7
32
Chemistry Letters Vol.36, No.6 (2007)
A Mild and Efficient Chemoselective Protection of Primary Alcohols
.
under Solvent-free Conditions
as Pivaloyl Esters Using La(NO ) 6H O as a Catalyst
3
3
2
Ã
P. Prabhakar, N. Suryakiran, and Y. Venkateswarlu
Organic Chemistry Division-I, Indian Institute of Chemical Technology,
Hyderabad 5000 07, India
(Received March 20, 2007; CL-070297; E-mail: luchem@iict.res.in)
Primary alcohols are selectively and efficiently protected
as their pivaloyl esters with pivaloyl chloride in the presence
and the products are obtained in excellent yields. Furthermore,
the reaction conditions are very mild, no by-products were
observed. We first examined the reaction of 2-phenylethanol
.
of catalytic amounts of La(NO3)3 6H2O at room temperature
under solvent-free conditions in excellent yields.
.
(1 mmol) with pivaloyl chloride (1.1 mmol) using La(NO3)3
6
H2O (5 mol %) at room temperature to form rapidly the corre-
sponding pivaloyl ester in 96% yield (Table 1, Entry 1). This
success has encouraged us to extend the generality of the reac-
tion. In order to establish the validity of the catalytic activity
Functional group protection strategies are central to target
molecule synthesis. The protection of alcohols is an important
1
,2
.
and useful transformation in organic synthesis. Among the
many protecting groups for alcohols, pivaloyl esters are impor-
tant and common intermediates in natural product synthesis
due to their stability and accessibility for easy interconversion.
In addition, they also serve as stable protecting groups in the syn-
of the La(NO3)3 6H2O, we carried out the reaction of various
primary alcohols (Table 1) with pivaloyl chloride to give the
corresponding pivaloyl esters in excellent yields. Moreover,
the acid labile-protected functional groups such as TBDMS
ethers and some acetonide-protected diols were intact under re-
action conditions (Table 1, Entries 2, 3, and 21). The substrates
contain both primary and secondary hydroxy groups; only
primary hydroxy group was protected with pivaloyl chloride to
yield the corresponding pivaloyl esters (Table 1 Entries 16 and
22). In a separate experiment a mixture of cyclohexanol and
benzyl alcohol (1:1) was taken and reacted with pivaloyl
3
–5
thesis of nucleoside and carbohydrate chemistry. The tradi-
tional methods involve reaction of alcohols with pivaloyl chlo-
6
ride in the presence of Lewis base, and using of carboxylic acid
7
–9
and alcohol in the presence of mineral acids, which are corro-
sive in nature and susceptible for acid labile protecting groups.
Further, modifications of methods have been made with alcohols
and acid chlorides in the presence of Lewis acids such as zinc
.
chloride in the presence of La(NO3)3 6H2O to form exclusively
chloride,10 magnesium, alumina, and clay. However, the
use of either strongly acidic or basic conditions frequently leads
to the formation of undesirable side products competing the re-
actions, hence a mild and chemoselective protection of alcohols
is highly desirable.
11
12
13
pivaloyl ester of benzyl alcohol (Scheme 2). This demonstrated
the chemo-selectivity catalyst.
CH OH OH
CH OPiv OH
2
2
La(NO ) .6H O
3
3
2
.
Recently, we explored La(NO3)3 6H2O as a mild and effi-
+
Piv Cl
0
20 min, rt
+
cient chemoselective catalyst in various organic transforma-
tions,14 such as tetrahydropyranylation of primary alcohols, de-
protection of acetonides, synthesis of quinazolinones, acetyla-
tion of alcohols and phenols, amines synthesis of ꢀ-amino
nitriles and benzodiazepines, and N-tert-butoxycarbonylation
of amines. In the above transformations, it has been observed
that the substrates containing other acid labile functional groups
such as TBDMS ethers, some isopropylidene-protected diols
and N-t-Boc-protected amines were intact in the presence of
1
solvent-free conditions
Scheme 2.
In conclusion, we described a mild and efficient method for
protection of primary alcohols as pivaloyl esters under solvent-
free conditions using La(NO3)3 6H2O as a catalyst.
Typical experimental procedure: to
alcohol (1 mmol) and pivaloyl chloride (1.1 mmol) was added
.
a
mixture of
.
.
La(NO3)3 6H2O. Herein, we wish to report the La(NO3)3
H2O-catalyzed chemoselective protection of primary alcohols
as their pivaloyl esters under solvent-free conditions.
In this report (Scheme 1), we describe an efficient and
chemoselective method for protection of primary alcohols. The
reaction proceeded efficiently and smoothly at room temperature
.
La(NO3)3 6H2O (5 mol %) and the reaction was stirred under
6
solvent-free conditions at room temperature for an appropriate
time (Table 1). After completion of the reaction as monitored
by TLC, the reaction mass was quenched with saturated
NaHCO3 solution (10 mL) and the product was extracted
into ethyl acetate (3 Â 20 mL). The combined organic layer
was washed with a brine solution, dried over anhydrous sodium
sulphate and concentrated under reduced pressure to give the
crude product, which was purified over silica-gel column
La(NO ) .6H O
O
3
3
2
R-OH
Piv Cl
0
20 min, rt
15
R-O
chromatography to afford the corresponding pivaloyl ester.
1
solvent-free conditions
The authors thank to Dr. J. S. Yadav, Director of IICT and to
MoES and DBT New Delhi, India for financial support.
Scheme 1.
Copyright Ó 2007 The Chemical Society of Japan
Prabhakar
