Catalytic Friedel-Crafts Acylation of Aniline Derivatives

Full text of DOI:10.1002/1615-4169(20010129)343:1<71::AID-ADSC71>3.0.CO;2-J

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Catalytic Friedel±Crafts Acylation
of Aniline Derivatives
Shu Kobayashi,* Ichiro Komoto, Jun-ichi Matsuo
Å
Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113±0033 Japan
Fax: +81 3 5684 0634; e-mail: skobayas@mol.f.u-tokyo.ac.jp
Received August 8, 2000; Accepted October 16, 2000
Friedel±Crafts acylation
provides a fundamental
and useful method for
the preparation of aro-
matic ketones. While cat-
alytic amounts of Lewis
the aniline derivatives. In
literature, it was reported
that Friedel±Crafts acyla-
tion of acylanilides using
more than stoichiometric
amounts of AlCl3 gave
Keywords: aryl ketones; Friedel-Crafts acylation;
gallium; homogeneous catalysis; Lewis acids; sol-
vent systems
acids are used in Friedel±Crafts alkylation, more than the corresponding acylated products in low yields.[8, 9]
stoichiometric amounts of Lewis acids such as AlCl3 Based on our findings that gallium tris(perfluoro-
are required for the acylation.[1] There is consider- alkanesulfonate) showed high catalytic activities in
able concern that large amounts of aluminum resi- Friedel±Crafts acylations of benzene and deactivated
dues as well as the use of harmful organic solvents benzenes,[5] we envisioned that these highly active
will induce some environmental problems, especially gallium catalysts would promote Friedel±Crafts acy-
in industrial-scale processes. To address this issue, lation of aniline derivatives. First, we tested the reac-
several excellent catalysts were developed, and cata- tion of acetanilide (1a) with acetic anhydride using
lytic acylation of activated benzenes such as anisole, 10 mol % of Ga(OTf)3.[10] Although Ga(OTf)3 itself
xylenes, and toluene was achieved.[2] However, cata- gave the desired adduct in a low yield in nitro-
lytic Friedel±Crafts acylation of benzene and deacti- methane (MeNO2), the addition of lithium perchlo-
vated benzenes such as chlorobenzene was still rate (LiClO4) to the reaction mixture improved the
difficult to realize. Recently, Dubac et al. and our yield dramatically (Table 1).[2j,o, 4a,b] As the amounts
[3]
group independently reported that Bi(OTf)3 and
[4]
Hf(OTf)4 were effective catalysts for the Friedel±
Crafts acylation of benzene and deactivated ben-
zenes. Quite recently, we have further demonstrated
Table 1. Effect of Lewis acids
that a gallium catalyst, especially gallium tris(per-
fluoroalkanesulfonate), showed the highest activity
in Friedel±Crafts acylation.[5]
On the other hand, p-ketoaniline structures are of-
ten observed in biologically active compounds as well
as in fine chemicals, and the controlled and efficient
synthesis of these structures is an important task.
Although Friedel±Crafts acylation of aniline deriva-
tives is a simple and straightforward method for the
synthesis of p-ketoanilines, no example of a catalytic
reaction has been reported, to the best of our knowl-
edge.[6, 7] In this paper, we describe the first example
of the catalytic Friedel±Crafts acylation of aniline de-
rivatives using a gallium compound.
The difficulty of Friedel±Crafts acylation of aniline
derivatives could be ascribed to the low activity of Le-
wis acid catalysts caused by basic nitrogen atoms of
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/asc/ or from
the author.
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Table 2. Friedel-Crafts acylation of aniline derivatives
of LiClO4 were increased, the yields of the desired ad-
ducts improved, and 93% yield of the acetylated ad-
duct was obtained in a 6.0 M MeNO2±LiClO4 solution.
While
gallium
tris(nonafluorobutanesulfonate)
(Ga(ONf)3) also catalyzed the reaction efficiently, the
catalytic activity of GaCl3 was low. We examined
other catalysts such as Sc(OTf)3, Sc(ONf)3, Hf(OTf)4,
Sb(OTf)3,[11] Bi(OTf)3, etc., and it was found that
Ga(OTf)3 gave the best result. It is noted that AlCl3, a
representative Lewis acid for Friedel±Crafts acyla-
tion, was not effective in this reaction. In a MeNO2±Li-
ClO4 solution, even more than stoichiometric
amounts of AlCl3 gave the desired adduct in a very
low yield. Independently, 1 a reacted with acetic an-
hydride in the presence of 3.2 equivalents of AlCl3 in
1,2-dichloroethane at 50 °C for 12 h to afford the
acetylated adduct in 9% yield.
Several examples of Ga(OTf)3- or Ga(ONf)3-cata-
lyzed Friedel±Crafts acylation of aniline derivatives
are shown in Table 2. In all cases, the reactions pro-
ceeded smoothly in the presence of a catalytic
amount of the gallium compound in MeNO2±LiClO4
in good to excellent yields. Not only acetanilide (1 a)
but also benzanilide (1 b) reacted with several acetic
anhydrides to afford the corresponding acylated ad-
ducts in high yields. Although N-methanesulfo-
nyl(Ms)-aniline reacted with acetic anhydride in the
presence of 10 mol % of Ga(OTf)3 to give the N-acety-
lated adduct in a high yield, N-methanesulfonyl(Ms)-
N-methylaniline (1 c) reacted with acetic anhydride
under the same reaction conditions to afford 2 e in
97% yield. Several o- and m-substituted aniline deri-
vatives also worked well in the presence of a catalytic
amount of Ga(OTf)3 or Ga(ONf)3. It is noted that sin-
gle regioisomers shown in Table 2 were obtained in
all these acylation reactions except for entry 7. For
benzoylation, 1 c and 1 k smoothly reacted with ben-
zoyl chloride in 1,2-dichloroethane under reflux for
24 h to afford the desired adducts (2 m and 2 n) in
high yields. A carboxylic acid was directly employed
in this reaction in combination with trifluoroacetic
anhydride, and the desired acetylated adduct (2 b)
was obtained in an excellent yield without formation
of trifluoroacetylated adducts.
(1 l and 1 m) were observed at lower field than those
of acylanilides (1 a and 1 b) in both cases. This means
that the electron density at the C4 position of N-
methylated acylanilides is lower than that of acylani-
lides.[12] This electronic factor can explain the ob-
served lower yields of N-methylated acylanilides in
the above-mentioned Friedel±Crafts acylation. This
lower electron density at the C4 positions of N-methy-
lated acylanilides is explained in terms of their con-
formations. The dihedral angles of N±Ph of 1 l and
1 m are 87.1° and 60.0°, respectively, in their crystal
structures, and it has been proved that these confor-
mations are maintained in their solution states.[13] In
these conformations, the conjugation between amido
During our investigation of the Friedel±Crafts acy-
lation of aniline derivatives, we found that the N-sub-
stituents of the aniline derivatives influenced the re-
action rate to
a large extent (Table 3). While
Ga(OTf)3-catalyzed acetylation of 1 a and 1 b pro-
ceeded smoothly, N-methylacetanilide (1 l) and N-
methylbenzanilide (1 m) reacted with acetic anhy-
dride sluggishly under the same reaction conditions.
To understand the difference in reactivities, we mea-
sured the 13C NMR spectra of the anilides and com-
pared the chemical shifts of the reaction sites (the C4
position). It was interesting to find that 13C NMR sig-
nals at the C4 position of N-methylated acylanilides
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Table 3. Effect of N-substitution of aniline derivatives (1)
0.5 ppm downfield. These results support the prefer-
ential coordination of Ga(OTf)3 to 1 a rather than 1 c.
In conclusion, we have discovered that the Frie-
del±Crafts acylations of aniline derivatives pro-
ceeded in good to excellent yields using a catalytic
amount of Ga(OTf)3 or Ga(ONf)3 in LiClO4±MeNO2.
While acylanilides reacted smoothly, acylation of N-
methylated acylanilides was difficult because of
electronic factors. On the other hand, N-alkylsulfo-
nyl-N-alkylanilines were more easily acylated than
acylanilides, presumably due to weak coordination
of the gallium compound with the sulfonyl groups.
It should be noted that this is the first example of
the catalytic Friedel±Crafts acylation of aniline deri-
vatives. Further investigations to clarify the precise
mechanism of this acylation including the catalytic
cycle as well as to apply this reaction to the synthesis
of biologically important compounds are now in pro-
gress.
nitrogens and aniline's phenyl rings is lost. On the
other hand, 1 a[13c] and 1 b[13a] have almost coplanar
structures in their crystals, and the conjugation be-
tween amido nitrogens and aniline's phenyl rings ex-
ists. This conjugation enables donation of electrons
from the nitrogens to the aniline's aromatic rings,
and causes higher reactivity in the electrophilic aro-
matic substitution reactions. According to the chemi-
cal shift value of the C4 position, the reactivity of tri-
fluoroacetylanilide (1 n) could be predicted.
Experimental Section
Typical Procedure for the Catalytic Friedel±Crafts Acyla-
tion
On the other hand, N-Ms-N-methylaniline (1c) was
acetylated more easily than 1a (Table 4). In terms of
the electronic factor, 1c has some disadvantages be-
cause the Ms group is a stronger electron-withdraw-
ing group than the acetyl group.[14] Actually, the lower
electron density of the aromatic ring of 1 c was sup-
ported by 13C NMR chemical shifts at the C4 position
of 1 c and 1 a (127.4 and 122.9 ppm, respectively). We
thought that the higher reactivity of 1c could be ex-
plained by assuming that coordination of Ga(OTf)3
with the oxygen of the sulfonamide structure of 1 c
was weaker than that of Ga(OTf)3 with the oxygen of
the amide group of 1 a, and that this caused increased
population of free Ga(OTf)3 in the Friedel-Crafts acy-
lation of 1 c. To confirm this hypothesis, we conducted
NMR experiments. Equimolar amounts of 1 a, 1 c, and
Ga(OTf)3 were combined in MeNO2-d3 at 50 °C, and
1H NMR spectrum was measured. While the chemical
To a stirred solution of acetanilide (108 mg, 0.80 mmol),
LiClO4 (1.28 g, 12.0 mmol), acetic anhydride (168 mg,
1.65 mmol), and nitromethane (2.0 mL) was added
Ga(OTf)3 (41.5 mg, 0.08 mmol) in one portion. After the mix-
ture had been stirred at 50 °C for 24 h, the reaction mixture
was quenched with saturated aqueous NaHCO3 (10 mL).
The aqueous layer was extracted with CH2Cl2 (3 ´ 15 mL).
The combined organic layers were dried over Na2SO4 and
concentrated to a residue that was subjected to column
chromatography (50:1 CHCl3/MeOH) on silica gel to give
2 a as a colorless solid; yield: 131 mg (93%); mp 169±171 °C
(lit. [15] mp 167±168 °C); 1H NMR (CDCl3): d = 2.22 (s, 3 H),
2.58 (s, 3 H), 7.63 (d, J = 8.8 Hz, 2 H), 7.75 (brs, 1H), 7.94 (d,
J = 8.8 Hz, 2 H); 13C NMR (CDCl3): d = 24.81 26.48, 118.85,
129.76, 132.80, 142.35, 168.68, 197.11.
Similarly, 10 mmol-scale experiments were successfully
performed and the same levels of yields were obtained.[16]
1
shifts of 1 c did not change, the H NMR signal of the
methyl group of 1 a became broad and moved by
Acknowledgments
This work was partially supported by CREST, Japan Science
and Technology Corporation (JST), and a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science,
Sports, and Culture, Japan.
Table 4. Effect of N-substitution of aniline derivatives (2)
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Supporting Information.
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