Efficient syntheses of 2-fluoroalkylbenzimidazoles and -benzothiazoles

Article abstract of DOI:10.1016/j.tetlet.2012.09.069

We report an efficient one-step route to 2-fluoroalkylbenzimidazoles and -benzothiazoles via the condensation of fluorinated carboxylic acids and aromatic diamines or aminothiophenols. Additionally, we describe the syntheses of fluoroalkyl-azabenzimidazoles, -purines, and -imidazolopyrazines. This method is high-yielding with broad scope and is operationally simple with potential application to parallel synthesis.

Full text of DOI:10.1016/j.tetlet.2012.09.069

Tetrahedron Letters 54 (2013) 201–204
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient syntheses of 2-fluoroalkylbenzimidazoles and -benzothiazoles
⇑
Olivier René, Alexandra Souverneva, Steven R. Magnuson, Benjamin P. Fauber
Discovery Chemistry, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2012
Revised 14 September 2012
Accepted 17 September 2012
Available online 23 September 2012
We report an efficient one-step route to 2-fluoroalkylbenzimidazoles and -benzothiazoles via the con-
densation of fluorinated carboxylic acids and aromatic diamines or aminothiophenols. Additionally, we
describe the syntheses of fluoroalkyl-azabenzimidazoles, -purines, and -imidazolopyrazines. This method
is high-yielding with broad scope and is operationally simple with potential application to parallel
synthesis.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazole
Azabenzimidazole
Purine
Benzothiazole
Fluoroalkylheterocycles
2-Fluoroalkylbenzimidazoles are widely applicable in the syn-
theses of pharmaceuticals and agrochemicals because of their abil-
ity to improve physiochemical properties, metabolic stabilities, and
binding potencies relative to their non-fluorinated analogs.1–4 Intro-
duction of fluoroalkyl groups at the 2-position of benzimidazole has
been the focus of several publications, and the synthetic approaches
can be classified into the following reaction types: Phillips
condensation5 with o-phenylenediamine and a carboxylic acid un-
der refluxing aqueous HCl conditions,1–4,6–8 reaction of a diamine
with a fluorinated dichloroazine,9 reaction of a diamine with a fluo-
rinated imidoyl chloride,10 and installation of the trifluoromethyl
group onto the heterocycle via C-H oxidation chemistry.11
There have been scattered reports of a simplified Phillips con-
densation in which o-phenylenediamines were treated with neat
trifluoroacetic acid (TFA) to generate the corresponding 2-(trifluo-
romethyl)benzimidazoles.12–18 However, these initial reports have
been limited to the reaction of TFA with o-phenylenediamines with
no additional exploration of scope. Herein, we would like to report
the expanded scope for this efficient condensation and its use in
the syntheses of 2-fluoroalkylbenzimidazoles, -azabenzimidazoles,
-purines, -imidazolopyrazines, and -benzothiazoles (Fig. 1).19
This improved one-step process, first reported by Middleton
and Parrick,12 is operationally simple using the fluorinated carbox-
ylic acid as the reagent, catalyst, and solvent. We demonstrate that
this procedure allows for broad substrate scope and high yield to
form a variety of heterocycles.
to 70 °C for 2 h to provide the corresponding 2-(trifluoro-
methyl)benzimidazole. Evaporation of the excess TFA afforded
the product in quantitative yield. Optionally, the product could
also be purified by silica gel column chromatography to obtain
analytically pure material in quantitative yield.
This convenient and efficient procedure allows for the rapid gen-
eration of 2-(trifluoromethyl)benzimidazole products, and illustra-
tive examples of the scope of the transformation are shown in
Table 1. In addition to o-phenylenediamine (Table 1, entry 1),
electron-withdrawing substituents on the ring, such as 4-cyano (Ta-
ble 1, entry 2), 4-nitro (Table 1, entry 3), 4-trifluoromethyl (Table 1,
entry 4), 4-carboxylic acid (Table 1, entry 5), 4,5-difluoro (Table 1,
entry 6), and a fused arene (Table 1, entry 7) were well tolerated
giving the corresponding products in 92% to 99% yields.
Sterically encumbered substrates containing an adjacent
3-methyl (Table 1, entry 8) or 3-methoxy substituent (Table 1,
entry 10) also provided the desired products in 99% and 94% yields,
respectively. The 4,5-dimethyl substrate also afforded the corre-
sponding product in 98% yield (Table 1, entry 9).
In addition to 1H-benzimidazoles, N-alkyl and N-phenyl benz-
imidazoles also can be prepared using this one-step procedure
from the corresponding diamine starting materials (Table 1, entries
11–14). For example, starting with N-methyl-o-phenylenediamine
O
NH2
N
Z
HO
70°C
Z = NH, N(R2), S
CxFy
In a typical procedure, o-phenylenediamine was combined with
trifluoroacetic acid (TFA) at 0.5 M overall concentration and heated
R1
N
R1
N
CxFy
H
Z
⇑
Corresponding author. Tel.: +1 650 467 5773; fax: +1 650 225 2061.
E-mail address: Fauber.Benjamin@gene.com (B.P. Fauber).
Figure 1. Efficient approach to fluoroalkyl-heterocycles.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.09.069

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O. René et al. / Tetrahedron Letters 54 (2013) 201–204
Table 1
Variation of the substituted o-phenylenediamines
NH2
N
N
TFA
R1
R1
CF3
70 °C
NH
R2
R2
Entry
Diamine
Product
Yielda (%)
99
NH2
N
CF3
CF3
CF3
1
N
H
NH2
NH2
NC
O2N
F3C
NC
N
2
3
4
92
99
99
N
H
NH2
NH2
O2N
N
N
H
NH2
NH2
F3C
N
CF3
N
H
NH2
NH2
O
O
N
HO
HO
5
99
CF3
N
H
NH2
NH2
F
F
F
F
N
CF3
6
7
99
99
N
H
N
NH2
NH2
CF3
N
H
NH2
NH2
Me
Me
N
8
9
99
98
94
CF3
N
H
NH2
NH2
Me
Me
Me
Me
N
CF3
N
H
NH2
NH2
OMe
OMe
N
10
CF3
N
H
N
NH2
NH2
CF3
11
12
99
99
Me
N
N
H
Me
O
O
NH2
N
EtO
EtO
CF3
Me
N
Me
N
H
NH2
N
CF3
13
14
95
66
Ph
N
Ph
N
H
H2N
NH2
H
N
O
N
Ph
CF3
N
H
CF3
N
Ph
a
Reaction conditions: 0.5 M diamine in trifluoroacetic acid, 70 °C, 16 h.
(Table 1, entry 11) or an analogous starting material bearing
an electron-withdrawing ethyl ester (Table 1, entry 12), the
N-methylbenzimidazoles were obtained in 99% yields. Similarly,
the reaction was also compatible with N-phenyl diamines to give
the corresponding N-phenylbenzimidazoles (Table 1, entries 13
and 14). In the case of a substrate bearing an additional 4-amino

O. René et al. / Tetrahedron Letters 54 (2013) 201–204
203
Table 2
Scope of reactions with o-diamino-azaheterocycles
NH2
TFA
N
N
R1
R1
CF3
N
N
70°C
NH
R2
R2
Entry
Diamine
Product
Yielda (%)
99
Entry
Diamine
Product
Yielda (%)
NH2
NH2
N
Br
NH2
NH2
Br
N
N
N
N
CF3
CF3
CF3
1
10
66b
79b
N
H
N
H
N
N
Cl
N
OH
Br
Br
NH2
NH2
NH2
N
N
N
N
2
3
61
80
11
12
CF3
N
N
N
N
H
N
H
N
N
N
NH2
NH2
Cl
N
NH2
Cl
N
CF3
CF3
88b
92b
N
Me
N
N
H
N
N
N
H
NH2
NH2
NH2
Me
Cl
N
Cl
O2N
O2N
Cl
N
Cl
N
NH2
CF3
N
N
H
CF3
CF3
4
5
48
75
13
14
N
Me
N
N
H
Me
NO2
NO2
N
N
NH2
N
N
N
NH2
N
54c
N
H
CF3
NH2
NH2
N
N
N
H
N
NH2
NH2
N
N
CF3
CF3
N
CF3
N
N
6
7
N
H
70b
99b
15
16
N
0c,d
N
N
NH2
NH2
NH2
NH
N
NH2
N
N
N
N
O
N
O
S
CF3
CF3
0c,e
N
N
N
H
N
H
NH2
NH2
Me
N
Me
N
N
NH2
NH2
S
N
72b
25b
17
0c,e
N
H
8
9
CF3
NH2
N
H
NH2
N
CF3
N
H
MeO
N
MeO
N
NH2
a
b
c
Reaction conditions: 0.5 M diamine in trifluoroacetic acid, 70 °C, 16 h.
The reaction was concentrated to dryness and subsequently treated with Et3N at 70 °C for 1 h to form the product.
The reaction was conducted in a sealed tube at 120 °C.
Only monoacylation was observed.
d
e
Only diacylation was observed.
Table 3
group, trifluoroacetylation of that amine was observed (Table 1,
entry 14).
Reactions with 2-aminothiophenols
NH2
N
TFA
The same convenient procedure could be utilized to synthesize
a variety of azaheterocycles (Table 2). In the case of pyrimidine
starting materials, simply heating the reaction to 70 °C was suffi-
cient to directly afford the corresponding fluoroalkyl-purines. For
example, 5,6-diamino-pyrimidine (Table 2, entry 1) produced the
corresponding 8-(trifluoromethyl)purine in 99% yield. Interest-
ingly, in the case of the 4-chloro-5,6-diaminopyrimidine, water
generated in the condensation step of the reaction was sufficient
to displace the chloride and yield 8-(trifluoromethyl)-6-hydroxyp-
urine (Table 2, entry 2), whereas 2,6-dichloro-3,4-diaminopyridine
reacted to produce the corresponding dichloro-azabenzimidazole
in 80% yield (Table 2, entry 3).
R
R
CF3
70°C
S
SH
Entry
Aminothiophenol
Product
Yielda (%)
99
NH2
N
S
CF3
CF3
1
SH
NH2
F3C
F3C
N
2
58
S
SH
a
Reaction conditions: 0.5 M diamine in trifluoroacetic acid, 70 °C, 16 h.

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O. René et al. / Tetrahedron Letters 54 (2013) 201–204
Diaminopyridines bearing an electron-withdrawing group also
polyfluoroalkylbenzimidazoles. For example, 2-fluoroacetic acid
(Table 4, entry 1), 2,2-difluoroacetic acid (Table 4, entry 2), 2,2-
difluoropropionic acid (Table 4, entry 3), and pentafluoropropionic
acid (Table 4, entry 4) were all successful in producing the desired
2-fluoroalkylbenzimidazoles in excellent yields. Additionally, 2,2-
difluoro-2-phenylacetic acid was also suitable for the reaction,
leading to the product in 71% yield (Table 4, entry 5).
participated in the cyclization reaction. For example, 2,3-diami-
no-5-nitropyridine and 3,4-diamino-5-nitropyridine reacted to
form the respective products in 48% and 75% yields (Table 2, en-
tries 4 and 5). If the pyridine substrate did not contain an elec-
tron-withdrawing group, then the cyclization did not occur and
only the trifluoroacetylated intermediates were identified in the
reaction mixture via mass-spectrometry analysis. It was presumed
that the trifluoroacetate salts of these pyridine substrates reduced
their nucleophilicity and did not allow for their condensation to
Acknowledgments
the trifluoromethyl-azabenzimidazole products.20 Therefore,
a
The authors acknowledge Baiwei Lin, Deven Wang, Christine
Gu, and Yanzhou Liu for their analytical chemistry support.
two-part procedure was required in which the trifluoroacetic acid
was removed via rotary evaporation, followed by treatment with
triethylamine to free-base the intermediate. Heating to 70 °C for
1 h provided the desired azabenzimidazoles (Table 2, entries 6-
13).21 2,3-Diaminopyrazine was also a suitable substrate, but re-
quired heating to 120 °C with trifluoroacetic acid in a sealed tube
to provide a 54% yield of the 2-(trifluoromethyl)imidazolo[4,5-b-
]pyrazine product (Table 2, entry 14).
Supplementary data
Supplementary data (synthetic procedures and analytical data
for all products) associated with this article can be found, in the
online version, at http://dx.doi.org/10.1016/j.tetlet.2012.09.069.
2-Aminothiophenols were also suitable substrates for this reac-
tion leading to the corresponding benzothiazoles, as shown in Ta-
ble 3. Using this approach, 2-(trifluoromethyl)benzothiazole was
obtained in quantitative yield (Table 3, entry 1). Even the elec-
tron-deficient 4-(trifluoromethyl)-2-aminobenzenethiol under-
went cyclization to form the desired benzothiazole in 58% yield
(Table 3, entry 2). 2-Aminophenols also were explored as partners
for this condensation reaction, but they only provided the triflu-
oroacetylated aminophenol intermediates and did not cyclize to
the benzoxazole products upon extended heating or subsequent
treatment with triethylamine.
References and notes
1. Navarrete-Vázquez, G.; Cedillo, R.; Hernández-Campos, A.; Yépez, L.;
Hernández-Luis, F.; Valdez, J.; Morales, R.; Cortés, R.; Hernández, M.; Castillo,
R. Bioorg. Med. Chem. Lett. 2001, 11, 187.
2. Kazimierczuk, Z.; Andrzejewska, M.; Kaustova, J.; Klimesoꢀva, V. Eur. J. Med.
Chem. 2005, 40, 203.
3. Hernández-Luis, F.; Hernández-Campos, A.; Castillo, R.; Navarrete-Vázquez, G.;
Soria-Arteche, O.; Hernández-Hernández, M.; Yépez-Mulia, L. Eur. J. Med. Chem.
2010, 45, 3135.
4. Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
5. Phillips, M. A. J. Chem. Soc., C 1928, 2393.
6. Smith, W. T.; Steinle, E. C. J. Am. Chem. Soc. 1953, 75, 1292.
7. Holan, G.; Samuel, E. L.; Ennis, B. C.; Hinde, R. W. J. Chem. Soc., C 1967, 20.
8. Fonesca, T.; Gigante, B.; Marques, M.; Gilchrist, T. L.; De Clercq, E. Bioorg. Med.
Chem. 2004, 12, 103.
9. Barlow, M. G.; Bell, D.; O’Reilly, N. J.; Tipping, A. E. J. Fluorine Chem. 1983, 23,
293.
In an effort to further evaluate the applicability of this efficient
transformation, we also reacted a variety of fluorinated carboxylic
acids with o-phenylenediamine to afford the respective mono- or
10. Ge, F.; Wang, Z.; Wan, W.; Lu, W.; Hao, J. Tetrahedron Lett. 2007, 48, 3251.
11. Chu, L.; Qing, F.-L. J. Am. Chem. Soc. 2012, 134, 1298.
12. Middleton, R. W.; Monney, H.; Parrick, J. Synthesis 1984, 740.
13. Buckle, D. R.; Foster, K. A.; Taylor, J. F.; Tedder, J. M.; Thody, V. E.; Webster, R. A.
B.; Bermudez, J.; Markwell, R. E.; Smith, S. A. J. Med. Chem. 1987, 30, 2216.
14. Jones, B. G.; Branch, S. K.; Thompson, A. S.; Threadgill, M. D. J. Chem. Soc. Perkin
Trans. 1 1996, 2685.
Table 4
Variation of the fluorinated carboxylic acid
O
15. Mewshaw, R. E.; Zhao, R.; Shi, X.; Marquis, K.; Brennan, J. A.; Mazandarani, H.;
Coupet, J.; Andree, T. H. Bioorg. Med. Chem. Lett. 2002, 12, 271.
16. Rückle, T.; Biamonte, M.; Grippi-Vallotton, T.; Arkinstall, S.; Cambet, Y.; Camps,
M.; Chabert, C.; Church, D. J.; Halazy, S.; Jiang, X.; Martinou, I.; Nichols, A.;
Sauer, W.; Gotteland, J.-P. J. Med. Chem. 2004, 47, 6921.
NH2
NH2
HO
CxFy
70°C
N
CxFy
N
H
}
17. Pete, B.; Szokol, B.; Toke, L. J. Heterocycl. Chem. 2008, 45, 343.
Entry
Acid
Product
Yielda (%)
94
18. Pelletier, J. C.; Chengalvala, M.; Cottom, J.; Feingold, I.; Garrick, L.; Green, D.;
Hauze, D.; Huselton, C.; Jetter, J.; Kao, W.; Kopf, G. S.; Lundquist, J. T.; Mann, C.;
Mehlmann, J.; Rogers, J.; Shanno, L.; Wrobel, J. Bioorg. Med. Chem. 2008, 16,
6617.
19. The authors recognize that the following entries included in this Letter have
been previously synthesized using the featured methodology: Table 1, entries
1, 4, 7, and 10; Table 3, entry 1. These examples were subjected to the featured
methodology within our labs, and the corresponding yields we achieved are
reported in this Letter.
O
O
F
N
F
F
1
HO
N
H
N
F
F
2
3
99
99
HO
HO
HO
N
H
F
20. Calculations for the theoretical pKa’s of the conjugate acids were conducted
using the Molecular Discovery Ltd. MoKa v1.1.0 software package (2009).
Calculated conjugate acid pKa’s for Table 2, entry 3 starting material = 2.58;
O
O
F
N
F
F
F
entry
starting material = 6.87; entry
material = 7.47; entry
4
starting material = 3.57; entry
5
starting material = 3.04; entry
6
N
H
Et
7
starting material = 9.31; entry
8
starting
Et
9
starting material = 5.04; entry 10 starting
F
material = 5.10; entry 11 starting material = 7.54; entry 12 starting
material = 5.11; and entry 13 starting material = 5.91. The methods for these
calculations are described further in: Milletti, F.; Storchi, L.; Sforna, G.;
Cruciani, G. J. Chem. Inf. Model 2007, 47, 2172.
N
F
F
F
4
5
99
71
N
H
CF3
CF3
21. Based on the observed differential reactivity of the substituted diamino-
pyridines (Table 2, entries 3–13) and analyses of their respective calculated
conjugate acid pKa’s (Ref. 19), we propose a guideline that diamino-pyridines
with conjugate acid pKa’s <4 will probably accommodate the one-step TFA
cyclization protocol. Whereas pyridine substrates with calculated conjugate
acid pKa’s >4 will probably require subsequent treatment with triethylamine to
facilitate formation of the azabenzimidazole products.
O
F
N
F
F
HO
F
N
H
Ph
Ph
a
Reaction conditions: 0.5 M diamine in trifluoroacetic acid, 70 °C, 16 h.