pubs.acs.org/joc
and carbohydrate chemistry.2 The traditional methods in-
An Efficient Protocol for Alcohol Protection Under
Solvent- and Catalyst-Free Conditions
volve the reaction of alcohols with pivaloyl chloride in the
presence of Lewis acid3a and base,3b using carboxylic acid
and alcohol in the presence of mineral acids,3c-e which are
corrosive in nature and susceptible to acid labile protecting
groups. Further, modified methods have been made with
alcohols and acid chlorides in the presence of Lewis acids
such as zinc chloride,4a magnesium,4b alumina,4c and clay.4d
We reported3a protection of alcohols using pivaloyl chloride
Ch. Bhujanga Rao, B. Chinnababu, and Y. Venkateswarlu*
Natural Products Laboratory, Organic Chemistry Division-I,
Indian Institute of Chemical Technology, Hyderabad-500 007,
India
in the presence of La (NO3) 3 6H2O.
3
However, most of these methods still have certain limita-
tions such as expense and the air-sensitive nature of catalysts,
restrictions for large-scale applications, critical product iso-
lation procedures, and difficulty in recovery of high-boiling
solvents. These methods may lead to contamination of final
products with traces of transition metals and side products.
The development of a simple and efficient method under
green reaction conditions for selective protection of the
hydroxyl group with pivaloyl chloride has been advocated.
In continuation of our earlier report, we have developed such
a method for protection of alcohols using pivaloyl chloride
under solvent- and catalyst-free conditions.
In recent years the green context has become an eminent
issue. The reactions under catalyst- and solvent-free conditions
are considerably safe, nontoxic, environmentally friendly, and
inexpensive. Recently, a new method has been developed for
acylation of alcohols, amines, and thiols under green reaction
conditions,5a and N-phosphoramino R-aminophosphonates5b
are successfully synthesized under catalyst- and solvent-free
conditions. This inspired us to focus on protection of alcohol
derivatives under catalyst- and solvent-free conditions. Ac-
cording to our knowledge, this is the first report of solvent-free
pivaloyl protection of alcohol derivatives under catalyst-free
conditions.
Received June 27, 2009
A simple and highly efficient protocol for pivaloylation of
alcohols without using a catalyst under solvent-free con-
ditions has been developed. The key advantages of the
reaction are short reaction time, high yields, simple work-
up, and no need for further purification. Selectivity was
observed between primary alcohols vs. secondary alco-
hols and aliphatic alcohols vs. aromatic alcohols. The
accentuated and relevant phenomenon of this method
that we observed is in one-pot conversion of TBS protec-
tion into Piv protection of the hydroxyl group.
In recent years, the central objective in synthetic organic
chemistry is to develop a greener and more economically
competitive process for multifaceted synthesis. In the aspect
of total synthesis, selection of protecting groups is more
pivotal. To perform selective reactions at one reactive site,
others should be temporarily blocked while doing multi-
faceted synthesis of a multifunctional compound. Many
protective groups have been, and are being developed for
this purpose;1 among these groups, pivaloylation of alcohols
is an important and useful transformation for protecting
various alcohols. Pivaloylation of alcohols has received
considerable attention in synthesis due to the stability of
the pivaloyl group toward acidic reagents and its liability in
the presence of base, thus favoring the necessary transforma-
tions that are to be made with an acidic reagent. Because of
the above said reasons pivaloylation serves as a stable
protection for hydroxyl groups in natural product synthesis
TABLE 1. Solvent Effect for Pivaloyl Protectiona
entry
solvent
time(min)
yieldsb(%)
1
2
3
4
5
water
120
30
30
30
5
nil
89
72
83
CH2Cl2
CH3CN
ether
neat
100
aReaction conditions: alcohol (1.0 mmol), Piv-Cl (1.1 mmol), catalyst
free, at rt. bIsolated yields.
In a model reaction, the 2-phenylethanol (1) was reacted
with pivaloyl chloride (2) under neat conditions at room
temperature to yield phenethyl pivalate (3) in 100% yield
(1) (a) Greene, T. W.; Wuts, P. G. M. In Protective Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons Inc: New York, 1991; p 1. (b) Katritzky, A.
R.; Otto, C. M.; Charles, W. R. Comprehensive Organic Transformations; John
Wiley & Sons Inc: New York, 1996; Vol. 5. (c) Paquette, L. A. Encyclopedia of
Reagents for Organic Synthesis; Wiley Interscience: New York; 1995; Vol. 7, p
5525.
(2) (a) Kigoshi, H.; Ojika, M.; Ishigaki, T.; Suenaga, K.; Mutou, T.;
Sakakura, A.; Ogawa, T.; Yamda, K. J. Am. Chem. Soc. 1994, 116, 7443. (b)
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Yamda, K. J. Am. Chem. Soc. 1994, 116, 7441. (c) Matsushita, Y.; Sugamoto,
K.; Kita, Y.; Matsui, T. Tetrahedron Lett. 1997, 38, 8709.
(3) (a) Prabhakar, P.; Suryakiran, N.; Venkateswarlu, Y. Chem. Lett.
2007, 36, 732. (b) Robins, M. J.; Hawrelak, S. D.; Kanai, T.; Siefer, J. M.;
Mengel, R. J. Org. Chem. 1979, 44, 1317. (c) Hauser, C. R.; Hudson, B. E.;
Abramovisch, B.; Shivers, J. C. Organic Synthesis; John Wiley & Sons, Inc.: New
York, 1955; Vol. III, p 142. (d) Haslam, E. Tetrahedron 1980, 36, 2409. (e)
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2nd ed.;
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8856 J. Org. Chem. 2009, 74, 8856–8858
Published on Web 10/19/2009
DOI: 10.1021/jo901374k
r
2009 American Chemical Society