoroalkenes (1j,k). The 1,1-difluoroalkenes (1a−i) were
prepared according to the reported procedure.15 The symmetrical gem-
difluoroalkenes (1j,k) were prepared according to Hu’s reported
procedure.16
Synthesis of Compounds 3. A solution of azole 2 (1.0 mmol) in
DMF (1 mL) was added dropwise to a mixture of 1 (1.2 mmol) and
K3PO4 (424.0 mg, 2 mmol) in DMF (1 mL) via syring and then
stirred at room temperature for 12 h (monitored by TLC). After
completion of the reaction, the mixture was quenched with H2O (20
mL). The aqueous phase was extracted with CH2Cl2 (3 × 10 mL).
The organic layer was dried over MgSO4 and filtered, and the filtrate
was concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a hexane/dichloromethane (10:1)
mixture as eluent to afford the pure target compound 3.
C
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for 12 h (monitored by TLC). The reaction mixture was allowed to
cool to room temperature and quenched with H2O (20 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The organic
layer was dried over MgSO4 and filtered, and the filtrate was
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a hexane/dichloromethane (5:1)
mixture as eluent to afford (E)-5.
Table 3. N-Vinylation of Benzimidazole 2i with 1-Aryl-2,2-
difluoroethenes 1b−i
a
Synthesis of Compound (Z)-5. A solution of imidazole 2a (62.6
mg, 0.92 mmol) in DMF (1 mL) was added dropwise to a mixture of
(E)-3ab (200.6 mg, 0.92 mmol) and K3PO4 (381.6 mg, 1.8 mmol) in
DMF (1 mL) via syringe. The mixture was heated to 80 °C and stirred
for 12 h (monitored by TLC). The reaction mixture was allowed to
cool to room temperature and quenched with H2O (20 mL). The
aqueous phase was extracted with CH2Cl2 (3 × 10 mL). The organic
layer was dried over MgSO4 and filtered, and the filtrate was
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel using a hexane/dichloromethane (5:1)
mixture as eluent to afford (Z)-5.
b
entry
1
Ar
product 3
yield (%)
4-Me-C6H4 (1b)
(E)-3bi
(Z)-3bi
(E)-3ci
(Z)- 3ci
(E)-3di
(Z)-3di
(E)-3ei
(Z)-3ei
(E)-3fi
(Z)-3fi
(E)-3gi
(Z)-3gi
(E)-3hi
(Z)-3hi
(E)-3ii
(Z)-3ii
86
0
2
3
4
5
6
7
8
3,4-OCH2O-C6H3 (1c)
1-naphthyl (1d)
2-Br-C6H4 (1e)
3-Br-C6H4 (1f)
4-Br-C6H4 (1g)
3-Cl-C6H4 (1h)
3-I-C6H4 (1i)
94
0
81
11
55
38
47
40
69
23
57
33
60
39
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-imidazole ((E)-
3aa): yield 91% (198.4 mg), white solid; mp 93.5−94.5 °C; 1H
NMR (400 MHz, CDCl3) δ 7.50 (s, 1H), 7.08 (s, 1H), 6.96 (s, 1H),
6.67 (s, 4H), 6.16 (d, J = 10.0 Hz, 1H), 3.66 (s, 3H); 13C NMR (100
4
1
MHz, CDCl3) δ 159.4 (d, JCF = 1.4 Hz), 143.9 (d, JCF = 259.3 Hz),
136.8, 130.4, 129.1 (d, 3JCF = 3.4 Hz), 122.5 (d, JCF = 7.1 Hz), 118.2
3
(d, JCF = 2.8 Hz), 114.4, 103.6 (d, JCF = 33.7 Hz), 55.2; 19F NMR
(376 MHz, CDCl3) δ −86.8 (d, J = 10.0 Hz); HRMS (EI) calcd for
C12H11FN2O [M]+ 218.0855, found 218.0840.
3
2
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-pyrazole ((E)-3ab):
a
1
Reaction conditions: benzimidazole 2i (1 mmol), 1b−i (1.2 mmol),
K3PO4 (2 mmol), DMF (2 mL), 12 h, 25 °C. The configurations of
the E- and Z-isomers were determined by their JH−F coupling
constants in the H NMR spectra (ca. 32.0 Hz for Z-isomers and 8.0
yield 93% (202.7 mg), white solid; mp 95.0−96.0 °C; H NMR (400
b
MHz, CDCl3) δ 7.76 (d, J = 1.6 Hz, 1H), 7.47 (d, J = 2.5 Hz, 1H),
6.70 (s, 4H), 6.38−6.37 (m, 1H), 6.28 (d, J = 8.0 Hz, 1H), 3.71 (s,
3
1
1
3H); 13C NMR (100 MHz, CDCl3) δ 159.3, 146.2 (d, JCF = 260.5
Hz), 142.6, 131.4 (d, 4JCF = 1.7 Hz), 129.3 (d, 3JCF = 3.4 Hz), 123.0 (d,
3JCF = 6.6 Hz), 114.1, 107.9, 104.6 (d, 2JCF = 34.8 Hz), 55.2; 19F NMR
Hz for E-isomers).
(376 MHz, CDCl3) δ −88.2 (d, J = 8.9 Hz); HRMS (EI) calcd for
Scheme 2. N-Vinylation of Azoles with Symmetrical gem-
Difluoroalkenes
C12H11FN2O [M]+ 218.0855, found 218.0856.
a
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-2-phenyl-1H-benzo-
[d]imidazole ((E)-3ac): yield 87% (299.3 mg), white solid; mp 128.1−
1
129.1 °C; H NMR (400 MHz, CDCl3) δ 7.89−7.87 (m, 3H), 7.41−
7.34 (m, 6H), 6.59 (s, 4H), 6.52 (d, J = 8.0 Hz, 1H), 3.63 (s, 3H); 13C
4
NMR (100 MHz, CDCl3) δ 159.5 (d, 4JCF = 1.8 Hz), 152.0 (d, JCF
=
1
3
2.9 Hz), 143.3 (d, JCF = 262.6 Hz), 143.2, 134.6 (d, JCF = 4.2 Hz),
130.4, 129.1, 128.9 (d, 3JCF = 3.5 Hz), 128.6, 128.4, 124.4, 124.0, 122.4
(d, 3JCF = 6.6 Hz), 120.3, 114.3, 110.8, 108.9 (d, 2JCF = 36.4 Hz), 55.1;
19F NMR (376 MHz, CDCl3) δ −83.9 (d, J = 8.3 Hz); HRMS (EI)
calcd for C22H17FN2O [M]+ 344.1325, found 344.1319.
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-indole ((E)-3ad):
1
yield 89% (237.6 mg), white solid; mp 124.5−125.5 °C; H NMR
(400 MHz, CDCl3) δ 7.72−7.70 (m, 1H), 7.41−7.39 (m, 1H), 7.28−
7.26 (m, 2H), 7.14−7.13 (m, 1H), 6.77−6.70 (m, 5H), 6.40 (d, J = 8.0
Hz, 1H), 3.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.0, 146.2
(d, 1JCF = 261.2 Hz), 135.1 (d, 3JCF = 3.9 Hz), 129.1 (d, 3JCF = 3.4 Hz),
129.0, 126.7 (d, 4JCF = 3.2 Hz), 123.6 (d, 3JCF = 7.2 Hz), 123.4, 121.6,
a
Reaction conditions: azoles 2a and 2f (1 mmol), 1j and 1k (1.2
2
121.1, 114.1, 111.5, 106.1, 103.8 (d, JCF = 39.0 Hz), 55.2; 19F NMR
mmol), K3PO4 (2 mmol), DMF (2 mL), 12 h, 25 °C.
(376 MHz, CDCl3) δ −84.0 (d, J = 8.5 Hz); HRMS (EI) calcd for
C17H14FNO [M]+ 267.1059, found 267.1058.
Synthesis of Compound 4. A solution of imidazole 2a (163.2 mg,
2.4 mmol) in DMF (2 mL) was added dropwise to a mixture of 1a
(204.0 mg, 1.2 mmol) and K3PO4 (1017.6 mg, 4.8 mmol) in DMF (2
mL) via syringe. The mixture was heated to 80 °C and stirred for 20 h
(monitored by TLC). The reaction mixture was allowed to cool to
room temperature and quenched with H2O (20 mL). The aqueous
phase was extracted with CH2Cl2 (3 × 10 mL). The organic layer was
dried over MgSO4 and filtered, and the filtrate was concentrated in
vacuo. The crude product was purified by column chromatography on
silica gel using a hexane/dichloromethane (5:1) mixture as eluent to
afford 4.
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-benzo[d][1,2,3]-
triazole ((E)-3ae): yield 85% (228.6 mg), white solid; mp 126.6−127.5
1
°C; H NMR (400 MHz, CDCl3) δ 8.14−8.12 (m, 1H), 7.48−7.36
(m, 3H), 6.72−6.69 (m, 3H), 6.62 (d, J = 8.8 Hz, 2H), 3.66 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.7 (d, 4JCF = 1.6 Hz), 145.4, 142.3
(d, 1JCF = 263.6 Hz), 132.2 (d, 4JCF = 2.8 Hz), 129.4 (d, 3JCF = 3.4 Hz),
3
129.3, 125.0, 121.9 (d, JCF = 6.2 Hz), 120.3, 114.2, 110.0, 108.7 (d,
2JCF = 33.3 Hz), 55.1; 19F NMR (376 MHz, CDCl3) δ −89.7 (d, J =
8.8 Hz); HRMS (EI) calcd for C15H12FN3O [M]+ 269.0964, found
269.0965.
Synthesis of Compound (E)-5. A solution of pyrazole 2b (63.2
mg, 0.93 mmol) in DMF (1 mL) was added dropwise to a mixture of
(E)-3aa (202.7 mg, 0.93 mmol) and K3PO4 (281.6 mg, 1.8 mmol) in
DMF (1 mL) via syringe. The mixture was heated to 80 °C and stirred
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-1,2,4-triazole ((E)-
1
3af): yield 90% (197.1 mg), white solid; mp 96.0−97.1 °C; H NMR
(400 MHz, CDCl3) δ 8.10 (d, J = 8.0 Hz, 2H), 6.69 (s, 4H), 6.41 (d, J
= 8.0 Hz, 1H), 3.70 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.8,
D
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Scheme 3. Influence of the Amount and the Order of Addition of 1H-Azoles on the Formation of Dihetaryl-Substituted
a
Ethylene
a
Reaction conditions: 1.2 mmol of 1a, 0.92 mmol of (E)-3ab, 0.93 mmol of (E)-3aa, indicated amount of 1H-imidazole 2a, 1H-pyrazole 2b, and
K3PO4.
1
3
2
153.5, 145.1, 142.9 (d, JCF = 262.3 Hz), 129.3 (d, JCF = 3.3 Hz),
Hz), 105.8 (d, JCF = 35.1 Hz), 55.2; 19F NMR (376 MHz, CDCl3) δ
121.9 (d, JCF = 6.1 Hz), 114.5, 107.2 (d, JCF = 31.3 Hz), 55.3; 19F
NMR (376 MHz, CDCl3) δ −91.4 (d, J = 9.1 Hz); HRMS (EI) calcd
for C11H10FN3O [M]+ 219.0791, found 219.0791.
3
2
−87.8 (dd, J = 9.0, 2.9 Hz); HRMS (EI) calcd for C16H13FN2O [M]+
268.1012, found 268.1013.
(Z)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-benzo[d]imidazole
((Z)-3ai): yield 12% (32.2 mg), white solid; mp 134.0−135.0 °C; H
NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.76 (d, J = 8.0 Hz, 1H),
7.52 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 2H), 7.32−7.25 (m, 2H),
6.87 (d, J = 8.0 Hz, 2H), 5.84 (d, J = 32.0 Hz, 1H), 3.76 (s, 3H); 13C
1
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-5-(thiophene-2-yl)-
1H-pyrazole ((E)-3ag): yield 93% (279.0 mg), white solid; mp 100.3−
1
101.5 °C; H NMR (400 MHz, CDCl3) δ 7.46−7.44 (m, 2H), 7.33−
7.31 (m, 1H), 7.10−7.08 (m, 1H), 6.87−6.74 (m, 4H), 6.60 (d, J = 4.0
Hz, 1H), 6.31 (d, J = 8.0 Hz, 1H), 3.75 (s, 3H); 13C NMR (100 MHz,
1
NMR (100 MHz, CDCl3) δ 159.5, 143.7 (d, JCF = 270.7 Hz), 143.4,
CDCl3) δ 159.4 (d, 4JCF = 1.4 Hz), 149.8, 146.0 (d, JCF = 261.1 Hz),
1
141.3, 132.7 (d, 3JCF = 3.0 Hz), 130.0 (d, 3JCF = 7.4 Hz), 129.8, 124.6,
123.7, 120.8, 114.3, 111.2 (d, 4JCF = 2.4 Hz), 102.0 (d, 2JCF = 15.6 Hz),
55.3; 19F NMR (376 MHz, CDCl3) δ −95.4 (dd, J = 31.1, 2.7 Hz);
HRMS (EI) calcd for C16H13FN2O [M]+ 268.1012, found 268.1010.
(E)-1-(1-Fluoro-2-p-tolylvinyl)-1H-benzo[d]imidazole ((E)-3bi):
135.3, 133.0 (d, 4JCF = 1.7 Hz), 129.5 (d, 3JCF = 3.3 Hz), 127.6, 125.8,
125.2, 123.0 (d, 3JCF = 6.4 Hz), 114.2, 105.3 (d, JCF = 0.9 Hz), 104.6
4
(d, 2JCF = 34.7 Hz), 55.2; 19F NMR (376 MHz, CDCl3) δ −88.9 (d, J
= 8.9 Hz); HRMS (EI) calcd for C16H13FN2OS [M]+ 300.0733, found
300.0735.
1
yield 86% (216.7 mg), white solid; mp 122.4−123.7 °C; H NMR
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-indazole ((E)-3ah)
(400 MHz, CDCl3) δ 7.90−7.88 (m, 2H), 7.44−7.35 (m, 3H), 6.97
(d, J = 8.0 Hz, 2H), 6.72 (d, J = 8.0 Hz, 2H), 6.51 (d, J = 8.0 Hz, 1H),
and (E)-2-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-2H-indazole ((E)-
1
3ah′). Major product: yield 47% (126.2 mg), yellow oil; H NMR
2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.9 (d, JCF = 263.6
1
(400 MHz, CDCl3) δ 7.95 (d, J = 0.6 Hz, 1H), 7.71−7.69 (m, 1H),
7.53 (d, J = 8.0 Hz, 1H), 7.29−7.25 (m, 1H), 7.06−7.03 (m, 1H),
6.64−6.58 (m, 4H), 6.38 (d, J = 8.0 Hz, 1H), 3.63 (s, 3H); 13C NMR
Hz), 143.3, 141.8 (d, 4JCF = 2.6 Hz), 138.3 (d, 4JCF = 1.6 Hz), 132.1 (d,
3JCF = 3.9 Hz), 129.6, 127.7 (d, JCF = 3.4 Hz), 127.3 (d, JCF = 6.9
3
3
Hz), 124.7, 123.8, 120.7, 111.2 (d, 4JCF = 1.4 Hz), 105.9 (d, 2JCF = 34.6
Hz), 21.1; 19F NMR (376 MHz, CDCl3) δ −86.8 (d, J = 9.1 Hz);
HRMS (EI) calcd for C16H13FN2 [M]+ 252.1063, found 252.1064.
(E)-1-(2-(Benzo[d][1,3]dioxol-5-yl)-1-fluorovinyl)-1H-benzo[d]-
imidazole ((E)-3ci): yield 94% (265.1 mg), white solid; mp 126.5−
127.5 °C; 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), 7.88−7.85 (m,
1H), 7.37 (m, 3H), 6.61 (d, J = 8.0 Hz, 1H), 6.44 (d, J = 8.0 Hz, 1H),
6.41−6.39 (m, 1H), 6.18 (d, J = 1.7 Hz, 1H), 5.84 (s, 2H); 13C NMR
1
(100 MHz, CDCl3) δ 159.5, 150.3, 146.6 (d, JCF = 261.1 Hz), 129.5
(d, 3JCF = 3.3 Hz), 127.9, 125.2, 123.2, 122.6 (d, 3JCF = 6.5 Hz), 121.9,
120.8, 118.6, 114.2, 105.2 (d, JCF = 32.4 Hz), 55.2; 19F NMR (376
2
MHz, CDCl3) δ −88.8 (d, J = 9.7 Hz); HRMS (EI) calcd for
C16H13FN2O [M]+ 268.1012, found 268.1013. Minor product: yield
26% (69.9 mg), yellow oil; 1H NMR (400 MHz, CDCl3) δ 8.19 (d, J =
1.0 Hz, 1H), 7.70−7.67 (m, 1H), 7.28−7.24 (m, 1H), 7.17−7.14 (m,
2H), 6.64−6.62 (m, 2H), 6.55−6.53 (m, 2H), 6.43 (d, J = 8.0 Hz,
1H), 3.60 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.2, 145.2 (d,
(100 MHz, CDCl3) δ 148.1, 147.6 (d, 4JCF = 1.6 Hz), 143.5 (d, 1JCF
=
4
3
1JCF = 262.8 Hz), 139.4 (d, JCF = 3.1 Hz), 138.1, 129.3 (d, JCF = 3.4
4
3
262.6 Hz), 143.3, 141.8 (d, JCF = 2.6 Hz), 132.1 (d, JCF = 4.0 Hz),
124.7, 124.0 (d, 3JCF = 7.0 Hz), 123.8, 122.4 (d, 3JCF = 4.0 Hz), 120.8,
111.1 (d, 4JCF = 1.3 Hz), 108.7, 107.4 (d, 4JCF = 3.0 Hz), 105.9 (d, 2JCF
= 35.8 Hz), 101.3; 19F NMR (376 MHz, CDCl3) δ −87.4 (d, J = 9.1
Hz); HRMS (EI) calcd for C16H11FN2O2 [M]+ 282.0805, found
282.0806.
Hz), 128.0, 124.5, 123.2 (d, 3JCF = 6.6 Hz), 122.5, 121.2, 114.1 (d, 3JCF
= 21.5 Hz), 110.4, 106.2 (d, JCF = 37.3 Hz), 55.1; 19F NMR (376
2
MHz, CDCl3) δ −87.8 (d, J = 8.0 Hz); HRMS (EI) calcd for
C16H13FN2O [M]+ 268.1012, found 268.1011.
(E)-1-(1-Fluoro-2-(4-methoxyphenyl)vinyl)-1H-benzo[d]imidazole
1
(E)-1-(1-Fluoro-2-(naphthalen-1-yl)vinyl)-1H-benzo[d]imidazole
((E)-3di): yield 81% (233.3 mg), white solid; mp 120.7−122.0 °C; 1H
NMR (400 MHz, CDCl3) δ 7.86 (d, J = 8.0 Hz, 1H), 7.66−7.62 (m,
2H), 7.53−7.50 (m, 2H), 7.36−7.32 (m, 2H), 7.26−7.24 (m, 1H),
7.16−7.07 (m, 2H), 6.96−6.92 (m, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.71
((E)-3ai): yield 73% (195.6 mg), white solid; mp 121.7−122.6 °C; H
NMR (400 MHz, CDCl3) δ 7.81−7.76 (m, 2H), 7.29−7.24 (m, 3H),
6.64−6.56 (m, 4H), 6.38 (d, J = 8.0 Hz, 1H), 3.59 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.5 (d, 4JCF = 1.5 Hz), 143.3, 143.1 (d, 1JCF
=
3
3
264.6 Hz), 141.9, 132.1 (d, JCF = 3.9 Hz), 129.1 (d, JCF = 3.4 Hz),
124.7, 123.8, 122.4 (d, 3JCF = 6.8 Hz), 120.7, 114.4, 111.2 (d, 4JCF = 1.2
(d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 146.2 (d, 1JCF
=
E
dx.doi.org/10.1021/jo5005845 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
4
3
262.3 Hz), 143.1, 141.7 (d, JCF = 1.6 Hz), 133.6, 132.3 (d, JCF = 3.7
(Z)-1-(2-(4-Bromophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
1
3
((Z)-3gi): yield 23% (72.7 mg), white solid; mp 138.7−139.8 °C; H
Hz), 131.6 (d, JCF = 3.6 Hz), 128.9, 127.5, 127.4, 126.9, 126.4, 125.9
4
3
NMR (400 MHz, CDCl3) δ 8.06 (s, 1H), 7.79−7.77 (m, 1H), 7.55−
7.54 (m, 1H), 7.48−7.46 (m, 2H), 7.39−7.37 (m, 2H), 7.34−7.30 (m,
2H), 5.87 (d, J = 32.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 145.4
(d, JCF = 1.9 Hz), 125.6, 124.6, 123.7, 123.6, 120.7, 111.4 (d, JCF
=
2.5 Hz), 101.6 (d, J = 33.0 Hz); 19F NMR (376 MHz, CDCl3) δ −87.4
(d, J = 8.6 Hz); HRMS (EI) calcd for C19H13FN2 [M]+ 288.1063,
found 288.1062.
1
4
(d, JCF = 271.6 Hz), 143.5, 140.8, 132.3 (d, JCF = 2.8 Hz), 132.1,
3
3
130.2 (d, JCF = 6.1 Hz), 130.1 (d, JCF = 7.5 Hz), 124.8, 123.9, 122.1
(d, 3JCF = 3.4 Hz), 121.0, 111.3 (d, 4JCF = 2.7 Hz), 100.4 (d, 2JCF = 14.9
Hz); 19F NMR (376 MHz, CDCl3) δ −92.8 (d, J = 30.8 Hz); HRMS
(EI) calcd for C15H10BrFN2 [M]+ 316.0011, found 316.0012.
(Z)-1-(1-Fluoro-2-(naphthalen-1-yl)vinyl)-1H-benzo[d]imidazole
((Z)-3di): yield 11% (31.7 mg), white solid; mp 136.0−137.0 °C; H
1
NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 8.00 (d, J = 8.0 Hz, 1H),
7.91−7.85 (m, 4H), 7.70 (d, J = 8.0 Hz, 1H), 7.56−7.53 (m, 3H),
7.43−7.39 (m, 2H), 6.63 (d, J = 32.0 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 145.8 (d, 1JCF = 269.7 Hz), 143.6, 141.0, 133.7, 132.4, 131.3,
128.9, 128.8 (d, 4JCF = 0.8 Hz), 127.3 (d, 3JCF = 8.6 Hz), 127.2 (d, 3JCF
= 4.8 Hz), 126.7, 126.1, 125.5, 124.8, 123.9, 123.5, 121.0, 111.4 (d, 3JCF
(E)-1-(2-(3-Chlorophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
((E)-3hi): yield 57% (155.0 mg), white solid; mp 107.4−108.5 °C; 1H
NMR (400 MHz, CDCl3) δ 7.78−7.75 (m, 2H), 7.26−7.21 (m, 3H),
7.02 (d, J = 8.0 Hz, 1H), 6.92−6.88 (m, 1H), 6.82 (s, 1H), 6.47 (d, J =
8.0 Hz, 1H), 6.32 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
= 2.6 Hz), 97.8 (d, JCF = 16.3 Hz); 19F NMR (376 MHz, CDCl3) δ
2
1
3
145.2 (d, JCF = 264.9 Hz), 143.4, 141.5, 134.8, 132.2 (d, JCF = 7.6
−95.4 (d, J = 29.1 Hz); HRMS (EI) calcd for C19H13FN2 [M]+
288.1063, found 288.1064.
Hz), 130.1, 128.4, 128.3, 128.2, 125.4 (d, 3JCF = 2.9 Hz), 124.9, 124.0,
120.9, 111.2 (d, JCF = 1.2 Hz), 104.3 (d, JCF = 35.9 Hz); 19F NMR
(376 MHz, CDCl3) δ −84.0 (d, J = 8.7 Hz); HRMS (EI) calcd for
C15H10ClFN2 [M]+ 272.0517, found 272.0512.
4
2
(E)-1-(2-(2-Bromophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
((E)-3ei): Yield 55% (173.8 mg), white solid; mp 119.8−121.0 °C; 1H
NMR (400 MHz, CDCl3) δ 7.82−7.80 (m, 2H), 7.59 (d, J = 8.0 Hz,
1H), 7.37−7.32 (m, 3H), 7.07−7.03 (m, 1H), 6.97−6.93 (m, 1H),
6.65 (d, J = 8.0 Hz, 1H), 6.60−6.58 (m, 1H); 13C NMR (100 MHz,
(Z)-1-(2-(3-Chlorophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
1
((Z)-3hi): yield 33% (89.8 mg), white solid; mp 125.8−126.9 °C; H
NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.85−7.83 (m, 1H), 7.61−
CDCl3) δ 145.9 (d, 1JCF = 263.9 Hz), 143.1, 141.4 (d, JCF = 2.0 Hz),
4
7.57 (m, 2H), 7.44−7.29 (m, 5H), 5.90 (d, J = 32.0 Hz, 1H); 13C
133.0, 132.0 (d, 3JCF = 3.5 Hz), 129.7, 128.9, 128.8, 127.8, 124.8, 124.3
(d, 3JCF = 5.0 Hz), 123.8, 120.7, 111.3 (d, 4JCF = 2.1 Hz), 104.0 (d, 2JCF
= 36.5 Hz); 19F NMR (376 MHz, CDCl3) δ −86.4 (d, J = 8.4 Hz);
HRMS (EI) calcd for C15H10BrFN2 [M]+ 316.0011, found 316.0010.
(Z)-1-(2-(2-Bromophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
1
NMR (100 MHz, CDCl3) δ 145.8 (d, JCF4 = 272.1 Hz), 143.5, 140.8,
3
134.7, 133.0 (d, JCF = 6.0 Hz), 132.2 (d, JCF = 2.6 Hz), 130.1, 128.4
3
4
3
(d, JCF = 8.0 Hz), 128.1 (d, JCF = 2.0 Hz), 126.7 (d, JCF = 7.2 Hz),
124.8, 123.9, 120.9, 111.3 (d, 4JCF = 2.9 Hz), 99.7 (d, 2JCF = 14.5 Hz);
19F NMR (376 MHz, CDCl3) δ −92.4 (d, J = 30.8 Hz); HRMS (EI)
calcd for C15H10ClFN2 [M]+ 272.0517, found 272.0515.
1
((Z)-3ei): yield 38% (120.1 mg), white solid; mp 134.2−135.1 °C; H
NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.77−7.73 (m, 2H), 7.61−
7.59 (m, 1H), 7.54−7.52 (m, 1H), 7.32−7.27 (m, 3H), 7.07−7.06 (m,
1H), 6.29 (d, J = 32.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 145.9
(E)-1-(1-Fluoro-2-(3-iodophenyl)vinyl)-1H-benzo[d]imidazole
1
((E)-3ii): yield 60% (218.4 mg), white solid; mp 96.1−97.0 °C; H
NMR (400 MHz, CDCl3) δ 7.86−7.83 (m, 2H), 7.46 (d, J = 8.0 Hz,
1H), 7.35−7.30 (m, 4H), 6.80−6.77 (m, 1H), 6.60 (d, J = 8.0 Hz,
1H), 6.38 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 145.0
1
3
(d, JCF = 271.5 Hz), 143.7, 140.6, 133.0, 132.0, 131.1 (d, JCF = 5.9
Hz), 130.0 (d, 3JCF = 11.0 Hz), 129.4 (d, 4JCF = 1.3 Hz), 127.7, 124.9,
124.0, 123.9 (d, 4JCF = 1.8 Hz), 121.0, 111.4 (d, 4JCF = 2.5 Hz), 99.0 (d,
2JCF = 13.0 Hz); 19F NMR (376 MHz, CDCl3) δ −95.1 (d, J = 31.0
Hz); HRMS (EI) calcd for C15H10BrFN2 [M]+ 316.0011, found
316.0010.
1
4
3
(d, JCF = 265.0 Hz), 143.2, 141.3 (d, JCF = 2.4 Hz), 137.2 (d, JCF
=
4
3
3.9 Hz), 137.1 (d, JCF = 1.3 Hz), 132.5 (d, JCF = 7.4 Hz), 131.7 (d,
3JCF = 3.8 Hz), 130.5, 126.2 (d, JCF = 2.8 Hz), 124.9, 124.0, 120.9,
4
111.2 (d, JCF = 1.5 Hz), 104.0 (d, JCF = 35.8 Hz), 94.6; 19F NMR
(376 MHz, CDCl3) δ −84.0 (d, J = 8.7 Hz); HRMS (EI) calcd for
C15H10FIN2 [M]+ 363.9873, found 363.9872.
4
2
(E)-1-(2-(3-Bromophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
1
((E)-3fi): yield 47% (148.5 mg), white solid; mp 115.4−116.6 °C; H
NMR (400 MHz, CDCl3) δ 7.88−7.86 (m, 2H), 7.37−7.28 (m, 4H),
7.12−7.11 (m, 1H), 6.97−6.93 (m, 1H), 6.61 (d, J = 8.0 Hz, 1H), 6.42
(Z)-1-(1-Fluoro-2-(3-iodophenyl)vinyl)-1H-benzo[d]imidazole
1
((Z)-3ii): yield 29% (105.6 mg), white solid; mp 110.2−111.3 °C; H
(d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 145.2 (d, 1JCF
=
NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 7.92−7.91 (m, 1H), 7.85−
7.83 (m, 1H), 7.65−7.62 (m, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.39−7.36
(m, 2H), 7.15−7.11 (m, 1H), 5.87 (d, J = 32.0 Hz, 1H); 13C NMR
4
3
265.0 Hz), 143.3, 141.4 (d, JCF = 2.4 Hz), 132.5 (d, JCF = 7.6 Hz),
131.8 (d, 3JCF = 3.8 Hz), 131.3 (d, 3JCF = 3.9 Hz), 131.2 (d, 4JCF = 1.2
4
1
Hz), 130.4, 125.7 (d, JCF = 2.9 Hz), 124.9, 124.0, 122.9, 120.9, 111.2
(100 MHz, CDCl3) δ 145.7 (d, JCF = 272.1 Hz), 143.5, 140.8, 137.2
(d, JCF = 1.5 Hz), 104.2 (d, JCF = 35.9 Hz); 19F NMR (376 MHz,
CDCl3) δ −83.9 (d, J = 8.6 Hz); HRMS (EI) calcd for C15H10BrFN2
[M]+ 316.0011, found 316.0010.
4
2
3
4
3
(d, JCF = 7.8 Hz), 137.0 (d, JCF = 2.2 Hz), 133.4 (d, JCF = 6.1 Hz),
132.2 (d, 4JCF = 2.6 Hz), 130.5, 127.7 (d, 3JCF = 7.5 Hz), 124.8, 124.0,
121.0, 111.3 (d, JCF = 2.8 Hz), 99.6 (d, JCF = 14.6 Hz), 94.7; 19F
NMR (376 MHz, CDCl3) δ −92.4 (d, J = 30.5 Hz); HRMS (EI) calcd
for C15H10FIN2 [M]+ 363.9873, found 363.9872.
4
2
(Z)-1-(2-(3-Bromophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
((Z)-3fi): yield 40% (126.4 mg), white solid; mp 138.2−139.1 °C; H
1
NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 7.80−7.78 (m, 1H), 7.69−
7.68 (m, 1H), 7.57−7.55 (m, 1H), 7.45−7.43 (m, 1H), 7.39−7.35 (m,
1H), 7.34−7.31 (m, 2H), 7.23 (d, J = 8.0 Hz, 1H), 5.87 (d, J = 32.0
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 146.1 (d, 1JCF = 263.2 Hz),
143.6, 140.8, 133.3 (d, 3JCF = 6.1 Hz), 132.2, 131.4 (d, 3JCF = 8.0 Hz),
131.1 (d, 4JCF = 2.1 Hz), 130.4, 127.1 (d, 3JCF = 7.2 Hz), 124.8, 124.0,
1-(1-Fluoro-2,2-diphenylvinyl)-1H-imidazole (3ja): yield 90%
1
(237.8 mg), white solid; mp 102.2−103.4 °C; H NMR (400 MHz,
CDCl3) δ 7.46 (s, 1H), 7.40−7.37 (m, 5H), 7.29−7.27 (m, 3H),
7.06−7.03 (m, 3H), 6.96 (s, 1H); 13C NMR (100 MHz, CDCl3) δ
1
3
142.6 (d, JCF = 265.6 Hz), 137.3, 135.8 (d, JCF = 3.9 Hz), 135.6 (d,
3JCF = 3.4 Hz), 129.7, 129.6, 129.6, 129.5, 128.9, 128.4, 128.2 (d, 3JCF
=
4
2
123.0, 121.0, 111.3 (d, JCF = 2.8 Hz), 99.8 (d, JCF = 14.7 Hz); 19F
NMR (376 MHz, CDCl3) δ −92.1 (d, J = 30.6 Hz); HRMS (EI) calcd
for C15H10BrFN2 [M]+ 316.0011, found 316.0012.
6.0 Hz), 118.6, 115.7 (d, JCF = 20.1 Hz); 19F NMR (376 MHz,
CDCl3) δ −93.2 (s); HRMS (EI) calcd for C17H13FN2 [M]+ 264.1063,
found 264.1064.
2
(E)-1-(2-(4-Bromophenyl)-1-fluorovinyl)-1H-benzo[d]imidazole
1-((9H-Fluoren-9-ylidene)fluoromethyl)-1H-1,2,4-triazole (3kf):
1
1
((E)-3gi): yield 69% (218.0 mg), white solid; mp 118.3−119.4 °C; H
yield 91% (240.3 mg), white solid; mp 104.1−105.1 °C; H NMR
NMR (400 MHz, CDCl3) δ 7.90−7.87 (m, 2H), 7.38−7.30 (m, 5H),
6.70 (d, J = 8.0 Hz, 2H), 6.47 (d, J = 8.0 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 144.7 (d, 1JCF = 264.5 Hz), 143.3, 141.4 (d, 3JCF = 2.5
(400 MHz, CDCl3) δ 8.50 (s, 1H), 8.32 (s, 1H), 7.97 (d, J = 8.0 Hz,
1H), 7.67 (dd, J = 12.0, 8.0 Hz, 2H), 7.45−7.29 (m, 3H), 7.06−7.03
(m, 1H), 6.15 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ
3
1
4
Hz), 132.2, 131.8 (d, JCF = 3.9 Hz), 129.4, 129.3, 124.9, 124.0, 122.3
153.9, 145.9, 141.1 (d, JCF = 280.8 Hz), 140.7 (d, JCF = 5.0 Hz),
140.1, 134.2 (d, 3JCF = 6.7 Hz), 133.2 (d, 3JCF = 5.2 Hz), 129.9 (d, 4JCF
= 2.4 Hz), 129.6 (d, 4JCF = 2.3 Hz), 128.0, 127.6, 126.1 (d, 3JCF = 13.5
Hz), 122.6 (d, 4JCF = 2.5 Hz), 120.4, 120.1, 117.9 (d, 2JCF = 22.4 Hz);
4
2
(d, JCF = 1.6 Hz), 120.9, 111.2, 104.8 (d, JCF = 35.8 Hz); 19F NMR
(376 MHz, CDCl3) δ −84.4 (d, J = 8.7 Hz); HRMS (EI) calcd for
C15H10BrFN2 [M]+ 316.0011, found 316.0013.
F
dx.doi.org/10.1021/jo5005845 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
19F NMR (376 MHz, CDCl3) δ −80.2 (s); HRMS (EI) calcd for
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C16H10FN3 [M]+ 263.0860, found 263.0860.
1,1′-(2-(4-Methoxyphenyl)ethene-1,1-diyl)bis(1H-imidazole) (4):
yield 94% (250.0 mg), white solid; mp 86.8−87.8 °C; 1H NMR
(400 MHz, CDCl3) δ 7.64 (s, 1H), 7.55 (s, 1H), 7.24 (s, 1H), 7.12 (s,
1H), 6.96 (s, 2H), 6.76 (s, 4H), 6.59 (s, 1H), 3.76 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 160.0, 137.4, 135.8, 131.2, 130.7, 129.8, 125.1,
123.7, 118.7, 117.5, 116.4, 114.5, 55.3; HRMS (EI) calcd for
C15H14N4O [M]+ 266.1168, found 266.1169.
(E)-1-(1-(1H-Imidazol-1-yl)-2-(4-methoxyphenyl)vinyl)-1H-pyra-
zole ((E)-5): yield 86% (228.8 mg), white solid; mp 87.0−88.0 °C; 1H
NMR (400 MHz, CDCl3) δ 7.76 (s, 1H), 7.58 (d, J = 1.3 Hz, 1H),
7.42 (d, J = 2.4 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J = 2.4 Hz, 1H), 6.65−
6.60 (m, 4H), 6.38−6.37 (m, 1H), 6.24−6.23 (m, 1H), 3.64 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 159.5, 142.4, 141.6, 132.4, 131.1,
130.0, 127.9, 124.8, 115.4, 114.1, 108.0, 107.2, 55.2; HRMS (EI) calcd
for C15H14N4O [M]+ 266.1168, found 266.1170.
(Z)-1-(1-(1H-Imidazol-1-yl)-2-(4-methoxyphenyl)vinyl)-1H-pyra-
zole ((Z)-5): yield 85% (226.1 mg), white solid; mp 86.6−87.6 °C; 1H
NMR (400 MHz, CDCl3) δ 7.58 (s, 1H), 7.49 (s, 1H), 7.18 (s, 1H),
7.06 (s, 1H), 6.90 (s, 2H), 6.70 (s, 4H), 6.54 (s, 1H), 3.70 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 160.0, 137.4, 135.8, 131.2, 130.7, 129.8,
125.1, 123.7, 118.7, 117.5, 116.4, 114.5, 55.3; HRMS (EI) calcd for
C15H14N4O [M]+ 266.1168, found 266.1169.
́
15990. (j) Oshovsky, G. V.; Ouali, A.; Xia, N.; Zablocka, M.; Boere, R.
T.; Duhayon, C.; Taillefer, M.; Majoral, J. P. Organometallics 2008, 27,
5733.
ASSOCIATED CONTENT
(5) (a) Ichikawa, J.; Wada, Y.; Fujiwara, M.; Sakoda, K. Synthesis
2002, 13, 1917. (b) Zhang, W.; Huang, W.; Hu, J. Angew. Chem., Int.
Ed. 2009, 48, 9858. (c) Yamada, S.; Takahashi, T.; Konno, T.; Ishihara,
T. Chem. Commun. 2007, 3679. (d) Dutheuil, G.; Paturel, C.; Lei, X.;
Couve-Bonnaire, S.; Pannecoucke, X. J. Org. Chem. 2006, 71, 4316.
(6) (a) Karukurichi, K. R.; de la Salud-Bea, R.; Jahng, W. J.;
Berkowitz, D. B. J. Am. Chem. Soc. 2007, 129, 258. (b) Manca, I.;
Mastinu, A.; Olimpieri, F.; Falzoi, M.; Sani, M.; Ruiu, S.; Loriga, G.;
Volonterio, A.; Tambaro, S.; Bottazzi, M. E. H.; Zanda, M.; Pinna, G.
A.; Lazzari, P. Eur. J. Med. Chem. 2013, 62, 256. (c) Messaoudi, S.;
■
S
* Supporting Information
1H, 13C, and 19F NMR spectra and HRMS (EI) spectra of
1
compounds 3; H, 13C NMR spectra and HRMS (EI) spectra
of compounds 4, (E)-5, (Z)-5; X-ray analysis data of (E)-5.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: scao@ecust.edu.cn. Tel: +86-21-64253452.
■
́
Treguier, B.; Hamze, A.; Provot, O.; Peyrat, J.-F.; Losada, J. R. D.; Liu,
J.-M.; Bignon, J.; Wdzieczak-Bakala, J.; Thoret, S.; Dubois, J.; Brion, J.-
D.; Alami, M. J. Med. Chem. 2009, 52, 4538. (d) Yu, C.-S.; Chiang, L.-
W.; Wu, C.-H.; Hsu, Z.-K.; Lee, M.-H.; Pan, S.-D.; Pei, K. Synthesis
2006, 22, 3835.
Notes
The authors declare no competing financial interest.
(7) (a) Eddarir, S.; Abdelhadi, Z.; Rolando, C. Tetrahedron Lett.
2001, 42, 9127. (b) Katsutoshi, F.; Yasushi, N.; Koji, H.; Yu, K. JP
2006008579 A, 2006. (c) Alexande, S. WO 2004005268 A1, 2004.
ACKNOWLEDGMENTS
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We are grateful for financial support from the National Natural
Science Foundation of China (Grant Nos. 21272070,
21072057), the National Basic Research Program of China
(973 Program, 2010CB126101), and the Twelfth Five-year
Plan of China (2011BAE06B01-15).
(8) (a) Van der Veken, P.; Senten, K.; Kertes
̀
z, I.; Meester, I. D.;
Lambeir, A.-M.; Maes, M.-B.; Scharpe, S.; Haemers, A.; Augustyns, K.
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J. Med. Chem. 2005, 48, 1768. (b) Zhao, K.; Lim, D. S.; Funaki, T.;
Welch, J. T. Bioorg. Med. Chem. 2003, 11, 207. (c) Lin, J.; Toscano, P.
J.; Welch, J. T. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 14020. (d) Welch,
J. T.; Lin, J. Tetrahedron 1996, 52, 291. (e) Steert, K.; El-Sayed, I.; Van
der Veken, P.; Krishtal, A.; Alsenoy, C. V.; Westrop, G. D.; Mottram, J.
C.; Coombs, G. H.; Augustyns, K.; Haemers, A. Bioorg. Med. Chem.
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