Pd-catalyzed coupling reaction of fluorinated propargyl amidines with aryl iodides

Article abstract of DOI:10.1039/c2ob26377g

Catalyzed by ligand free Pd(OAc)₂, 2,5-disubstituted imidazole was prepared in good yield by the reaction of fluorinated propargyl amidines with iodoarene. Mechanistic studies indicated that this transformation occurs through a nitropalladation-reductive elimination pathway. The Royal Society of Chemistry.

Full text of DOI:10.1039/c2ob26377g

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Pd-catalyzed coupling reaction of fluorinated propargyl
amidines with aryl iodides†
Cite this: Org. Biomol. Chem., 2013, 11, 41
Received 17th July 2012,
Shan Li,a Yafen Yuan,a Yajun Li,a,b Zhengke Li,a Lisi Zhanga and Yongming Wu*a
Accepted 16th October 2012
DOI: 10.1039/c2ob26377g
www.rsc.org/obc
Catalyzed by ligand free Pd(OAc)2, 2,5-disubstituted imidazole
In our initial study, 2-trifluoromethyl N-(p-methoxyphenyl-
was prepared in good yield by the reaction of fluorinated propar- N-propargyl amidine 1aa was treated with p-methoxyl iodo-
gyl amidines with iodoarene. Mechanistic studies indicated that benzene 2a (1.2 equiv.) in the presence of K2CO3 (1.5 equiv.)
this transformation occurs through a nitropalladation–reductive and Pd(OAc)2 (10 mol%) in CH3CN at room temperature. The
elimination pathway.
desired product, 5-benzyl imidazole 3aaa was obtained in 26%
yield. In an effort to optimize the reaction, reaction conditions
were investigated by varying the temperature, base, solvent and
catalyst. The outcome, however, was not promising (Table 1 in
ESI†). In these reactions, 5-benzyl imidazole as the only
product was obtained in low yield, no byproduct such as
5-methyl imidazole or 3-(p-methoxphenyl) prop-2-ynyl amidine
was detected. The presence of the fluoroalkyl group increases
the acidity of the hydrogen atom on the amidinoyl group,
which leads to deprotonation under strong basic conditions,
and the increased amount of propargyl amidine anion will
promote the reaction. By using a 1.0 : 0.7 : 1.2 molar ratio of
1aa : 2a : K2CO3, an improved yield of 76% was obtained when
the reaction was carried out in CH3CN at 80 °C, in the pres-
ence of 10 mol% Pd(OAc)2 (Table 1, entry 1). A similar result
was obtained when K3PO4 was used as the base (Table 1, entry
2). The yield of 5-benzyl imidazole 3aaa was increased to 84%
when DMF was chosen as the solvent (Table 1, entry 5). The
concentration of propargyl amidine was found to affect the
yield of 3aaa, a lower yield was obtained with a higher concen-
tration of 1aa (Table 1, entries 12, 13).
The scope of the palladium-catalyzed coupling of fluori-
nated propargyl amidines with aryl iodides by this procedure
is summarized in Table 2. To our delight, this reaction shows
good compatibility towards aryl iodides containing many func-
tional groups, such as ester and acetyl groups (Table 2, entries
5, 6). Iodoarenes with both electron-donating and electron-
withdrawing groups gave moderate to good yields of the corre-
sponding products (Table 2, entries 1–7). Iodoarenes with an
electron-withdrawing group give a lower yield (Table 2, entries
5–7). Steric hindrance of iodoarene imposed by ortho-substi-
tution has little impact on the yield except for the substrate
with ortho-fluorine (Table 2, entries 8, 9, entry 10). Steric and
electronic effects of propargyl amidines were also negligible
for the coupling reaction (Table 2, entries 11–13). Substrates
Imidazoles as five-membered N-heterocyclic compounds occur
in a number of natural products, in particular alkaloids.1
Owing to their biological properties, many of these are impor-
tant ingredients for antibacterial, antiviral, antitumor, anti-
cardiovascular, and antiinflammatory agents.2,3 Recently,
imidazoles with fluorinated groups have received significant
attention based on the fact that the physicochemical proper-
ties of organic compounds can be greatly affected by introdu-
cing fluorinated groups.4,5 With CF3I and CF3SiMe3 as the
fluorinating reagents, direct trifluoromethylation has become
an important approach to access these compounds.6 However,
this method suffers from the use of expensive or hazardous
reagents, harsh reaction conditions, and poor yield. Alterna-
tively, imidazoles bearing fluorinated groups can be prepared
from fluorinated building blocks. For example, treatment of
fluorocarboxylic acid or fluorinated 1,3-dicarbonyl compounds
with 1,2-diaminobenzene successfully formed 2-fluoroalkyl
benzimidazoles.7 Multi-substituted imidazoles are also accessi-
ble by applying other fluorinated building blocks.8 Fluorinated
propargyl amidines presented some unique properties in our
work.10b Considering the reaction pattern, propargyl amidine
was suitable for the preparation 2,5-disubstituted imidazoles.
Herein, we disclose the synthesis of 2-fluoroalkyl-5-benzyl imid-
azoles from fluorinated propargyl amidines and aryl iodides
using ligand free palladium acetate as the catalytic source.
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: ymwu@sioc.ac.cn; Fax: (+86)-021-54925190
bSchool of Chemistry and Chemical Engineering, Huazhong University of Science and
Technology, 1037 Luoyu Road, Wuhan, Hubei 430074, China
†Electronic supplementary information (ESI) available: General procedure for
2,5-disubstituted imidazole synthesis; Characterization data and NMR spectra
for compounds 3aaa–3cea, 3aaba. See DOI: 10.1039/c2ob26377g
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Org. Biomol. Chem., 2013, 11, 41–43 | 41

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(5-imidazolymethyl) palladium intermediate, which then
undergoes reductive elimination to form 5-benzyl imidazole
(path I). Alternatively, 3-aryl prop-2-yne amidine would be pro-
duced first from the σ-aryl palladium complex with a terminal
alkyne, and then it undergoes 5-exo-dig cyclization to give the
desired product (path II).
Table 1 Optimized condition for the synthesis of 3aaa
With the inductive electron-withdrawing effect of fluoro-
alkyl, deprotonation of amidinolyl readily takes place under
basic conditions, and then undergoes intramolecular nucleo-
philic reaction with the activated alkyne to give the desired
product. In our system, 5-benzyl imidazole was found to be the
sole product. To distinguish these two pathways, we prepared
N-(3-phenyl) prop-2-ynyl amidine 1aab. Under the same con-
ditions, only a low yield (63%) of 5-benzyl imidazole 3aab was
detected by 19F NMR, which was lower than from the reaction
of fluorinated proparygyl amidine with iodobenzene (Table 2,
entry 2). In the presence of an iodoarene, 1aab underwent a
cyclization–arylation to give 5-diarymethyl imidazole 3aaba in
very low yield due to large steric hindrance. Judging from
these observations, it is very likely that the transformation pro-
ceeds through path I. The proposed mechanism is shown in
Scheme 1. 5-Benzyl imidazole 3 is most likely generated by
reductive elimination from the intermediate B, which is more
stable than the σ-vinyl-σ-aryl palladium species A (Scheme 2).10
Entry
Catalyst
Solvent
Base
Temp/°C
Yield/%a
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(PPh3)2Cl2
Pd(OAc)2
CH3CN
CH3CN
CH3CN
CH3CN
DMF
DMF
DMF
DMF
CH3CN
DMF
DMF
DMF
K2CO3
K3PO4
Na2CO3
Py
K2CO3
K3PO4
Py
K2CO3
K2CO3
K2CO3
K3PO4
K2CO3
K2CO3
80
80
80
80
80
80
80
60
80
80
80
80
80
76
71
65b
58b
84
75
46b
70
9
68
77
10
11
12
13
62
74c
55b,d
Pd(OAc)2
DMF
a Isolated yield. b Calculated by 19F NMR. c The molar ratio of 1aa : 2a =
1 : 0.8. d The molar ratio of 1aa : 2a = 1 : 1.
Table 2 Pd-catalyzed formation of 2-fluoroalkyl-5-benzyl imidazole 3
Entry
Rf
R1
R2
Yield/%a
1
2
3
4
5
6
7
8
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF3
–CF2Br
–CF2H
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-Cl
p-OCH3
H
p-Cl
m-CH3
p-COOEt
p-COCH3
p-CF3
o-OCH3
o-CF3
3aaa/84
3aab/80
3aac/85
3aad/74
3aae/61
3aaf/68
3aag/79
3aah/81
3aai/75
3aaj/42
3aba/72
3aca/86
3ada/80
—
Scheme 1 Transformations of 1aab catalyzed by Pd(OAc)2.
9
10
11
12
13
14
15
o-F
p-OCH3
p-OCH3
p-OCH3
p-OCH3
p-OCH3
o-OCH3
Naphth
p-OCH3
H
3cea/77
a Isolated yield.
with –CF2Br are too unstable under the reaction condition to
afford any product (Table 1, entry 14), while good yield was
obtained from substrates with –CF2H (Table 1, entry 15).
This transformation may proceed through two pathways.9
In path I, the C–C triple bond in the propargyl amidine coordi-
nates to the σ-aryl palladium complex. A nitrogen atom attacks
the activated C–C triple bond and the propargyl amidine
accepts the attack of the nitrogen atom to afford a σ-aryl-σ-
Scheme 2 Proposed mechanism for the formation of 2,5-disubstituted
imidazoles.
42 | Org. Biomol. Chem., 2013, 11, 41–43
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In conclusion, a convenient protocol to generate 2,5-di-
substituted imidazoles has been developed. With ligand free
Pd-(OAc)2 as the catalyst, 2-fluoroalkyl-5-benzyl imidazoles can
be obtained in moderate to good yields from the reaction of
fluorinated propargyl amidines with aryl iodides. This trans-
formation is compatible with a wide range of functional
groups. Mechanistic investigations revealed that the reaction
most likely proceeds via a nitropalladation–reductive elimin-
ation pathway.
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