Synthesis of N-substituted 2-fluoromethylbenzimidazoles via bis(trifluoroacetoxy)iodobenzene-mediated intramolecular cyclization of N,N-disubstituted fluoroethanimidamides

Article abstract of DOI:10.1055/s-0029-1218377

A mild and efficient method for the synthesis of N-substituted 2-fluoromethylbenzimidazoles via [bis(trifluoroacetoxy)-iodo]benzene-mediated intramolecular cyclization of N,N′-disubstituted bromodifluoro (or trifluoro) ethanimidamides was described. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0029-1218377

LETTER
3299
Synthesis of N-Substituted 2-Fluoromethylbenzimidazoles via
Bis(trifluoroacetoxy)iodobenzene-Mediated Intramolecular Cyclization
of N,N¢-Disubstituted Fluoroethanimidamides
N
-Substitu
i
ted 2-F
a
luorometh
n
ylbenzimidaz
g
oles tao Zhu,a Haibo Xie,a Zixian Chen,a,b 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, P. R. of China
Fax +86(21)54925190; E-mail: ymwu@mail.sioc.ac.cn
Department of Chemistry, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P. R. of China
b
Received 18 September 2009
reaction between N,N¢-disubstituted imidamides and hy-
pervalent iodine(III) reagents. Herein, we would like to
describe a novel method for the synthesis of N-substituted
2-fluoromethylbenzimidazoles 2 by the reaction of
[bis(trifluoroacetoxy)iodo]benzene (BTI) with N,N¢-dis-
ubstituted fluoroethanimidamides 1.
Abstract: A mild and efficient method for the synthesis of N-sub-
stituted 2-fluoromethylbenzimidazoles via [bis(trifluoroacetoxy)-
iodo]benzene-mediated intramolecular cyclization of N,N¢-disub-
stituted bromodifluoro (or trifluoro) ethanimidamides was de-
scribed.
Key words: fluoroethanimidamides, benzimidazoles, BTI, oxida-
tive coupling
2-Bromo-2,2-difluoro-N,N¢-diphenylacetimidamide (1a),
as the initial starting material, was prepared from the reac-
tion of 2-bromo-2,2-difluoro-N-phenylacetimidoyl chlo-
ride with aniline using potassium carbonate in DMF at 80
°C.9 This substrate was treated with 1.1 equivalents of
BTI in MeCN at room temperature for 12 hours to furnish
the desired product, 2-(bromodifluoromethyl)-1-phenyl-
1H-benzo[d]imidazole (2a), in only 34% yield. When the
reaction time was reduced to 10 minutes at 60 °C, the
yield was raised to 62%. To optimize the reaction condi-
tions, other solvents such as THF, CH2Cl2, EtOH, toluene,
trifluoroethanol, and EtOAc were screened, but they were
found to be inferior to MeCN. When DIB and [hy-
droxy(tosyloxy)iodo]benzene (HTIB) were used as the
oxidizing agents, a complex mixture of products were
formed under the similar conditions. Thus the optimized
Organofluorine compounds, especially fluorinated het-
erocycles, have received a great deal of attentions in the
fields of medicine, agricultural, and material chemistry
because of the unique property of the fluorine atom.1
Among them, 2-fluoroalkylbenzimidazoles are potential-
ly useful as herbicides and insecticides.2 Recently, we and
others have reported syntheses of benzimidazoles from o-
iodoanilines through the use of copper or palladium cata-
lysts.3 The main drawbacks of these methods included the
limited diversity of the starting anilines and the uses of
transition metals as the catalysts. Recently, Uneyama and
co-workers demonstrated that electrochemical oxidation
of N,N¢-disubstituted trifluoroethanimidamides could
provide N-substituted 2-trifluoromethylbenzimidazoles in
dry acetonitrile.4 However, in this process symmetric
imidamides were needed, as the formation of the benzim-
idazoles would suffer from low yields when unsymmetri-
cal substrates were used. They also reported another
method for the preparation of benzimidazoles by Lewis
acid promoted cyclization of the p-benzoquninone imine
derivatives.5 Other procedures such as photoinduced and
oxidative intramolecular cyclizations by sodium hypo-
chlorite and lead(IV) acetate have been reported.6 Howev-
er, the yields and the tolerance were generally not
satisfactory.
Table 1 Synthesis of N-Alkyl-2-fluoromethylbezimidazolesa
R2
R1
N
N
PhI(OOCCF3)2
HN
Rf
MeCN, 60 °C
10 min
Rf
R1
N
R2
1b–g
2b–g
Entry
R1
R2
Rf
Yield of 2 (%)b
2b 68
1
H
Bn
Bn
Bn
Bn
Bu
Bn
CF3
2
OMe
Cl
CF3
2c 75
Hypervalent iodine organic compounds with low toxicity
have been used as oxidizing reagents in the transformation
of complex organic molecules.7 Synthesis of benzimida-
zoles from N-substituted amidines oxidized by (diacetoxy-
iodo)benzene (DIB) was reported by Ramsden.8
However, till now there are no reports on the study of the
3c
4
CF3
2d 58
H
CF2Br
CF2Br
CF2Br
2e 65
5
H
2f 48
6c
CF3
2g 45
a Conditions: to ethanimidamides 1 (0.5 mmol) in MeCN (10 mL) was
added BTI (0.55 mmol) at 60 °C for 10 min.
b Isolated yield after silica gel chromatography.
c Stirred for 10 h.
SYNLETT 2009, No. 20, pp 3299–3302
Advanced online publication: 18.11.2009
DOI: 10.1055/s-0029-1218377; Art ID: W14909ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
0
9

3300
J. Zhu et al.
LETTER
conditions were treating the substrate with BTI (1.1 Next, symmetrical or unsymmetrical N,N¢-diarylfluoro-
equiv) in MeCN at 60 °C for 10 minutes.
ethanimidamides were employed, and the results were
summarized in Table 2. All imidamides led to the corre-
sponding benzimidazoles in good yields except for the
case when both aromatic rings possessed a NO2 group
(Table 2, entry 4). Theoretically, two possible products
could be formed when an unsymmetrical N,N¢-diarylfluo-
roethamidaimade was used as the reactant (Table 2, en-
tries 6–13). As shown in Table 2, this reaction showed
good regioselectivity, the cyclization reaction took place
preferentially on the electron-rich benzene ring (Table 2,
entry 6). On the other hand, when a strong electron-with-
drawing (NO2, COOEt, CN, CF3, Ac) group was present
at the para position of one benzene ring, the cyclization
Having established the optimal conditions, we probed the
scope and limitation of this transformation. A series of N-
aryl-N¢-alkylfluoroethanimidamides were firstly tested,
and fluoromethylbenzimidazoles 2b–g were obtained in
moderate yields (Table 1). It was found that the reaction
of the substrate with an electron-donating group (4-OMe)
on the aromatic ring (2c, Table 1, entry 2) was faster than
that of the substrates with some electron-withdrawing
groups such as 4-Cl (2d) and 4-CF3 (2g, Table 1, entries 3
and 6). In the later circumstance the acetanilide was
formed as a byproduct.
Table 2 Synthesis of N-Aryl-2-fluorobenzimidazolesa
R1
N
N
Rf
Rf
R1
R2
N
N
PhI(OOCCF3)2
+
H
N
MeCN, 60 °C
10 min
N
Rf
R2
R1
R2
2
2'
1
Entry
1
R1
R2
Me
H
Rf
Yield of 2 (%)b
2h 82
2i 83
2/2¢c
Me
H
CF3
CF3
CF3
CF3
2
3
Cl
NO2
H
Cl
2j 90
4
NO2
H
–
5
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
CF2Br
2a 62
2k 54
2l 73
6d
7
H
OMe
Me
F
<1:99
1:6.7
H
8
H
2m 65
2n 69
2o 63
2p 83
2q 83
2r 77
2s 81
2t 87
1:3.3
9
H
Cl
1.44:1
1.27:1
1:1.2
10
11
12
13
14
15
16
17
19
20
H
Br
I
H
H
COOEt
CN
>99:1
>99:1
>99:1
>99:1
>99:1
1:6.7
H
H
CF3
H
NO2
Ac
H
2u 78
2v 70
2w 71
2x 71
H
t-Bu
OMe
t-Bu
OMe
t-Bu
a Conditions: to ethanimidamides 1 (0.5 mmol) in MeCN (10 mL) was added BTI (0.55 mmol).
b Isolated yield after silica gel chromatography.
c Obtained by 19F NMR.
d Stirred for 1 h at r.t.
Synlett 2009, No. 20, 3299–3302 © Thieme Stuttgart · New York

LETTER
N-Substituted 2-Fluoromethylbenzimidazoles
3301
EWG
O
+N
EWG
EWG
O
O
CF3
CF3
I
Rf
N
N
O
5
Rf
N
O
H
N
N
EWG
– CF3COOH
I
Rf
Ph
O
CF3
1
N
3
Rf
N
+
4
EWG
EWG
N
N
Rf
H
+
+N
N
Rf
N
Rf
N
EWG
2
4a
6
Scheme 1 The proposed mechanism of this transformation
occurred exclusively at the other benzene ring (Table 2, imidazoles from the corresponding N,N¢-disubstituted
entries 12–16). However, for the substrates with moderate ethanimidamides by oxidative cyclization with BTI.
electron-withdrawing or electron-donating groups (F, Cl, Compared to the existing methods, our strategy can be
Br, I, Me, t-Bu), both isomers 2 and 2¢ were formed carried out more easily since the imidamide substrates
(Table 2, entries 7–11, 17).
need not be halogenated at the ortho position of the ben-
zene ring. Further investigations of this reaction are ongo-
ing in our laboratories.
To the best of our knowledge, there are two possible
mechanisms for this transformation. The first mechanism
features the oxidation of 1 by BTI to generate a nitrenium
ion intermediate which would act as an electrophile to at-
tack the benzene ring and to afford the benzimida-
zoles.10Another mechanism involves radical intermediate
which demonstrated by Zhao’s synthesis of indoles via
BTI-mediated intramolecular cyclization.11 In our reac-
tion, the radical mechanism could be ruled out as addition
of p-dinitrobenzene did not effect the rate of the reaction
and the yields of the products. On the other hand, accord-
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank the National Natural Science Foundation (Nos 20532040
and 20772145) for financial support.
ing to the results of this study and related literature,4b
a
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Synlett 2009, No. 20, 3299–3302 © Thieme Stuttgart · New York

3302
J. Zhu et al.
LETTER
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Synlett 2009, No. 20, 3299–3302 © Thieme Stuttgart · New York

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