Al(OTf)3 as a highly efficient catalyst for the rapid acetylation of alcohols, phenols and thiophenols under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2007.03.162

Aluminium triflate (0.01-0.1 mol %) was found to be an efficient catalyst for the acylation of alcohols, phenols, thiols and sugars with acetic anhydride in high yields under solvent-free conditions in a short reaction time at room temperature. Racemization of optically active alcohols and epimerization of sugars were not observed. The acylation efficacy of various acyl donors was also investigated.

Full text of DOI:10.1016/j.tetlet.2007.03.162

Tetrahedron Letters 48 (2007) 3813–3818
Al(OTf)3 as a highly efficient catalyst for the rapid acetylation
of alcohols, phenols and thiophenols under solvent-free conditions
Ahmed Kamal,* M. Naseer A. Khan, K. Srinivasa Reddy, Y. V. V. Srikanth
and T. Krishnaji
Biotransformation Laboratory, Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 21 February 2007; revised 16 March 2007; accepted 29 March 2007
Available online 4 April 2007
Abstract—Aluminium triflate (0.01–0.1 mol %) was found to be an efficient catalyst for the acylation of alcohols, phenols, thiols and
sugars with acetic anhydride in high yields under solvent-free conditions in a short reaction time at room temperature. Racemization
of optically active alcohols and epimerization of sugars were not observed. The acylation efficacy of various acyl donors was also
investigated.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Acylation of alcohols and phenols is an important and
routinely utilized transformation in organic synthesis.1
Despite a number of precedents, new efficient methodol-
ogies for acylation are still in demand. Acid anhydrides
have been the most commonly used reagents in the pres-
ence of an acid or base catalyst.2 Although a number of
methods are available for the preparation of acetates,
the use of acetic acid or a protic acid or acetic anhydride
and pyridine are the most commonly used reagents.1 4-
(Dimethylamino)pyridine (DMAP) and 4-pyrrolidino-
pyridine (PPY) catalyze the acetylation of alcohols.3
Further, other catalysts such as CoCl2,4 TaCl5–SiO2,5
ZnCl2,6a ZnO,6b,c InCl3,7a ZrCl4,7b LiClO4,7c Ru-cata-
lysts,7d Mg(ClO4)2,7e SmI2,7f CeCl3,7g ZrOCl2Æ8H2O,7h
montmorillonite,8a TMS–Cl,8b PTSA,9a NH2SO3H,9b
distannoxane,9c ionic liquids,9d solid supported reagents
and lipase enzymes9e and various triflates10 have been
used for acetylation of alcohols.
Although a large number of methods for acetylation
are available, many suffer from limitations such as long
reaction times, harsh reaction conditions, use of expen-
sive, moisture sensitive and toxic catalysts, formation of
side products and poor yields of the desired products. In
view of the demands of organic synthesis, there is still a
need to develop mild and efficient protocols for the acet-
ylation of alcohols.
Al(OTf)3 has been used for the Friedel–Crafts alkylation
and acylation of aromatic compounds.12a In recent
years, it was found to be an efficient catalyst for epoxide
ring opening,12b,c esterification of carboxylic acids with
alcohols,12d thiol protection12e and silylation of alcohols
and phenols.12f Herein, we report that a number of
alcohols, phenols and thiophenols can be acetylated
with acetic anhydride, in excellent yields, in the presence
of 0.1 mol % of Al(OTf)3 at room temperature under
solvent-free conditions in short times (10–40 s) (Scheme
1). Encouraged by the success of this reaction various
primary, secondary, benzylic and cyclic alcohols and
phenols were subjected to acylation in excellent yields.
The product structures were established from their
Most of the above procedures can be applied for the
acylation of various acid/base sensitive substrates.
Recently, perchlorates7c,e were reported to catalyze the
acetylation of alcohols; however, perchlorates, particu-
larly of lithium, are known to be explosive and moisture
sensitive. More recently, molecular iodine,11a 3-nitro-
benzeneboronic acid11b and La(NO3)3Æ6H2O11c cata-
lyzed acetylations of alcohols were also reported.
Al(OTf)3
(0.01-0.1 mol %)
R OAc
R OH
Ac2O (1.5 equiv.), rt
*
Corresponding author. Tel.: +91 40 27193157; fax: +91 40
27193189; e-mail: ahmedkamal@iict.res.in
Scheme 1.
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.162

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A. Kamal et al. / Tetrahedron Letters 48 (2007) 3813–3818
Table 1. Acetylation of alcohols and phenols catalyzed by 0.1 mol % aluminium triflatea
Entry
1
Substrate
Product
Time (s)
15
Yieldb (%)
96
OH
OAc
OH
OAc
2
20
10
98
99
F
F
OH
3a
OAc
Cl
OH
Cl
3b
(12.85 g scale)
15
10
96
95
Cl
OH
OAc
OAc
Cl
Cl
4
OH
5
6
7
8
10
25
30
20
99
95
96
99
OCH3
OH
OCH3
OAc
NO2
OH
NO2
OAc
CN
OH
CN
OAc
COOCH3
COOCH3
OH
OH
OAc
OAc
9
30
30
95
95
OH
OAc
10
OH
OAc

A. Kamal et al. / Tetrahedron Letters 48 (2007) 3813–3818
3815
Table 1 (continued)
Entry
Substrate
Product
Time (s)
25
Yieldb (%)
OH
OAc
11
12
13
96
OH
OAc
OAc
OH
30
10
90
98
O
O
O
CH3
CH3
CH3
HO
HO
AcO
AcO
O
CH3
14
15
20
15
96
98
OH
OH
OAc
OAc
OH
OAc
16
17
30
20
95
96
HO
AcO
OH
OAc
OH
OAc
18
19
20
30
96
95
O
O
HO
AcO
OH
OAc
HO
AcO
OH
OAc
20
21
20
15
98c
HO
O
O
AcO
O
O
95
(continued on next page)
OH
OAc
O
O

3816
A. Kamal et al. / Tetrahedron Letters 48 (2007) 3813–3818
Table 1 (continued)
Entry
Substrate
Product
Time (s)
15
Yieldb (%)
98c
22
23
24
O
OH
O
OAc
N3
N3
OH
CN
OAc
CN
20
20
98
99
OH
OAc
CH3
CH3
25
26
20
10
98
98
OH
CH3
OAc
CH3
H3C
SH
H3C
SAc
SH
SAc
27
28
15
40
95
D-Mannitol
Hexa-O-acetyl-D-mannitol
95c
a All the reactions were performed using 1.5 equiv of acetic anhydride unless otherwise stated.
b Isolated yields.
c To solubilize solid substrates, 5 equiv of acetic anhydride was added.
spectral properties13 (NMR, mass and IR) and by com-
parison with available literature data. In the absence of
a catalyst, using the same reaction conditions, the corre-
sponding products were obtained in low yields (25–40%)
even after prolonged reaction times of 1.5 h. The general
applicability and efficiency of this reaction is evident
from the wide range of compounds studied (Table 1).
Deactivated substrates, such as aromatic and benzylic
alcohols, could also be acetylated rapidly. For example,
strongly deactivated p-nitrophenol and p-cyanophenol
(Table 1, entries 6 and 7) quantitatively afforded the cor-
responding acetates within 25–30 s.
phenols. All the phenols afforded good yields of acetates
in 5–7 min in the presence of isopropenyl acetate
(1.5 equiv) and Al(OTf)3 (0.5 mol %) at room tempera-
ture (Table 2). However, when vinyl acetate was used
as the acylating agent, p-methoxy and p-nitrophenols
gave 50–70% yields after prolonged reaction times of
2 h (Table 2, entries 2 and 3) and phenol was not acety-
lated under the same conditions (Table 2, entry 1). Acet-
ylation of phenols did not take place in the presence of
acetic acid using Al(OTf)3 at room temperature (Table
2).
In conclusion, we have shown that Al(OTf)3 is an effi-
cient and versatile catalyst for the acylation of alcohols,
phenols, thiols, thiophenols and sugars using acetic
anhydride under solvent-free conditions at room
temperature. The advantages of this method over earlier
reported processes includes its simplicity, clean and
rapid reactions, high yields, absence of organic solvents,
large scale synthesis and retention of chirality.
Furthermore, when stereogenic centres were present in
the substrates, racemization or epimerization were not
observed to any extent in the acetylated products.14 In
order to increase the scope of the present method, a
large scale acylation of phenol was carried out (Table
1, entry 3b) using 0.01 mol % of the catalyst, the reac-
tion proceeded rapidly and in high yield.
We have also investigated the acetylating efficiency of
other acylating agents such as isopropenyl acetate, vinyl
acetate and acetic acid using the same catalyst on unsub-
stituted phenol and electron rich and electron deficient
Typical experimental procedure: To a mixture of alcohol/
phenol (2 mmol) and acetic anhydride (3 mmol),
Al(OTf)3 (0.01–0.1 mol %) was added. The reaction mix-
ture was stirred at room temperature for the appropriate

A. Kamal et al. / Tetrahedron Letters 48 (2007) 3813–3818
3817
Table 2. Acetylating efficacy of various acyl donors catalyzed by 0.5 mol % Al(OTf)3 under solvent-free conditions
Entry
Substrate
Acetic anhydride
Ta (s) Yb (%)
Isopropenyl acetate
Vinyl acetate
Ta (h) Yb (%)
Acetic acid
Ta (h) Yb (%)
Ta (min)
Yb (%)
OH
1
15
96
7
95
90
2
0
2
0
OH
2
10
99
7
5
2
70
2
0
OCH3
OH
3
25
95
95
2
50
2
0
NO2
a Time.
b Isolated yields after purification.
6. (a) Backer, R. H.; Bordwell, F. G. Org. Synth. 1955, 3,
141; (b) Sarvari, M. H.; Sharghi, H. Tetrahedron 2005, 61,
10903; (c) Tamaddon, F.; Amrollahi, M. A.; Sharafat, L.
Tetrahedron Lett. 2005, 46, 7841.
amount of time (Tables 1 and 2). Completion of the
reaction was monitored by TLC after quenching with
a saturated solution of NaHCO3 and the products were
extracted into ethyl acetate (3 · 25 mL). The combined
organic layer was washed with water, dried over anhy-
drous Na2SO4 and concentrated in vacuo. If necessary
the product was purified by column chromatography
on silica gel in hexane/ethyl acetate. All products were
characterized by comparison of their spectral data and
physical properties with those of authentic samples.
7. (a) Chakraborti, A. K.; Gulhane, R. Tetrahedron Lett.
2003, 44, 3521; (b) Chakraborti, A. K.; Gulhane, R.
Synlett 2004, 657; (c) Bandgar, B. P.; Kamble, V. T.;
Sadavarte, V. S.; Uppalla, L. S. Synlett 2002, 735; (d)
Martin-Matute, B.; Edin, M.; Bogar, K.; Backvall, J.-E.
Angew. Chem., Int. Ed. 2004, 43, 6535; (e) Bartoli, G.;
Bosco, M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi, M.;
Rinaldi, S.; Sambri, L. Synlett 2003, 39; (f) Ishii, Y.;
Takeno, M.; Kawasaki, Y.; Muromachi, A.; Nishiyama,
Y.; Sakaguchi, S. J. Org. Chem. 1996, 61, 3088; (g)
Torregiani, E.; Gianfranco, S.; Minassi, A.; Appendino,
G. Tetrahedron Lett. 2005, 46, 2193; (h) Ghosh, R.;
Swarupananda, M.; Chakraborty, A. Tetrahedron Lett.
2005, 46, 177.
Large scale acetylation: To a mixture of p-chlorophenol
(12.85 g, 0.1 mol) and acetic anhydride (14.18 mL,
0.15 mol) (entry 3b) at room temperature, was added
Al(OTf)3 (4.7 mg, 0.01 mol %). After 15 s, a saturated
solution of NaHCO3 was added to the reaction mixture
and the acetylated product was isolated by the above
described method.
8. (a) Li, A.-I.; Li, T.-S.; Ding, T.-H. Chem. Commun. 1997,
1389; (b) Kumareswaran, R.; Gupta, A.; Vankar, Y. D.
Synth. Commun. 1997, 27, 277.
9. (a) Cope, A. C.; Herrick, E. C. Org. Synth. 1963, 4, 304;
(b) Jin, T.-S.; Ma, Y.-R.; Zhang, Z.-H.; Li, T.-S.
Synth.Commun. 1998, 28, 3173; (c) Orita, A.; Sakamoto,
K.; Hamada, Y.; Mitsutome, A.; Otera, J. Tetrahedron
1999, 55, 2899; (d) Lee, S. G.; Park, J. H. J. Mol. Catal. A:
Chem. 2003, 194, 49; (e) Berger, B.; Rabiller, D. G.;
Konigsberger, K.; Faber, K.; Griengl, H. Tetrahedron:
Asymmetry 1991, 1, 541.
Acknowledgements
The authors (M.N.A.K., K.S.R. and T.K.) thank the
CSIR and Y.V.V.S. thanks the UGC, New Delhi, for
the award of research fellowships.
10. (a) Procopiou, P. A.; Baugh, S. P. D.; Flack, S. S.;
Inglis, G G. A. J. Org. Chem. 1998, 63, 2342; (b) Ishihara,
K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560; (c) Orita, A.; Tanahashi, C.;
Kakuda, A.; Otera, J. Angew. Chem., Int. Ed. 2000,
39, 2877; (d) Orita, A.; Tanahashi, C.; Kakuda, A.; Otera,
J. J. Org. Chem. 2001, 66, 8926; (e) Saravanan, P.; Singh,
V. K. Tetrahedron Lett. 1999, 40, 2611; (f) Chauhan, K.
K.; Frost, C. G.; Love, I.; Waite, D. Synlett 1999,
1743.
11. (a) Ahmed, N.; Van Lier, E. Tetrahedron Lett. 2006, 47,
5345; (b) Tale, R. H.; Adude, R. N. Tetrahedron Lett.
2006, 47, 7263; (c) Srikanth Reddy, T.; Narasimhulu, M.;
Suryakiran, N.; Chinni Mahesh, K.; Ashalatha, K.;
Venkateswarlu, Y. Tetrahedron Lett. 2006, 47, 6825.
References and notes
1. Green, W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999; p
150.
2. Larock, R. C. Comprehensive Organic Transformations;
VCH: New York, 1989, p 980.
3. (a) Scriven, E. F. V. Chem. Soc. Rev. 1983, 12, 129; (b)
Hofle, G.; Steglich, V.; Vorbruggen, H. Angew. Chem., Int.
Ed. Engl. 1978, 17, 569.
4. Iqbal, J.; Srivastava, R. R. J. Org. Chem. 1992, 57, 2001.
5. Chandrasekhar, S.; Ramachandar, T.; Shyamsunder, T.
Indian J. Chem. 2004, 43B, 813, and references cited
therein.

3818
A. Kamal et al. / Tetrahedron Letters 48 (2007) 3813–3818
12. (a) Olah, G. A.; Farooq, O.; Farnia, S. M. F.; Olah, J. A.
J. Am. Chem. Soc. 1988, 110, 2560; (b) Williams, D. B. G.;
Lawton, M. Org. Biomol. Chem. 2005, 3, 3269; (c)
Williams, D. B. G.; Lawton, M. Tetrahedron Lett. 2006,
47, 6557; (d) Terblans, Y. M.; Huyser, J.; Huyser, M.;
Green, M. J.; Yound, D. A.; Sibiya, M. S. Can J. Chem./
Rev. Can. Chim. 2005, 83, 854; (e) Firouzabadi, H.;
Iranpoor, N.; Kohmareh, G. Synth. Commun. 2003, 33,
167; (f) Firouzabadi, H.; Iranpoor, N.; Sobhani, S.;
Ghassamipour, S. Synthesis 2005, 4, 595.
13. Selected spectral data for the acetylated products: Tetra-
hydro-2-furanylmethyl acetate (entry 18), semi solid, 1H
NMR (CDCl3, Me4Si, 300 MHz) d (ppm): 4.02–4.14
(m, 2H), 3.92–4.00 (m, 1H), 3.86 (q, J = 6.80 Hz, 1H),
3.77 (q, J = 7.55 Hz, 1H), 2.08 (s, 3H, COCH3), 1.84–2.07
(m, 3H), 1.54–1.68 (m, 1H). IR (KBr) (m/cmꢀ1): 2955,
2874, 1742 (OC@O), 1370, 1237 (CO–O), 1040. EI-MS:
M+ 144. Anal. Calcd for C7H12O3: C, 58.32; H, 8.39.
Found: C, 58.39; H, 8.36. 3-(Acetyloxy)-2,2-di[(acetyl-
oxy)methyl]propyl acetate (entry 19), mp 78–80 ꢁC, 1H
NMR (CDCl3, 300 MHz) 2.08 (s, 12H, 4COCH3), 4.10 (s,
8H). IR (KBr) (m/cmꢀ1): 2975, 2906, 1738 (OC@O), 1236
(CO–O), 1041. LC-MS: 327 [M+Na]+. Anal. Calcd for
C13H20O8: C, 51.38; H, 6.62. Found: C, 51.45; H, 6.58. 2-
Oxo-2H-7-chromenyl acetate (entry 20), mp 143–145 ꢁC,
1H NMR (CDCl3, Me4Si, 200 MHz) d (ppm): 7.68
(d, J = 9.37 Hz, 1H), 7.48 (d, J = 8.59 Hz, 1H), 7.12 (d,
J = 2.34 Hz, 1H), 7.04 (dd, J = 8.59, 2.34 Hz, 1H), 7.38 (d,
J = 9.37 Hz, 1H), 2.35 (s, 3H, COCH3). IR (KBr)
(m/cmꢀ1): 1742 (OC@O), 1621, 1203, 1186 (CO–O), 848.
EI-MS: M+ 204. Anal. Calcd for C11H8O4: C, 64.71; H,
3.95. Found: C, 64.75; H, 3.94. 9-Oxo-9H-2-fluorenyl
acetate (entry 21), mp 158–159 ꢁC, yellow crystalline solid.
1H NMR (CDCl3, Me4Si, 200 MHz) d (ppm): 7.62 (d,
J = 7.81 Hz, 1H), 7.48 (d, J = 7.81 Hz, 2H), 7.44 (s, 1H),
7.35 (d, J = 2.34 Hz, 1H), 7.24–7.32 (m, 1H), 7.15 (dd,
J = 8.59, 2.34 Hz, 1H), 2.31 (s, 3H, COCH3). 13C NMR
(CDCl3, Me4Si, 75 MHz) d (ppm): 192.5, 169.0, 151.4,
143.8, 141.6, 135.5, 134.8, 134.3, 128.8, 127.3, 124.4, 121.0,
120.2, 118.0, 20.9. IR (KBr) (m/cmꢀ1): 3060, 1762
(OC@O), 1716 (C@O), 1600, 1455, 1196, 1126 (CO–O),
1013, 736. EI-MS: M+ 238; M+-42 (196, base peak). Anal.
Calcd for C15H10O3: C, 75.62; H, 4.23. Found: C, 75.69;
H, 4.21. Dibenzo[b,d]furan-3-yl acetate (entry 22), mp
110–112 ꢁC, 1H NMR (CDCl3, Me4Si, 300 MHz) d (ppm):
7.86 (d, J = 7.55 Hz, 1H), 7.63 (d, J = 2.26 Hz, 1H), 7.50–
7.55 (m, 2H), 7.42 (dt, J = 8.31, 1.51 Hz, 1H), 7.24–7.34
(m, 1H), 7.12 (dd, J = 9.06, 2.26 Hz, 1H), 2.33 (s, 3H,
COCH3). IR (KBr) (m/cmꢀ1): 1755 (OC@O), 1446, 1222,
1158 (OC–O), 1012, 745. EI-MS: M+ 226. Anal. Calcd for
C14H10O3: C, 74.33; H, 4.46. Found: C, 74.39; H, 4.43.
14. (R)-3-Acetyloxy-3-phenylpropanenitrile (entry 24):
A
25
white solid; mp 120–121 ꢁC {lit.15a mp 121–124 ꢁC}; ½aꢁD
30
+70 (c 1.0, CHCl3) {lit.15a ½aꢁD +71.9 (c 1.0, CHCl3)}.
25
Menthyl acetate (entry 25): ½aꢁD +79 (c 1.0, CHCl3) {lit.15b
[a]D +80}. 1,2,3,4,5,6-Hexa-O-acetyl-D-mannitol (entry
28): A white crystalline solid; mp 121–122 ꢁC {lit.15c mp
25
30
123–124 ꢁC} ½aꢁD +26 (c 1.0, CHCl3) {lit.15c ½aꢁD +27 (c
1.0, CHCl3)}.
15. (a) Kamal, A.; Khanna, G. B. R.; Ramu, R. Tetrahedron:
Asymmetry 2002, 13, 2039; (b) Kantam, M. L.; Aziz, K.;
Likhar, P. R. Catal. Commun. 2006, 7, 484; (c) Dasgupta,
F.; Singh, P. P.; Srivastava, H. C. Carbohydr. Res. 1980,
80, 346.