Nucleophilic acylation of arylfluorides catalyzed by imidazolidenyl carbene

Article abstract of DOI:10.1039/b302062b

Imidazolidenyl carbene catalyzes nucleophilic acylation reaction of arylfluorides with electron withdrawing groups to give benzophenone derivatives.

Full text of DOI:10.1039/b302062b

Nucleophilic acylation of arylfluorides catalyzed by imidazolidenyl
carbene
Yumiko Suzuki,* Tomonori Toyota, Fumie Imada, Masayuki Sato and Akira Miyashita
School of Pharmaceutical Sciences, University of Shizuoka, 52-1, Yada, Shizuoka, 422-8526, Japan.
E-mail: suzuyumi@smail.u-shizuoka-ken.ac.jp; Fax: +81 542645755; Tel: + 81 542645755
Received (in Cambridge, UK) 21st February 2003, Accepted 9th April 2003
First published as an Advance Article on the web 6th May 2003
Imidazolidenyl carbene catalyzes nucleophilic acylation
reaction of arylfluorides with electron withdrawing groups
to give benzophenone derivatives.
obenzaldehyde (5e) gave the corresponding benzophenones 6a–
e in good to moderate yields. It is well known that fluoride is
often a better leaving group than the other halogens in
nucleophilic aromatic substitution.8 The attempt at nucleophilic
acylation of 4-chloronitrobenzene ended in the recovery of
starting materials both in refluxing THF and in DMF at 0 °C.
The reaction mechanism of the acylation of 4 is considered to
be as shown in Scheme 2. The intermediate 3 adds to the carbon
atom bearing fluorine, followed by loss of the fluorine as an
anion. Base-promoted elimination of a proton and 2 from the
tetrahedral intermediate 8 takes place to afford 6. 2 is then
recycled as a catalyst.
The acylation of other fluoroarenes with electron-with-
drawing groups was also examined (Table 2). The reaction of
4-cyanofluorobenzene (9) and 4-fluorobenzophenone (10) with
5a gave 4-cyanobenzophenone (12) and 4-benzoylbenzophe-
none (13), respectively, but the yields were poor. The reaction
of 3,4-difluoronitrobenzene (11) with 5a, 3-chlorobenzaldehye
(5f), and 3-methoxybenzaldehyde (5g) afforded the correspond-
ing benzophenones 14–16 in good yield.
In conclusion, we succeeded in carrying out the nucleophilic
acylation of fluorobenzenes with electron-attracting groups.
The reaction proceeds by the catalytic action of imidazolidenyl
carbene, and the substitution occurs via an addition–elimination
mechanism. It is impossible to directly introduce acyl groups to
electron-deficient positions of benzene rings with ‘ordinal’
reactions such as the Friedel–Crafts reaction. As such, the
acylation reaction using imidazolidenyl carbene as a catalyst is
Nucleophilic aromatic substitution is an important process in
synthetic aromatic chemistry.1 As for substitution by carbon
nucleophiles, one of the most significant examples is the
vicarious nucleophilic substitution of hydrogen.2 Displacement
of methoxy group by organometallics is a convenient route to
alkylate arenes.3 The organometallic complexes with the
methoxy and the ortho-activating group to facilitate the
substitution reaction. In contrast to these examples, nucleophilic
aromatic substitutions of halogen atoms by carbanions are less
common,1,2 as halonitroarenes often react with carbanions by
electron-transfer processes2,4 or intra- or intermolecular redox
processes.2,5
We have previously reported the nucleophilic aromatic
substitutions of haloheteroarenes to afford aroylheteroarenes.6
This reaction proceeds by the catalytic action of imidazolidenyl
carbene 2. 2 and aromatic aldehyde form the intermediate 3
known as an ‘activate aldehyde’,7 which is an ‘aroyl anion
equivalent’. 3 behaves as a carbon nucleophile, and its addition
to heteroarenes at the carbon-bearing halogen, followed by
elimination of halogen and 2, results in nucleophilic acylation
(Scheme 1).
Herein we report the first example of nucleophilic acylation
of nitrobenzenes. In refluxing THF, 4-fluoronitrobenzene (4)
was found to react with benzaldehyde (5a) in the presence of
1,3-dimethylimidazolium iodide (1) and sodium hydride to
afford 4-nitrobenzophenone in 47% yield (Table 1). In DMF at
0 °C, the yield increased to 57%.† Under the same conditions in
DMF, the reaction of 4 with 4-chlorobenzaldehydes (5b),
4-anisaldehyde (5c), 3-fluorobenzaldehyde (5d), and 2-fluor-
Scheme 1
Table 1 Acylation of 4-fluoronitrobenzene (4)
Ar
Solvent
Yield (% )
Ph
Ph
a
a
b
c
d
e
THFa
46
57
61
77
63
49
DMFb
DMFb
DMFb
DMFb
DMFb
4-ClC6H5
4-MeOC6H5
3-FC6H5
2-FC6H5
a Conditions: reflux, 1 h. b Conditions: 0 °C, 1 h.
Scheme 2 Reaction mechanism of acylation of 4-fluoronitrobenzene (4).
1314
CHEM. COMMUN., 2003, 1314–1315
This journal is © The Royal Society of Chemistry 2003

View Article Online
Table 2 Benzoylation of fluoroarenes
R
Fluoroarene
Ar
Aldehyde
Reaction conditions
Products
Yield (%)
4-CN
9
10
11
11
11
Ph
Ph
Ph
5a
5a
5a
5f
0 °C, 20 min. and then r.t., 2 h
0 °C, 20 min. and then r.t., 2 h
0 °C, 1.5 h
12
13
14
15
16
37
32
75
56
60
4-C6H5CO
2-F-4-NO2
2-F-4-NO2
2-F-4-NO2
3-ClC6H5
3-MeOC6H5
0 °C, 1.5 h
5g
215 °C, 30 min. and then r.t., overnight
3 (a) M. Reuman and A. I. Meyers, Tetrahedron, 1995, 41, 837; (b) T.
Hattori, J. Sakamoto, N. Hayashizaka and S. Miyano, Synthesis, 1994,
199; (c) T. Hattori, H. Tanaka, Y. Okaishi and S. Miyano, J. Chem. Soc.,
Perkin Trans. 1, 1995, 235; (d) T. Hattori, M. Suzuki, Y. Komuro and S.
Miyano, J. Chem. Soc., Perkin Trans. 1, 1995, 1473.
a useful method for introducing acyl groups to arenes with
electron-deficient substituents.
4 (a) G. A. Russel, E. G. Janzen and E. T. Storm, J. Am. Chem. Soc., 1964,
86, 1807; (b) R. D. Guthrie, D. A. Hrovat, F. G. Prahl and I. J. Swam, J.
Org. Chem., 1981, 46, 498.
5 (a) R. B. Davis and L. C. Pizziri, J. Org. Chem., 1960, 25, 1884; (b) R.
B. Davis, L. C. Pizziri and E. J. Bara, J. Org. Chem., 1961, 26, 4270; (c)
M. Makoska, M. Jagusztyn-Grochowska, M. Ludwikow and M.
Jawdosiuk, Tetrahedron, 1974, 30, 3723.
6 (a) A. Miyashita, Y. Suzuki, K. Iwamoto, E. Oishi and T. Higashino,
Heterocycles, 1998, 49, 405–413; (b) A. Miyashita, Y. Suzuki, K.
Iwamoto and T. Higashino, Chem. Pharm. Bull., 1998, 46, 390–399; (c)
A. Miyashita, K. Obae, Y Suzuki, E. Oishi, K. Iwamoto and T. Higashino,
Heterocycles, 1997, 45, 2159–2173; (d) A. Miyashita, Y. Suzuki, I.
Nagasaki, C. Ishiguro, K. Iwamoto and T. Higashino, Chem. Pharm.
Bull., 1997, 45, 1254–1258.
Notes and references
† Procedure for nucleophilic acylation of 4: sodium hydride (160 mg, 4
mmol) was added to a mixture of 4 (423 mg, 3 mmol), 5a (382 mg, 3.6
mmol), and 1 (224 mg, 1 mmol) in DMF (20 ml). The mixture was stirred
at 0 °C for 1 hour and then poured into ice-water. The product was extracted
with ethyl acetate, washed with water and brine, and dried over Na2SO4.
The combined organic layers were concentrated, and the residue was
purified by silica gel column chromatography (hexane/ethyl acetate) to give
6a (386 mg, 57 %). Recrystallization of the crude product from methanol
yielded crystals of 6a as slightly orange needles. Mp. 136–137 °C (lit.,9 138
°C).
1 (a) F. Terrier, Nucleophilic Aromatic Displacement, VCH, New York,
1991; (b) C. Paradisi, Comprehensive Organic Synthesis, Pergamon
Press, 1991, vol. 4, ch 2.1.
2 (a) M. Makosza, J. Golinski and J. Baran, J. Org. chem., 1984, 49, 1488;
(b) M. Makosza and J. Winiarski, J. Acc. Chem. Res., 1987, 20, 282.
7 R. Breslow, J. Am. Chem. Soc., 1958, 80, 3719.
8 G. P. Briner, J. Mille, M. Liveris and P. G. Lutz, J. Chem. Soc., 1954,
1265.
9 Beilstein Handbook of Organic Chemistry, 1925, vol. 7, , 426.
CHEM. COMMUN., 2003, 1314–1315
1315
Typeset and printed by Black Bear Press Limited, Cambridge, England