J. Chil. Chem. Soc., 56, Nº 4 (2011)
HIGHLY EFFICIENT AND VERSATILE ACETYLATION OF ALCOHOLS, PHENOLS AND AMINES
CATALYZED BY METHYLENEDIPHOSPHONIC ACID (MDP) UNDER SOLVENT-FREE CONDITIONS
MINHAO XIE*, HONGYONG WANG, JUN WU, YONGJUN HE, YALING LIU, PEI ZOU
*Jiangsu Institute of Nuclear Medicine, Wuxi, 214063, P. R. China
(Received: March 1, 2011 - Accepted: July 12, 2011)
ABSTRACT
Methylenediphosphonic Acid (MDP) was found to be a simple, cheap and reusable heterogeneous catalyst for the acetylation of structurally diverse alcohols,
phenols and amines with acetic anhydride under solvent-free conditions at room temperature. This method showed preferential selectivity for the acetylation of the
amino group in the presence of hydroxyl group. The method is very mild and the yields were in excellent.
Keywords: Bisphosphonic acid, MDP, Solvent-free, Acetylation.
INTRODUCTION
With increasing environmental concerns and the regulatory constraints
faced in the synthesis of valuable industrial and pharmaceutical compounds,
the development of new synthetic methods and reactions using new and
environmental friendly reagents is becoming more attractive. The acetylation
of alcohols is an important and E-mail: xiemh0704@sina.com Fax number:
+086 510 85513113 frequently used transformation in organic synthesis
1. The most commonly used reagent combination for this reaction uses
an acid anhydride in the presence of an acid or base catalyst 2. The various
Scheme 1: Acetylation of Alcohols and Phenols
catalysts developed for acetylation include the use of Bu3P 3, metal triflates
5
9
such as Sc(OTf)3 4, TMSOTf , Sc(NTf2)3 6, Cu(OTf)2 7, In(OTf)3 8, Bi(OTf)3
,
Method A: Alcohol (2.5 mmol), MDP (0.25 mmol) and Ac2O (3.0m mol)
were added and stirred continued at room temperature for the appropriate time
(monitored by TLC). After completion, the reactant was filtered and water
(10mL) was added to the filtrate. The mixture was extracted with ethyl acetate
(10mL×2) and the combined organic layer was washed with saturated NaHCO3
(10mL×2), brine (10mL), dried (Na2SO4) and concentrated to give the pure
liquid product (Scheme 1).
ZrO(OTf)210; p-toluenesulfonic acid 11, Nafion-H 12, Montmorillonite K-10 and
KSF clay 13, yttria–zirconia 14, NBS 15, Zeolites 16, 3-nitrobenzeneboronic acid
17, La(NO3)3 (NH4)2.5H0.5PW12O40 19, H5PV2W10O40 and molecular iodine
21. The catalys,ts suffer from certain drawbacks. They are rather expensive or
moisture sensitive. Nevertheless, there is still a great demand for acid catalysts
to generate esters under mild conditions.
18
20
Method B: Alcohol (2.5 mmol), MDP (0.25 mmol) and Ac2O (3.0 mmol)
were added and stirred continued at room temperature for the appropriate time
(monitored by TLC). After completion, the reactant was quenched with cold
water (10mL). The mixture was filtered to give the pure solid product.
Chemoselective N-acetylation of bifunctional substrates using MDP
The substrate containing –NH2 and –OH groups (2.5 mmol) was treated
with Ac O (2.5 mmol) in the presence of MDP (0.25 mol ) under neat conditions
at room2temperature. After the end of the reaction, the reactant was quenched
with cold water and extracted with ethyl acetate. To concentrate the organic
layer, the product was obtained without further purification.
Bisphosphonic acids are commonly used as antiresorptive agents for the
treatment of osteoporosis. Methylenediphosphonic Acid (MDP) is cheap,
stable and the simplest organic bisphosphonic acid with usefulness in a wide
range of applications, such as a coordination ligand of inorganic meterials
22, a bone imaging agent to delineate areas of altered osteogenesis in clinic
23
and a heavy-metal decorporating agents 24. Due to its unique physical and
chemical properties such as acidity, selectivity, thermal stability, solubility and
security, we have explored its catalytic activity and discovered it can catalyze
acetylation of alcohols, phenols and amines very efficiently. Here we report
a mild, efficient and environmentally friendly method for the acetylation of
alcohols, phenols and amines using acetic anhydride in the presence of MDP
under solvent-free conditions at room temperature. The catalyst was reused
five consecutive times giving excellent yields.
Reuse and Recycling of the Catalyst
The reuse and recycling properties of the catalysts were tested by
acetylation of 2-phenylethanol. MDP was filtered from the reaction mixture,
reused to catalyse the next reaction without any treatment.
EXPERIMENTAL
RESULTS AND DISCUSSION
All commercial chemicals were used as received. Methylenediphosphonic
Acid (MDP) was provided by Jiangyuan Pharmaceutical Factory. Products
are all known compounds and their structures were established through IR,
MS and 1H NMR by comparing of their physical and spectra data with those
in the literature. IR spectra were recorded on BRUKER TENSOR 27 FT-
IR spectrometer using KBr pellets. Mass spectra were recorded on a Waters
Q-TOF-MS apparatus. 1H NMR spectra were run on a BRUKER AVAVCE
400 spectrometer using CDCl3 or DMSO-D6 as solvent.
Several examples illustrating the novel and rapid procedure for acetylation
ofalcohols, phenolsandaminesarepresentedinTable1. Thereactionconditions
were standardised after conducting the acetylation of 2-phenylethanol with
Ac2O using various amounts of MDP at room temperature without any solvent
(entries 4, Table 1). The acetylation of 2-phenylethanol with 1.2 equiv.
of Ac O in presence of 1, 2.5, 5, 10 mol % MDP afforded 24, 43, 67, 97%
yields2in 2 h respectively, while 5% yield was obtained without MDP at the
same reaction conditions. Encouraged by the success of this reaction, various
primary, secondary and tertiary alcohols, phenols and amine were subjected to
acetylation. Several primary and secondary alcohols underwent the acetylation
reactions in excellent yields (entries 1-8, Table 1). It is very interesting to note
that tertiary alcohols such as t-butanol and 2-methyl-2-butanol (entries 9 and
10, Table 1) can also be acetylated with satisfactory yields and there was no
elimination product in the mixture
General Procedure of Acetylation Reaction
e-mail: hxydc@swu.edu.cn
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