Ethyl acetate as an acetyl surrogate for the iodine catalyzed acetylation of alcohols

Article abstract of DOI:10.1016/j.tetlet.2017.10.005

The use of readily available ethyl acetate in the presence of iodine as an alternative acetylating agent is reported. Amines and phenols were unreactive under the examined reaction conditions, indicating that the method is highly chemoselective.

Full text of DOI:10.1016/j.tetlet.2017.10.005

Accepted Manuscript
Ethyl acetate as an acetyl surrogate for the iodine catalyzed acetylation of al-
cohols
Grace Basumatary, Ghanashyam Bez
PII:
S0040-4039(17)31273-X
https://doi.org/10.1016/j.tetlet.2017.10.005
TETL 49367
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
11 September 2017
27 September 2017
3 October 2017
Please cite this article as: Basumatary, G., Bez, G., Ethyl acetate as an acetyl surrogate for the iodine catalyzed
acetylation of alcohols, Tetrahedron Letters (2017), doi: https://doi.org/10.1016/j.tetlet.2017.10.005
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Graphical Abstract
Ethyl acetate as an acetyl surrogate for the
iodine catalyzed acetylation of alcohols
Grace Basumatary and Ghanashyam Bez
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1
Tetrahedron Letters
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Ethyl acetate as an acetyl surrogate for the iodine catalyzed acetylation of alcohols
Grace Basumatarya and Ghanashyam Beza*
aDepartment of Chemistry, North Eastern Hill University, Shillong-793022, Meghalaya, India
ARTICLE INFO
ABSTRACT
Article history:
Received
The use of readily available ethyl acetate in the presence of iodine as an alternative acetylating
agent is reported. Amines and phenols were unreactive under the examined reaction conditions,
indicating that the method is highly chemoselective.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Acetylation
Ethyl acetate
Iodine
Chemoselective
Introduction
employing ethyl acetate as an acetyl surrogate as well as solvent
(Scheme 1).
Acetylation is one of the most essential transformations in
organic synthesis. Protection of the hydroxyl functionality by an
acetyl group has advantages over various protecting groups in
view of its easy introduction, stability towards acidic reaction
conditions, and mild removal by alkaline hydrolysis.1
Scheme 1. Alcohol acetylation
Acetic anhydride2 is the most commonly used acetyl source,
albeit acetyl chloride and vinyl acetate3 find applications in the
acetylation of alcohols and amines. In the acetylation of alcohols,
acetyl donors, such as acid anhydrides or acid chlorides, are
activated with a stoichiometric quantity of an amine base in the
presence of a basic catalyst. The Fischer esterification of acetic
acid with alcohols in the presence of various Lewis acids4 is also
known, however it has not drawn as much attention.
Initially, a solution of the model compound benzyl alcohol
(0.108 g, 1 mmol) and iodine (10 mol%) in ethyl acetate (excess)
was stirred at room temperature; no conversion was observed
after 24 h (Table 1, entry 1). Heating the reaction to 40 oC and 60
oC gave the acetylated product in 30% and 50% yield,
respectively (Entries 2, 3). The reaction took only 2 h at reflux to
give the acetylated product in 97% yield (Entry 5). Next, the
effect of catalyst loading was examined. The reaction employing
5 mol% catalyst gave 1a in 72% yield after a prolonged reaction
time (Entry 4). Further increasing the catalyst loading to 15
mol% did not result in any significant increase in yield (Entry 6).
The reaction did not proceed in the absence of iodine, even after
heating at reflux for 24 h (Entry 9).
The acetylation of alcohols using ethyl acetate as an acetyl
surrogate is intriguing despite its low electrophilicity. However,
the use of ethyl acetate in the place of commonly used acetic
anhydride can be complicated by reversible trans-esterification.
Therefore, selection of a suitable catalyst to avoid reversibility is
vital. Hatano and Ishihara accomplished the acetylation of
alcohols with ethyl acetate in the presence of catalytic La(Oi-Pr)3
and 2-(2-methoxyethoxy)ethanol.5 Matta and co-workers used
ethyl acetate for the selective acetylation of primary over
secondary alcohols in sugar diols in the presence of Woelm
After optimization of the reaction conditions, the substrate
scope of the protocol was explored (Table 2).8 Both aliphatic and
benzylic alcohols showed high to excellent conversion to the
corresponding acetates. Functional groups such as nitro (Entries
2-4), cyano (Entry 6) and acetonide (Entry 22) were not affected.
Secondary alcohols also reacted well to give the acetylated
products in good to excellent yields (Entries 15-20). However,
tertiary alcohols remained unreacted even after prolonged
reaction times. This inertness towards tertiary alcohols may be
attributed to steric repulsion between ethyl acetate and the
hindered alcohol.3 The double bond was also not affected, as
observed in the case of 9-decen-1-ol where the acetate derivative
was formed in 98% yield (Entry 13). As expected, o-cresol,
aniline, and n-hexylamine (Entries 23-25) did not undergo
acetylation, thereby making the protocol highly chemoselective.
neutral
alumina
at
60-65
oC.6
The
use
of
CBr4/triphenylphosphine7 and distannoxane8 have also been
reported. More recently, Singha and co-workers reported the
selective acetylation of primary alcohols using ethyl acetate in
the presence of KOt-Bu.9 Unfortunately, many of the aforesaid
methods suffer from drawbacks such as high cost, requiring
azeotropic reflux in hexane,5 poor environmental compatibility,7,8
long reaction times,7,8 and poor reactivity profiles.6,7As a result,
there is still demand for the development of reactions using ethyl
acetate as an acetylating agent. Herein, we report preliminary
observations on the iodine catalyzed acetylation of alcohols

2
Tetrahedron Letters
Table 1. Reaction conditions optimizationa
Entry
Iodine (mol%)
EtOAc (mL)
Temp.
22 oC
Time (h)
24
Yield 1a (%)b
1
10
2
0
2
3
4
10
10
5
2
2
2
40 oC
60 oC
reflux
24
24
12
30
50
72
5
6
7
8
9
10
15
10
10
0
2
2
3
1
2
reflux
reflux
reflux
reflux
reflux
2
2
97
96
96
62
0
2
2
24
aReagents and conditions: benzyl alcohol (1 mmol); bIsolated yield
Table 2. Substrate scopea
Substrate
Product
Time (h)
2
Yield 1 (%)b
Entry
1
2
97
90
2.5
2.5
3
4
90
90
2.5
2
5
93
6
7
8
2
2
2
97
95
95
OAc
NC
1f
9
2
2
97
98
10
11
12
2
2
98
98
13
13
2
98
98
2.5
14
15
2
3
97
89
OAc
1p
16
17
3
3
89
85

3
18
19
3
4
82
89
20
4
87
22
23
4.5
24
88
0
24
25
24
24
0
0
aReagents and conditions: alcohol (1 mmol), EtOAc (2 mL), iodine (10 mol%), reflux
bIsolated yield
On the basis of this observation, we proposed that the reaction
of alcohol with iodine forms an alkoxyiodide and hydroiodic acid
that protonates the ester carbonyl to enable nucleophilic addition
of the alkoxide to generate intermediate A. Elimination of
ethanol generates the acetylated derivative (Scheme 3).
The related acylation of alcohols or amines with isopropenyl
acetate2c in the presence of catalytic iodine might be driven by
the formation of acetone. However, the same is not true in the
case of ethyl acetate as the acetyl source, where the amine in
intermediate B may undergo protonation to form intermediate C
under acidic conditions and regenerates the amine instead of the
acetyl derivative (Scheme 4).
Scheme 2. Acetylation of cholesterol
Since the hydroxyl group and ethyl acetate can compete to
react with in-situ formed HI, the reaction of β-cholesterol with
ethyl acetate was carried out under the developed reaction
conditions. If the hydroxyl group of cholesterol reacts with HI, it
should generate a carbocation which upon reaction with ethyl
acetate should, in principle, give a mixture of diastereoisomeric
acetate derivatives (Scheme 2). Interestingly, the product was
found to be β-cholesteryl acetate (2a) as evident from the specific
Scheme 4. Plausible reason for the lack of amine reactivity
24
rotation (observed [α]D = −42, c 2.0 CHCl3) and melting point
o
(108-109 C) which are close to the literature data ([α]D = -42,
To understand our proposed mechanism for the inhibition of
acetylation, a solution of stearyl amine in ethyl acetate was
heated at reflux in the absence of iodine for 24 h to give the
acylated stearyl amine in 29% yield (Scheme 5). Unfortunately,
the reaction reaches equilibrium and further improvement was
not observed after 48 h.
o
CHCl3; m.p. 112-116 C).10 Moreover, the NMR,11 IR and mass
data also confirmed the formation of β-cholesteryl acetate (2a).
Scheme 5. Catalyst-free acylation of amines in ethyl acetate
In conclusion, we have developed a practical method for the
acetylation of alcohols employing ethyl acetate as an acetyl
Scheme 3. Plausible mechanism for alcohol acetylation

4
Tetrahedron
source in the presence of catalytic iodine. Easy access to the
acetyl source and catalyst, high chemoselectivity and short
reaction times are distinctive features of the protocol.
Acknowledgments
Grace Basumatary is grateful to the Department of Science
and Technology (DST), Govt. of India for an INSPIRE
Fellowship. The Sophisticated Analytical Instruments Facility,
NEHU is acknowledged for analytical support.
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Supplementary Material
Supplementary materials (procedures, data and NMR spectra)
can be found in the website www….

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Graphical Abstract
Leave this area blank for abstract info.
Ethyl acetate as an acetyl surrogate for the
iodine catalyzed acetylation of alcohols
Grace Basumatary and Ghanashyam Bez

6
Tetrahedron
Highlight
Ethyl acetate as an acetyl surrogate for the
iodine catalyzed acetylation of alcohols
ꢀ Use of ethyl acetate as an acetyl source for the
acetylation of alcohols
ꢀ An easily accessible iodine catalyst is used.
ꢀ Highly chemoselective towards alcohols,
amines are not acetylated