Simple and improved procedure for regioselective acylation of aromatic ethers with carboxylic acids on the solid surface of alumina in the presence of trifluoroacetic anhydride

Full text of DOI:10.1021/jo9615413

9546
J . Org. Chem. 1996, 61, 9546-9547
Sch em e 1
Sim p le a n d Im p r oved P r oced u r e for
Regioselective Acyla tion of Ar om a tic
Eth er s w ith Ca r boxylic Acid s on th e Solid
Su r fa ce of Alu m in a in th e P r esen ce of
Tr iflu or oa cetic An h yd r id e
Brindaban C. Ranu,* Keya Ghosh, and Umasish J ana
Ta ble 1. Acyla tion of Ar om a tic Eth er s w ith Ca r boxylic
Acid s on th e Su r fa ce of Alu m in a
Department of Organic Chemistry, Indian
Association for the Cultivation of Science,
J adavpur, Calcutta 700 032, India
Received August 7, 1996
The Friedel-Crafts acylation of aromatic rings is one
of the most fundamental and useful reactions in organic
synthesis.1 The disadvantages associated with the clas-
sical procedures include the use of toxic acid chloride as
the acylating agent and stoichiometric amounts of alu-
minum trichloride as a Lewis acid, which entails envi-
ronment pollution. In order to minimize this problem,
some catalytic Friedel-Crafts acylations have been
developed recently.2 In addition, acylations involving
carboxylic acids and less toxic Lewis acids3 or apparently
nonhazardous acid catalysts4 have been studied, although
these procedures are not quite successful as practical and
general synthetic methods. For instance, a recent
methodology4b of acylation of anisole with carboxylic acids
over HZSM-5 zeolite, although environmentally safe, has
limitations with regard to generality (no reaction with
higher acids) and efficiency (reaction time of 48 h and
concomitant O-acylation). Thus, a reliable general method
for this useful reaction involving nonhazardous reagents
is in demand. As a part of our continued efforts to utilize
surface-mediated reactions for useful synthetic transfor-
mations5 we wish to disclose here a very simple and
highly efficient method for regioselective acylation of
aromatic ethers with carboxylic acids in the presence of
trifluoroacetic anhydride on the surface of alumina
without any solvent (Scheme 1).
a
All yields refer to pure isolated products, fully characterized
1
b
by IR and H NMR. The reaction was carried out in a microwave
In a typical reaction, a mixture of carboxylic acid and
trifluoroacetic anhydride was added to an aromatic ether
oven. c The product is 2,5-dimethoxyacetophenone. The product
d
is 2-methoxy 5-methylacetophenone. e The product is 2-acetyl-
thiophene. f The product is 2-acetylfuran, and the reaction was
carried out at 0-5 °C.
(1) (a) Olah, G. A. Friedel-Crafts and Related Reactions; Inter-
science: New York, 1964; Vol. III, Part 1. (b) Heaney, H. In
Comprehensive Organic Synthesis; Trost, B. M., Ed.; Pergamon Press:
Oxford, 1991; Vol. 2, p 753.
adsorbed on the surface of activated acidic alumina and
mixed uniformly with shaking. The mixture was kept
at room temperature with occasional shaking for a
certain period of time until the reaction was complete.
The product was isolated by simple extraction of the solid
mass by ether followed by usual workup. Several struc-
turally varied aromatic ethers underwent acylations with
a wide range of carboxylic acids including acyclic, cyclic,
and aromatic ones. The results are presented in Table
1. The reactions are remarkably clean, and no chromato-
graphic separation is necessary to get the spectra-pure
compounds except in a few cases (Table 1, entries 8, 11,
and 13) where some starting ethers remained, the
conversion being less than 100%. Acylation occurs
exclusively at the position para to -OMe for all of the
ethers studied in almost quantitative yields. However,
in cases where the para positions are blocked (Table 1,
entries 11 and 13) the acyl group is introduced ortho to
the ether moiety. This procedure is also good enough for
the acylation of thioethers like thioanisole (Table 1, entry
14), giving 4-acylthioanisole, as well as thiophene and
furan (Table 1, entries 15 and 16), producing the corre-
(2) (a) Nomita, K.; Sugaya, Y.; Sasa, S.; Miwa, M. Bull. Chem. Soc.
J pn. 1980, 53, 2089. (b) Yamaguchi, T.; Mitoh, A.; Tanabe, K. Chem.
Lett. 1982, 1229. (c) Mukaiyama, T.; Nagaoka, H.; Ohshima, M.;
Murakami, M. Chem. Lett. 1986, 165. (d) Mukaiyama, T.; Ohno, T.;
Nishimura, T.; Han, S. J .; Kobayashi, S. Chem. Lett. 1991, 1059. (e)
Mukaiyama, T.; Suzuki, K.; Han, S. J .; Kobayashi, S. Chem. Lett. 1992,
432. (f) Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 545.
(g) Hachiya, I.; Moriwaki, M.; Kobayashi, S. Bull. Chem. Soc. J pn.
1995, 68, 2053. (h) Kobayashi, S.; Nagayama, S. J . Org. Chem. 1996,
61, 2256.
(3) Schiemenz, G. P.; Schmidt, U. Liebigs Ann. Chem. 1976, 1514.
(4) (a) Chiche, B.; Finiels, A.; Gauthier, C.; Geneste, P. J . Org. Chem.
1986, 51, 2128. (b) Wang, Q. L.; Ma, Y.; J i, X.; Yan, H.; Qiu, Q. J .
Chem. Soc., Chem. Commun. 1995, 2307.
(5) (a) Ranu, B. C.; Bhar, S.; Sarkar, D. C. Tetrahedron Lett. 1991,
32, 2811. (b) Ranu, B. C.; Bhar, S. Tetrahedron 1992, 48, 1327. (c)
Ranu, B. C.; Bhar, S.; Chakrabori, R. J . Org. Chem. 1992, 57, 7349.
(d) Ranu, B. C.; Bhar, S. J . Chem. Soc., Perkin Trans. 1 1992, 365. (e)
Ranu, B. C.; Sarkar, D. C.; Chakraborty, R. Synth. Commun. 1992,
22, 1095. (f) Ranu, B. C.; Saha, M.; Bhar, S. Tetrahedron Lett. 1993,
34, 1989. (g) Ranu, B. C.; Chakraborty, R. Tetrahedron 1993, 49, 5333.
(h) Ranu, B. C.; Chakraborty, R.; Saha, M. Tetrahedron Lett. 1993,
34, 4659. (i) Ranu, B. C.; Saha, M.; Bhar, S. J . Chem. Soc., Perkin
Trans. 1 1994, 2197. (j) Ranu, B. C.; Saha, M. J . Org. Chem. 1994,
59, 8269. (k) Ranu, B. C.; Majee, A.; Das, A. R. Synth. Commun. 1995,
25, 363. (l) Ranu, B. C.; Sarkar, A.; Saha, M.; Bhar, S. Pure Appl.
Chem. 1996, 68, 775. (m) Ranu, B. C.; Saha, M.; Bhar, S. Synth.
Commun., in press.
S0022-3263(96)01541-1 CCC: $12.00 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 26, 1996 9547
sponding 2-acylated products in excellent yields. The
reactions are reasonably fast even with the higher acids
and cyclohexane carboxylic acid; however, benzoic acid
reacts rather slow, although satisfactory conversion was
achieved by 10 min of microwave irradiation. The
reaction conditions are mild enough not to induce any
dealkylation of an ether residue ortho to the introduced
acyl group (Table 1, entries 11 and 13) as observed in
the acylation reaction with carboxylic acid catalyzed by
BF3.3
Although the use of trifluoroacetic anhydride for the
acylation of anisole with carboxylic acid has been re-
ported previously (only three examples), no attempt has
been made for generalization.6 Moreover, this procedure
on the solid surface of alumina offers significant improve-
ments over the earlier method,6 reducing the reaction
time considerably (10 min compared to 3 h), minimizing
the amount of trifluoroacetic anhydride from 3-4 equiv
to 1.5 equiv, and above all, increasing the yield remark-
ably; the most marked examples are thiophene and furan,
where yields were raised from 50% and 39% to 95% and
75%, respectively.
For comparison, when silica gel (HF 254, activated)
was used in place of alumina in the reactions of anisole
with acetic acid and with propionic acid, both reactions
were found to be very slow. In fact, only 5-10% progress
was observed by the time at which the reactions were
complete using alumina. Thus, alumina was found to
be the better choice for this reaction.
In conclusion, the present method provides a very
convenient and efficient procedure for acylation of aro-
matic ethers. The notable advantages of this methodol-
ogy are direct use of carboxylic acid, mild conditions
(room temperature), fast reaction (10 min to 3 h),
operational simplicity, generality, excellent regioselec-
tivity, no side reactions, and quantitative yields, and
thus, it offers significant improvements over other pro-
cedures involving Friedel-Crafts acylation of aromatic
ethers.2-4,6,8 We believe this will find significant applica-
tion in the field of organic synthesis.
Exp er im en ta l Section
Gen er a l Meth od s. General information regarding instru-
ments and techniques used are the same as mentioned in our
previous paper.5j
Alumina (acidic, Brockmann activity, grade 1 for column
chromatography, SRL, India) was activated by heating at 200
°C for 4 h under vacuum followed by cooling under N2 and was
used for all the reactions. (Activated alumina can be stored
under N2 for 1 week for subsequent use without much loss of
activity). The aromatic ethers and carboxylic acids are all
commercial materials and were purified by distillation or
recrystallization before use.
Gen er a l P r oced u r e for Acyla tion of Ar om a tic Eth er s.
Rep r esen ta tive P r oced u r e. A mixture of acetic acid (120 mg,
2 mmol) and trifluoroacetic anhydride (610 mg, 2.9 mmol, Fluka)
was added to anisole (216 mg, 2 mmol) adsorbed on alumina (2
g) and mixed uniformly by shaking. Color (usually pink, but in
few cases green or blue) developed immediately and darkened
with progress of the reaction. The reaction mixture was kept
under moisture guard at room temperature with occasional
shaking for a certain period of time (Table 1) as required to
complete the reaction (monitored by TLC). The solid mass was
then eluted with Et2O (50 mL), and the ether extract was then
washed with an aqeuous solution of sodium bicarbonate and
brine and dried over anhydrous sodium sulfate. Evaporation
of solvent furnished practically pure (GC, 100%) 4-methoxyace-
tophenone (298 mg, 99%). This was further purified by filtering
it through
a short column of silica gel (eluted with 95/5
petroleum ether-ether mixture) to afford the analytically pure
product (290 mg, 96%). The identity of this compound was easily
1
established by comparison of its H NMR spectrum with that of
an authentic sample.7
All of the acylated products are known compounds and
characterized easily by comparison with authentic samples (IR,
1H NMR, mp) except one (Table 1, entry 7), whose spectral and
analytical data are furnished.10
Although the results reported in Table 1 were based on mmol
scale reactions, gram-scale reactions also afforded the corre-
sponding products in analogously excellent yields.
Ack n ow led gm en t . Financial support from CSIR,
New Delhi (01/1364/95), is gratefully acknowledged.
K.G. and U.J . also thank CSIR for their fellowships.
J O9615413
(6) Bourne, E. J .; Stacey, M.; Tatlow, J . C.; Tedder, J . M. J . Chem.
Soc. 1951, 719.
(7) Pouchert, C. J . The Aldrich Library of NMR Spectra, 2nd ed.;
Aldrich Chemical Co., Inc.: Milwaukee, 1983; Vol. 2.
(8) Effenberger, F.; Epple, G. Angew. Chem., Int. Ed. Engl. 1972,
11, 300.
(10) IR(neat): 1600, 1670 cm-1 1H NMR δ: 1.12-2.22 (10H, m),
.
2.92-3.24 (1H, m), 3.82 (3H, s), 6.82 (2H, d, J ) 9 Hz), 7.84 (2H, d, J
) 9 Hz). Anal. Calcd for C14H18O2: C, 77.02; H, 8.31. Found: C,
76.91; H, 8.12.
(11) Awad, W. I.; EL-Neweihy, M. F.; Selin, S. F. J . Org. Chem. 1958,
23, 1783.
(9) Matsuda, S.; Ogawa, M.; Okazaki, T.; Benden, M. M. Chem. Abst.
1958, 52, 10930f.
(12) Mathur, K. B. L.; Sharma, J . N.; Venkataramanan, K.; Krish-
namurthy, H. G. J . Am. Chem. Soc. 1957, 79, 1957.