N-heterocyclic carbene-catalyzed nucleophilic aroylation of fluorobenzenes

Article abstract of DOI:10.1021/jo7023569

(Chemical Equation Presented) In N-heterocyclic carbene (NHCs) catalyzed nucleophilic substitution of fluorobenzenes, fluoro groups are replaced by aroyl groups, which are derived from aromatic aldehydes. 1,3,4,5-Tetramethylimidazol- 2-ylidene is found to be an efficient catalyst. The catalyst loading can be reduced to 1 mol % without a significant decrease in the product yields. Polysubstituted benzophenones are synthesized from fluorobenzenes and benzaldehydes by the NHC-catalyzed aroylation.

Full text of DOI:10.1021/jo7023569

In our laboratory, the NHCs have been employed as catalysts
for benzoin condensation,10 retro-benzoin condensation,11 nu-
cleophilic substitutions,12-15 asymmetric acylations,16 and cy-
anosilylations.17 The NHCs catalyze the nucleophilic substitution
of electron-deficient haloheteroarenes,12 N-phenylimidoyl chlo-
rides,13 and fluorobenzenes bearing electron-withdrawing groups.14
In this nucleophilic substitution, the halogen substituents of these
compounds are replaced by aroyl groups originating from
N-Heterocyclic Carbene-Catalyzed Nucleophilic
Aroylation of Fluorobenzenes
Yumiko Suzuki,* Shinya Ota, Yoshinori Fukuta,
Yuki Ueda, and Masayuki Sato
School of Pharmaceutical Sciences, UniVersity of Shizuoka,
52-1 Yada, Suruga-ku, Shizuoka 422-8526, Japan
suzuyumi@u-shizuoka-ken.ac.jp
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ReceiVed NoVember 5, 2007
In N-heterocyclic carbene (NHCs) catalyzed nucleophilic
substitution of fluorobenzenes, fluoro groups are replaced
by aroyl groups, which are derived from aromatic aldehydes.
1,3,4,5-Tetramethylimidazol-2-ylidene is found to be an
efficient catalyst. The catalyst loading can be reduced to 1
mol % without a significant decrease in the product yields.
Polysubstituted benzophenones are synthesized from fluo-
robenzenes and benzaldehydes by the NHC-catalyzed aroy-
lation.
N-heterocyclic carbenes (NHCs) have become an indispen-
sable class of ligands for transition-metal catalysis because of
their characteristic similarities and superiority to ubiquitous
phosphine ligands.1,2 In addition to functioning as ligands, the
NHCs play an important role as organocatalysts in a number
of reactions.1,3 Besides the widely known benzoin condensation4
and Stetter reaction,5 the use of the NHCs as organocatalysts
has recently been extended to a variety of reactions such as
transesterification/amidation, living ring-opening polymerization,
and homoenolate reaction.6-9
(10) Miyashita, A.; Suzuki, Y.; Kobayashi, M.; Kuriyama, N.; Higashino,
T. Heterocycles 1996, 43, 509.
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(e) Miyashita, A.; Obae, K.; Suzuki, Y.; Iwamoto, K.; Oishi, E.; Higashino,
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Commun. 2003, 1314.
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Commun. 2004, 2770. (b) Suzuki, Y.; Muramatsu, K.; Yamauchi, K.; Sato,
M. Tetrahedron 2006, 62, 302.
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D´ıez-Gonza´lez, S.; Nolan, S. P. Coord. Chem. ReV. 2007, 251, 874. (c)
N-Heterocyclic Carbenes in Transition Metal Catalysis; Glorius, F., Ed.;
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(3) For reviews, see: (a) Enders, D.; Balensiefer, T. Acc. Chem. Res.
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10.1021/jo7023569 CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/22/2008
2420
J. Org. Chem. 2008, 73, 2420-2423

SCHEME 1. Nucleophilic Aroylation of 1 Previously
Reported by Our Group
SCHEME 2. Plausible Mechanism for Aroylation of
4-Fluoronitrobenzene 1
TABLE 1. Benzoylation of 1 Using 3a-f as NHC Precursors
entry
cat. (mol %)
conditiona
yield (%)
1
2
3
4
5
6
7
8
9
3a (30)
3b (30)
3c (30)
3d (30)
3e (30)
3f (30)
3f (10)
3f (1)
A
A
A
A
A
A
B
B
B
66
45
70
76
75
quant
81
79
39
CHART 1. Imidazolium Salts 3b-f
3f (0.5)
a A: -15 °C to rt. B: -15 °C, 10 min, and then to -5 to 0 °C.
aldehydes to obtain keto compounds. For example, the reaction
of 1 with benzaldehyde 2a using 30 mol % of the NHC derived
from 3a at 0 °C for 1 h in DMF affords 4-nitrobenzophenone
4a in 57% yield (Scheme 1).14 As shown in Scheme 2, it is
considered that the reaction pathway includes the “Breslow
intermediate,”1 as in the benzoin and Stetter reactions.
In this study, we have examined the aroylation of fluoroben-
zenes using imidazolium salts with various substituents as NHC
precursors to improve the yields and reduce catalyst loading.
TABLE 2. Aroylation of Benzene Derivatives 1, 5-7
a A: -15 °C, 10 min, and then to 0 °C, 2 h. B: 0 °C, 10 min, rt, 30 min, and then to 80 °C, 1.5 h. b 8 was obtained in 10% yield.
J. Org. Chem, Vol. 73, No. 6, 2008 2421

SCHEME 3. Synthesis of Xanthones and Acridones via
NHC-Catalyzed Nucleophilic Aroylation
We have also examined the synthesis of polysubstituted
benzophenones from fluorobenzenes and aldehydes using the
NHC-catalyzed aroylation.
The nucleophilic aryolation of 1 was examined using various
imidazolium salts 3a-f as the NHC precursors (Chart 1), while
3a has been used as the NHC precursor in the nucleophilic
aroylation of fluorobenzenes in the previous reports.14,15
The reaction with 2a was carried out using 30 mol % of 3a
as the NHC precursor and sodium hydride at -15 °C up to
room temperature in DMF (Table 1, entry 1). The NHC was
generated in situ and catalyzed the reaction to obtain 4a in 66%
yield. The reactions using the other imidazolium salts were also
examined under the same reaction conditions. While 1,3-
dimethylimidazolium methanesulfonate 3b afforded a lower
product yield (entry 2), the use of liquid unsymmetrical
imidazolium salts 3c-e increased the product yields to 70-
76% (entries 3-5). It was expected that the electron-donating
effect of the methyl groups at C-4 and C-5 of imidazol-2-ylidene
would increase the nucleophilicity of the carbene center and
accelerate the reaction. In fact, the reaction in the presence of
the NHC derived from 1,3,4,5-tetramethylimidazolium iodide
3f yielded 4a quantitatively (entry 6). When the catalyst loading
was decreased to 10 mol %, the reaction using 3f proceeded in
81% product yield (entry 7). Even with 1 mol % of 3f, the
product yield did not drop significantly, and 4a was obtained
in 79% yield under the same condition (entry 8). However, the
use of 0.5 mol % of 3f lowered the product yield (entry 9).
The aroylation of 1 with the other aldehydes 2b-d was also
carried out with 10 mol % of 3f at -15 °C up to room
temperature in DMF, and the benzophenones 4b-d were
obtained in good yields (Table 2, entries 1-3). The benzoylation
of 4-fluorobenzophenone 5 with 2a at 80 °C afforded 8 in 53%
yield (entry 4).
Chlorobenzenes are far less susceptive to the nucleophilic
aroylation as compared to fluorobenzenes. In the case of
TABLE 3. Synthesis of Polysubstituted Benzophenones 1,5-7
a A 1 equiv portion of 2e-g was used in entries 1-5, and 1.5 equiv of 2h was used in entries 5 and 6. b 3f was used instead of 3a.
2422 J. Org. Chem., Vol. 73, No. 6, 2008

4-chloronitrobenzene 6 instead of 1, the yield of 4a was only
8% and 1,4-dibenzoylbenzene 8 was produced in 10% yield by
the substitution of the nitro group of 4a (entry 5). On the other
hand, in the reaction of 1,4-dinitrobenzene 7 with 2a, the nitro
group underwent a smooth substitution to obtain 4a in 81% yield
(entry 6).
(Friedel-Crafts reaction). We believe that we have broadened
the scope of accessible benzophenones. The applications of this
reaction to the syntheses of natural products containing a
xanthone nucleus are currently underway in our laboratories.
Experimental Section
The synthesis of the polysubstituted benzophenones was
examined. Benzophenones are versatile building blocks. For
example, we have reported the synthesis of heterocyclic
compounds such as xanthones and acridones from 2,2′-difluo-
robenzophenones that were prepared by aroylation (Scheme 3).15
The fluoride 9 was subjected to aroylation with the aldehydes
2e-h (Table 3). Since 3a is more readily available than 3f, 3a
(30 mol % or 10 mol %) was used as the catalyst precursor
(entries 1,3-6). The reactions were carried out at -15 °C up
to the ambient temperature to obtain the polysubstituted
benzophenones 11e-h in 52-72% yields (entries 1,3-5). When
3f (10 mol %) was used instead of 3a (30 mol %) in the reaction
of 9 and 2e, 11e was obtained in the slightly higher yield (entry
2). The aroylation of 10 with 2h (1.5 equiv) using 10 mol % of
3a occurred at 0 °C for 50 min to obtain 12 in good yield (89%,
entry 6).
In conclusion, we have demonstrated that the NHC derived
from 1,3,4,5-tetramethylimidazolium iodide is a powerful
catalyst for the nucleophilic aroylation. The catalyst loading can
be reduced to 1 mol % without a significant drop in the product
yield of the reaction between 1 and 2a. We have also shown
that this aroylation is useful for the synthesis of polysubstituted
benzophenones. This organocatalytic aroylation enables us to
synthesize the benzophenones (such as 4d, 11g, 11h, and 12)
that are not accessible via conventional electrophilic aroylation
Typical Prodedure for Aroylation: 4-Nitrobenzophenone
(4a). Under an argon atmosphere, 60% sodium hydride in oil (160
mg, 4 mmol) was added to a mixture of 4-fluoronitrobenzene 1
(141 mg, 1 mmol), benzaldehyde 2a (106 mg, 1 mmol), and 1,3-
dimethylimidazolium iodide 3a (22 mg, 0.1 mmol) in DMF (7 mL).
The mixture was stirred at -15 °C for 15 min; then, the reaction
temperature was allowed to rise to -5 °C, and the mixture was
continually stirred for 2 h altogether. After the reaction, the mixture
was poured into ice water. The products were extracted with ethyl
acetate. The organic layer was washed with water and brine, dried
over Na2SO4, and concentrated. The residue was purified by silica
gel column chromatography (n-hexane/ethyl acetate) to obtain
benzophenone 4a. The recrystallization of the crude product from
methanol yielded the crystals of 4a in the form of slightly orange
needles: mp 136-137 °C (lit.18 136-138 °C); IR (KBr): 1643
1
(CO), 1508, 1354 (NO2) cm-1. H NMR (270 MHz, CDCl3): δ
7.53 (2H, t, J ) 8 Hz), 7.66 (1H, t, J ) 8 Hz), 7.81 (2H, d, J ) 8
Hz), 7.94 (2H, d, J ) 9 Hz), 8.35 (2H, d, J ) 9 Hz).
Supporting Information Available: Compound characterization
data and copies of spectra and chromatograms. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO7023569
(18) Beilstein Handbook of Organic Chemistry; Springer: Heidelberg,
Germany, 1925; Vol. 7, 426.
J. Org. Chem, Vol. 73, No. 6, 2008 2423