Lewis acid-catalyzed Friedel-Crafts acylation reaction using carboxylic acids as acylating agents

Article abstract of DOI:10.1016/j.tetlet.2003.08.099

Rare-earth metal Lewis acids, in particular Eu(NTf₂) ₃, were found to be efficient catalysts for Friedel-Crafts acylation reaction using aliphatic as well as aromatic carboxylic acids as acylating agents at high temperature.

Full text of DOI:10.1016/j.tetlet.2003.08.099

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 7715–7717
Lewis acid-catalyzed Friedel–Crafts acylation reaction using
carboxylic acids as acylating agents
Masato Kawamura, Dong-Mei Cui, Teruyuki Hayashi and Shigeru Shimada*
National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba Central 5, Tsukuba, Ibaraki 305-8565, Japan
Received 17 July 2003; revised 21 August 2003; accepted 27 August 2003
Abstract—Rare-earth metal Lewis acids, in particular Eu(NTf2)3, were found to be efficient catalysts for Friedel–Crafts acylation
reaction using aliphatic as well as aromatic carboxylic acids as acylating agents at high temperature.
© 2003 Elsevier Ltd. All rights reserved.
Friedel–Crafts acylation reaction is one of the most
important methods to prepare aromatic ketones.1 The
conventional method, which uses acid chlorides or acid
anhydrides as acylating agents and a stoichiometric or
an excess amount of reaction promoter such as AlCl3 or
HF, suffers from severe corrosion, waste, and safety
problems and does not meet recent requirement for
environmentally benign chemical processes. Direct use
of carboxylic acids, precursors for acid chlorides and
anhydrides, as acylating agents with a catalytic amount
of and a reusable reaction promoter produces water as
the only by-product and will be a cleaner alternative to
the conventional Friedel–Crafts acylation. Zeolites,2
heteropoly acids and their salts,3 clay,4 and Lewis acids5
are reported to catalyze Friedel–Crafts acylation using
carboxylic acids as acylating agents. However, the cata-
lytic efficiency and/or applicable substrate range are
very limited.
course of our research, a patent using rare-earth metal
triflates as catalysts with azeotropic removal of water
has appeared, although the catalytic efficiency seems
not to be very high, and scope and limitation of the
procedure are not clear.7 As our initial approach to the
Friedel–Crafts acylation reactions using carboxylic
acids as acylating agents, we examined the catalytic
efficiency of metal triflates and bis(trifluoromethanesul-
fonyl)amides to know their scope and limitation.8 Here
we report that Eu(NTf2)3 is efficient catalysts when the
reaction is performed at high temperature.9
The reaction of p-xylene with hexanoic and heptanoic
acids was examined using various rare-earth metal
Lewis acids with excess of p-xylene (50–65 equiv. to
carboxylic acids) in a sealed glass tube without
azeotropic removal of water. Table 1 shows representa-
tive results. At 180°C, Sc(OTf)3 (20 mol%) afforded
1-(2,5-dimethylphenyl)-1-hexanone 1a in the highest
yield, 39%, among 12 commercially available rare-earth
metal triflates tested (Table 1, entry 1). Eu(OTf)3 and
Yb(OTf)3 also afforded 1a but in lower yields (Table 1,
entries 2 and 3). Although even at 180°C conversions of
the carboxylic acid were much higher than the yields of
1a (Table 1, entries 1–3), which suggested considerable
side-reactions, higher reaction temperature, 250°C,
unexpectedly improved the yield of ketone significantly;
in particular, Yb(OTf)3 afforded 1b in 83% yield (Table
1, entry 6). Further improvement was attained by using
Eu(NTf2)3;10 1b was obtained nearly quantitatively
Recently many reports described a catalytic amount of
Lewis acids efficiently promote Friedel–Crafts acylation
reactions using acid chlorides or acid anhydrides as
acylating agents.6 However, only a few reports are
published on the Friedel–Crafts acylation reactions
using carboxylic acids as acylating agents with a cata-
lytic amount of Lewis acids without stoichiometric
additives. In 1996, Kobayashi’s group reported Friedel–
Crafts acylation of phenols and naphthols with car-
boxylic acids using a catalytic amount of Lewis acids
such as Hf(OTf)4, Zr(OTf)4 and Sc(OTf)3.5b During the
11
(Table 1, entry 8). Sc(NTf2)3 also afforded ketone in
higher yield than Sc(OTf)3 (Table 1, entry 7) while
Keywords: Friedel–Crafts acylation; carboxylic acid; Lewis acid; rare-
earth metal.
* Corresponding author. Tel.: +81-29-861-4588; fax: +81-29-861-4511;
e-mail: s-shimada@aist.go.jp
12
Yb(NTf2)3 showed poorer results than Yb(OTf)3
(Table 1, entry 11). Bi(NTf2)3,13 which is an excellent
catalyst for the intramolecular Friedel–Crafts cycliza-
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.08.099

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M. Kawamura et al. / Tetrahedron Letters 44 (2003) 7715–7717
Table 1. Reaction of p-xylene with hexanoic and hep-
Table 2. Reaction of p-xylene with aliphatic and aromatic
carboxylic acids catalyzed by Eu(NTf2)3
tanoic acidsa
a
Entries 1–3: hexanoic acid was used. Entries 4–12: heptanoic acid
was used. The ratio of p-xylene/carboxylic acid was 65/1 for entries
1–6 and 8 and 50/1 for entries 7 and 9–12.
a
Conversion of carboxylic acids determined by GC analysis using
docosane as an internal standard.
b Conversion of carboxylic acids determined by GC analysis using
naphthalene (for entries 1–3) or docosane (for entries 4–12) as an
internal standard.
b Isolated yields.
c Not determined.
c Yields are based on carboxylic acids and were determined by GC
analysis using naphthalene (for entries 1–3) or docosane (for entries
4–12) as an internal standard.
product only in 4% yield under the same reaction
conditions (Table 3, entry 4). As expected, acylation of
anisole is faster than that of alkylbenzenes and gave the
acylated product in high yield with >97% p-selectivity
(Table 3, entry 5).
tion of 4-arylbutyric acids,9 was also effective although
less efficient than Eu(NTf2)3 (Table 1, entry 12).
Tables 2 and 3 summarize the preliminary scope and
limitation of Eu(NTf2)3-catalyzed Friedel–Crafts
acylation of aromatic compounds with carboxylic
acids.14 As seen in Table 2, this procedure is effective
for a wide range of aliphatic carboxylic acids with
various chain lengths as well as aromatic carboxylic
acids although the yields decreased to some extent in
the case of short chain carboxylic acids such as acetic
acid and propionic acid (Table 2, entries 1 and 2) as
well as branched carboxylic acids, in particular at the
a-position (Table 2, entries 4, 6, 8). This wide appli-
cability is the advantage of this procedure over previ-
ously reported zeolite2 and heteropoly acid salts
catalysts.3
Eu(NTf2)3 was found still active after the reaction at
250°C. After the reaction of p-xylene with heptanoic
acid at 250°C (isolated yield of 1b was 78%), Eu(NTf2)3
was recovered in 77% yield by the extraction of the
reaction mixture dissolved in hexane with water. The
recovered Eu(NTf2)3 catalyzed the same reaction with-
out decrease in catalytic activity (isolated yield of 1b
was 78%).
It is noteworthy that the acylation using aliphatic car-
boxylic acids was successful despite high reaction tem-
perature because Friedel–Crafts acylation reaction of
aliphatic acid chlorides with a catalytic amount of
Lewis acids is often only successful for highly reactive
aromatic compounds such as anisole.15 At higher reac-
tion temperature, side-reactions of ketone products are
suggested.6d,e
Table 3 shows the reaction of several aromatic com-
pounds with heptanoic acid. Monoalkylbenzenes are
efficiently acylated with good p-selectivity (Table 3,
entries 1 and 2). m-Xylene was also efficiently acylated
(Table 3, entry 3) while benzene afforded acylation
In summary, we have examined the scope and limita-
tion of Lewis acid catalysts for Friedel–Crafts acylation

M. Kawamura et al. / Tetrahedron Letters 44 (2003) 7715–7717
7717
Table 3. Reaction of various aromatic compounds with
heptanoic acid catalyzed by Eu(NTf2)3
1997, 44, 129–133; (f) De Castro, C.; Primo, J.; Corma,
A. J. Mol. Catal. A 1998, 134, 215–222.
3. (a) Izumi, Y.; Ogawa, M.; Nohara, W.; Urabe, K. Chem.
Lett. 1992, 1987–1990; (b) Kaur, J.; Kozhevnikov, I. V.
Chem. Commun. 2002, 2508–2509.
4. Chiche, B.; Finiels, A.; Gautheir, C.; Geneste, P. J. Mol.
Catal. 1987, 42, 229–235.
5. (a) Suzuki, K.; Kitagawa, H.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 1993, 66, 3729–3734; (b) Kobayashi, S.;
Moriwaki, M.; Hachiya, I. Tetrahedron Lett. 1996, 37,
4183–4186.
6. For recent examples of Friedel–Crafts acylation with acid
chlorides or acid anhydrides as acylating agents using a
catalytic amount of Lewis acids, see: (a) Kawada, A.;
Mitamura, S.; Matsuo, J.; Tsuchiya, T.; Kobayashi, S.
Bull. Chem. Soc. Jpn. 2000, 73, 2325–2333; (b) Singh, R.
P.; Kamble, R. M.; Chandra, K. L.; Saravanan, P.;
Singh, V. K. Tetrahedron 2001, 57, 241–247; (c) Duris, F.;
Barbier-Baudry, D.; Dormond, A.; Desmurs, J. R.;
Bernard, J. M. J. Mol. Catal. A 2002, 188, 97–104; (d) Le
Roux, C.; Dubac, J. Synlett 2002, 181–200; (e) Prakash,
G. K. S.; Yan, P.; Torok, B.; Bucsi, I.; Tanaka, M.; Olah,
G. A. Catal. Lett. 2003, 85, 1–6.
7. Walker, M. US Patent 5,362,375, 2002; Chem. Abstr.
2002, 136, 262987.
8. For a recent review on rare-earth metal Lewis acids in
organic synthesis, see: Kobayashi, S.; Sugiura, M.; Kita-
gawa, H.; Lam, W. W. Chem. Rev. 2002, 102, 2227–2302.
9. We have recently reported Lewis acid-catalyzed
intramolecular Friedel–Crafts cyclization of 4-arylbutyric
acids to form 1-tetralones, see: Cui, D.-M.; Kawamura,
M.; Shimada, S.; Hayashi, T.; Tanaka, M. Tetrahedron
Lett. 2003, 44, 4007–4010.
10. Synthesis of Eu(NTf3)2: A mixture of HNTf2 (4.58 g, 16.3
mmol) and Eu2O3 (956 mg, 2.72 mmol) in 100 mL of
water was stirred at 140°C for 3 h. The resulting mixture
was filtered and the filtrate was evacuated at 140°C to
remove water. Further drying at 180°C for 6 h under
vacuum gave Eu(NTf2)3 as a highly hygroscopic colorless
solid (4.90 g, 91%). Anal. calcd for C6EuF18N3O12S6: C,
7.26; F, 34.46; N, 4.23. Found: C, 7.15; F, 33.92; N, 4.36.
11. Ishihara, K.; Kubota, M.; Yamamoto, H. Synlett 1996,
265–266.
a
Isolated yield. The ratios of regioisomers were determined by GC
analysis using docosane as an internal standard unless otherwise
noted.
b o-/m-/p-isomers =22/5/73.
c (o- + m-)/p-isomers=15/85.
d 1-(2,4-dimethylphenyl)-1-heptanone/other regioisomers=96/4 by
GC-MS.
e The ratio of p-/o-isomers was determined to be >97/3 by 1H NMR
analysis.
reaction using carboxylic acids as acylating agents and
found Eu(NTf2)3 is an efficient catalyst at high reaction
temperature. Further studies to clarify the side reac-
tions and to improve the reaction efficiency at lower
reaction temperature are underway.
12. Mikami, K.; Kotera, O.; Motoyama, Y.; Tanaka, M.
Inorg. Chem. Commun. 1998, 1, 10–11.
13. Picot, A.; Repicheta, S.; Le Roux, C.; Dubac, J.; Roques,
Acknowledgements
N. J. Fluorine Chem. 2002, 116, 129–134.
14. Typical procedure: A mixture of Eu(NTf2)3 (87.8 mg,
0.0885 mmol), octanoic acid (85.1 mg, 0.590 mmol),
docosane (22.3 mg, an internal standard for GC analysis)
and p-xylene (3.62 ml, 29.5 mmol) was stirred at 250°C
for 12 h with periodical monitoring of octanoic acid
conversion by GC. After cooling to room temperature,
water (3 mL) was added to the mixture and the organic
layer was separated. The aqueous layer was extracted
with ethyl acetate (3×10 mL). The combined organic
layers were dried over MgSO4 and concentrated under
reduced pressure. The residue was purified by preparative
D.C. thanks New Energy and Industrial Technology
Development Organization (NEDO) for a postdoctoral
fellowship.
References
1. Olah, G. A. Friedel–Crafts and Related Reactions; Wiley-
Interscience: New York, 1964; Vol. III, Part 1.
2. (a) Chiche, B.; Finiels, A.; Gauthier, C.; Geneste, P. J.
Org. Chem. 1986, 51, 2128–2130; (b) Gauthier, C.;
Chiche, B.; Finiels, A.; Geneste, P. J. Mol. Catal. 1989,
50, 219–229; (c) Wang, Q. L.; Ma, Y.; Ji, X.; Yan, H.;
Qiu, Q. J. Chem. Soc., Chem. Commun. 1995, 2307–2308;
(d) Singh, A. P.; Pandey, A. K. J. Mol. Catal. A 1997,
123, 141–147; (e) Pandey, A. K.; Singh, A. P. Catal. Lett.
TLC
(hexane/EtOAc=27/1)
to
give
1-(2,5-
dimethylphenyl)-1-octanone as a pale yellow oil (109 mg,
80% yield).
15. For successful examples of less reactive aromatic com-
pounds, see: (a) Kobayashi, S.; Iwamoto, S. Tetrahedron
Lett. 1998, 39, 4697–4700; (b) Ref. 6e.