Perchloric acid adsorbed on silica gel as a new, highly efficient, and
versatile catalyst for acetylation of phenols, thiols, alcohols, and amines†
Asit K. Chakraborti* and Rajesh Gulhane
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER),
Sector 67, S. A. S. Nagar 160 062 Punjab, India. E-mail: akchakraborti@niper.ac.in;
Fax: +91-172-214692; Tel: +91-172-214682
Received (in Cambridge, UK) 15th April 2003, Accepted 3rd June 2003
First published as an Advance Article on the web 25th June 2003
Perchloric acid adsorbed on silica gel efficiently catalyses
acetylation of structurally diverse phenols, alcohols, thiols,
and amines under solvent free conditions.
reagents. The activity and selectivity of a reagent dispersed on
the surface of a support is improved as the effective surface area
of the reagent can be increased up to one hundred times. The
fact that supported reagents have good thermal and mechanical
stabilities, can be easily handled as they are invariably low
toxic, non-corrosive free flowing powders and are easily
separated from the reaction mixture through filtration and
reused make them suitable for industrial applications.
The results incorporated in Table 1 demonstrate the general-
4 2
ity and scope of HClO –SiO during the acetylation of
structurally diverse phenols, thiols, amines and alcohols under
solvent free conditions. The reaction could be carried out with
one equiv. of Ac O at room temperature in 5–30 min. Sterically
2
hindered and electron deficient phenols and amines (entries 3, 4,
8, 9, 18, and 19) are efficiently acetylated under solvent free
conditions. Excellent chemoselectivity was observed in that
secondary and tertiary alcohols do not experience any com-
petitive dehydration (entries 22, 24–34) and no rearrangement
took place for allylic and propargylic substrates (entries 30–34).
Optically active substrates were efficiently acetylated without
any detrimental effect on the optical purity (entries 25–27)
demonstrating the mildness of the acetylation process. Ster-
ically hindered alcohols could be effectively acetylated (entries
24, 28 and 34). The catalyst was recovered and reused five
consecutive times giving excellent yields.17
The prevalence of phenol, thiol, alcohol, and amine functional-
ities in drugs and pharmaceuticals makes the protection of these
functional groups a prime importance while carrying out
reactions sensitive to such functionalities in a multifunctional
substrate having one or more of these groups. Protection is
1
usually achieved through acylation with anhydrides due to the
ease of deprotection.1 The poor nucleophilicity of hydroxylic
compounds, particularly phenols, makes it essential to activate
the anhydride. Recent procedures for acylation with anhydride
,2
3
4
include the use of Bu
3
P, metal triflates such as Sc(OTf)
3
9,10
,
5
,6 Cu(OTf)
7
8
TMSOTf, Sc(NTf
2
)
3
2 3 3
, In(OTf) , Bi(OTf) ,
clays,11 zeolite, Nafion-H, and yttria-zirconia. The limita-
12
13
14
tions of the existing protocols realized in terms of longer
reaction time, stringent conditions, use of halogenated solvents,
1
use of hazardous materials (e.g. DMAP is highly toxic, Bu
3
P is
flammable and air sensitive), use of costly and water sensitive
catalysts (e.g. the triflates), special efforts required to prepare
the catalyst (e.g. Bi(OTf) , Nafion-H, yttria-zirconia), need to
3
use excess acylating agent, potential side reactions with acid-
sensitive substrates and in most of the cases being applicable to
alcohols only make the necessity to develop a better acylation
method in high demand.
4 2
The superiority of HClO –SiO as acetylation catalyst over
Although recently the triflates have emerged as the most
effective catalysts, the strong Lewis acid character of the
triflates makes their use for acid-sensitive substrates difficult
necessitating the use of a large excess of acylating agent and
carrying out the reaction at low temperature to avoid potential
side reactions. The high cost and susceptibility to aqueous
medium of the metal triflates become a major concern for their
industrial applications.
the metal triflates could be established while comparing the
results obtained with a few representative acid-sensitive
4
and TMSOTf5 catalyzed
substrates. Thus, the Sc(OTf)
3
acetylation of 1-methylcyclohexanol used 5 equiv. of Ac
220 and 210 °C respectively to afford comparable results
obtained with 1 equiv. of Ac O at room temperature under the
catalytic influence of HClO –SiO (entry 24). The Bi(OTf)
Sc(OTf) and TMSOTf catalyzed acetylation of 1-ethynylcy-
clohexanol afforded 94, 88, and 62% yields in 4, 4, and 2 h,
2
O at
2
4
2
3
,
3
It has been proposed that during the triflate catalyzed
acylation, the liberated TfOH acts as the actual catalytic agent.10
respectively, with 10 equiv. of Ac
9
2
O whereas the correspond-
We reasoned that the large negative H value of 214.1 of
0
ing acetylated product could be obtained in 90% yields in 15
TfOH15 might be the reason for the potential competitive side
reactions with acid-sensitive substrates during the use of metal
triflates. Therefore, the use of a protic acid weaker than TfOH
should permit acylation without any potential side reaction.
2 4 2
min with 1 equiv. of Ac O in the presence of HClO –SiO
(entry 34). The TMSOTf5 catalyzed acetylation of linalool
results in the formation of the rearranged product geranyl
4
acetate and the Sc(OTf)
3
catalyzed reaction carried out at 220
Since HClO
planned to evaluate its catalytic activity during the reaction of
-naphthol with Ac O. Although the use of 0.1–1 mol% of
aqueous HClO resulted in almost quantitative formation of
-naphthyl acetate in 15 min, acylation of acid-sensitive
substrates such as geraniol and linalool catalyzed by aqueous
HClO led to the formation of rearranged products. Anticipating
that the aqueous conditions might be the reason for the
detrimental effect, we planned to use HClO supported on silica
). Moreover, the increasing pressure from
4
is the next strongest protic acid known, we
°C affords a 68% yield of linalyl acetate and 8% geranyl acetate
even with the use of Ac O as solvent. An 80% yield of linalyl
acetate is obtained in the presence of Bi(OTf) with 10 equiv. of
–SiO catalyzed
acetylation affords an 80% yield of linalyl acetate using 1 equiv.
of Ac O. While the acetylation of 1-adamantanol with 10 equiv.
of Ac O afforded 98, 99, and 94% yields in 6, 8.5, and 3.5 h,
respectively, during the Bi(OTf) , Sc(OTf) and TMSOTf
catalyzed acetylation, a 90% yield was obtained with 1 equiv.
of Ac O in 15 min in the presence of HClO –SiO (entry 28). To
compare the catalytic activity of HClO –SiO with the
conceptually related H SO –SiO , linalool was treated with
stoichiometric quantities of Ac O in MeCN for 1 h at room
temperature. An 80% yield of the acetylated product was
obtained under the catalytic influence of HClO –SiO whereas
no significant amount of acetylation took place in the presence
of H SO –SiO
2
2
2
3
9
4
Ac
2
O. Contrary to these findings, the HClO
4
2
2
2
4
2
3
3
9
4
16
gel (HClO
4
–SiO
2
2
4
2
environmentalists has led to a search for more friendly forms of
catalysis. The leading contender for an environmentally accept-
able alternative to the acylation processes is the use of supported
4
2
2
4
2
2
†
Electronic supplementary information (ESI) available: general experi-
mental details, spectral data, comparison of HClO –SiO with other
reported catalysts. See http://www.rsc.org/suppdata/cc/b3/b304178f/
4
2
4
2
2
4
2
.
1
896
CHEM. COMMUN., 2003, 1896–1897
This journal is © The Royal Society of Chemistry 2003