A mild, highly selective and remarkably easy procedure for deprotection of aromatic acetates using ammonium acetate as a neutral catalyst in aqueous medium

Article abstract of DOI:10.1016/S0040-4020(02)01635-6

Ammonium acetate was found to catalyze efficiently the selective deprotection of aromatic acetates in the presence of various sensitive functionalities in aqueous methanol under neutral conditions at room temperature to yield the corresponding phenols in excellent yields. The method has been utilized for deprotection of acetates of several naturally occurring bioactive phenolic compounds and for preparation of venkatasin, a natural coumarino-lignan, from the anticancer compound cleomiscosin A.

Full text of DOI:10.1016/S0040-4020(02)01635-6

Tetrahedron 59 (2003) 1049–1054
A mild, highly selective and remarkably easy procedure for
deprotection of aromatic acetates using ammonium acetate
as a neutral catalyst in aqueous mediumq
*
C. Ramesh, G. Mahender, N. Ravindranath and Biswanath Das
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 August 2002; revised 27 November 2002; accepted 12 December 2002
Abstract—Ammonium acetate was found to catalyze efficiently the selective deprotection of aromatic acetates in the presence of various
sensitive functionalities in aqueous methanol under neutral conditions at room temperature to yield the corresponding phenols in excellent
yields. The method has been utilized for deprotection of acetates of several naturally occurring bioactive phenolic compounds and for
preparation of venkatasin, a natural coumarino-lignan, from the anticancer compound cleomiscosin A. q 2003 Elsevier Science Ltd. All
rights reserved.
1. Introduction
metalloenzymes,5d metal complexes5e–g and antibodies5h
have earlier been utilized for selective deprotection of aryl
acetates in the presence of alkyl acetates. However, most of
these methods suffer from certain drawbacks including
drastic reaction conditions, tedious experimental pro-
cedures, use of nonavailable and expensive reagents, long
reaction times and unsatisfactory yields. Recently aromatic
thiols in the presence of catalytic amount of K2CO3 have
been utilized for deprotection of aryl acetates but the utility
of the methods in the presence of aliphatic acetates has not
properly been studied.3 Moreover, the reaction mixture
should be refluxed at a very high temperature. More recently
a mild procedure has applied natural kaolinitic clay as a
catalyst but this clay is not commercially available and
it was collected from a specific geographic region.6 The
catalyst also worked at a very high temperature and the time
required was high. Thus, there is a need to develop a mild,
efficient and practical procedure for the selective depro-
tection of aromatic acetates using an easily available,
inexpensive and neutral reagent. Here, we wish to report a
very suitable procedure by applying ammonium acetate as
catalyst.
Phenolic hydroxyl groups are frequently observed in various
bioactive natural products. The modifications and synthesis
of these compounds generally require the protection of these
hydroxyl groups.2 This protection is usually carried out by
making the acetates of the compounds as the acetates can
easily be prepared and again be converted into the parent
hydroxyl compounds. Deprotection of aromatic acetates can
classically be carried out under acidic or basic conditions, or
by hydrogenolysis.2 However, these deprotection methods
may effect several sensitive functional groups present in
the molecules. Different methods are also now known for
the deprotection of aromatic acetates but the number of
processes for selective deprotection of these groups are
limited.3 However, selective deprotection of aromatic
acetates is very useful in synthetic organic chemistry.
Several manipulations can be carried out on the regenerated
phenolic hydroxyl groups of a molecule in the presence of
alkyl acetate groups and other sensitive functionalities and
this method can be utilized in multistep organic transform-
ations and synthesis. Moreover, some bioactive natural
products contain alkyl acetate groups with the free phenolic
hydroxyl groups.4 For preparation of these compounds
selective deacetylation of aromatic acetates in the presence
of aliphatic acetates will be highly valuable. The methods
involving specific micelles,5a Zn–MeOH,5b cyclodextrin,5c
2. Results and discussion
In continuation of our work on the development on novel
synthetic methodologies we have discovered that ammo-
nium acetate is a highly efficient catalyst for the selective
deprotection of aromatic acetates at room temperature and
in neutral conditions. The catalyst worked efficiently in
aqueous medium. Several aromatic acetates underwent
deprotection in the presence of the catalyst to produce the
corresponding phenols (Table 1) in excellent yields.
q For Part 18 see Ref. 1.
Keywords: aromatic acetates; ammonium acetate; deprotection; bioactive
phenolic compounds; venkatasin.
*
Corresponding author. Tel.: þ91-40-7173874; fax: þ91-40-7160512;
e-mail: biswanathdas@yahoo.com
0040–4020/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(02)01635-6

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C. Ramesh et al. / Tetrahedron 59 (2003) 1049–1054
Table 1. Deprotection of aromatic acetates using ammonium acetate
Entry
1
Substrate
Time (h)
4
Product
Isolated yield (%)
98
2
3
4
97
97
4.5
4
5
3
100
95
3.5
6
7
2.5
2
100
99
8
4
96
99
96
98
9
4.5
5
10
11
3.5
12
13
3.5
97
93
5

C. Ramesh et al. / Tetrahedron 59 (2003) 1049–1054
1051
Table 1 (continued)
Entry
Substrate
Time (h)
5
Product
Isolated yield (%)
14
96
15
4.5
97
16
17
4
3
100
99
18
19
6
5
96
94
20
6
96
21
6
94
22
5
95
(continued on next page)

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C. Ramesh et al. / Tetrahedron 59 (2003) 1049–1054
Table 1 (continued)
Entry
Substrate
Time (h)
4
Product
Isolated yield (%)
23
24
25
97þ100 (respectively)
3.5
100þ99 (respectively)
6
No reaction
26
27
6
6
No reaction
No reaction
28
6
No reaction
29
30
6
6
No reaction
No reaction
31
32
6
6
No reaction
No reaction
33
6
No reaction
Ammonium acetate is readily available and inexpensive.
The experimental procedure is remarkably easy. Deprotec-
tion of aromatic acetates can be carried out in the presence
of various functionalities like double bonds, aldehydes and
azide groups, lactone rings and ether and dioxane linkages.
Excellent chemoselectivity of the process was observed as
several other protecting groups such as THP ether, tosyl and
t-butoxycarbonyl (Boc) were unaffected under the experi-
mental conditions. The method showed unique selectivity
for deprotection of aryl acetates in the presence of
benzoates, N-acetyl groups and alkyl acetates. Thus,
4-acetoxymethylbenzoate (entry 6), 4-acetoxyacetanilide
(entry 9) and 4-acetoxyphenylethylacetate (entry 10),
afforded 4-hydroxymethylbenzoate (100%), 4-hydroxy-
acetanilide (99%) and 4-hydroxyphenylethylacetate
(96%), respectively. Fries rearrangement products or
undesired side products were not obtained in any case.
The presence of electron donating (e.g. –Me) or electron
withdrawing group (e.g. –NO2) in the aromatic ring did not
show any change in the yields of the products. The
structures of all the regenerated phenols were established
from their analytical and spectral (IR, H NMR and MS)
data, and by direct comparison with available authentic
samples.
1
The remarkable selectivity of the present procedure was also
demonstrated by intermolecular competition experiments.
Thus, when a mixture (1:1) of phenylacetate and phenyl-
ethylacetate was treated with ammonium acetate in aqueous
MeOH under the experimental conditions the latter was

C. Ramesh et al. / Tetrahedron 59 (2003) 1049–1054
1053
totally recovered unchanged along with phenol (97%).
Similarly, when the reaction was carried out with a mixture
(1:1) of acetanilide and 4-acetoxymethylbenzoate the first
compound remained totally intact while the other compound
afforded the product, 4-hydroxymethylbenzoate (99%).
stirred at room temperature and the progress of the reaction
was monitored by TLC. After 2.5 h the mixture was con-
centrated and the residue was extracted with EtOAc (3£
10 ml). Evaporation of the solvent afforded the deprotected
product, 4-hydroxymethylbenzoate (152 mg, 1.0 mmol, 100%).
The interesting point is that the present methodology has
been applied to the acetyl derivatives of several bioactive
natural products (entries 17–22). Thus, rhododendrol
diacetate7 (entry 18) afforded rhododendrol monoacetate
(96%) with selective regeneration of phenolic hydroxyl
group. Both the diphyllin acetate8 (entry17) and fraxetin
diacetate9 (entry 19) underwent deacetylation to form the
parent phenols, diphyllin (99%) and fraxetin (94%),
respectively. (þ) Mesquitoll0 and (2) epicatechin11 contain
five hydroxyl groups, four of them aromatic and one is
aliphatic. Penta acetates of these compounds (entries 20 and
21) afforded tetrahydroxymonoacetate (having intact the
aliphatic acetate group) under experimental conditions.
Finally the method has been utilized for conversion of the
anticancer compound, cleomiscosin A into venkatasin, both
are naturally occurring coumarino-lignoids.4 The former
contains one aliphatic and one phenolic hydroxyl groups
while venkatasin contains only the phenolic hydroxyl group
along with aliphatic acetate. The diacetate of cleomiscosin
A (entry 22) was treated with ammonium acetate to produce
venkatasin (95%) directly.
The characterization data of some compounds (which are
unknown or whose spectral data are not completely known)
prepared by following the above method is given below.
4.2.1. N-Acetyl-p-aminophenol (entry 9). Pale yellow
solid, mp 152–1548C; [Found: C, 63.24; H, 5.92; N, 9.12.
C8H9NO2 requires C, 63.56; H, 6.00; N, 9.27%]; nmax (KBr)
3324, 3165, 1653, 1562, 1508 cm21; dH (DMSO-d6) 9.24
(brs, 1H, –OH), 8.76 (1H, brs, –NH–), 7.26 (2H, d, J¼
8.0 Hz, Ar-H), 6.64 (2H, d, J¼8.0 Hz, Ar-H), 2.02 (3H, s,
–Ac); EIMS: m/z 151 (Mþz), 109, 80.
4.2.2. (S)-Menthyl ester of N-Boc-tyrosine (entry 15).
Viscous; [Found: C, 68.32; H, 8.83; N, 3.22. C24H37NO5
requires C, 68.71; H, 8.89; N, 3.34%]; [a]2D5¼þ18.28 (c
1.13, MeOH); nmax (KBr) 3436, 1730, 1695, 1635, 1615,
1503, 1450 cm21; dH (CDCl3): 6.97 (2H, d, J¼8.0 Hz,
Ar-H), 6.62 (2H, d, J¼8.0 Hz, Ar-H), 4.86 (1H, m, carbinol
proton from menthyl moiety), 4.64 (1H, brs, –NH–), 4.44
(1H, m, H-2), 3.04–2.77 (2H, m, H2-3), 2.02–0.88 (9H, m,
menthyl moiety), 1.24 (9H, s, –OCMe3), 0.82, 0.80, 0.68
(3H, each, d, J¼7.0 Hz, 3£–Me); LSIMS: m/z 419 (Mþz),
420 (Mþ1).
3. Conclusion
4.2.3. 3-O-Acetyl-(1)-mesquitol (entry 20). White solid,
mp 162–1648C; [Found: C, 61.32; H, 4.75. C17H16O7
requires C, 61.44; H, 4.85%.]; [a]2D5¼þ73.18 (c 1.21,
In conclusion, we have developed a very simple, mild and
highly efficient practical protocol with remarkable selec-
tivity for deprotection of aromatic acetates. The catalyst is
cheap, readily available and neutral. It works at room
temperature and in aqueous medium. The present procedure
is thus environmentally benign. The yields of the regener-
ated phenols are excellent. The method is quite suitable for
deprotection of acetates of several naturally occurring
complex bioactive phenols (both chiral and nonchiral)
having different sensitive functionalities. For direct prepa-
ration of some of the natural phenols the present protocol
will be highly useful.
MeOH); nmax (KBr) 3476, 3331, 1724, 1613, 1474 cm21
;
dH (CDCl3þDMSO-d6): 8.68, 8.22, 8.06, 7.78 (4H, brs
each, 4£–OH), 6.82–6.60 (3H, m, Ar-H), 6.41–6.30 (2H,
m, Ar-H), 5.22 (1H, m, H-3), 5.11 (1H, d, J¼4.5 Hz, H-2),
2.94 (1H, dd, J¼12.5, 4.5 Hz, H-4), 2.65 (1H, dd, J¼12.5,
6.5 Hz, H-4), 2.00 (3H, s, –OAc); EIMS: m/z332 (Mþz),
272, 176, 152.
4.3. 3-O-Acetyl-(2)-epicatechin (entry 21)
White solid, mp 140–1428C; [Found: C, 61.22; H, 4.67.
C17H16O7 requires C, 61.44; H, 4.85%]; [a]2D5¼240.48 (c
1.05, MeOH); nmax (KBr) 3475, 3312, 1723, 1624,
1475 cm21; dH (CDCl3þDMSO-d6): 8.80, 8.62, 8.24, 7.98
(4H, brs each, 4£–OH), 6.96 (1H, m, Ar-H), 6.82–6.56
(2H, m, Ar-H), 6.24 (1H, d, J¼1.5 Hz, Ar-H), 6.08 (1H, d,
J¼1.5 Hz, Ar-H) 5.24 (1H, m, H-3), 4.85 (1H, d, J¼6.5 Hz,
H-2), 3.04–2.52 (2H, m, H2-4), 2.18 (3H, s, –OAc); EIMS:
m/z 332 (Mþz), 290, 272, 212, 123.
4. Experimental
4.1. General methods
All the phenols and amines, except the naturally occurring
compounds, were obtained commercially. The natural
products were isolated earlier from the reported plant
sources and were available in our laboratory. NH4OAc was
obtained from Rankem laboratories, India. The spectra were
run on the following instruments: IR, Perkin–Elmer (RX1
FT-IR), 1H NMR: Varion Gemini 200 MHz and EIMS: VG
Micromass 7070 H (70 eV).
4.4. Competition experiment
A mixture of acetanilide (135 mg, 1.0 mmol) and 4-acetoxy
methylbenzoate (194 mg, 1.0 mmol) was dissolved in
aqueous MeOH (1:4, 20 ml). NH4OAc (618 mg,
8.0 mmol) was added. The mixture was stirred at room
temperature. After 3 h the mixture was concentrated to
afford a residue which was extracted with EtOAc (3£20 ml).
The extract was purified by column chromatography (15%
EtOAc/hexane) over silica gel to obtain 4-hydroxymethyl-
4.2. Typical experimental procedure
To a solution of 4-acetoxymethylbenzoate (194 mg,
1.0 mmol) in aqueous MeOH (1:4, 10 ml) NH4OAc
(618 mg, 8.0 mmol) was added. The resulting mixture was

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C. Ramesh et al. / Tetrahedron 59 (2003) 1049–1054
4. Das, B.; Venkataiah, B.; Kashinatham, A. Nat. Prod. Lett.
1999, 13, 293.
benzoate (150 mg, 0.986 mmol, 99%) and the unchanged
acetanilide (135 mg, 1.0 mmol, 100%).
5. (a) Kunitake, T.; Okahata, Y.; Sakamoto, T. J. Am. Chem. Soc.
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Chem. 1994, 59, 7602. (d) Crampton, M. R.; Holt, K. E.;
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(e) Beisselier, V. L.; Postal, M.; Dunach, E. Tetrahedron Lett.
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Acknowledgements
The authors thank UGC and CSIR New Delhi, for financial
assistance. They are also thankful to Dr B.Venkataiah for
helpful discussion and to Mr R. Jagadeshwar Rao (SRF)
for supplying (þ) mesquitol and (2) epicatechin.
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