Zinc oxide (ZnO) as a new, highly efficient, and reusable catalyst for acylation of alcohols, phenols and amines under solvent free conditions

Article abstract of DOI:10.1016/j.tet.2005.09.002

Zinc oxide (ZnO) is a highly efficient catalyst for the acylation of a variety of alcohols, phenols and amines with acid chlorides or acid anhydrides under solvent free conditions. Primary, secondary, tertiary, allylic and benzylic alcohols, diols and phenols with electron donating or withdrawing substituents can be easily acylated in good to excellent yield.

Full text of DOI:10.1016/j.tet.2005.09.002

Tetrahedron 61 (2005) 10903–10907
Zinc oxide (ZnO) as a new, highly efficient, and reusable catalyst
for acylation of alcohols, phenols and amines
under solvent free conditions
*
Mona Hosseini Sarvari and Hashem Sharghi
*
Department of Chemistry, Faculty of Science, Shiraz University, Shiraz 71454, Islamic Republic of Iran
Received 2 April 2005; revised 8 August 2005; accepted 1 September 2005
Available online 23 September 2005
Abstract—Zinc oxide (ZnO) is a highly efficient catalyst for the acylation of a variety of alcohols, phenols and amines with acid chlorides or
acid anhydrides under solvent free conditions. Primary, secondary, tertiary, allylic and benzylic alcohols, diols and phenols with electron
donating or withdrawing substituents can be easily acylated in good to excellent yield.
q 2005 Published by Elsevier Ltd.
1. Introduction
dehydration and rearrangement and might not be fully
compatible for the acylation reactions with substrates
bearing acid-sensitive groups.
The acylation of alcohols, phenols and amines is an
important transformation in organic synthesis.1 Acylation
of such functional groups is often necessary during the
course of various transformation in a synthetic sequence,
especially in the construction of polyfunctional molecules
such as nucleosides, carbohydrates, steroids and natural
products. Various catalysts developed for acylation include
DMAP,2 CoCl2,3 Bu3P,4 Triflates,5–10 TaCl5,11 zeolite,12
clays,13 Nafion-H,14 Yttria-zirconia,15 LiClO4,16
Mg(ClO4)2,17 ionic liquids,18 InCl3,19 ZrCl4,20 Cu(BF4)$
xH2O,21 RuCl3,22 P2O5/SiO2,23 ZrOCl2$8H2O,24 and
alumina.25 However, the reported methodologies suffer
from various disadvantages, such as potential hazard
associated with handling of the catalyst [e.g., the LD50
(intravenous in rat) value of 56 mg kgK1 of DMAP makes it
highly toxic26 and Bu3P is flammable with a flash point of
37 8C and undergoes aerial oxidation],27 expensive or
commercially unavailable reagents, requirement of longer
reaction times, harsh reaction conditions, use of halogenated
solvents and excess acylating agents. Triflates are costly and
moisture sensitive, and special efforts are required to
prepare the catalyst [e.g., Bi(OTf)3, Nafion-H, and yttria-
zirconia]. In most of the cases the reported methods work
well on primary or secondary alcohols only and failed to
protect tertiary alcohols or less reactive phenols. A few of
these methods also suffer from side reactions such as
Synthetic chemists continue to explore new methods to
carry out chemical transformations. One of these new
methods is to run reactions on the surface of solids. As the
surfaces have properties that are not duplicated in the
solution or gas phase, entirely new chemistry may occur.
Even in the absence of new chemistry, a surface reaction
may be more desirable than a solution counterpart, because
the reaction is more convenient to run, or a high yield of
product is attained. For these reasons, synthetic surface
organic chemistry is a rapidly growing field of study.
Experiments using these solid phase catalysts generally
have the following features: (i) it is often easy to isolate the
products and to separate the catalyst; (ii) comparing the
reaction conditions with those of related homogeneous
reactions, they are so mild that a high yield of specific
products and suppression of by-product formation are
expected; (iii) selectivity and activity of the catalysts are
often comparable to those of enzymes.28 Several classes of
solids have commonly been used for surface organic
chemistry including aluminas, silica gels, and clays. Zinc
oxide (ZnO) is certainly one of the most interesting of these
solids because it has surface properties that suggest that a
very rich organic chemistry may occur there.29,30d
Although numerous methods to achieve acylation reactions
are known, newer methods continue to attract attention for
their experimental simplicity and effectiveness. In continu-
ation of our systematic evaluation of the efficacy of metal
Keywords: Zinc oxide; Phenols; Alcohols; Amines; Solvent free.
*
Corresponding authors. Tel.: C98 711 2284822; fax: C98 711 2280926;
e-mail addresses: hossaini@susc.ac.ir;
shashem@susc.ac.ir
0040–4020/$ - see front matter q 2005 Published by Elsevier Ltd.
doi:10.1016/j.tet.2005.09.002

10904
M. Hosseini Sarvari, H. Sharghi / Tetrahedron 61 (2005) 10903–10907
Table 1. Acetylation of phenol (1 mmol) based on ZnO and AcCl (1 mmol)
in different reaction conditions
Acylation
reagenta
Time
(min)
Yield
(%)b
Entry
11
Substrate
Entry
Equiv of
ZnO
Solvent
Time
Yield (%)
PhCOCl
CH3COCl
15
8
78c
80c
1
2
3
4
5
6
7
0.5
0.5
0.5
0.5
1
0.1
No catalyst
CH3CN
PhCH3
CH2Cl2
No solvent
No solvent
No solvent
No solvent
6 h
10 h
5 h
15 min
20 min
40 min
10 h
30
10
30
94
87
83
Trace
PhCOCl
CH3COCl
300
20
83c
87c
12
PhCOCl
CH3COCl
15
10
92
90
13
14
PhCOCl
CH3COCl
20
10
89
92
oxysalts as catalysts,30 we report, herein, our results on
acylation of alcohols, phenols, aliphatic and aromatic
amines using ZnO at room temperature under solvent free
conditions (Scheme 1, Tables 2 and 3). To the best of our
knowledge, this is the first demonstration of the ZnO based
acylation.
PhCOCl
CH3COCl
15
10
85
90
15
16
PhCOCl
CH3COCl
30
20
91d
82d
PhCOCl
CH3COCl
90
30
67e
65e
17
18
PhCOCl
CH3COCl
30
15
82d
85d
Scheme 1.
PhCOCl
CH3COCl
30
15
95
94
The reaction conditions were standardized after conducting
the acylation of phenol in different reaction conditions using
varying amounts of ZnO (Table 1). Thus, under optimum
conditions, phenol (1 equiv) was acetylated at room
temperature almost quantitatively with acetyl chloride
(1 equiv) in the presence of 0.5 equiv ZnO without use of
any solvents (Table 1, entry 4). Attempted acetylation of
phenol with acetic anhydride in the presence of ZnO failed.
19
20
PhCOCl
CH3COCl
40
20
94
90
PhCOCl
CH3COCl
20
15
93
90
21
22
23
PhCOCl
CH3COCl
20
15
85
92
Table 2. ZnO (0.5 mmol) catalyzed acylation of alcohols and phenols
(1 mmol) using acid chlorides (1 mmol)
PhCOCl
CH3COCl
30
20
91
90
Entry
Substrate
Acylation
reagenta
Time
(min)
Yield
(%)b
82f
87f
PhCOCl
CH3COCl
Ac2O
15
10
180
180
91
95
—
—
PhCOCl
CH3COCl
40
20
1
CH3CH2OH
24
(PhCO)2O
PhCOCl
PhCOCl
30
30
92 g
90 h
PhCOCl
CH3COCl
15
10
87
90
2
3
4
5
6
CH3(CH2)5CH2OH
CH3(CH2)2CH2OH
CH3(CH2)6CH2OH
25
26
PhCOCl
CH3COCl
15
10
84
86
CH3CH2OH
a Acylation reagent (1 equiv) for every OH function was used.
b Isolated yields.
PhCOCl
CH3COCl
15
10
86
78
c The corresponding dibenzoate and diacetate was prepared.
d The reaction was carried out in CH2Cl2.
e The reaction was carried out at !0 8C.
PhCOCl
CH3COCl
240
30
78
80
f
The reaction was carried out at 90 8C.
g Only the aliphatic alcohol was benzoylated with the use of 1 equiv of
acylating agent.
PhCOCl
CH3COCl
240
30
81
70
h The reaction was carried out on 100 mmol scale.
PhCOCl
CH3COCl
60
20
84
86
7
PhCOCl
CH3COCl
15
8
73
70
8
The results of the reactions of a diverse range of alcohols
and phenols are summarized in Table 2. An acid chloride
was preferred over the corresponding acid anhydride. The
reaction with acid anhydride was too slow to have practical
application. Both primary and secondary alcohols react very
PhCOCl
CH3COCl
20
8
53
58
9
PhCOCl
CH3COCl
15
8
85c
91c
10

M. Hosseini Sarvari, H. Sharghi / Tetrahedron 61 (2005) 10903–10907
10905
Table 3. ZnO (0.5 mmol) catalyzed acylation of amines (1 mmol) using acid anhydrides (1 mmol)
Entry
Substrate
Acylation reagenta
(CH3CO)2O
(PhCO)2O
Products
Time (min)
Yield (%)b
1
2
3
4
10
10
15
15
96
92
94
94
(BuCO)2O
CH3COCl
5
6
(CH3CO)2O
(CH3CO)2O
15
20
95
95
7
(CH3CO)2O
15
95
8
(CH3CO)2O
(CH3CO)2O
20
20
87
82
9
10
(CH3CO)2O
(CH3CO)2O
40
40
58
11
12
96c
(PhCO)2O
(CH3CO)2O
20
10
93
95
(PhCO)2O
20
67
13
(CH3CO)2O
10
40
84
64
14
15
(PhCO)2O
(CH3CO)2O
10
10
90
87
16
(CH3CO)2O
(CH3CO)2O
17
20
83
a Acylation agent (1 equiv) for every NH2 function was used.
b Isolated yields.
c The reaction was carried out on 100 mmol scale.
well (entries 1–16) and tertiary alcohol (entry 17) is also
acylated smoothly without any side products observed. The
conversion of ethanol into ethyl benzoate on a 100 mmol
scale (entry 26) proceeded just as well as the 1 mmol
reaction. Acylation of optically active substrate resulted in
excellent yield (entry 7). Allyl and propargyl alcohols were
also satisfactorily acylated under similar reaction conditions
and no rearrangement was observed (entries 8 and 9). To
extend the scope and generality of the use of the ZnO for
this type process we have also investigated the acylation of
diols. No selectivity between primary and secondary
hydroxyl groups was observed.
Phenolic compounds containing both electron-withdrawing
and donating groups (entries 18–24) reacted equally
efficiently under the standard reaction conditions. Acylation
of 2,4-dinitrophenol at room temperature was, however,
sluggish; it could be completely acylated in an oil bath at
90 8C (entry 24). According to Table 2, the reaction of
phenols with acid chlorides was slow in comparison to those
aliphatic alcohols. Indeed, a mixture of benzyl alcohol and
phenol furnished only the expected benzyl benzoate on
reaction with 1 equiv of PhCOCl (entry 25). Finally, the
reaction of benzoin and 4-hydroxybiphenyl (entries 16 and
18) were very slow under similar conditions. Even after

10906
M. Hosseini Sarvari, H. Sharghi / Tetrahedron 61 (2005) 10903–10907
Table 4. Comparison of protocols for the acylation of alcohols and phenols
Entry
Substrate
Reagent/catalyst Acylating agent
Time
Temperature
(8C)
Yield (%)
References
a
ZnO
Al2O3
Bi(OTf)3
ZrOCl2$8H2O
PhCOCl
PhCOCl
(PhCO)2O
CH3COCl
60 min
120 min
60 min
1.5 day
25
25
Reflux
25
84
96
95
93
25
9e
24
1
2
3
a
ZnO
Al2O3
PhCOCl
PhCOCl
15 min
90 min
25
25
85
99
25
a
ZnO
Al2O3
Bi(OTf)3
ZrOCl2$8H2O
PhCOCl
PhCOCl
(PhCO)2O
PhCOCl
90 min
25
67
45
No reaction
80 min
No report
25
9e
24
Reflux
a
ZnO
Al2O3
Bi(OTf)3
ZrOCl2$8H2O
PhCOCl
PhCOCl
(PhCO)2O
PhCOCl
30 min
No reaction
45 min
21 h
25
91
25
9e
24
4
Reflux
25
95
98
a Present work.
vigorous stirring for 4 h at 25 8C, the reactions were
incomplete. However, acylation was achived in 91 and
82% yields with benzoin and 4-hydroxybiphenyl, respect-
ively, at 25 8C for 30 min in the presence of dichloro-
methane (CH2Cl2).
Another interesting behaviour of zinc oxide (ZnO) lies in the
fact that it can be re-used after simple washing with CH2Cl2,
rendering thus process more economic. The yields of
acetanilide (a model compound for amines) and phenyl
benzoate (a model compound for phenols) in the 2nd, 3rd, 4th
and 5th uses of the ZnO were almost as high as in the first use.
The experimental results of the acylation of amines are
summarized in Table 3. It is significant to note that acid
anhydrides were preferred to the acid chlorides. All the
amines reacted very rapidly within 10–40 min The
conversion of aniline into acetanilide on a 100 mmol scale
(entry 11) proceeded just as well as the 1 mmol reaction.
Other functional groups such as keto and cyano remained
unaffected during the acylation reaction (entries 7 and 9).
In conclusion, we have presented a simple, solvent free, and
efficient protocol for the acylation of alcohols, phenols, and
amines. Furthermore, an alcohol can be acylated in the
presence of phenols with very high selectivity. No
competitive Fries rearrangement was observed for phenolic
substrates. Secondary and tertiary alcohols did not
experience any competitive dehydration. Also, the advan-
tages include the low cost of the catalyst, operation at room
temperature, large scale treatment, high yields, and
excellent chemoselectivity.
The reactions of amines with Ac2O were so fast in
comparison to those of the aliphatic alcohols that the
selective protection of an amine in the presence of aliphatic
alcohols appeared to be a distinct possibility (entry 14).
Also, the amino group in aminophenol was selectivity
acylated (entries 15 and 16). It is noteworthy that, entry 17
can survive in the present method indicating mildness of
reaction conditions.
2. Experimental
2.1. General procedure
To a mixture of ZnO (dry powder, 0.04 g, 0.5 mmol) and an
acid chloride or anhydride (1 mmol), alcohol, phenol or
amine (1 mmol) was added. The reaction mixture was
stirred with a mechanical stirrer for a certain period of time
(Tables 2 and 3) as required to complete the reaction
(monitored by TLC) at room temperature. The solid mass
(ZnO) was then eluted with CH2Cl2 (20 mL), and the
CH2Cl2 extract was then washed with an aqueous solution
of sodium bicarbonate and dried over anhydrous sodium
sulfate. Evaporation of solvent furnished, practically pure,
the corresponding product. The identity of these compounds
A comparison of the catalytic efficiency of ZnO with
selected previously known catalysts is collected in Table 4
to demonstrate that the present protocol is indeed superior to
several of the other protocols. Menthol is completely
benzoylated in less than 60 min at 25 8C in 84% isolated
yield using the present protocol. Most of the other protocols
listed take either longer time for completion or use high
temperature. Benzoylation of t-butanol with 1 equiv of
PhCOCl afforded 67% yields in 270 min under solvent free
conditions in the presence of ZnO but Al2O3 and
ZrOCl2.$8H2O did not catalyze the same reaction. The
ZnO catalyzed benzoylation of 2-naphthol with stoichio-
metric amount of PhCOCl afforded 94% yield at room
temperature for 30 min while the 2-naphthol and other
phenols did not react at all in the presence of Al2O3. The use
of ZrOCl2$8H2O is equally effective, however, it requires
long times to completion. This is in contrast to the use of
ZnO that was very effective for acylation of phenols.
1
was easily established by comparison of their H NMR
spectra with those of authentic samples.31
2.1.1. 7-Acetyl-5,6,7,8,9,10-hexahydro-2H,1,13,4,7,10-
benzodioxatriazacyclopentadecine-3,11(4H,12H)-dione
(entry 17, Table 3). To a mixture of ZnO (dry powder,
0.04 g, 0.5 mmol) and an acetic anhydride (1 mmol,
0.094 mL), 5,6,7,8,9,10-hexahydro-2H-1,13,4,7,10-benzo-
dioxatriazacyclopentadecine-3,11(4H,12H)-dione (1 mmol

M. Hosseini Sarvari, H. Sharghi / Tetrahedron 61 (2005) 10903–10907
10907
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mechanical stirrer for 20 min as required to complete the
reaction (monitored by TLC) at room temperature. The solid
mass (ZnO) was then eluted with CH2Cl2 (20 mL), and the
CH2Cl2 extract was then washed with an aqueous solution
of sodium bicarbonate and dried over anhydrous sodium
sulfate. Evaporation of solvent furnished practically pure
the corresponding product. This was further purified by
recrystallization with suitable solvent (ether or CHCl3) gave
the title compound as a white solid, mp 218–220 8C.
[Found: C 57.21; H, 6.22. C16H21N3O5 requires C, 57.30; H,
6.31%]; dH (250 MHz, CDCl3) 7.85 (2H, s, –NH), 7.00–7.08
(4H, m, Ph), 4.50 (4H, s, CH2CO), 3.53 (8H, s, NHCH2-
CH2N), 3.00 (3H, s, MeCO); dC (62.9 MHz, CDCl3) 16.2,
41.1, 45.7, 77.6, 112.1, 120.8, 147.9, 165.8, 169.3; m/z 335
(100 MHC).
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Acknowledgements
We gratefully acknowledge the support of this work by the
Shiraz University Research Council.
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