An efficient method to access 2-fluoroalkylbenzimidazoles by PIDA oxidation of amidines

Article abstract of DOI:10.1016/j.jfluchem.2011.06.007

A mild and practical strategy for the synthesis of 2-bromodifluoromethyl (or trifluoromethyl)-1H-benzimidazoles via PIDA-mediated oxidative intramolecular cyclization of the fluorinated amidines is described. The approach has the advantages of superior yi

Full text of DOI:10.1016/j.jfluchem.2011.06.007

Journal of Fluorine Chemistry 133 (2012) 134–138
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
An efficient method to access 2-fluoroalkylbenzimidazoles by PIDA oxidation
of amidines
Jiangtao Zhu a, Zixian Chen a,b, Haibo Xie a, Shan Li a, Yongming Wu a,
*
a Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
b Department Chemistry, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A mild and practical strategy for the synthesis of 2-bromodifluoromethyl (or trifluoromethyl)-1H-
benzimidazoles via PIDA-mediated oxidative intramolecular cyclization of the fluorinated amidines is
described. The approach has the advantages of superior yields, excellent functional groups tolerance and
mild reaction conditions.
Received 6 May 2011
Received in revised form 3 June 2011
Accepted 8 June 2011
Available online 15 June 2011
ß 2011 Elsevier B.V. All rights reserved.
Keywords:
Fluorinated-1H-benzimidazoles
PIDA-mediated
Intramolecular cyclization
Fluorinated amidines
1. Introduction
2. Results and discussion
Benzimidazoles are known as an important class of heterocyclic
compounds that exhibit a wide range of biological properties [1].
Among many 2-substituted benzimidazoles, 2-fluoroalkylbenzi-
midazole derivatives have received considerable attention due to
their potential bioactivities such as antiviral, antifungal, antibac-
terial, antiparasitic and anti-tumor activities [2]. Recently, 2-
trifluoromethyl-1H-benzimidazole derivatives with various 5- and
6-position bioisosteric substituents (–Cl, –F, –CF3, and –CN),
showed higher or equal activity against protozoa Giardia intesti-
nalis and Trichomonas vaginalis in comparison with Albendazole
and Metronidazole [3]. The classical methods generally used for
the preparation of 2-fluoroalkylbenzimidazoles include the
condensation of ortho-aminoanilines and reductive cyclization of
ortho-nitroanilines with fluorinated carboxylic acids [4]. The
drawbacks of these procedures are the limited diversity of the
starting materials and harsh reaction conditions. Herein, we wish
to describe a novel and facile synthesis of 2-bromodifluoromethyl
(or trifluoromethyl)-1H-benzimidazoles by the reaction of PIDA
(phenyliodine (III) diacetate) with N-arylbromodifluoro (or tri-
fluoro)acetamidines.
In 1995, Ramsden and Rose reported a reaction of N-substituted
amidines with PIDA and found out that the nature of the amidine
substituents and the reaction temperature determined the
products [5]. Only four benzimidazole derivatives were synthe-
sized by this approach. After that, the cyclization of amidines by
oxidative means using iodine(III) compounds as reagents has not
widely used owing to a rather narrow functional group tolerance.
Recently, we described a mild method for the synthesis of N-
substituted 2-fluoroalkylbenzimidazole via PIFA (phenyliodine
(III) bis(trifluoroacetate))-mediated intramolecular cyclization of
N,N0-disubstituted fluoroalkyl enthanimidamides [6]. It is only
logical to extend our approach to the synthesis of N-H-2-
fluoroalkylbenzimidazoles from N-arylfluoroacetamidines.
N-phenylbromodifluoroacetamidine 2a, was chosen as a model
substrate to optimize the reaction conditions, which was efficiently
prepared by the reaction of 2-bromo-2,2-difluoro-N-phenylaceti-
midoyl chloride 1a with ammonia in toluene at room temperature
for 2 h [7]. When the substrate 2a was treated with 1.2 equiv of PIDA
in CH3CN at room temperature for 12 h, 2-bromodifluoromethyl-
benzimidazole 3a was formed in 82% yield. Whereas PIFA gave only
40% yield of 3a under the similar conditions despite the starting
material 2a was consumed completely. Screening the solvents and
the temperature revealed that 2a was converted completely to the
desired product 3a in CH3CN at 60 8C in 1 h. With the optimal
reaction conditions in mind, we went ahead to explore the scope and
limitations of this transformation. A series of substituted amidines
which were synthesized from the corresponding imidoyl chlorides
* Corresponding author. Tel.: +86 21 54925190; fax: +86 21 64166128.
E-mail address: ymwu@sioc.ac.cn (Y. Wu).
0022-1139/$ – see front matter ß 2011 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2011.06.007

J. Zhu et al. / Journal of Fluorine Chemistry 133 (2012) 134–138
135
Table 1
Synthesis of 2-fluoroalkylbenzimidazoles.a
.
Entry
RF
Substrate (1)
2/yield (%)b
3/yield (%)b
1c
2c
3c
4
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF3
H(1a)
2a/95
2b/98
2c/97
2d/97
2e/96
2f/94
2g/96
2h/89
2i/99
2j/93
2k/98
2l/98
2m/96
2n/97
2o/98
2p/97
2q/97
2r/98
3a/82
3b/70
3c/65
3d/65
3e/87
3f/80
3g/84
3h/92
3i/97
3j/95
3k/94
3l/83
3m/78
3n/90
3o/88
3p/84
3q/83
3r/97
p-Me(1b)
p-OMe(1c)
p-I(1d)
5
p-Br(1e)
p-Cl(1f)
6
7
p-CF3(1g)
p-CN(1h)
p-Ac(1i)
8
9
10
11
12
13
14
15d
16d
17
18
p-COOEt(1j)
p-NO2(1k)
o-Me(1l)
o-I(1m)
o-CF3(1n)
m-Me(1o)
m-CF3(1p)
p-CF3(1q)
p-CN(1r)
CF3
a
Conditions: the amidines 2 (1 mmol), PIDA (386 mg, 1.2 mmol) in CH3CN (10 mL) at 60 8C for 1 h.
Isolated yields.
b
c
At room temperature for 12 h.
The ratio of 5(6):4(7) ꢁ 1.5:1.
d
were treated with PIDA to afford 2-bromodifluoromethylbenzimi-
were taken on a Bruker AM-300 (282 MHz) spectrometer using
CFCl3 as external standard. 13C NMR spectra were taken on a Bruker
AM-400 (100 MHz) spectrometer. IR spectra were obtained with a
Nicolet AV-360 spectrophotometer. All reagents were used as
received from commercial sources. Column chromatography over
silica gel (300–400 mesh) and petroleum ether/ethyl acetate
combination was used as the eluent.
dazoles in good yields. The results are summarized in Table 1. The
substrates bearing the electron-donating (Me, OMe, entries 2, 3 and
12) and electron-withdrawing groups (CF3, CN, Ac, COOEt, NO2,
entries 7–11 and 14) in the para or ortho position of the benzene ring
led to the corresponding benzimidazoles in good yields. Halogens
could survive under the reaction conditions, providing a useful
handle for further cross-coupling reactions (entries 4–6 and 13) [8].
The intramolecular cyclization of meta-substituted amidines furn-
ished a mixture of 5(6)-substituted and 4(7)-substituted regioi-
somers (entries 15 and 16). 5(6)-Substituted ones were detected as
the major products, but the isomers could not be isolated by silica gel
column chromatography. It is worth noting that 2,5(6)-ditrifluor-
omethylbenzimidazole 3q and 5(6)-cyano-2-trifluoromethylbenzi-
midazole 3r which were described above as potential antiprotozal
agents were obtained in good yields by utilizing this method (entries
17 and 18).
4.2. General procedure for the synthesis of fluorinated amidines 2
To a stirred mixture of fluorinated acetimidoyl chlorides 1
(3 mmol) in toluene (20 mL), the gas of ammonia was aerated
slowly. The mixture was stirred at room temperature for 30 min
and then filtered, washed by ethyl ether, after removing the
solvent under reduced pressure, the product 2 was obtained
quantitatively by flash column chromatography.
4.3. Spectroscopic data of 2-bromodifluoro (or trifluoro)-N-
3. Conclusion
arylacetamidines 2
In conclusion, we have successfully developed an efficient
method for the generation of 2-fluoroalkyl-1H-benzimidazoles by
the PIDA oxidation of fluorinated amidines. The process has
obviated using ortho-aminoanilines and ortho-haloanilines as the
starting materials. The biological study of the benzimidazoles
obtained in this paper is currently underway.
4.3.1. 2-Bromo-2,2-difluoro-N-phenylacetamidine (2a)
1H NMR (300 MHz, CDCl3):
d 7.39–7.34 (m, 2H), 7.11 (t,
J = 7.2 Hz, 1H), 6.93 (d, J = 7.8 Hz, 1H), 4.89 (brs, 2H). 19F NMR
(282 MHz, CDCl3):
d
ꢀ57.45 (s, 2F). 13C NMR (100 MHz, CDCl3):
d
149.9 (t, J = 26.0 Hz), 146.2, 129.6, 124.3, 120.5, 113.0 (t,
J = 305.9 Hz). MS (EI): m/z (%): 248 (17.31) [M+], 119 (100.00).
Anal. Calcd. for C8H7BrF5N2: C, 38.58; H, 2.83; N, 11.25; Found: C,
4. Experimental
38.91; H, 2.66; N, 11.23. IR (film):
1594, 1499, 1238, 1130, 933 cmꢀ1
n 3440, 3320, 3181, 1728, 1678,
.
4.1. General
4.3.2. 2-Bromo-2,2-difluoro-N-p-tolylacetamidine (2b)
1H NMR (300 MHz, CDCl3):
7.14 (d, J = 7.8 Hz, 2H), 6.80 (d,
J = 7.8 Hz, 2H), 4.92 (brs, 2H) 2.31 (s, 3H). 19F NMR (282 MHz,
1H NMR spectra were recorded on a Bruker AM-300 spectrom-
eter (300 MHz) with TMS as internal standard. 19F NMR spectra
d

136
J. Zhu et al. / Journal of Fluorine Chemistry 133 (2012) 134–138
CDCl3):
d
ꢀ57.32 (s, 2F). 13C NMR (100 MHz, CDCl3):
d
150.0,
Found: C, 41.74; H, 3.08; N, 9.81. IR (KBr):
n
3404, 3325, 3211,
.
143.3, 133.7, 130.1, 120.4, 113.0 (t, J = 305.9 Hz). MS (EI): m/z
(%): 262 (23.00) [M+], 133 (100.00). Anal. Calcd. for C9H9BrF2N2:
C, 41.09; H, 3.45; N, 10.65; Found: C, 41.41; H, 3.40; N, 10.49. IR
1674, 1654, 1590, 1258, 1176, 1135, 918 cmꢀ1
4.3.9. Ethyl-4-(1-amino-2-bromo-2,2-
(film):
n
3442, 3329, 3147, 1673, 1506, 1242, 1170, 1121,
difluoroethylideneamino)benzoate (2j)
934 cmꢀ1
.
White solid, mp: 126–127 8C. 1H NMR (300 MHz, CDCl3):
d
8.02
(d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 5.00 (brs, 2H), 4.34 (q,
J = 6.9 Hz, 2H), 1.39 (t, J = 6.9 Hz, 3H). 19F NMR (282 MHz, CDCl3):
d 166.1, 150.9, 149.6 (t,
J = 26.0 Hz), 131.1, 126.0, 120.4, 112.8 (t, J = 305.9 Hz), 60.8, 14.1.
MS (EI): m/z (%): 320 (27.44) [M+], 191 (100.00). Anal. Calcd. for
d
4.3.3. 2-Bromo-2,2-difluoro-N-(4-iodophenyl)acetamidine (2d)
White solid, mp: 96 8C. 1H NMR (300 MHz, CDCl3):
7.67 (d,
ꢀ57.68 (s, 2F). 13C NMR (100 MHz, CDCl3):
d
J = 8.4 Hz, 2H), 6.69 (d, J = 8.4 Hz, 2H), 4.93 (brs, 2H). 19F NMR
(282 MHz, CDCl3):
d
ꢀ57.62 (s, 2F). 13C NMR (100 MHz, CDCl3):
d
C
11H11BrF2N2O2: C, 41.14; H, 3.45; N, 8.72; Found: C, 41.39; H,
3.42; N, 8.71. IR (KBr): 3389, 3164, 2977, 1697, 1655, 1598, 1280,
1248, 1172, 1114, 920, 873 cmꢀ1
150.0 (t, J = 26.0 Hz), 145.9, 138.6, 122.8, 112.8 (t, J = 305.2 Hz),
88.0. MS (EI): m/z (%): 374 (38.79) [M+], 245 (100.00). Anal. Calcd.
for C8H6BrF2IN2: C, 25.63; H, 1.61; N, 7.47; Found: C, 25.75; H, 1.61;
n
.
N, 7.51. IR (KBr):
n 3484, 3238, 3169, 1670, 1607, 1477, 1241, 1152,
1119, 1005, 919 cmꢀ1
.
4.3.10. 2-Bromo-2,2-difluoro-N-(4-nitrophenyl)acetamidine (2k)
White solid, mp: 168–170 8C. 1H NMR (300 MHz, CDCl3):
8.21
d
(d, J = 8.7 Hz, 2H), 7.06 (d, J = 8.7 Hz, 2H), 5.08 (brs, 2H). 19F NMR
4.3.4. 2-Bromo-N-(4-bromophenyl)-2,2-difluoroacetamidine (2e)
White solid, mp: 52 8C. 1H NMR (300 MHz, CDCl3):
7.48 (d,
(282 MHz, CDCl3):
d
ꢀ57.66 (s, 2F). 13C NMR (100 MHz, d6-DMSO):
d
d
155.3, 151.3 (t, J = 26.0 Hz), 143.3, 125.6, 122.4, 113.7 (t,
J = 8.4 Hz, 2H), 6.81 (d, J = 8.4 Hz, 2H), 4.88 (brs, 2H). 19F NMR
J = 305.6 Hz). MS (EI): m/z (%): 293 (22.35) [M+], 164 (100.00).
(282 MHz, CDCl3):
d
ꢀ57.68 (s, 2F). 13C NMR (100 MHz, CDCl3):
d
Anal. Calcd. for C8H6BrF2N3O2: C, 32.68; H, 2.06; N, 14.29; Found: C,
150.1 (t, J = 26.0 Hz), 145.2, 132.6, 122.4, 117.2, 112.8 (t,
J = 305.9 Hz). MS (EI): m/z (%): 328 (40.81) [M+], 197 (100.00).
Anal. Calcd. for C8H6Br2F2N2: C, 29.30; H, 1.84; N, 8.54; Found: C,
33.04; H, 1.96; N, 14.32. IR (KBr):
n 3392, 3301, 3157, 1670, 1589,
1507, 1343, 1248, 1176, 1127, 932, 874 cmꢀ1
.
29.42; H, 1.64; N, 8.55. IR (KBr):
n 3462, 3345, 3177, 1731, 1675,
.
4.3.11. 2-Bromo-2,2-difluoro-N-o-tolylacetamidine (2l)
1H NMR (300 MHz, CDCl3):
7.19–7.12 (m, 2H), 7.03–7.00 (m,
1483, 1244, 1170, 1127, 928 cmꢀ1
d
1H), 6.74 (d, J = 7.8 Hz, 1H), 4.81 (brs, 2H), 2.10 (s, 3H). 19F NMR
4.3.5. 2-Bromo-N-(4-chlorophenyl)-2,2-difluoroacetamidine (2f)
1H NMR (300 MHz, CDCl3):
7.31 (d, J = 7.8 Hz, 2H), 6.84 (d,
J = 7.8 Hz, 2H), 5.05 (brs, 2H). 19F NMR (282 MHz, CDCl3):
ꢀ57.60
(s, 2F). 13C NMR (100 MHz, CDCl3):
150.2 (t, J = 26.0 Hz), 144.7,
(282 MHz, CDCl3):
d
ꢀ57.37 (s, 2F). 13C NMR (100 MHz, CDCl3):
d
d
149.4 (t, J = 26.2 Hz), 144.4, 131.1, 129.2, 127.0, 124.4, 119.7, 113.0
(t, J = 304.8 Hz). MS (EI): m/z (%): 262 (20.25) [M+], 133 (100.00).
HRMS (EI) Calcd. for C9H9BrF2N2: 261.9917; Found: 261.9916. IR
d
d
129.6, 129.4, 121.9, 112.8 (t, J = 305.9 Hz). MS (EI): m/z (%): 282
(18.88) [M+], 153 (100.00). HRMS (EI) Calcd. for C8H6BrClF2N2:
281.9371; Found: 281.9375. IR (film):
1485, 1403, 1246, 1163, 1130, 928 cmꢀ1
(film):
n 3457, 3306, 3169, 1670, 1597, 1484, 1242, 1170, 1126,
925, 800 cmꢀ1
.
n 3455, 3253, 3138, 1667,
.
4.3.12. 2-Bromo-2,2-difluoro-N-(2-iodophenyl)acetamidine (2m)
White solid, mp: 78 8C. 1H NMR (300 MHz, CDCl3):
7.84 (d,
d
4.3.6. 2-Bromo-2,2-difluoro-N-(4-
J = 7.7 Hz, 1H), 7.35–7.30 (m, 1H), 6.86–6.80 (m, 2H), 4.87 (brs, 2H).
19F NMR (282 MHz, CDCl3):
d
ꢀ57.46 (s, 2F). 13C NMR (100 MHz,
(trifluoromethyl)phenyl)acetamidine (2g)
White solid, mp: 100–101 8C. 1H NMR (300 MHz, CDCl3):
d 7.62
CDCl3):
d 149.8 (t, J = 26.2 Hz), 139.7, 129.4, 125.8, 120.4, 112.6 (t,
(d, J = 8.4 Hz, 2H), 7.02 (d, J = 8.4 Hz, 2H), 4.89 (brs, 2H). 19F NMR
J = 307.5 Hz), 90.2. MS (EI): m/z (%): 374 (30.92) [M+], 245 (100.00).
(282 MHz, CDCl3):
(100 MHz, CDCl3):
d
d
ꢀ57.83 (s, 2F), ꢀ62.52 (s, 3F). 13C NMR
Anal. Calcd. for C8H6BrF2IN2: C, 25.63; H, 1.61; N, 7.47; Found: C,
150.2 (t, J = 26.0 Hz), 149.5, 126.8 (q,
25.73; H, 1.47; N, 7.44. IR (KBr):
n 3465, 3238, 3157, 1678, 1599,
1458, 1148, 1126, 1013, 934, 829 cmꢀ1
.
J = 3.7 Hz), 126.3 (q, J = 32.8 Hz), 124.0 (q, J = 271.0 Hz), 120.8,
112.6 (t, J = 300.6 Hz). MS (EI): m/z (%): 316 (14.71) [M+], 187
(100.00). Anal. Calcd. for C9H6BrF5N2: C, 34.09; H, 1.91; N, 8.84;
4.3.13. 2-Bromo-2,2-difluoro-N-(2-
Found: C, 34.41; H, 1.91; N, 9.05. IR (KBr):
n
3458, 3259, 3146,
.
(trifluoromethyl)phenyl)acetamidine (2n)
1H NMR (300 MHz, CDCl3):
7.65 (d, J = 7.8 Hz, 1H), 7.53–7.48
1670, 1611, 1512, 1324, 1165, 1123, 929 cmꢀ1
d
(m, 1H), 7.22–7.16 (m, 1H), 6.90 (d, J = 7.8 Hz, 1H), 4.88 (brs, 2H).
19F NMR (282 MHz, CDCl3):
NMR (100 MHz, CDCl3):
(q, J = 6.0 Hz), 124.0, 123.6 (q, J = 271.2 Hz), 121.7 (q, J = 30.0 Hz),
112.7 (t, J = 305.5 Hz). MS (EI): m/z (%): 316 (16.71) [M+], 187
(100.00). HRMS (EI) Calcd. for C9H6BrF5N2: 315.9635; Found:
d
ꢀ57.99 (s, 2F); ꢀ63.00 (s, 3F). 13C
4.3.7. 2-Bromo-N-(4-cyanophenyl)-2,2-difluoroacetamidine (2h)
White solid, mp: 180–182 8C. 1H NMR (300 MHz, CDCl3):
7.64
d
d
150.0 (t, J = 26.2 Hz), 144.9, 133.1, 127.1
(d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.1 Hz, 2H), 5.70 (brs, 2H). 19F NMR
(282 MHz, CDCl3):
d
ꢀ57.40 (s, 2F). 13C NMR (100 MHz, CDCl3):
d
151.6, 150.6, 133.5, 121.8, 118.9, 112.8, 106.9. MS (EI): m/z (%):
273 (13.45) [M+], 144 (100.00). Anal. Calcd. for C9H6BrF2N3: C,
39.44; H, 2.21; N, 15.33; Found: C, 39.81; H, 2.34; N, 15.46. IR
315.9633. IR (film):
n 3500, 3406, 3312, 3186, 1682, 1603, 1488,
1452, 1319, 1170, 1125, 930 cmꢀ1
.
(KBr):
931 cmꢀ1
n 3354, 3143, 2231, 1670, 1599, 1498, 1249, 1161, 1118,
.
4.3.14. 2-Bromo-2,2-difluoro-N-m-tolylacetamidine (2o)
1H NMR (300 MHz, CDCl3):
7.24–7.18 (m, 1H), 6.89 (d,
d
J = 7.3 Hz, 1H), 6.72–6.66 (m, 2H), 5.00 (brs, 2H), 2.31 (s, 3H). 19F
4.3.8. N-(4-acetylphenyl)-2-bromo-2,2-difluoroacetamidine (2i)
White solid, mp: 130–132 8C. 1H NMR (300 MHz, CDCl3):
7.93
(d, J = 7.8 Hz, 2H), 7.13 (brs, 2H), 6.94 (d, J = 7.8 Hz, 2H), 2.53 (s, 3H).
ꢀ57.30 (s, 2F). 13C NMR (100 MHz,
d
NMR (282 MHz, CDCl3):
CDCl3):
d
d
149.8 (t, J = 30.7 Hz), 146.3, 139.6, 129.5, 125.1, 121.1,
117.4, 113.3 (t, J = 304.8 Hz). MS (EI): m/z (%): 262 (16.78) [M+], 133
19F NMR (282 MHz, CDCl3):
d
ꢀ51.87 (s, 2F). 13C NMR (100 MHz,
CDCl3):
d 196.6, 151.9, 150.4 (t, J = 26.0 Hz), 132.5, 129.9, 120.8,
(100.00). HRMS (EI) Calcd. for C9H9BrF2N2: 261.9917; Found:
113.0 (t, J = 306.5 Hz), 26.2. MS (EI): m/z (%): 290 (44.22) [M+], 161
261.9919. IR (film):
n 3462, 3308, 3169, 1670, 1600, 1484, 1267,
1171, 1123, 933, 805 cmꢀ1
.
(100.00). Anal. Calcd. for C10H9BrF2N2O: C, 41.26; H, 3.12; N, 9.62;

J. Zhu et al. / Journal of Fluorine Chemistry 133 (2012) 134–138
137
4.3.15. 2,2,2-Trifluoro-N-(3-(trifluoromethyl)phenyl)acetamidine
(2p)
1H NMR (300 MHz, CDCl3):
2.60; N, 10.29. IR (KBr):
1117, 995 cmꢀ1
n
3292, 1635, 1458, 1276, 1242, 1170,
.
d
7.49–7.44 (m, 1H), 7.37 (d,
J = 7.8 Hz, 1H), 7.16 (s, 1H), 7.07 (d, J = 7.2 Hz, 1H), 5.07 (brs, 2H).
4.5.4. 2-(Bromodifluoromethyl)-6(5)-iodo-1H-benzo[d]imidazole
(3d)
19F NMR (282 MHz, CDCl3):
NMR (100 MHz, CDCl3):
d
ꢀ62.56 (s, 3F), ꢀ73.02 (s, 3F). 13C
White solid, mp: 160–162 8C. 1H NMR (300 MHz, d6-DMSO):
d
d
146.7, 146.0 (q, J = 36.0 Hz), 132.2 (q,
J = 32.0 Hz), 124.0, 123.8 (q, J = 270.5 Hz), 121.2 (q, J = 3.6 Hz),
118.0 (q, J = 276.4 Hz), 117.6 (q, J = 3.7 Hz). MS (EI): m/z (%): 256
(49.45) [M+], 187 (100.00). HRMS (EI) Calcd. for C9H6F6N2:
13.90 (brs, 1H), 8.07 (s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.53 (d,
J = 8.4 Hz, 1H). 19F NMR (282 MHz, d6-DMSO):
ꢀ48.17 (s, 2F). MS
(EI): m/z (%): 372 (17.05) [M+], 293 (100.00). HRMS (EI) Calcd. for
C8H4BrF2IN2: 371.8571; Found: 371.8573. IR (KBr): 3022, 1531,
1431, 1302, 1135, 986, 887, 799 cmꢀ1
d
256.0435; Found: 256.0437. IR (film):
1608, 1449, 1331, 1163, 900 cmꢀ1
n 3492, 3317, 3181, 1678,
n
.
.
4.3.16. 2,2,2-Trifluoro-N-(4-(trifluoromethyl)phenyl)acetamidine
4.5.5. 6(5)-Bromo-2-(bromodifluoromethyl)-1H-benzo[d]imidazole
(3e)
(2q)
1H NMR (300 MHz, CDCl3):
d 7.62 (d, J = 8.7 Hz, 2H), 7.00 (d,
White solid, mp: 180–182 8C. 1H NMR (300 MHz, d6-DMSO):
d
J = 8.7 Hz, 2H), 4.99 (brs, 2H). 19F NMR (282 MHz, CDCl3):
d
ꢀ62.12
13.90 (brs, 1H), 7.93 (s, 1H), 7.68 (d, J = 8.7 Hz, 1H), 7.52 (dd,
(s, 3F), ꢀ73.22 (s, 3F). 13C NMR (100 MHz, CDCl3):
d 149.4, 145.9 (q,
J1 = 8.7 Hz, J2 = 1.8 Hz, 1H). 19F NMR (282 MHz, d6-DMSO):
d
J = 35.7 Hz), 126.9, 126.5 (q, J = 32.5 Hz), 124.1 (q, J = 269.9 Hz),
121.2, 117.9 (q, J = 276.4 Hz). MS (EI): m/z (%): 256 (68.06) [M+],
187 (100.00). Anal. Calcd. for C9H6F6N2: C, 42.20; H, 2.36; N, 10.94;
ꢀ48.20 (s, 2F). MS (EI): m/z (%): 326 (26.61) [M+], 245 (100.00).
HRMS (EI) Calcd. for C8H4Br2F2N2: 323.8709; Found: 323.8705. IR
(KBr):
n
3015, 1525, 1480, 1432, 1306, 1234, 1135, 1123, 988,
.
Found: C, 42.52; H, 2.30; N, 11.13. IR (film):
n 3489, 3362, 3197,
807 cmꢀ1
1736, 1685, 1612, 1527, 1462, 1327, 1162, 1115, 1065, 833 cmꢀ1
.
4.5.6. 2-(Bromodifluoromethyl)-6(5)-chloro-1H-benzo[d]imidazole
(3f)
4.3.17. N-(4-Cyanophenyl)-2,2,2-trifluoroacetamidine (2r)
White solid, mp: 160–161 8C. 1H NMR (300 MHz, CDCl3):
d 7.64
White solid, mp: 180–182 8C. 1H NMR (300 MHz, d6-DMSO):
d
(d, J = 7.8 Hz, 2H), 7.03 (d, J = 7.8 Hz, 2H), 5.07 (brs, 2H). 19F NMR
7.70–7.65 (m, 2H), 7.33 (d, J = 8.4 Hz, 1H). 19F NMR (282 MHz, d6-
(282 MHz, CDCl3):
d
ꢀ73.18 (s, 3F). 13C NMR (100 MHz, CDCl3):
d
DMSO):
d
ꢀ47.42 (s, 2F). MS (EI): m/z (%): 280 (10.46) [M+], 201
151.7, 146.2 (q, J = 35.2 Hz), 133.4, 121.9, 118.8, 118.0 (q,
J = 276.9 Hz), 106.4. MS (EI): m/z (%): 213 (72.18) [M+], 144
(100.00). Anal. Calcd. for C9H6F3N3: C, 50.71; H, 2.84; N, 19.71;
(100.00). Anal. Calcd. for C8H4BrClF2N2: C, 34.14; H, 1.43; N, 9.95;
Found: C, 34.51; H, 1.53; N, 10.00. IR (KBr):
1308, 1134, 1122, 989, 809 cmꢀ1
n 2925, 1531, 1435,
.
Found: C, 50.92; H, 2.73; N, 19.91. IR (KBr):
n 3473, 3342, 3149,
.
2243, 1686, 1601, 1498, 1264, 1150, 870 cmꢀ1
4.5.7. 2-(Bromodifluoromethyl)-6(5)-(trifluoromethyl)-1H-
benzo[d]imidazole (3g)
4.4. General procedure for the synthesis of 2-
White solid, mp: 170–172 8C. 1H NMR (300 MHz, d6-DMSO):
d
fluoroalkylbenzimidazoles 3
14.32 (brs, 1H), 8.13 (s, 1H), 7.91–7.70 (m, 2H). 19F NMR (282 MHz,
d6-DMSO):
(10.93) [M+], 235 (100.00). Anal. Calcd. for C9H4BrF5N2: C, 34.31; H,
1.28; N, 8.89; Found: C, 34.34; H, 1.36; N, 8.87. IR (KBr): 3031,
1464, 1337, 1158, 1128, 1052, 888 cmꢀ1
d
ꢀ48.80 (s, 2F), ꢀ59.45 (s, 3F). MS (EI): m/z (%): 314
A mixture of fluoroacetamidine 2 (1.0 mmol) and PIDA (386 mg,
1.2 mmol) in CH3CN (10 mL) was stirred at 60 8C for 1 h. Then the
mixture was concentrated under reduced pressure. The residue
was then purified by column chromatography on silica gel using
petroleum ether/ethyl acetate as eluent to provide the desired
product 3.
n
.
4.5.8. 2-(Bromodifluoromethyl)-1H-benzo[d]imidazole-6(5)-
carbonitrile (3h)
White solid, mp: 160–162 8C. 1H NMR (300 MHz, d6-DMSO):
d
4.5. Spectroscopic data of 2-fluoroalkylbenzimidazoles 3
14.41 (brs, 1H), 8.35 (s, 1H), 7.86–7.74 (m, 2H). 19F NMR (282 MHz,
d6-DMSO):
d
ꢀ49.10 (s, 2F). MS (EI): m/z (%): 271 (8.68) [M+], 212
4.5.1. 2-(Bromodifluoromethyl)-1H-benzo[d]imidazole (3a) [4b]
1H NMR (300 MHz, d6-DMSO):
d 13.90 (brs, 1H), 7.68–7.65 (m,
(100.00). Anal. Calcd. for C9H4BrF2N3: C, 39.73; H, 1.48; N, 15.45;
2H), 7.35–7.31 (m, 2H). MS (EI): m/z (%): 246 (18.08) [M+], 167
Found: C, 39.67; H, 1.52; N, 15.69. IR (KBr):
1309, 1132, 1114, 997, 887 cmꢀ1
n 3072, 2233, 1474,
.
(100.00).
4.5.9. 1-(2-(Bromodifluoromethyl)-1H-benzo[d]imidazol-6 (5)-
yl)ethanone (3i)
4.5.2. 2-(Bromodifluoromethyl)-6(5)-methyl-1H-benzo[d]imidazole
(3b)
White solid, mp: 134–135 8C. 1H NMR (300 MHz, d6-DMSO):
d
White solid, mp: 144 8C. 1H NMR (300 MHz, d6-DMSO):
d
7.57
(d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.18 (d, J = 8.4 Hz, 1H), 2.44 (s, 3H).
19F NMR (282 MHz, d6-DMSO):
ꢀ47.25 (s, 2F). MS (EI): m/z (%):
260 (12.56) [M+], 181 (100.00). HRMS (EI) Calcd. for C9H7BrF2N2:
259.9761; Found: 259.9762. IR (KBr): 2927, 1445, 1319, 1152,
1118, 990, 885, 802 cmꢀ1
14.14 (brs, 1H), 8.41–7.67 (m, 3H), 2.67 (s, 3H). 19F NMR (282 MHz,
d6-DMSO):
d
ꢀ48.26 (s, 2F). MS (EI): m/z (%): 288 (22.21) [M+], 209
d
(100.00). Anal. Calcd. for C10H7BrF2N2O: C, 41.55; H, 2.44; N, 9.69;
Found: C, 41.77; H, 2.44; N, 9.67. IR (KBr):
1313, 1281, 1111, 992, 888, 801 cmꢀ1
n 3227, 1668, 1616,
n
.
.
4.5.10. Ethyl-2-(bromodifluoromethyl)-1H-benzo[d]imidazole-6(5)-
4.5.3. 2-(Bromodifluoromethyl)-6(5)-methoxy-1H-
benzo[d]imidazole (3c)
carboxylate (3j)
1H NMR (300 MHz, d6-DMSO):
d
14.19 (brs, 1H), 8.31 (s, 1H),
7.98 (d, J = 8.1 Hz, 1H), 7.79 (s, 1H), 5.85 (q, J = 7.2 Hz, 2H), 1.36 (t,
J = 7.2 Hz, 3H). 19F NMR (282 MHz, d6-DMSO):
ꢀ48.64 (s, 2F). MS
(EI): m/z (%): 318 (10.54) [M+], 239 (100.00). Anal. Calcd. for
11H9BrF2N2O2: C, 41.40; H, 2.84; N, 8.78; Found: C, 41.49; H, 2.93;
White solid, mp: 144–146 8C. 1H NMR (300 MHz, CDCl3):
d 7.61
(d, J = 9.0 Hz, 1H), 7.08 (d, J = 2.1 Hz, 1H), 7.03 (dd, J1 = 9.0 Hz,
J2 = 2.1 Hz, 1H), 3.83 (s, 3H). 19F NMR (282 MHz, CDCl3):
d
ꢀ48.20
d
(s, 2F). MS (EI): m/z (%): 276 (11.86) [M+], 197 (100.00). Anal. Calcd.
C
for C9H7BrF2N2O: C, 39.01; H, 2.55; N, 10.11; Found: C, 38.88; H,

138
J. Zhu et al. / Journal of Fluorine Chemistry 133 (2012) 134–138
N, 8.91. IR (KBr):
n
2991, 1708, 1456, 1320, 1287, 1108, 918,
4.5.16. 2-(Trifluoromethyl)-1H-benzo[d]imidazole-6(5)-carbonitrile
(3r) [3]
751 cmꢀ1
.
1H NMR (300 MHz, d6-DMSO):
d 15.01 (brs, 1H), 8.74 (s, 1H),
4.5.11. 2-(Bromodifluoromethyl)-6(5)-nitro-1H-benzo[d]imidazole
(3k)
8.27–8.17 (m, 2H). 19F NMR (282 MHz, d6-DMSO):
MS (EI): m/z (%): 211 (100.00) [M+].
d
ꢀ62.91 (s, 3F).
White solid, mp: 175–176 8C. 1H NMR (300 MHz, d6-DMSO):
d
14.57 (brs, 1H), 8.63 (s, 1H), 8.26–8.24 (m, 1H), 7.87 (d, J = 8.1 Hz,
Acknowledgement
1H). 19F NMR (282 MHz, d6-DMSO):
d
ꢀ49.47 (s, 2F). MS (EI): m/z
(%): 291 (10.77) [M+], 212 (100.00). Anal. Calcd. for C8H4BrF2N3O2:
C, 32.90; H, 1.38; N, 14.39; Found: C, 33.35; H, 1.49; N, 14.71. IR
This work was supported by the National Natural Science
Foundation of China (No. 20772145).
(KBr):
n
3091, 2771, 1627, 1521, 1349, 1319, 1124, 992, 887,
.
740 cmꢀ1
References
4.5.12. 2-(Bromodifluoromethyl)-4(7)-methyl-1H-
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benzo[d]imidazole (3l)
(b) A.J. Battershill, L.J. Scott, Drugs 66 (2006) 51–83;
1H NMR (300 MHz, d6-DMSO):
d
7.48 (d, J = 8.1 Hz, 1H), 7.28–
7.23 (m, 1H), 7.14 (d, J = 7.2 Hz, 1H), 2.56 (s, 3H). 19F NMR
(282 MHz, CDCl3):
ꢀ47.30 (s, 2F). MS (EI): m/z (%): 260 (11.86)
[M+], 181 (100.00). HRMS (EI) Calcd. for C9H7BrF2N2: 259.9761;
Found: 259.9759. IR (KBr): 2926, 1456, 1311, 1128, 1000, 890,
745 cmꢀ1
(c) R.B. Baudy, H. FletcherIII, J.P. Yardley, M.M. Zaleska, D.R. Bramlett, R.P. Tasse,D.M.
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d
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n
.
(b) M. Andrzejewska, L. Ye´pez-Mulia, R. Cedillo-Rivera, A. Tapia, L. Vilpo, J. Vilpo, Z.
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(3m)
´
´
´
(c) F. Hernandez-Luis, A. Hernandez-Campos, R. Castillo, G. Navarrete-Vazquez, O.
Soria-Arteche, M. Herna´ndez-Herna´ndez, L. Ye´pez-Mulia, Eur. J. Med. Chem. 45
(2010) 3135–3141;
White solid, mp: 154–155 8C. 1H NMR (300 MHz, d6-DMSO):
d
(d) G. Navarrete-Va´zquez, L. Ye´pez, A. Herna´ndez-Campos, A. Tapia, F. Herna´ndez-
Luis, R. Cedillo, J. Gonza´lez, A. Martı´nez-Ferna´ndez, M. Martı´nez-Grueiro, R. Cas-
tillo, Bioorg. Med. Chem. 11 (2003) 4615–4622;
(e) G. Navarrete-Va´zquez, R. Cedillo, A. Herna´ndez-Campos, L. Ye´pez, F. Herna´n-
dez-Luis, J. Valdez, R. Morales, R. Cortes, M. Hernandez, R. Castillo, Bioorg. Med.
14.14 (brs, 1H), 7.78 (d, J = 7.7 Hz, 1H), 7.65 (d, J = 7.7 Hz, 1H), 7.19
(t, J = 7.7 Hz, 1H). 19F NMR (282 MHz, d6-DMSO):
d
ꢀ48.26 (s, 2F).
MS (EI): m/z (%): 372 (18.08) [M+], 293 (100.00). Anal. Calcd. for
´
´
C8H4BrF2IN2: C, 25.76; H, 1.08; N, 7.51; Found: C, 25.83; H, 1.12; N,
Chem. Lett. 11 (2001) 187–190;
7.74. IR (KBr):
887 cmꢀ1
n
3018, 1574, 1453, 1309, 1257, 1140, 1116, 997,
(f) K.C. Joshi, R. Jain, A. Dandia, K. Sharma, J. Fluorine Chem. 56 (1992) 1–27.
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(2006) 135–141.
.
4.5.14. 2-(Bromodifluoromethyl)-4(7)-(trifluoromethyl)-1H-
benzo[d]imidazole (3n)
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White solid, mp: 146–148 8C. 1H NMR (300 MHz, d6-DMSO):
d
14.35 (brs, 1H), 7.95 (s, 1H), 7.74–7.54 (m, 2H). 19F NMR (282 MHz,
d6-DMSO):
(11.93) [M+], 235 (100.00). Anal. Calcd. for C9H4BrF5N2: C, 34.31; H,
1.28; N, 8.89; Found: C, 34.18; H, 1.29; N, 9.22. IR (KBr): 3131,
1456, 1340, 1313, 1198, 1123, 996, 891, 758 cmꢀ1
d
ꢀ48.64 (s, 2F), ꢀ59.57 (s, 3F). MS (EI): m/z (%): 314
n
.
4.5.15. 2,6(5)-Bis(trifluoromethyl)-1H-benzo[d]imidazole (3q) [3]
1H NMR (300 MHz, d6-DMSO):
13.93 (brs, 1H), 8.16 (s, 1H),
7.95 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H). 19F NMR (282 MHz,
d6-DMSO):
ꢀ59.78 (s, 3F), ꢀ63.42 (s, 3F). MS (EI): m/z (%): 254
(100.00) [M+].
d
(c) K. Tamura, H. Mizukami, K. Maeda, H. Watanabe, K. Uneyama, J. Org. Chem. 58
(1993) 32–35.
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d