Selective acetylation of primary alcohols by ethyl acetate

Article abstract of DOI:10.1016/j.tetlet.2016.10.088

A KO^tBu and ethyl acetate mediated efficient methodology has been developed for the acetylation of primary and secondary alcohols where ethyl acetate is the source of acetyl group. The reaction is fast, mild, efficient, and highly selective towards the primary alcohols.

Full text of DOI:10.1016/j.tetlet.2016.10.088

Tetrahedron Letters 57 (2016) 5395–5398
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Selective acetylation of primary alcohols by ethyl acetate
Raju Singha a,b, Jayanta K. Ray a,
⇑
a Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur 721302, India
b Department of Chemistry, Panskura Banamali College, Panskura R.S. 721152, India
a r t i c l e i n f o
a b s t r a c t
A KOtBu and ethyl acetate mediated efficient methodology has been developed for the acetylation of pri-
mary and secondary alcohols where ethyl acetate is the source of acetyl group. The reaction is fast, mild,
efficient, and highly selective towards the primary alcohols.
Article history:
Received 30 September 2016
Revised 21 October 2016
Accepted 22 October 2016
Available online 24 October 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Acetylation
Alcohol
Ethyl acetate
KOtBu
Introduction
diverse alcohols with acetic anhydride. Although, most of these
methods have successfully perform the desired transformation,
Acetylation of alcohols is one of the most commonly employed
transformations in organic chemistry for the synthesis of different
fine chemicals, drugs, food preservatives, perfumes, plasticizers,
pharmaceuticals etc. [1]. Acetylation of a drug molecule increases
its activity and therefore various drug molecules contains acetyl
group in their structure such as aspirin (1a), acetylcarnitine (1b),
heroin (1c) [2] (see Fig. 1).
Depending upon their tremendous applications in organic syn-
thesis, so many synthetic procedures for the acylations of alcohols
have been developed in recent years. Acetyl chloride and acetic
anhydride are most commonly employed for the acetylation of
alcohols in presence of either acid [3] or base catalysts [4]. Recently
differently metal triflates [5] and other metal salts [6] have been
used as the efficient catalysts for the acetylation of structurally
however they suffers from some disadvantages such as toxicity,
long reaction time, drastic reaction conditions, thermal stability,
explosiveness of reagents and most importantly the selectivity
problems. Thus in spite of the recent advances, the development
of a simple, mild and time efficient procedure with high level of
selectivity is still of critical importance.
Herein, we are reporting a short, mild and efficient methodol-
ogy for the acetylation at room temperature with excellent yields
and selectivity towards primary alcohols. There are few reports
for the esterification of alcohols by ethyl acetate in presence of dif-
ferent transition metal catalysts [7] under refluxing reaction condi-
tions and herein we are wishing to develop a simple methodology
for acetylation under ambient reaction conditions using ethyl acet-
ate as the source of acetyl group. We envisioned that if we reacts
any alkoxide (1, Scheme 1) with excess amount of ethyl acetate
then the equilibrium (1) (Scheme 1) will lie exclusively towards
CH3
N
O
CH3
COOH
O
O
O
O
H3C
O
CH3
+
OEt
O
R
+
R
O
N
H3C
(Excess)
O
O
H3C
O
O
O
O
O
2
O
equilibrium-1
CH3
1a: Aspirin
1b: Acetylcarnitine
1c: Heroin
H2O
Fig. 1. Drug molecules containing acetyl group.
O
+
R
OH
H3C
O
3
⇑
Corresponding author.
E-mail addresses: author@university.edu, jkray@chem.iitkgp.ernet.in (J.K. Ray).
Scheme 1. Proposed reaction pathway.
http://dx.doi.org/10.1016/j.tetlet.2016.10.088
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

5396
R. Singha, J.K. Ray / Tetrahedron Letters 57 (2016) 5395–5398
Table 2
right side. Thus, after workup with water, we will get the O-acety-
lated product 3.
Acetylation of different arylmethanols.a,b
O
i. KOtBu, DMSO,
Argon, 10 min
OH
n
Ar
O
n
Results and discussion
Ar
ii. EtOAc (1 mL), 10 min
iii. water workup
2a-z
At first we had chosen naphthalen-2-ylmethanol as the model
substrate and treated it with different bases in various solvents
for 10 min and then we added excess amount of ethyl acetate to
the reaction mixture and stirred for the required times. The results
are given in Table 1.
3a-z
OAc
OAc
MeO
OAc
OAc
At first we stirred the substrate 2a with KOtBu (1.0 equiv.) in
DMSO (2 mL) at room temperature for 10 min and then 1.0 mL of
ethyl acetate was added and the progress of the reaction were
monitored by TLC. After 10 min, we observed that the substrate
was vanished and then we isolated the acetylated product 3a in
81% yield. Then we increased the amount of base and found that
it gave 92% of acetylated product with two equivalents of KOtBu
and on further increase of equivalent of base did not affect the
yield of product. Then we varied the solvents and we found that
DMF, DMA and MeCN gave the product in poor yields (Table 1,
entries 4–6). The hydrocarbon solvents benzene and toluene also
resulted the acetylated product in moderate yields (entry 7, 9).
Then we employed different bases and observed that NaOAc,
Na2CO3 and K2CO3 were failed to carry out the reaction. We also
employed NaOtBu and it afforded 2a in 77% of yield. In absence
of KOtBu the starting material remained unreacted. Thus the opti-
mized reaction conditions were: substrate (0.5 mmol), KOtBu
(1.0 mmol), DMSO (2 mL) and stirred at room temperature under
argon atmosphere for 10 min. Then 1.0 mL of EtOAc was added
and stirred for an additional 10 min. Then the reaction mixture
was diluted with water.
After getting the standard reaction conditions we employed dif-
ferent substrates to examine the versatility of the methodology. At
first different aryl-2-ylmethanols were used for the reaction and
the corresponding acetylated products were obtained in moderate
to good yields (Table 2). It was found that the electron rich sub-
strates (Table 2, entries 3b, 3d, 3e, 3g, 3o, 3p) gave slightly higher
yields than the electron poor substrates (entries 3c and 3f). The
halogen containing substrates (entries 3i-3l) gave the products in
moderate yields. The thiophene-2-ylmethanol and furan-2-
ylmethanol afforded the product in lower yields probably due to
the decomposition of the substrates under strong basic conditions.
The biphenyl-2-ylmethanols gave the product in good yields
whereas the (4-nitrophenyl)methanol did not give any acetylated
product due to the decomposition of the substrates as no starting
MeO
3b, Y= 87%
OMe
3d, Y= 92%
3c, Y= 76%
OAc
3a, Y= 92%
OAc
MeO
OAc
OAc
MeO
MeO
MeO
MeO
OMe
3g, Y= 86%
OMe
3e, Y= 88%
OAc
3f, Y= 83%
OAc
F
3h, Y= 84%
OAc
OAc
Cl
Br
Br
Cl
3i, Y= 72%
3j, Y= 60%
3k, Y= 67%
3l, Y= 75%
OAc
OAc
OAc
OAc
MeO
3n, Y= 82%
OMe
3p, Y= 85%
3m, Y= 84%
3o, Y= 94%
OAc
OAc
S
O
OAc
OAc
Br
3q, Y= 65%
3r, Y= 49%
3s, Y= 82%
3t, Y= 83%
OAc
OAc
Ph
OAc
O2N
OMe
OAc
3w, Y= 62%
3v, Y= 0 %
3u, Y= 88%
OAc
Ph
Ph
OAc
Ph
3z, Y= 96%
3x, Y= 86%
3y, Y= 97%
a
Isolate yields.
Reaction conditions: substrate (0.5 mmol), KOtBu (1.0 mmol), DMSO (2 mL) and
stirred at room temperature under argon atmosphere for 10 min. Then 1.0 mL of
EtOAc was added and stirred for an additional 10 min. Then the reaction mixture
was diluted with water.
b
Table 1
Screening of the reaction conditions.a
material was recovered. The propargyl acetate (3w) was formed
in moderate yield where as the cinnamyl alcohol got acetylated
in good yield (3x). The saturated long chain alcohols got acetylated
in quantitative yield (3y and 3z).
Entry
Solvent
Base
Time (min)
Yieldb
1
2
3
4
5
6
7
8
DMSO
DMSO
DMSO
DMF
KOtBu(1)
KOtBu(2)
KOtBu(3)
KOtBu(2)
KOtBu(2)
KOtBu(2)
KOtBu(2)
KOtBu(2)
KOtBu(2)
NaOAc(2)
Na2CO3(2)
K2CO3(2)
NaOtBu(2)
–
10
10
10
30
30
30
30
30
81
92
92
24
18
32
66
37
71
00
00
00
77
00
After successful acetylation of primary alcohols, we wished to
employ the screened reaction condition on different substituted
secondary alcohols to examine the scope of the reaction. When
we applied the standard reaction condition on 1-phenylethanol
(4a), we got the acetylated product only in 34% of yield. Then we
increased the reaction time both in step I and step II and we
observed the increase of yield to 51%. Then this modified reaction
condition was applied on various 2° alcohols and we got the corre-
sponding acetylated products in lower to moderate yields (Table 3).
The electron rich substrates (Table 3, entries 5b, 5c and 5h) gave
the products in slight higher yields than the analogous electron
poor substrates. The 1,2-dihydroacenaphthylen-1-ol afforded
higher yield than the other secondary alcohols.
DMA
MeCN
Benzene
Cy-hexane
Toluene
DMSO
DMSO
DMSO
DMSO
DMSO
9
30
10
11
12
13
14
120
120
120
30
120
a
Reaction conditions: (i) substrate 79 mg (0.5 mmol), base (equivalent), solvent
2 mL, r.t., 10 min; (ii) EtOAc (1 mL), r.t., 10 min, (iii) diluted with water.
b
Isolated yield.

R. Singha, J.K. Ray / Tetrahedron Letters 57 (2016) 5395–5398
5397
Table 3
Acetylation of secondary alcohols.a,b
+
OH
Step-I
+
O
O
R
O
OH
R
OAc
OH
i. KOtBu, DMSO,
O
O
Argon, 30 min
Step-II
Ar
5a-h
Ar
4a-h
+
+
R
+
R
O
H3C
H3C
OEt
O
ii. EtOAc (1 mL), 30 min
iii. water workup
H3C
O
O
O
Step-III
H2O
R
R
O
+
H3C
O
OH
OAc
OAc
OAc
OAc
MeO
MeO
Scheme 3. Reaction mechanism.
MeO
5b, Y= 58%
OAc
5c, Y= 66%
5a, Y= 51%
5d, Y= 70%
OAc
OAc
Ph
Ph
OAc
+
+
eq. 1
eq. 2
eq. 3
eq. 4
HO
O
O
OH
Phenol, pka ~ 10
MeO
O
+
+
HO
R
O
R
O
5e, Y= 55%
OH
pka ~ 18
5g, Y= 56%
5f, Y= 54%
5h, Y= 61%
1o alcohol, pka ~ 16
a
R
R
Isolate yields.
Reaction conditions: substrate (0.5 mmol), KOtBu (1.0 mmol), DMSO (2 mL) and
b
+
+
HO
R
O
R
O
OH
stirred at room temperature under argon atmosphere for 30 min. Then 1.0 mL of
EtOAc was added and stirred for an additional 30 min. Then the reaction mixture
was diluted with water.
2o alcohol, pka ~ 17
pka ~ 18
Ph
Ph
+
+
H2N
HN
O
OH
Aniline, pka ~ 25
After getting success in the acetylation of primary and sec-
ondary alcohols, we employed our methodology on other systems
and we found that phenol and aniline remained intact under the
standard reaction conditions. Then we wanted to check the selec-
tivity of the methodology and for that we examined the reaction
on a substrate 6 (Scheme 2) containing both phenolic and alcoholic
OH groups and we observed that only the alcoholic OH group got
acetylated and afforded the product 7 in 75% yield. The structure
of compound 7 was confirmed from the X-ray crystal structure
(CCDC No. 1403960). Then we performed the reaction with a sub-
strate 8 having both primary and secondary hydroxyl group and
we found that the mono acetylation occurred selectively to the pri-
mary hydroxyl group with one equivalent Of KOtBu while the two
equivalent Of KOtBu gave both mono- and di-acetylated product in
41% and 30% of yields respectively (Scheme 2).
pka ~ 18
Scheme 4. Mode of equilibrium at step-I.
depends upon stability of the alkoxide and ethoxide. The step-III is
basically quenching of alkoxide. Phenol is much more acidic
(pka ꢀ 10) than tert-butanol (pka ꢀ 18) as well as ethanol
(pka ꢀ 16). Thus the equilibrium at step-I remains exclusively
towards right (Scheme 4, Eq. (1)) but the step-II remains towards
left as the phenoxide is much more stable than ethoxide. For ani-
line (pka ꢀ 25) the equilibrium at step-I remains solely towards left
(Scheme 4, Eq. (4)). Thus phenol and aniline remain intact under
the reaction condition. For the primary alcohols, both the step-I
and step-II lies towards right side and hence the acetylation occurs
with high yield. In case of secondary alcohols the equilibrium at
step-I lies slightly on right side but due to increase of steric crowd-
ing the rate at step-II becomes slow. Thus for secondary alcohol the
rate of reaction is slower and gave lower yields.
From the experimental results we observed that primary alco-
hols are the most suitable substrate and phenols, anilines are the
worst substrate for acetylation under the reaction condition. The
order of reactivity of alcohols are 1° > 2° > 3°. All the results can
be explained using the following three step reaction mechanism
(Scheme 3).
Conclusions
The step-I is a typical acid base reaction and hence there will be
an equilibrium between tert-butoxide and the alkoxide as formed.
The step-II is a transesterification reaction [8] and the equilibrium
In conclusion, we have developed a KOtBu mediated mild, short
and efficient methodology for the acetylation of alcohols at room
temperature where EtOAc serves as the source of acetyl group
[9]. The versatility and generality of the method was examined
using different aliphatic, benzylic, allylic and propargylic alcohols.
We hope that our methodology will be very much useful in organic
synthesis because of its short reaction time, cheap reagent, and
good selectivity with excellent yield and finally easily manageable
reaction conditions at room temperature.
OH
OAc
i. KOtBu, DMSO,
Argon, 10 min
Br
Br
ii. EtOAc (1 mL), 10 min
iii. water workup
OH
OH
OMe
OMe
7, Y = 75%
6
Acknowledgement
OH
OAc
i. KOtBu, DMSO,
Argon, 10 min
OAc
We would like to thank DST, Government of India for financial
support.
+
ii. EtOAc (1 mL), 10 min
iii. water workup
10
Me
9
8
Me
OH
Me
OH
OAc
Y = trace
Supplementary data
KOtBu (1 eqv.)
KOtBu (2 eqv.)
Y = 77%
Y = 41%
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.10.
088.
Y = 30%
Scheme 2. Selectivity study.

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R. Singha, J.K. Ray / Tetrahedron Letters 57 (2016) 5395–5398
2877;
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