Part 148 in the series "studies on novel synthetic methodologies:" Selective acetylation of alcohols, phenols and amines and selective deprotection of aromatic acetates using silica-supported phosphomolybdic acid

Article abstract of DOI:10.1002/adsc.200700292

An environmentally friendly silica-supported phosphomolybdic acid was found to be a highly efficient catalyst for the selective acetylation of alcohols, phenols and amines in the absence of any solvent and also for the chemoselective deprotection of aromatic acetates under very mild conditions. This method has been used for the protection of the hydroxy groups as well as for the deprotection of the acetates of several naturally occurring bioactive phenolic compounds. The catalyst can be easily recovered and reused.

Full text of DOI:10.1002/adsc.200700292

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DOI: 10.1002/adsc.200700292
Part 148 in the Series “Studies on Novel Synthetic Methodolo-
gies:” Selective Acetylation of Alcohols, Phenols and Amines
and Selective Deprotection of Aromatic Acetates using
Silica-Supported Phosphomolybdic Acid
Biswanath Das,a,* Ponnaboina Thirupathi,a Rathod Aravind Kumar,a
and Keetha Laxminarayanaa
a
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad – 500007, India
Fax : (+91)-40-2716-0512; e-mail: biswanathdas@yahoo.com
Received: June 15, 2007; Published online: November 27, 2007
Abstract: An environmentally friendly silica-sup-
ported phosphomolybdic acid was found to be a
highly efficient catalyst for the selective acetylation
of alcohols, phenols and amines in the absence of
any solvent and also for the chemoselective depro-
tection of aromatic acetates under very mild condi-
tions. This method has been used for the protection
of the hydroxy groups as well as for the deprotec-
tion of the acetates of several naturally occurring
bioactive phenolic compounds. The catalyst can be
easily recovered and reused.
one or more drawbacks such as non-availability of the
reagents, harsh reaction conditions, long reaction
times, unsatisfactory yields and disturbance to other
functional groups. Moreover, the selectivity of acety-
lation is also important in multistep syntheses. Thus, a
suitable, efficient and selective method for the acety-
lation of alcohols, phenols and amines would be
highly useful.
In recent years, heterogeneous catalysts have
gained considerable importance due to environmental
and economic considerations. In continuation of our
work[6] on the application of the heterogeneous cata-
lysts for the development of useful synthetic method-
ologies, we have observed that silica-supported phos-
phomolybdic acid[7] is very suitable to catalyze the
acetylation of alcohols and phenols with acetic anhy-
dride to form the corresponding acetates at room
temperature (Scheme 1).This catalyst is important
from an environmental point of view as it possesses
Keywords: alcohols; amines; heterogeneous cata-
lysts; protecting groups; silica-supported phospho-
molybdic acid; solvent-free conditions
Protection of functional groups is highly essential in excellent activity, low toxicity and high stability to-
organic synthesis. Alcohols, phenols and amines are wards humidity. It can be recovered from the reaction
frequently protected as acetates, which are generally mixture and reused.
prepared by reaction with Ac2O in the presence of
The catalytic activity of silica-supported phospho-
pyridine.[1] 4-(Dimethylamino)pyridine (DMAP) and molybdic acid was determined initially by preparing
4-pyrrolidinopyridine (PPY) are also known to cata- acetyl-3-methoxyphenol in high yield (78%) from the
lyze the acetylation of alcohols.[2] Several Lewis acids, reaction of 3-methoxyphenol and acetic anhydride
such as metal halides,[3] metal triflates[4] and micro- using the catalyst in CH2Cl2 at room temperature
wave irradiation[5] have recently been introduced for within 3.0 h. (Table 1, entry 1). We used different sol-
the preparation of acetates from alcohols and phenols. vents such as CHCl3, C HCl2, THF, MeCN or Et2O
2
However, many of these methods are associated with for the reaction but the conversion proceeded best
Scheme 1.
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Table 1. Acetylation of alcohols, phenols and amines using silica-supported phosphomolybdic acid under solvent-free condi-
tions.
Entry
Substrate
Product[a]
Time[b]
[h or min]
Yield[c]
[%]
1
2
3.0
3.5
72
70
3
4
5
6
3.0
3.0
3.0
3.0
71
70
68
69
7
8
2.5
8
72
96
9
10
98
10
11
10
8
97
94
12
10
96
13
14
12
10
95
92
15
10
8
95
93
16
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Selective Acetylation of Alcohols, Phenols and Amines
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Table 1. (Continued)
Entry
Substrate
Product[a]
Time[b]
[h or min]
Yield[c]
[%]
17
18
19
20
10
91
97
95
96
12
10
10
21
22
10
8
98
94
23
24
8
8
95
93
25
10
96
26
8
93
27
28
10
12
90
92
29
30
15
95
10
13
91
94
31
[a]
1
All the compounds were characterized by H NMR and mass spectral data.
Reaction times for entries 1–6 are in h, those for entries 7–31 in min.
Isolated yields after column chromatography.
[b]
[c]
under solvent-free conditions. In the absence of the
A wide variety of phenols (mono- and bicyclic), al-
catalyst the product was not formed while in the ab- cohols (aromatic, aliphatic, primary, secondary, allylic
sence of phosphomolybdic acid and only with SiO2 and benzylic) and amines (aromatic and aliphatic)
the transformation took a long time and the yield was were converted into their corresponding acetates in
only 12% after 5 h.
excellent yields (Table 1). The conversion was com-
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plete within 8–15 min. In the present case the acetyla-
Phenolic hydroxy groups are present in several bio-
tion of alcohols was carried out keeping intact other active naturally occurring compounds. Hence protec-
hydroxy and amine protecting groups, such as benzyl tion and subsequent deprotection of this group is nec-
(Table 1, entry 10), tosyl (entry 13), BOC(entry 11)
essary for multistep transformations and synthesis of
and acetonide (entries 12 and 13). The isomerization these compounds.[1] Deprotection of aromatic acetates
of an unsaturated alcohol (entry 20) and epimeriza- can be carried out under acidic, basic or hydrogena-
tion of a chiral alcohol (entry 9) were not observed. tion conditions.[1] However, the deprotection methods
Phenols having both electron-donating as well as elec- may effect several sensitive functional groups present
tron-withdrawing substituents underwent the reaction in the molecules. A limited number of methods exist
smoothly giving the desired products in moderate to for the selective deprotection of aromatic acetates in
good yields (the results are summarized in Table 1). the presence of aliphatic acetates.[12] Although these
Several naturally occurring compounds having phe- methods have certain applicabilities, most of them
nolic hydroxy groups were also transformed into the have certain drawbacks such as operational complexi-
corresponding acetates (entries 4–7). Another applica- ty, harsh conditions, use of costly reagents, long reac-
tion of the present method is the preparation of tion times and low yields. The recovery of the catalyst
Baylis–Hillman acetates from the corresponding ad- is also a problem.
ducts (entries 14–17). Baylis–Hillman acetates are
We have observed that silica-supported phospho-
useful for the synthesis of stereo-defined trisubsiituted molybdic acid is a highly efficient catalyst for selec-
alkenes.[8] However, on acetylation with Ac2O-pyri- tive deprotection of aromatic acetates in methanol at
dine Baylis–Hilaman adducts generally form isomeric room temperature within 2–3 h. Several aromatic ace-
acetates along with normal acetylation products.[9] tates underwent deprotection in the presence of the
This problem can be solved by acetylation of the ad- catalyst to produce the corresponding parent phenols
ducts with Ac2O catalyzed by silica-supported phos- (Table 2). The yields of regenerated phenols were typ-
phomolybdic acid.
ically excellent. We also used various other solvents
The chemoselectivity of the present acetylation such as THF, CHCl3, C HCl2, MeCN, and Et2O for
2
method is remarkable. An alcoholic hydroxy group the reaction but the conversion proceeded best in the
can conveniently be acetylated keeping intact the presence of methanol. Alkyl acetates were uneffected
phenolic hydroxy group in a molecule (entries 18 and by the catalyst under the present experimental condi-
21) within 8–15 min (when both reactants are in a 1:1 tions. The catalyst showed similar activity towards the
ratio). If the reaction was carried out using excess of deprotection of aromatic acetates containing electron-
Ac2O the diacetyled product (entry 18) was obtained donating and electron-withdrawing groups (results are
in less yield (34%) after 3 h. This selectivity is highly summarized in Table 2).
important to carry out modifications to two different
The present methodology has been applied for de-
types of hydroxy groups at different stages of a reac- protection of acetyl derivatives of several bioactive
tion sequence. Acetylation of symmetrical diols using natural products. Thus acetylbonducellin (entry 7), tri-
silica-supported phosphomolybdic acid under the acetylsappanone (entry 11), acetyl-2’-methoxybondu-
present experimental conditions afforded only the cellin (entry 8), acetyl-2’-methoxydihydrobonducellin
monoacetates (entries 22 and 23) in excellent yields. (entry 10), diacetyl-3’-methoxybonducellin (entry 9),
The selective monoacetylation of these symmetrical and scopoletin (entry 15) underwent deacetylation ef-
diols is possibly due to the preferential adsorption of ficiently to form the corresponding parent phenols.
these compounds, but not monoacetates, on the sur- Rhododendol diacetate and cleomiscosin A diacetate
face of the used catalyst where acetylation takes afforded rhododendol monoacetate (entry 18) and
place.[10] When in a molecule both hydroxy and amine venkatasin (entry 19), respectively, with chemoselec-
groups were present (entries 30 and 31) only the tive regeneration of phenolic hydroxy groups in very
amine group was protected selectively. The interesting high yields (Scheme 2).
selectivity of the present method can be utilized for
In conclusion, we have developed a simple and effi-
the preparation of bioactive natural products. Thus, cient method for acetylation of alcohols, phenols and
cleomiscosin A, a natural anticancer agent, was di- amines with Ac2O using silica-supported phosphomo-
rectly converted into another natural coumarino- lybdic acid as a heterogeneous catalyst. The catalyst
lignan, venkatasin[11] (entry 21) by acetylation with has also been applied for the deprotection of aromatic
Ac2O in the presence of silica-supported phosphomo- acetates. The salient features of this protocol include
lybdic acid. Anilines containing both electron-with- operational simplicity, mild reaction conditions, short
drawing groups (entry 29) and electron-donating reaction times, excellent yields, application of an inex-
groups (entry 28) in the aromatic ring underwent ace- pensive heterogeneous catalyst, compatibility with
tylation smoothly. Acetylation of aliphatic amines other hydroxy and amine protecting groups, high che-
(entries 24 and 26) was somewhat faster than that of moselectivity and monoprotection of symmetrical
anilines (entries 27–31).
diols. The method is quite suitable for the direct prep-
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Selective Acetylation of Alcohols, Phenols and Amines
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Table 2. Deprotection of aromatic acetates using silica-supported phosphomolybdic acid.
Entry
1
Substrate
Product[a]
Time [h]
2.0
Yield[b] [%]
98
2
2.0
96
3
4
5
2.5
3.0
2.0
96
89
95
6
2.0
2.5
2.5
2.5
2.0
2.7
96
93
94
96
92
95
7
8
9
10
11
12
2.0
96
13
14
2.5
2.8
94
90
15
16
3.0
2.0
94
97
17
2.5
98
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Table 2. (Continued)
Entry
Substrate
Product[a]
Time [h]
2.5
Yield[b] [%]
95
18
19
2.0
98
[a]
1
All the compounds were characterized by H NMR and mass spectral data.
Isolated yields after column chromatography.
[b]
Scheme 2.
aration of venkatasin, a natural coumarino-lignan tion the catalyst was filtered off and washed with MeOH
(2”5 mL). The filtrate was concentrated and extracted with
EtOAc (3”8 mL). The concentrated extract was purified by
column chromatography (silica gel, 35% EtOAc in hexane)
over silica gel to afford the parent phenol. The recovered
catalyst was also used here consequently three times and the
yield was found to be unaffected.
from anticancer agents, cleomiscosin A and for the
preparation of Baylis–Hillmans acetates from the cor-
responding adducts without simultaneous isomeriza-
tion. The catalyst was reused without any pretreat-
ment. The efficiency and stability of the catalyst were
found to be good even after three cycles.
Experimental Section
Acknowledgements
Acetylation of Alcohols, Phenols and Amines
The authors thank CSIR and UGC, New Delhi for financial
assistance.
To a mixture of an alcohol, phenol or amine (1 mmol) and
Ac2O (1.5 mmol) under solvent-free conditions silica-sup-
ported phosphomolybdic acid (113 mg) was added. The mix-
ture was stirred at room temperature and the reaction was
monitored by TLC. After completion of the reaction the
mixture was filtered and the catalyst was recovered after
washing the residue with methanol (2”5 mL). The filtrates
was concentrated and the residue was subjected to column
chromatography (silica gel, 20% EtOAc in hexane) to
obtain the pure acetate. The recovered catalyst was reused
three times subsequently for the same reaction without af-
fecting the yield of the product.
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