Tetrahedron Letters
Zinc triflate catalyzed acylation of alcohols, phenols, and thiophenols
N. Uday Kumar a, B. Sudhakar Reddy a, V. Prabhakar Reddy b, Rakeshwar Bandichhor a,
⇑
a Integrated Product Development, Innovation Plaza, Dr. Reddy’s Laboratories Ltd, Bachupalli, Qutubullapur, R.R. Dist. 500072, Andhra Pradesh, India
b Department of Chemistry, Osmania University, Hyderabad 500007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An expedient procedure for the acylation of alcohols, phenols, and thiophenols using catalytic amount of
Zn(OTf)2 is described. This procedure is highly suitable for industrial application due to use of less toxic
metal as a part of catalyst, short reaction time at ambient temperature, without any racemization of
chiral alcohols.
Received 28 September 2013
Revised 8 December 2013
Accepted 14 December 2013
Available online 18 December 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Acylation
Zinc triflate
Catalysis
Acylation of an alcohol is an important transformation in
organic synthesis. Although a myriad of literature evidence are
available for acylation, the use of acyl chloride or acetic anhydride
in the presence of pyridine1 is the most commonly used procedure.
Stoichiometric acylation is always considered to be inferior
practice than the catalytic version of this reaction (Scheme 1).
Herein, we include hitherto known methods of acylation such
as 4-(dimethyl amino)pyridine (DMAP),2 CoCl2,3 ZnCl2,4a ZnO,4b,c
CeCl3,5 ZrOCl2Á8H2O,6 molecular iodine,7a,b 3-nitro benzene boronic
acid,8 La(NO3)3Á6H2O,9 P2O5/Al2O3,10 NiCl2,11 Co(II)salen-com-
plex,12 melamine trisulfonic acid,13 Sn(TPP)(BF4)2,14 alkylorthofor-
mate–ZnCl2–Ac2O,15 vanadium (IV) tetraphenylporphyrin,16
[TiIV(salophen)(OTf)2],17 N-acyl 1,5-diazabicyclo [4.3.0] non-5-ene
(DBN) tetraphenylborate salts,18 iron(III) tosylate,19 Al(HSO4)3,20
and NbCl5.21
work-up is required that becomes expensive due to material loss.
Therefore, we attempted to develop non-or less toxic metal triflate
catalyzed acylation and the catalyst is readily and cheaply avail-
able in the market. In comparison to other metals (Fig. 1), Zn is
one of the most widely recommended due to its less toxic nature.
Zn(OTf)2, is very efficient and addresses the associated problems
up to great extent. In general, such a catalytic process adds value
to a better process efficiency as one can avoid purifications and
thereby increase the isolated yield in comparison to hitherto
known procedures.
In our endeavor, catalytic quantity of Zn(OTf)2 was opted for
acetylation of primary, secondary, benzylic and cyclic alcohols,
phenols, and thiophenols using acetic anhydride, in excellent
yields at room temperature using dichloromethane as solvent
As evident, a large number of methods for acylation are avail-
able, many of them suffer from limitations such as long reaction
times, harsh reaction conditions, and use of expensive, moisture
sensitive and toxic metal containing catalysts, formation of side
products, and poor yields of desired products. In view of these lim-
itations, there is still a need to develop mild and efficient catalytic
protocol for the acetylation of alcohols.
Conventional
Ac2O, DMAP
0-5 °C
Pyridine
LA
O
O
Metal triflate catalyzed acylation procedures are well docu-
mented.22 In most of the cases, the toxic metals as part of catalysts
are not recommended for the synthesis of active pharmaceutical
ingredients (APIs) due to stringent requirements by regulatory
agencies as the traces of these need to be controlled in the order
of ppms (parts per millions).23,24 To accomplish this, a tedious
Acetylation
H3C
O
CH3
ROH
ROAc
H
O
R
Ac2O
Zn(OTf)2, 25 °C
Catalytical
⇑
Corresponding author.
Scheme 1. Conventional and catalytic acylation.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.