One-pot synthesis of 2-trifluoromethyl and 2-difluoromethyl substituted benzo-1,3-diazoles

Article abstract of DOI:10.1016/j.tetlet.2007.03.015

2-Trifluoromethyl and 2-difluoromethyl substituted benzimidazole, benzoxazole and benzothiazole derivatives were efficiently prepared through a one-pot reaction of trifluoroacetic acid and difluoroacetic acid, respectively, with commercially available o-p

Full text of DOI:10.1016/j.tetlet.2007.03.015

Tetrahedron Letters 48 (2007) 3251–3254
One-pot synthesis of 2-trifluoromethyl
and 2-difluoromethyl substituted benzo-1,3-diazoles
a
a
a
a
a,b,
*
Fenglian Ge, Zengxue Wang, Wen Wan, Wencong Lu and Jian Hao
a
Department of Chemistry, Shanghai University, 99 Shangda Road, Shanghai 200444, China
b
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
54 Fenglin Road, Shanghai 200032, China
3
Received 21 December 2006; revised 2 March 2007; accepted 5 March 2007
Available online 7 March 2007
Abstract—2-Trifluoromethyl and 2-difluoromethyl substituted benzimidazole, benzoxazole and benzothiazole derivatives were effi-
ciently prepared through a one-pot reaction of trifluoroacetic acid and difluoroacetic acid, respectively, with commercially available
o-phenylenediamines, 2-aminophenols, and 2-aminobenzenethiols in good to excellent yields. Subsequential bromination of 2-diflu-
oromethyl groups by photolysis with NBS led to the formation of bromodifluoromethyl benzo-1,3-diazoles which may be utilized to
prepare the new generation of gem-difluoromethylene linked identical or non-identical twin molecules for drug synthesis.
Ó 2007 Elsevier Ltd. All rights reserved.
Benzo-1,3-diazoles are a biologically important class of
molecules and are widely used in pharmaceutical pro-
duction. The studies of structure–activity relationship
interestingly reveal that change of the structure of sub-
stituent group at C-2 position commonly results the
change of its bioactivity. Among those 2-substituted
benzo-1,3-diazole derivatives, 2-fluoroalkyl substituted
molecules have already received considerable attention
alkyl substituted benzo-1,3-diazole derivatives, we wish
to report a new application of Uneyama’s preparation
of fluorinated imidoyl chlorides to the efficient synthe-
4
sis of various 2-trifluoromethyl and 2-difluoromethyl
substituted benzo-1,3-diazole derivatives via a rapid
and mild one-pot intramolecular cyclization process.
Subsequential bromination of 2-difluoromethyl benzo-
1,3-diazole products by the photolysis with NBS leads
to the formation of bromodifluoromethyl benzo-1,3-
diazoles, which provides us an opportunity to access
and design a new generation of corresponding gem-
difluoromethylene linked identical or non-identical twin
1
,2
due to their potential bioactivities. Some known com-
pounds, such as 2-trifluoromethyl and 2-difluoromethyl
substituted benzo-1,3-diazole derivatives were reported
3
having the potential anti HIV-1 bioactivities. However,
5
to date, only a few methods have been developed for the
synthesis of these important molecules. Most of these
procedures are only applicable to the synthesis of certain
type of benzo-1,3-diazole molecules. Many new types of
molecules for drug synthesis (Scheme 1).
R CO H, PPh
3
Et N (excess)
3
XH
F
2
X
N
2
-fluoroalkyl substituted benzo-1,3-diazole derivatives
R
R
RF
CCl , refluxing
4
are still remain uninvestigated due to the lack of a
general and mild synthetic approach. This encourage
us to develop a general method which can be applied
to synthesize a broad range of 2-fluoroalkyl substituted
benzo-1,3-diazole derivatives for bioactivity screening.
Y
NH2
Y
2, 72 - 99%
R = CF , CF H
F
3
2
X = NH, S, O
Y = C, N
R = CF H
X = S, O
R = H, 4-Cl refluxing
Y = C
F
2
NBS/CCl4
Sunlamp/
As one part result from our ongoing research project for
the synthesis and pharmaceutical applications of 2-fluoro-
X
R
CF Br
2
N
Keywords: Fluorinated benzo-1,3-diazoles; Fluorinated carboxylic
acids; Fluorinated heterocycles; Bromination; Synthesis.
3, 35 - 38%
*
Corresponding author. Tel./fax: +86 21 6613 3380; e-mail: jhao@
mail.shu.edu.cn
Scheme 1. Synthetic route to 2-fluoroalkyl substituted benzo-1,3-
diazole derivatives and 2-bromodifluoromethyl benzo-1,3-diazoles.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.015

3252
F. Ge et al. / Tetrahedron Letters 48 (2007) 3251–3254
Our initial inspiration came from the electrophilicity of
imino group of fluorinated N-aryl imidoyl chloride. It
was supposed that the intramolecular nucleophilic sub-
stitution should occur if there is a nucleophilic substitu-
ent (–XH in 1, Scheme 2) presented at the ortho position
on benzene ring in N-aryl imidoyl chloride intermediate
(1), and lead to the formation of 2-fluoroalkyl benzo-
1,3-diazole derivatives (2).
This consideration was experimentally proved when the
excess amount of triethylamine was employed in reac-
tion system, and successfully formed 2-trifluoromethyl
benzimidazole (2a) in our first trial. After that, this
method was extended to the synthesis of various 2-fluoro-
alkyl substituted benzo-1,3-diazole derivatives in good
to excellent yields under mild condition (Table 1).
XH
XH
N
Slow
Fast
R
R
Cl
NH2
RF
1
It is assumed that the imidoyl chloride intermediate (1)
is initially formed under Uneyama’s condition. Once 1
is formed, the subsequential intramolecular nucleophilic
substitution by neighboring group (–XH) under basic
condition rapidly occurred to form the desired product
2 (Scheme 2). Although the substituent group R does
X
R
RF
N
2
Scheme 2. Postulated mechanism of intramolecular cyclization.
a
Table 1. Synthesis of 2-fluoroalkyl substituted benzo-1,3-diazole derivatives 2
Entry
R
F
X
Y
R
Product 2
Yield (%)
87
H
N
1
CF
3
3
NH
C
H
2a
CF3
N
H
N
H CO
3
2
3
CF
NH
NH
C
C
4-OCH
3
2b
91
78
CF3
N
H
N
CF
3
4-NO
2
2c
CF3
N
O N
2
S
N
O
N
4
5
6
7
8
CF
CF
CF
CF
CF
3
3
3
3
3
S
C
C
C
C
N
H
H
CF3
2d
2e
72
91
90
89
82
O
O
O
O
CF3
O
N
4-CH
4-Cl
H
3
CF3
2f
O
CF3
2g
N
Cl
O
N
CF3
2h
N
H
N
9
CF
2
2
H
H
NH
NH
C
C
H
2i
84
89
CF H
2
N
H
N
H CO
3
1
1
0
1
CF
4-OCH
3
2j
CF H
2
N
H
N
CF
2
H
NH
C
4-NO
2
2k
77
CF H
2
N
O N
2

F. Ge et al. / Tetrahedron Letters 48 (2007) 3251–3254
3253
Table 1 (continued)
Entry
R
F
X
S
Y
C
R
H
Product 2
Yield (%)
85
S
1
2
3
CF
CF
2
H
H
CF H
2l
2
N
O
1
2
O
O
O
C
C
C
H
CF H
2m
98
99
92
2
N
O
N
1
1
4
5
CF
CF
2
H
H
4-CH
3
CF H
2n
2
O
N
4-Cl
CF
2
H
2o
2
Cl
a
The yields listed in this table are isolated yields.
not affect the yield of 2 too much, electron-releasing
properties of R groups are found to be propitious to this
cyclization. The position of R group in benzimidazole
products is affirmed by the X-ray crystallographic
assignment.
H
N
H3CO
CF3
N
Electron-releasing group, such as methoxyl group,
enhances the nucleophilicity of its para-amino group
to form the imidoyl chloride intermediate (1) with prio-
rity. The following intramolecular cyclization leads to
the formation of 2 with substituent group at 6-position
2
b
H
N
(
2b, Fig. 1). In contrast, the electron-withdrawing
CF3
group, such as nitro group, significantly reduces the elec-
tron density of N-electron lone-pair of its para-amino
group and diminishes the nucleophilicity of this amino
group. Instead, the neighboring amino group partici-
pates the reaction to form the corresponding imidoyl
chloride intermediate (1) with priority. The following
intramolecular cyclization leads to the formation of 2
with substituent group at 5-position (2c, Fig. 1).
N
O2N
2
c
Figure 1. ORTEP diagram of 2b and 2c.
Among those products we described here, 2-difluoro-
methyl substituted benzo-1,3-diazole molecules attracted
us much more attention. It is not only because of the
potential bioactivities themselves but also the potential
application to synthesize the gem-difluoromethylene
linked identical or non-identical twin molecules which
contain the benzo-1,3-diazole moiety. C–H bond activa-
tion of difluoromethyl group is a key issue in this assign-
ment. Our previous experience from bromination of
other fluorine-containing arenes encouraged us to test
the photolytic bromination of 2-difluoromethyl substi-
tuted benzo-1,3-diazoles though there is no successful
report on the bromination of difluoro-methyl group in
The calculations of total energy and dipole moment of
2
b and 2c by using the MM+ force field also revealed
that 2b (methoxyl group at 6-position) and 2c (nitro
group at 5-position) are relatively more stable thermo-
dynamically than corresponding compounds with meth-
oxyl group at 5-position and nitro group at 6-position,
respectively. No compound with methoxyl group at 5-
position or with nitro group at 6-position was detected
experimentally.
The reaction of this one-pot synthesis is generally fast
and clean. Interestingly, 2-amino-3-hydroxypyridine
also yielded 2-(trifluoromethyl)oxazolo[4,5-b]pyridine
3
d
benz-fused 1,3-diazole molecules.
(
2h, Table 1, entry 8) in 82% yield. This result gives us
The initial test of bromination of 2-difluoromethyl
benzothiazole with NBS under UV irradiation in quartz
glass reactor failed to get any products. Fortunately,
the bromination of difluoromethyl group finally suc-
ceeded while sunlamp was used to replace the UV lamp
though the yield was still low. The same condition was
also applied to the bromination of 2-difluoromethyl
benzoxazole and formed the desired brominated prod-
uct (Scheme 3).
an information that this approach is possibly applicable
to synthesize other interested heterocyclic ring fused 1,3-
diazole molecules besides those benz-fused ones.
CCDC 631281 and 631282 contain the Supplementary Crystallo-
graphic Data. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.

3254
F. Ge et al. / Tetrahedron Letters 48 (2007) 3251–3254
NBS
CCl4
and build up various biologically interested gem-difluoro-
methylene linked identical and non-identical twin drug
molecules.
X
N
X
N
R
CF2H
R
CF Br
2
Sunlamp
refluxing
3
3
3
a (38%, X=S, R=H)
b (35%, X=O, R=4-Cl)
Acknowledgments
Scheme 3. Bromination of CF
2
H group with sunlamp.
This work was financially supported by National Natu-
ral Science Foundation of China (No. 20472049) and
Key Laboratory of Organofluorine Chemistry, Chinese
Academy of Sciences. The authors also thank Dr. H.
Deng, Ms M. Shao and The Instrumental Analysis &
Research Center of Shanghai University for structural
determination.
S
N
F
F
S
PhOH
CF Br
2
NaH, DMF
rt, 85%
N
O Ph
3
a
4
Scheme 4. Reaction of 3a with sodium phenolate.
It should be pointed out that directly using the commer-
cially available bromodifluoroacetic acid instead of
difluoroacetic acid in the synthesis of 2 will also yield
the 2-bromodifluoromethyl substituted benzo-1,3-di-
azole products. However, the cost will be significantly
increased because of the higher retail price of
bromodifluoroacetic acid. It is worth mentioning that
this bromination method is also possibly applicable to
other difluoromethyl substituted heterocycles. The opti-
mization and generality of this method is currently
under investigation.
References and notes
1
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methyl benzothiazole with phenol in the presence of
NaH in DMF successfully yielded the gem-difluoro-
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3
c
sidered going through a SET mechanism. The typical
SN2 process of 3a with nucleophile, such as NaCN in
methanol failed to give the desired product.
(
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5
and non-identical twin drugs.
In summary, 2-trifluoromethyl and 2-difluoromethyl
substituted benzo-1,3-diazole derivatives were success-
fully prepared through a facile one-pot synthesis from
commercially available trifluoroacetic acid and diflu-
oro-acetic acid, respectively, with o-phenylenediamines,
5
385–5394.
4
5
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Tamura, K.; Mizukami, H.; Maeda, K.; Watanabe, H.;
Uneyama, K. J. Org. Chem. 1993, 58, 32–35.
. Contreras, J. M.; Bourguignon, J. J. Identical and Non-
identical Twin Drugs. In The Practice of Medicinal Chem-
istry; Wermuth, C. G., Ed.; Academic Press: New York,
2003; p 251.
2
-aminophenols and 2-aminobenzenethiols in good to
excellent yields. The bromination of 2-difluoromethyl
benzo-1,3-diazoles by photolysis with NBS led to the
formation of bromodifluoromethyl benzo-1,3-diazoles.
This approach provides us with the possibility to explore