A novel synthesis of 2-per(poly)fluoroalkyl-1H-benzimidazoles or 2-per(poly) fluoroalkyl benzothiazoles

Article abstract of DOI:10.1016/S0022-1139(99)00012-3

A new method for the preparation of 2-per(poly)fluoroalkyl-1H-benzimidazoles or 2-per(poly)fluoroalkyl benzothiazoles from reaction of readily available α-per(poly)fluoroalkyl aldehydes with o-phenylenediamine or 2-aminobenzenethiol is presented. A possible reaction pathway is suggested.

Full text of DOI:10.1016/S0022-1139(99)00012-3

Journal of Fluorine Chemistry 95 (1999) 141±143
A novel synthesis of 2-per(poly)¯uoroalkyl-1H-benzimidazoles
or 2-per(poly) ¯uoroalkyl benzothiazoles
Quan-Fu Wang, Yun-Yu Mao, Shi-Zheng Zhu*, Chang-Ming Hu
Laboratory of Organo¯uorine Chemistry, Shanghai Institute of Organic Chemistry, Chines Academy of Sciences, 354 Fenglin Lu, Shanghai 200032, China
Received 8 October 1998; accepted 5 February 1999
Abstract
A new method for the preparation of 2-per(poly)¯uoroalkyl-1H-benzimidazoles or 2-per(poly)¯uoroalkyl benzothiazoles from reaction
of readily available a-per(poly)¯uoroalkyl aldehydes with o-phenylenediamine or 2-aminobenzenethiol is presented. A possible reaction
pathway is suggested. # 1999 Elsevier Science S.A. All rights reserved.
Keywords: 2-Per(poly)¯uoroalkyl-1H-benzimidazoles; 2-Per(poly)¯uoroalkyl benzothiazoles; a-Per(poly)¯uoroalkyl aldehydes; o-Phenylenediamine;
2-Aminobenzenethiol
1. Introduction
The length of the per(poly)¯uoroalkyl chain and the
presence of w-bromine showed little effect on the reaction
and all the substrates afforded product 2 in nearly the same
yield.
Solvent has little effect on the reaction; when other
solvents such as acetonitrile, 1,4-dioxane, THF or acetic
acid were used, they all gave similar results.
In order to enlarge the scope of the reaction, 2-amino-
benzenethiol was used to react with a-per(poly)¯uoroalkyl
aldehydes. The expected 2-per(poly)¯uoroalkyl benzothia-
2-Per(poly)¯uroalkyl-1H-benzimidazoles or 2-per(poly)-
¯uoroalkyl benzothazoles not only posses high bioactivity
[1±3], but also serve as important synthetic intermediates.
Various methods have been introduced for the synthesis of
such compounds. 2-Per(poly)¯uoroalkyl-1H-benzimida-
zoles were prepared by photochemical reaction of RfI with
1H-benzimidazole and a mixture of various Rf substituted
products was obtained [4], other methods generally used
include condensation of an o-diamine with a carboxylic acid
[5], reduction of an N-(o-nitropheynyl)per¯uoroalkanamide
with concomitant cyclisation of the o-amino-derivative [5]
and cyclocondensation of phenylenediamine with RfCOOH
in the presence of catalyst [6]. 2-Per(poly)¯uoroalkyl ben-
zothiazoles were prepared by the reaction of 2-aminoben-
zenethiol with ¯uorinated b-diketones [7] or with b-chloro-
a-(tri¯uoromethyl)acrolein [8].
Scheme 1.
2. Results and discussion
Table 1
Reaction of o-pheynlenediamine with a-per(poly)fluoroalkyl aldehydes
In our continuing study of ¯uoroalkyl-containing hetero-
cylic compounds, it was found that the reaction of o-phe-
nylenediamine with the a-per(poly)¯uoroalkyl aldehydes
[9,10] could give 2-per(poly)¯uoroalkyl-1H-benzimida-
zoles in moderate yield (Scheme 1). The results are shown
in Table 1.
Entry
Substrate
Rf
Product
Yield (%)a
1
2
3
4
5
1a
1b
1c
1d
1e
CF3
ClCF2
2a
2b
2c
2d
2e
55
53
54
60
62
BrCF2
Cl(CF2)3
CF3(CF2)4
a Isolated yield based on a-per(poly)fluoroalkyl aldehydes.
*Corresponding author.
0022-1139/99/$ ± see front matter # 1999 Elsevier Science S.A. All rights reserved.
PII: S 0 0 2 2 - 1 1 3 9 ( 9 9 ) 0 0 0 1 2 - 3

142
Q.-F. Wang et al. / Journal of Fluorine Chemistry 95 (1999) 141±143
A general procedure for the preparation of compounds
2a±2e was as follows:
Compound (10 mmol) and o-phenylenediamine
1
(20 mmol) were dissolved in 40 ml 95% ethanol. After
re¯uxing at 808C for 6 h, the mixture was cooled, poured
into 50 ml ice water and extracted with diethyl ether
(3Â40 ml). The organic extracts were combined, washed
with brine and dried over Na2SO4. The solvent was removed
by distillation. The crude product was further puri®ed by
silica gel column chromatography, using a mixture of
petroleum ether (bp: 60±908C) and ethyl acetate as eluant
(10:1 by volume).
Scheme 2.
Table 2
Reaction of 2-aminobenzenethiol with a-per(poly)fluoroalkyl aldehydes
Entry
Substrate
Rf
Product
Yielda
1
2
3
4
5
1a
1b
1c
1d
1e
CF3
CF2Cl
3a
3b
3c
3d
3e
48
50
46
52
53
Data for compound 2a: mp: 210±2118C; 19F NMR
CF2Br
15.7 (s, CF3); 1H NMR (90 MHz,
DMSO-d6) ꢀ 13.80 (br, NH, 1H), 7.50 (m, 2H), 7.20 (m,
Cl(CF2)3
CF3(CF2)4
(DMSO-d6)
ꢀ
‡
‡
a Isolated yield based on a-per(poly)fluoroalkyl aldehydes.
2H); MS (m/e) 186 (M , 100), 166 (M -1-F, 66.45), 116
‡
(M -1-CF3, 19.57); Anal. Calc. for C8H5F3N2: C, 51.62; H,
2.71; N, 15.05; F, 30.62, Found: C, 51.70; H, 2.63; N, 15.12;
F, 30.58%.
zoles were obtained (Scheme 2) and the results are listed in
Table 2. However, solvent has great in¯uence on this reac-
tion. Acetic acid was the best choice. When other solvents
such as ethanol, acetonitrile, 1,4-dioxane or THF were used,
they all give complicated results, which is different from the
above mentioned.
A possible reaction mechanism is suggested in Scheme 3.
The reaction of 2-aminophenol with a-per(poly)¯uor-
oalkyl aldehydes was quite different from the two above
mentioned reaction and will be discussed in later work.
Compound 2b: mp: 208±2098C; 19F NMR (DMSO-d6) ꢀ
28.0 (s, CF2Cl); H NMR (90 MHz, DMSO-d6) ꢀ 13.80
(br, NH, 1H), 7.50 (m, 2H), 7.20 (m, 2H); MS (m/e) 202
1
‡
‡
(M , 40.34), 167 (M ±Cl, 100); Anal. Calc. for
C8H5ClF2N2: C, 47.43; H, 2.49; N, 13.83; F, 18.76, Found:
C, 47.50; H, 2.43; N, 13.80; F, 18.83%.
Compound 2c: mp: 206±2088C; IR: 3400±2500 br, 1592,
1494, 1458, 1442, 1392, 1316, 1282, 1233, 1141; 19F NMR
(DMSO-d6) ꢀ
DMSO-d6) ꢀ 13.60 (br, NH, 1H) 7.60 (m, 2H), 7.30 (m,
33.0 (s, CF2Br); 1H NMR (90 MHz,
‡
‡
2H); MS (m/e) 248 (M -1, 29.42), 246 (M -1, 25.30), 167
‡
3. Experimental
(M -1-Br±F, 100); HRMS Calc. for C8H579BrF2N2:
245.9604, Found: 245.9600.
All melting points were uncorrected. IR spectra were
1
Compound 2d: mp: 204±2068C; IR: 3400±2500 br, 1593,
1496, 1456, 1440, 1320, 1230, 1182, 1141; 19F NMR
(DMSO-d6) ꢀ 9.5 (s, CF2Cl), 34.0 (m, CF2), 44.5 (m,
CF2); 1H NMR (90 MHz, DMSO-d6; ꢀ 13.80 (br, NH, 1H),
measured with a Shimadzu IR-440 spectrometer. H NMR
spectra were recorded at 300 and 90 MHz on Bruker AM300
or JEDLFX-90Q. 19F NMR spectra were recorded on an
EM-360L spectrometer at 56.4 MHz using TFA as external
standard and positive for up®eld shifts. Mass and HRMS
spectra were taken on a Finnigan GC±MS-4021 spectro-
meter. Elements analysis were done by the Elemental
Analysis Group of SIOC.
‡
7.70 (m, 2H), 7.30 (m, 2H)) MS (m/e): 302 (M , 50.32), 267
‡
‡
(M ±Cl, 14.87), 167 (M ±C2F5Cl, 100); HRMS. Cac. for
35ClC10H5F6N2; 302.0045, Found: 302.0010; Anal. Calc.
For C10H5ClF6N2: C, 39.74; H, 1.66; N, 9.27; F, 37.75,
Found: C, 39.63; H, 1.32; N, 9.20; F, 37.44%.
Scheme 3.

Q.-F. Wang et al. / Journal of Fluorine Chemistry 95 (1999) 141±143
143
Compound 2e: mp: 187±1888C; IR: 3400±2500 br, 1594,
1496, 1456, 1439, 1358, 1318, 1237, 1204, 1144; 19F NMR
(DMSO-d6) ꢀ 3.4 (s, 3F), 33.5 (m, 2F), 45.0 (m, 4F), 49.0
Compound 3d: colorless oil; IR: 3071, 1557, 1512, 1460,
1321, 1296, 1234, 1188, 1126, 1085; 19F NMR (CDCl3) ꢀ
10.5 (s, CF2Cl), 37.8 (m, CF2), 42.6 (m, CF2); H NMR
(300 MHz, CDCl3) ꢀ 8.25 (m, 1H), 8.01 (m, 1H), 7.63 (m,
1
1
(m, 2F); H NMR (90 MHz, DMSO-d6) ꢀ 13.90 (br, NH,
‡
‡
‡
1H), 7.60 (m, 2H), 7.30 (m, 2H); MS (m/e): 386 (M ,
2H); MS (m/e) 319 (M , 28.79), 284 (M ±Cl, 9.39), 184
‡
‡
‡
52.02), 367 (M ±F, 13.85), 167 (M ±C4F9, 100); Anal.
Calc. for C12H5F11N2: C, 37.31; H, 1.30; N, 7.25, F, 54.14,
Found: C, 37.52; H, 1.04; N, 7.22; F, 54.33%.
A general procedure for the preparation of compounds
3a±3e was as follows:
(M ±C2F4Cl, 100); Anal. Calc. for C10H4ClF6NS: C, 37.56;
H, 1.25; N, 4.38; F, 35.68, Found: C, 37.50; H, 1.02; N, 4.42;
F, 35.57.
Compound 3e: mp: 43±448C; IR: 3070, 1556, 1506, 1457,
1434, 1361, 1323, 1236, 1205, 1138, 1109, 1080, 1049,
1014; 19F NMR (CDCl3) ꢀ 5.0 (s, 3F), 30.0 (m, 2F), 46.0 (m,
Compound
1 (10 mmol) and 2-aminobenzenethiol
1
(20 mmol) were dissolved in 40 ml acetic acid. After
re¯exuing at 1208C for 8 h, the mixture was cooled, poured
into 50 ml ice water and extracted with diethyl ether
(3Â40 ml). The organic extracts were combined, washed
with saturated NaHCO3 aqueous solution, brine and dried
over Na2SO4. The solvent was removed by distillation. The
crude product was further puri®ed by silica gel column
chromatography, using a mixture of petroleum ether (bp:
60±908C and ethyl acetate as eluant (101 by volume).
Compound 3a: mp 24±258C; 19F NMR (CDCl3) ꢀ 15.8
(s, CF3); 1H NMR (300 MHz, CDCl3) ꢀ 8.22 (m, 1H), 8.01
4F), 50.3 (m, 2F); H NMR (CDCl3) ꢀ 8.23 (m, 1H), 8.01
‡
(m, 1H), 7.60 (m, 2H); MS (m/e) 403 (M , 51.78), 384
‡
‡
(M ±F, 12.71), 184 (M ±C4F9, 100); Anal. Calc. for
C12H4F11NS: C, 35.73; H, 0.99; N, 3.47; F, 51.86, Found:
C, 35.86; H, 0.88; N, 3.54; F, 51.82.
Acknowledgements
We thank the National Science Foundation of China for
®nancial support (no. 29772043).
‡
‡
(m, 1H), 7.60 (m, 2H); MS (m/e) 203 (M , 100), 184 (M ±
‡
F, 25.45), 134 (M ±CF3, 16.69); Anal. Calc. for C8H4F3NS:
C, 47.29; H, 1.98; N, 6.89; F, 28.05, Found: C, 47.34; H,
2.01; N, 6.93; F, 27.98%.
References
[1] C. Ogretir, S. Demiragak, Doga. Biyol. Ser. 10 (1986) 193.
[2] A. Shuto, M. Ohgai, M. Eto, Nippon Noyaku Gakkaishi 14 (1989)
69.
Compound 3b: colorless oil; IR: 1559, 1514, 1459, 1434,
1320, 1284, 1252, 1137, 1122, 1077, 1037, 1015; 19F NMR
(CDCl3) ꢀ 29.0 (s, CF2Cl); 1H NMR (300 MHz CDCl3) ꢀ
8.19 (m, 1H), 7.97 (m, 1H), 7.57 (m, 2H); MS (m/e) 219
(M , 84.77), 184 (M ±Cl, 100); HRMS Calc. for
37ClC8H4F2NS: 220.9692, Found: 220.9706.
[3] D.P. Clifford, R.V. Edwards, R.T. Hewson, J. Agric. Food Chem. 29
(1981) 640.
‡
‡
[4] H. Kimoto, S. Fujii, L.A. Cohen, J. Org. Chem. 47 (1982) 2867.
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(1986) 37.
Compound 3c: mp: 32±348C; IR: 1627, 1556, 1503, 1457,
1430, 1322, 1284, 1252, 1168, 1141, 1124, 1079, 1032,
1015; 19F NMR (CDCl3) ꢀ 32.0 (s, CF2Br); 1H NMR
(300 MHz, CDCl3) ꢀ 8.18 (m, 1H), 7.95 (m, 1H), 7.56
[7] E.C. Alyea, A. Malek, J. Heterocyl. Chem. 22 (1985) 1325.
[8] G. Alvernhe, B. Langlois, A. Laurent, D.I. Le, A. Selmi, M.
Weissenfels, Tetrahedron Lett. 32 (1991) 643.
‡
‡
[9] W.Y. Huang, L. Lu, Chin. J. Chem. 9 (1991) 167.
[10] S.Z. Zhu, C.Y. Qin, B. Xu, J. Fluorine Chem. 79 (1996) 77.
(m, 2H); MS (m/e) 265 (M H, 25.24), 263 (M -1,
‡
20.85), 184 (M ±Br, 100); HRMS Calc. for
79BrC8H4F2NS: 262.9216, Found: 262.9194.