Highly selective acylation of alcohols and amines by an indium triiodide-catalysed transesterification process

Article abstract of DOI:10.1039/b002181o

A very simple method has been developed for the acylation of alcohols and amines by ethyl acetate through an indium triiodide-catalysed transesterification process. Using this method acylation of a primary OH group in the presence of secondary and phenolic OH groups, and of a primary NH₂ in the presence of secondary NH and primary OH have been achieved with high selectivity. The Royal Society of Chemistry 2000.

Full text of DOI:10.1039/b002181o

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Highly selective acylation of alcohols and amines by an indium
triiodide-catalysed transesterification process
Brindaban C. Ranu,* Pinak Dutta and Arunkanti Sarkar
1
A wide range of structurally varied alcohols and amines were
subjected to acylation by this procedure. The results are
reported in Table 1. It was found that primary alcohols (entries
1–9) underwent smooth acylation whereas phenol (entry 10)
and secondary alcohols (entries 12, 13) remained inert even
after prolonged treatment (20 h) under the present experimental
conditions. Thus, selective acylation of a primary OH group is
achieved efficiently in compounds containing phenolic (entry
11) and secondary (entries 14, 15) hydroxy functionalities
together with the primary hydroxy group in the same molecule
and no appreciable diacetate (less than 5%) was isolated in each
case. A tertiary alcohol on the other hand, suffered dehydration
under these conditions (entry 18). The reaction conditions are
mild enough not to induce any isomerisation of the double or
triple bond in allylic and propargylic (propargyl = prop-2-ynyl)
alcohols (entries 6, 7). More significantly, acid-sensitive func-
tionalities such as ketal (entry 8) and TBDMS ether (entry 16)
remained unaffected. In addition, a variety of other functional
groups like OEt (entry 4), NO2 (entry 5) and keto carbonyl
(entry 9) also survived under the present reaction conditions.
Like primary alcohols, primary amines (entries 19, 20) were
also readily acylated by this procedure. However, secondary and
aromatic amines did not undergo any change (entries 21, 22).
Very interestingly, in a competitive acylation reaction with an
equimolar mixture of benzyl alcohol and benzylamine by this
procedure, the amine is acylated selectively leaving behind the
alcohol almost unaffected (acylation of OH group is less than
5% by 1H NMR). Thus, acylation of amino alcohols produced
the corresponding acetamides only (entries 23, 24, 25); the
hydroxy moiety remained untouched. This selective acylation
of a primary NH2 over a primary OH by this process is of
considerable synthetic importance and is difficult to achieve
with many other reagents.2,3
Department of Organic Chemistry, Indian Association for the Cultivation of Science, Jadavpur,
Calcutta—700 032, India. Fax: 91-033-473-2805. E-mail: ocbcr@mahendra.iacs.res.in
Received (in Cambridge, UK) 17th March 2000, Accepted 19th May 2000
Published on the Web 26th June 2000
A very simple method has been developed for the acylation of alcohols and amines by ethyl acetate through an
indium triiodide-catalysed transesterification process. Using this method acylation of a primary OH group in
the presence of secondary and phenolic OH groups, and of a primary NH2 in the presence of secondary NH
and primary OH have been achieved with high selectivity.
The acylation of alcohols and amines is one of the most fre-
quently used transformations in organic synthesis as it provides
an efficient and inexpensive means for protecting hydroxy and
amino groups in a multistep synthetic process.1 Acetyl chloride
and acetic anhydride are usually employed as the acylating
agents in the presence of a convenient acidic2 or basic3 catalyst.
However, both of these reagents, being corrosive and a lachry-
mator respectively, are not always ideal. Moreover, the acidic
conditions in Lewis acid acylations lead to the cleavage of sensi-
tive functional groups such as acetals and TBDMS ethers. On
the other hand, most of the acidic and basic catalysts lack the
ability to select between primary and secondary hydroxy and
amino groups. Thus, acylation by transesterification with an
ester or an enol ester constitutes a simple and practical altern-
ative. A variety of procedures involving different catalysts have
been developed for this purpose4 and this process is under con-
stant review to make it more effective and selective.5
The reactions involving indium() halides have been the
subject of current interest because of their unique capability to
impart high regio- and chemoselectivity in various chemical
transformations.6 Our recent experience with indium triiodide6h
thus prompted us to explore the utility of this Lewis acid for the
acylation of alcohols and amines. We were particularly inter-
ested in selectivity5b,7 for substrates having more than one OH
or NH2 group, since selective monoacylation of diols and
diamines is often needed in the synthesis of complex natural
products and unfortunately is not always clean because of
competing diacylation.5e We have discovered that indium tri-
iodide catalyzes the acylation of primary alcohols and amines
with ethyl acetate very efficiently (Scheme 1).
The reactions are, in general, very clean giving very good
yields, and no side product has been isolated. The reactions
proceeded well with 0.1 equivalent of InI3 and use of
an increased amount of catalyst does not make much differ-
ence. The outcome of acylations either with preformed InI3
or with in situ formed InI3 (as mentioned in the experimental
procedure) is more or less same.
Scheme 1 Reagents and conditions: i, In, I2, EtOAc, reflux.
Results and discussion
In a typical experimental procedure, the alcohol was heated
under reflux in ethyl acetate in the presence of a catalytic
amount of indium triiodide, generated in situ from indium
metal and iodine, for a certain period of time as required to
complete the reaction (monitored by TLC). The reaction mix-
ture was then extracted with ether. The ether extract, after being
washed with sodium thiosulfate and brine, was evaporated to
furnish the product.
In conclusion, the present procedure using indium triiodide
provides a novel and efficient method for acylation of primary
alcohols and amines. The notable advantages of this procedure
are: (a) operational simplicity; (b) excellent selectivity for
primary OH over secondary and phenolic OH groups, and
for NH2 groups over NH and primary OH; (c) general applic-
ability; (d) reaction conditions tolerant to several acid-sensitive
functional groups such as acetal and TBDMS ether and (e)
DOI: 10.1039/b002181o
J. Chem. Soc., Perkin Trans. 1, 2000, 2223–2225
This journal is © The Royal Society of Chemistry 2000
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Table 1 InI3-Catalysed acetylation of alcohols and amines by EtOAc
Entry
Alcohol/Amine
t/h
Product
Yield (%)a
1
2
3
4
PhCH2OH
14
12.5
15
PhCH2OAc
82
80
81
78
PhCH2CH2OH
CH3(CH2)14CH2OH
EtOCH2CH2OH
PhCH2CH2OAc
CH3(CH2)14CH2OAc
EtOCH2CH2OAc
14
5
16
79
6
7
12.5
13.5
80
75
᎐
᎐
᎐–CH2OH
᎐–CH2OAc
᎐
᎐
8
14
78
82
9
10
11
13.5
20
No reaction
15
83
12
13
PhCH(OH)Prn
Me2CHOH
20
20
No reaction
No reaction
14
14
80
85
15
16
16
17
15.5
12.5
85
80
18
19
Me3COH
PhCH2NH2
12
10
Me2C᎐CH2
PhCH2NHAc
75
82
᎐
20
21
13
20
80
No reaction
22
23
Dicyclohexylamine
HOCH2CH2NH2
20
15
No reaction
HOCH2CH2NHAc
82
80
83
24
25
15
16
HOCH2(CH2)3CH2NH2
HOCH2(CH2)3CH2NHAc
a Refers to yields of pure isolated products properly characterised by spectral data.
good yields. We believe this will present a better and more prac-
tical alternative to the existing methodologies for selective
acylation of primary alcohols and amines and thus will find
useful applications in the synthesis of complex natural products
where selective protection of hydroxy and amino groups is
required.
and distilled before use. Alcohols and amines were obtained
commercially or prepared by standard methods.
General procedure for acylation
Representative procedure. Benzyl alcohol (108 mg, 1 mmol)
was heated at reflux in ethyl acetate (5 cm3) in the presence of
indium metal slices (12 mg, 0.1 mmol) and iodine (38 mg, 0.15
mmol) for 14 h (monitored by TLC). The reaction mixture was
then extracted with ether (4 × 10 cm3). The ether extract was
washed successively with a solution of sodium thiosulfate,
brine, and dried (Na2SO4). Evaporation of ether produced the
Experimental
Indium metal (Ingot, SRL, India) was cut into small slices and
used directly without any treatment. Iodine crystal was used
as obtained commercially. Ethyl acetate was dried over CaCl2
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Table 2 IR and 1H NMR data of some selected acetates and acetamides
Entry
νmax/cmϪ1
δH/ppm
5
6
7
1730
1725
1725
2.16 (s, 3H), 4.8 (s, 2H), 7.47–7.51 (m, 2 H), 8.16–8.20 (m, 2H)
2.1 (s, 6H), 4.5–4.65 (d, 4H, J 9), 5.7–5.85 (t, 2H, J 9)
2.0 (s, 3H), 2.2 (t, 1H, J 3), 4.2 (d, 2H, J 3)
8
9
11
14
15
23
24
1720
1725, 1715
1715
1715
1725
1680
1675
1.1–2.0 (m, 6H), 2.2 (s, 3H), 2.4–2.7 (m, 3H), 4.0 (s, 4H), 4.05–4.15 (broad d, 2H)
1.1 (s, 3H), 1.7–1.95 (m, 6H), 2.1 (s, 3H), 2.2–2.4 (broad t, 2H), 4.1–4.2 (d, 2H, J 6)
2.07 (s, 3H), 5.01 (s, 2H ), 6.76–6.85 (m, 4H ), 7.13–7.17 (m, 1H)
2.06 (s, 3H), 3.65–3.70 (m, 1H), 4.04 (d, 5H, J 3)
1.2–2.0 (m, 9H), 2.15 (s, 3H), 3.15–3.4 (m, 2H), 4.8 (broad d, 2H)
2.0 (s, 3H), 2.8 (broad s, 1H), 3.3 (t, 2H, J 12), 3.65 (t, 2H, J 12) 7.0 (broad s, 1H)
1.25 (s, 6H), 2.0 (s, 3H), 3.0 (broad s, 1H), 3.75 (s, 2H), 6.2 (broad s, 1H)
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crude product which was purified by column chromatography
over silica gel to furnish pure benzyl acetate (oil, 123 mg, 82%)
which is in full agreement with spectral data of an authentic
sample.
The reaction was also carried out with preformed InI3 in
which a mixture of indium metal and iodine was refluxed in
ethyl acetate for half an hour and then benzyl alcohol was
added. The results in both the procedures are the same.
The first procedure is followed for acylation of all the sub-
strates included in Table 1. Gram-scale reactions also afforded
analogously good yields. All the products are simple and known
compounds and are easily identified by comparison of their
spectra with those of authentic samples.8 However, IR and
1H NMR data of some selected acetates and acetamides whose
spectra are not available for comparison are presented in
Table 2.
Acknowledgements
We are pleased to acknowledge financial support from CSIR,
New Delhi [Grant No. 01(1504)/98] for this investigation. P. D.
thanks CSIR for his fellowship.
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