Selective acylation of aliphatic alcohols in the presence of phenolic
hydroxyl groups¤
Gowravaram Sabitha,* Basi V. Subba Reddy, Garudammagari S. Kiran Kumar Reddy and
Jhillu S. Yadav
L e t t e r
Organic Chemistry Division-I, Indian Institute of Chemical T echnology,
Hyderabad-500 007, India
Received (in Montpellier, France) 13th October 1999, Accepted 1st December 1999
A new and efficient method for the selective acylation of ali-
phatic hydroxyl groups in the presence of phenolic groups using
a mixture of trimethyl orthoacetate and trimethylsilyl chloride
at room temperature is reported. The reactions are selective,
high yielding and complete within 3–6 h.
wise, in the case of cinnamyl alcohols, Claisen-rearranged
product formation was observed by 1H NMR spectroscopy.
In conclusion, this method provides higher selectivity for
alkyl hydroxyl groups in the presence of phenolic groups and
a†ords better yields than conventional acylation methods. As
the method is mild and highly selective, it is an attractive
addition to the existing methods.
Performing chemoselective transformations is a challenging
problem in organic synthesis, especially when identical func-
tional groups in similar chemical environments are present.
Selective acylation of aliphatic hydroxyl groups in the pres-
ence of aromatic hydroxyl groups is an important process.1 In
the case of phenols it has been previously carried out using
Experimental
A mixture of alcohol (10 mmol), trimethyl orthoacetate (10
mmol) and trimethylsilyl chloride (10 mmol) was stirred in
dichloromethane under a nitrogen atmosphere for the time
given in the table. After complete conversion, as monitored by
TLC, the reaction mass was diluted with water and extracted
with dichloromethane (20 ml). The combined organic layers
were dried over anhydrous Na SO and concentrated in vacuo
metal sulfates supported on silica gel,2a the Ac O-catalytic
2
BF É Et O reagent system2b or over an alumina surface2c in
3
2
ethyl acetate solvent. In recent years orthoesters were suc-
cessfully used for the conversion of carbonyl compounds to
their acetals,3 for the esteriÐcation of acids,4a for the etheriÐ-
cation of alcohols4b and also used for the alkylation of
amines4c and active methylene compounds.4d In a further
e†ort to conceive new methods for the selective acylation of
aliphatic hydroxyl groups in the presence of phenolic
hydroxyl groups we explored the applicability of orthoesters
as acylating agents. We have found that the trimethyl
orthoacetateÈTMSCl system is especially e†ective for the
selective acylation of aliphatic hydroxyl groups.
2
4
to a†ord crude product, which was further puriÐed by column
chromatography on silica gel (100È200 mesh) using ethyl
acetate and hexane (3 : 7) to yield pure monoacylated product.
Entry b. 1H NMR (CDCl ):
d
1.96 (2H, m,
ÈCH CH CH È), 2.01 (3H, S, ÈCOCH ), 2.57 (2H, t, J \ 8.0
3
2
2
2
2
2
3
Hz, ArCH CH È), 4.04 (2H, t, J \ 6.0 Hz, ÈCH OAc), 5.56 (br
2
s, OH), 6.58È6.91 (4H, AB type, J \ 8 Hz, aromatic).
A number of substrates, bearing both aliphatic and aro-
matic hydroxyl groups, were selectively acylated at the ali-
phatic hydroxyl groups by using 1 equiv. trimethylsilyl
chloride and 1 equiv. trimethyl orthoacetate in dichloro-
methane at room temperature (see Scheme 1). The selectivity
may be attributed to the in situ generation of anhydrous HCl
from TMSCl5 and aliphatic alcohols.
The alkyl hydroxyl groups, including primary and second-
ary alcohols, were selectively acylated in the presence of
phenolic hydroxyl groups in good yields (Table 1). Chemosel-
ectivity was achieved under these reaction conditions due to
the greater nucleophilicity of aliphatic hydroxyl groups com-
pared to phenolic groups. When we tried to acylate benzyl
alcohol it gave only the dimerised product (benzyl ether); like-
References
1
W. T. Greene and P. G. M. Wuts, in Protective Groups in Organic
Synthesis, Wiley, New York, 2nd edn., 1991, pp. 88È92.
(a) G. W. Breton, J. Org. Chem., 1997, 62, 8952; (b) Y. Nagao, E.
Fujitha, T. Kohno and M. Yagi, Chem. Pharm. Bull., 1981, 29,
3202; (c) G. H. Posner and M. Oda, T etrahedron L ett., 1981, 22,
5003.
2
3
4
(a) S. A. Patwardhan and S. Dev, Synthesis, 1974, 348; (b) E. C.
Taylor and C. S. Chiang, Synthesis, 1977, 467; (c) R. Wohi, Syn-
thesis, 1974, 38; (d) C. A. Mackenzie and J. H. Stocker, J. Org.
Chem., 1955, 20, 1695; (e) B. Perio, M. J. Dozias, P. Jacquault
and J. Hamelin, T etrahedron L ett., 1997, 38, 7867.
(a) J. I. Trujillo and A. S. Gopalan, T etrahedron L ett., 1993, 34,
7355; (b) H. M. Sampath Kumar, B. V. Subba Reddy, P. K.
Mohanty and J. S. Yadav, T etrahedron L ett., 1997, 38, 3619; (c)
S. Padmanabhan, N. L. Reddy and G. J. Durant, Synth.
Commun., 1997, 27, 691; (d) M. Selva and P. Tundo, J. Org.
Chem., 1998, 63, 9560.
5
A. Rodriguez, M. Nomen and B. W. Spur, T etrahedron L ett.,
1998, 39, 8563.
Scheme 1
¤ IICT Communication No. 4358.
L etter a908235b
New J. Chem., 2000, 24, 63È64
This journal is ( The Royal Society of Chemistry and the Centre National de la Recherche ScientiÐque 2000
63
Sabitha, Gowravaram
