Mixed metal MgO-ZrO2 nanoparticle-catalyzed O-tert-Boc protection of alcohols and phenols under solvent-free conditions

Article abstract of DOI:10.1002/aoc.2846

An environmentally benign method for O-tert-Boc protection of alcohols and phenols catalyzed by MgO-ZrO₂ nanoparticles under solvent-free conditions is described. A variety of phenols, alcohols (aliphatic and aromatic) were converted to corresponding O-tert-Boc products in good to excellent yield (50-95%). The present protocol is expedient, simple, and efficient under solvent-free conditions. The MgO-ZrO₂ Nps are easily prepared from inexpensive precursors, and are reusable, recyclable and chemoselective. Copyright 2012 John Wiley & Sons, Ltd. Copyright

Full text of DOI:10.1002/aoc.2846

Full Paper
Received: 7 February 2012
Revised: 23 February 2012
Accepted: 23 February 2012
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI 10.1002/aoc.2846
Mixed metal MgO–ZrO2 nanoparticle-catalyzed
O-tert-Boc protection of alcohols and phenols
under solvent-free conditions
Manoj B. Gawande,a* Sharad N. Shelke,b Paula S. Branco,a Anuj Rathic and
Rajesh K. Pandeyd
An environmentally benign method for O-tert-Boc protection of alcohols and phenols catalyzed by MgO–ZrO2 nanoparticles under
solvent-free conditions is described. A variety of phenols, alcohols (aliphatic and aromatic) were converted to corresponding
O-tert-Boc products in good to excellent yield (50–95%). The present protocol is expedient, simple, and efficient under solvent-free
conditions. The MgO–ZrO2 Nps are easily prepared from inexpensive precursors, and are reusable, recyclable and chemoselective.
Copyright © 2012 John Wiley & Sons, Ltd.
Supporting information may be found in the online version of this article.
Keywords: O-tert-butoxycarbonylation; phenol and alcohol; mixed metal oxides; nanoparticles; solvent-free; reusable and recyclable
In brief, an efficient and simple protocol for the synthesis of
tert-butyl carbonates under environmentally friendly conditions
Introduction
is still lacking. O-tert-Butoxycarbonylation is a suitable alternative
as the O-tert-Boc moiety is compatible with reaction conditions
Functional group protection strategies are synthetically impor-
tant in targeting molecule synthesis. The protection of alcohols
is imperative and useful in organic synthesis.[1,2] Protection and
routinely adopted in organic synthesis. A literature survey
revealed that a mild method has been used for protection of
deprotection of alcohols and phenols have received great atten-
tion in recent years, not only because of their fundamental
importance but also for their role in multistep drug synthesis.
alcohols as t-butyl ethers.[11b]
Recently, Chakraborti et al briefly studied butoxycarbonylation
of alcohols[12a] and amines using Lewis acid and protic acid type
High selectivity is frequently requested for a given hydroxy group
catalysts.[12b–e]
in polyol chemistry, as well as simplicity and mildness in preparing
and removing the specific function.
In continuation of our efforts for greener organic transforma-
tions[13] and design of heterogeneous catalysts for important
Among the many protecting groups for alcohol, organic car-
organic raw materials,[14] we present herein an ecofriendly,
bonates are important, since they are more stable than the
corresponding esters under basic conditions.[3] In addition; their
chemoselective and simple O-tert-butoxycarbonylation of phe-
nols and alcohols over MgO–ZrO2 nanoparticles (NPs) under
solvent-free conditions. The MgO–ZrO2 NPs have been prepared
by a simple ultradilution procedure by using inexpensive
importance has been increasing in the past few years both in
industry and in academic research.[4]
Traditionally, organic carbonates were prepared by using very
toxic reagents,[5] such as phosgene, pyridine and carbon monox-
precursors and characterized by several techniques such as
X-ray diffraction (XRD), FT-IR, scanning electron microscopy–
ide; thus much effort has been devoted recently to developing
more environmentally friendly procedures for their synthesis.[6]
energy dispersive spectroscopy (SEM-EDS), X-ray photoelectron
spectroscopy and transmission electron microscopy (TEM) tech-
Most methods for the synthesis of mixed carbonates suffer
niques[15] (supporting information). The TEM image of nano
drawbacks, such as low selectivity, limited scope and limited
availability of the substrate. Among carbonic acid derivatives used
MgO–ZrO2 is depicted in Fig. 1. The TEM image of MgO–ZrO2
as protecting groups, tert-butyl carbonates (O-Boc alcohols) and
carbamates (N-Boc amines) are of great importance in organic
chemistry. Although N-Boc derivatives are extensively used for
protecting amino groups,[7] O-Boc protection is restricted to aryl
alcohols. All these methodologies work in basic media[8] or in
the presence of a Lewis base.[9] Various acylating groups have
been used for the protection of hydroxyl groups, but for
the deprotection of these acylating reagents strong basic
conditions are needed. Recently, oxometallic species such as
oxovanadium[10] and oxomolybdenum[11a] were introduced
as amphoteric catalysts for nucleophilic acyl substitutions of
anhydrides and dicarbonates.
*
Correspondence to: Manoj B. Gawande, REQUIMTE, Departamento de Química,
Faculdade de Ciênciase Tecnologia, FCT, Universidade Nova de Lisboa, Portugal.
Email: m.gawande@fct.unl.pt; mbgawande@yahoo.co.in
a REQUIMTE, Departamento de Química, Faculdade de Ciênciase Tecnologia,
FCT, Universidade Nova de Lisboa, Portugal
b Department of Chemistry, SSGM College, Kopargaon, MH-423601, India
c
Jubilant Chemsys Ltd., B-34, Sector-58, New Delhi, Noida-201301, India
d Department of Chemistry, Marquette University, Milwaukee, WI-53233, USA
Appl. Organometal. Chem. (2012)
Copyright © 2012 John Wiley & Sons, Ltd.

M. B. Gawande et al.
For optimization of the reaction conditions, we have chosen the
model reaction of phenol (4) and Boc anhydride (5), to yield tert-butyl
phenyl carbonate (6a) (Scheme 2). The results are depicted in Table 1.
Initially, we tested the reaction under catalyst-free and solvent-
free condition at room temperature, but no corresponding product
formation was observed (Table 1, entry 1). The same reaction was
repeated at 60ꢀC, but we observed only a trace amount of product
(Table 1, entry 2). With MgO–ZrO2 NPs (TEM, 20–35 nm) at room
temperature after 24 h yield of 6a was 85% (Table 1, entry 3), while
at 60ꢀC after 2 h the yield was 92% (Table 1, entry 4).
The effect of normal component, nano component and nano
mixed oxides over O-tert-butoxycarbonylation of phenol was
studied. Notably, mixed oxide MgO–ZrO2 NPs is a better candi-
date compared to its component oxides. For MgO, ZrO2, nano
MgO, nano ZrO2 and MgO-ZrO2, 58%, 35%, 68%, 43% and 92%
yield corresponding to O-tert-Boc-phenol was obtained (Table 1,
entries 4–8). The stirring effect over Boc protection of phenol
and other optimized conditions are briefly described in supporting
information (ESI†). Thus, on the whole, nano MgO–ZrO2 catalyst is
more effective and efficient in terms of yield as compared to its
component nano oxides (nano MgO, nano ZrO2, and mechanical
mixture of nano MgO–ZrO2). Even a stoichiometric amount of
component oxides for protection of phenol possesses lower yields
than that of nano MgO–ZrO2 (supporting information and Table 1,
entries 6–8). We therefore explored further the substrate scope
for O-tert-butoxycarbonylation of phenol and alcohols, as shown
in Table 2.
Figure 1. TEM of nano MgO–ZrO2 at 100 nm.
mixed metal oxides reveals that the size of the MZ catalyst is in
the nano range (20–35 nm).
Recently, Bartoli et al.[11b] reported the synthesis of t-butyl octyl
ether using tert-butyl dicarbonate 3 over Mg(ClO4)2. In our
case, by using MgO–ZrO2 NPs under solvent-free conditions,
we selectively obtained 4-methoxy phenol O-tert-Boc protected
product 2, not t-butyl octyl ether 3 (Scheme 1).
O
O
MgO–ZrO2 NPs were used for O-tert-Boc protection of various
structurally and electronically diverse aliphatic and aromatic
hydroxy compounds under solvent-free condition (Table 2, entries
1–21). The results are reported herein.
O
O
O
1. (Boc)2O
2
2. Solvent-free
OH
3 . 60 o
C
1
O
The reaction of phenol with Boc2O gives a 92% yield of the
desired product within 2 h (Table 2, entry 1). Aryl alcohols
possessing electron-donating and electron-withdrawing groups
such as -Cl, -NO2, -OMe, -CN, -CH3 and Br afforded good to excellent
yields of the desired products (Table 2, entries 2–10). Phenols
MgO-ZrO2
X
O
3
Scheme 1. Chemoselective Boc protection of 4-methoxyphenol.
O
OH
O
O
O
O
MgO-ZrO2
+
O
O
O
Solvent-free
60 oC
5
4
6a
Scheme 2. O-tert-Butoxycarbonylation of phenol.
Table 1. O-tert-Butoxycarbonylation of phenola
No.
Catalyst
Temperature
Time (h)
Isolated yield 6a (%)
1
2
3
4
5
6
7
8
Catalyst-free, solvent-free
Catalyst-free, solvent-free
MgO–ZrO2 NPs (20–35 nm)
MgO–ZrO2 NPs (20–35 nm)
MgO nano (25–40 nm )
ZrO2 nano (25–45 nm)
MgO
Room temp.
60ꢀC
24
24
24
2
NR
Trace
85
Room temp.
60ꢀC
60ꢀC
60ꢀC
60ꢀC
92
2
68
2
43
2
58
ZrO2
60ꢀC
2
35
aReaction conditions: phenol = 10 mmol, (Boc)2O = 12 mmol, catalyst = 20 wt% with respect to phenol, NR= No reaction.
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Appl. Organometal. Chem. (2012)

MgO–ZrO2 nanoparticle-catalyzed O-tert-Boc protection of alcohols and phenols
a
Table 2. O-tert-Butoxycarbonylation of alcohols and phenols on MgO–ZrO2
No.
1
Hydroxy compounds
Product
Time (h)
2
Isolated yield (%)
92[16]
6a
6b
2
2
90[16]
84[16]
82[16]
93[16]
91[20]
90[16]
94[16]
85[16]
92[16]
90[16]
91[17]
93[18]
93[18]
95[19]
90[19]
94[18]
3
6c
2
4
6d
6f
2
5
6e
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
2.0
2.0
2.0
2.0
6
7
6g
6h
6i
8
9
10
11
12
13
14
15
16
17
6j
6k
6l
6m
6n
6o
6p
6q
6r
18
19
4
3
50[17]
6s
90[18]
Appl. Organometal. Chem. (2012)
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M. B. Gawande et al.
Table 2. (Continued)
No.
20
Hydroxy compounds
Product
Time (h)
1.5
Isolated yield (%)
87[19]
6t
21
1.5
93[18]
6u
aReaction conditions: Hydroxy compound = 10 mmol; Boc2O = 12 mmol; nano MgO–ZrO2 = 20 wt% w.r.t. hydroxyl compounds, solvent-free, 60ꢀC.
having functional groups such as -OMe, -Cl, -CH3 and -Br were
well tolerated, affording their corresponding -O-Boc derivatives in
excellent yield. The presence of a substituent -NO2 group at the
para and meta position of the phenol did not have much effect
on the reaction (Table 2, entries 3 and 4).
MgO–ZrO2-mediated O-tert-butoxycarbonylation by carrying out
competitive reaction of 2-isopropyl-5-methylcyclohexanol and
4-methoxyphenol (Scheme 3). Notably, 4-methoxyphenol reacted
exclusively in the presence of 2-isopropyl-5-methylcyclohexanol,
which was confirmed by thin-layer chromatography (TLC) and
NMR. Thus this chemoselective process can be useful for selective
protection of the aromatic alcohol group in the presence of
aliphatic alcohol, in natural product chemistry and various
drug intermediates.
The O-tert-butoxycarbonylation of a bulky phenol such as
2-naphthol also proceeded smoothly under the present reaction
conditions, providing 2-naphthyl tert-butyl carbonate in 90% yield
within 1.5h (Table 2, entry 11). Various substituted benzyl alcohols
afforded excellent yields of the desired products (Table 2, entries
12–14). Unsaturated alcohols such as cinnamyl alcohol also easily
underwent Boc protection without affecting the ethylenic bond
and afforded 90% yields of the desired product (Table 2, entry 16).
Primary and secondary aliphatic alcohols also reacted smoothly
under the present conditions, giving the corresponding O-Boc
derivatives in moderate to good yield (Table 2, entries 17–21). Thus
both primary and secondary alcohols were viable partners for this
transformation. The scope of this methodology was further
extended by investigating the possible chemoselectivity of the
We have proposed the possible mechanism for Boc protection
of phenol as depicted in Scheme 4.
In the first step, the -OH group of phenol and carbonyl oxygen
of Boc anhydride is adsorbed on MgO–ZrO2 nano catalyst as
shown in I. It is well known that functional groups containing
electronegative atoms such as N, O and S are adsorbed on a
metal or Lewis acid site and hydrogen adsorbed on oxygen of
the catalyst.[21] Then, in a second step, electrophilicity of carbonyl
carbon of Boc anhydride is increased, generating an intermediate
state, which, finally yields the final product along with liberation
O
O
O
O
1. MgO-ZrO2 ( 20 wt %)
2. (Boc)2O
O
100 %
5 mmol
+
OH
3. solvent-free, 60 oC
OH
O
O
5 mmol
5 mmol
O
0 %
Scheme 3. Chemoselective O-tert-butoxycarbonylation of alcohols.
O
O
H
O
O
O
O
O
O
O
O
O
- H
ZrO2
O
O
+
ZrO2
+ CO2 +
HO
ZrO2
O
O
Reused
and Recycle
I
Mg
O
Scheme 4. Possible mechanism Boc protection of phenol.
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Appl. Organometal. Chem. (2012)

MgO–ZrO2 nanoparticle-catalyzed O-tert-Boc protection of alcohols and phenols
zirconium oxychloride [ZrOCl2.8H2O] (8.11g) were dissolved
together in a 2 l flask with 1 l deionized water. Dilute ammonia
solution was added dropwise with vigorous stirring (RPM-5000)
until the precipitation was complete (around 6–8 h and pH 10.0).
The resultant precipitate was filtered and washed with distilled
water until free from chloride ions. The residue was dried for 24 h
at 383 K in an oven and the obtained precipitate of metal hydroxides
was heated in a porcelain crucible progressively to 873 K for 10 h. The
XRD profile and TEM analysis is given in supporting information.
General Procedure for Boc Protection of Alcohols
Boc2O (12 mmol), MgO–ZrO2 NPs (20 wt% of phenol or alcohol) at
room temperature were added to a mixture of phenol/alcohol
(10 mmol), and the reaction was stirred under solvent-free
conditions at 60ꢀC for an appropriate time (Table 2). After com-
pletion of the reaction, as monitored by TLC, ethyl acetate
(10 ml) was added to the reaction mixture and the catalyst
separated by simple filtration. The reaction mixture was washed
with a brine solution and the product extracted in ethyl acetate
(3 Â 10 ml) and concentrated under reduced pressure to give
the crude product, which was purified over a silica-gel column
to afford the corresponding tert-O-Boc derivatives in good to
excellent yield.
Figure 2. Reusability of MgO–ZrO2 NPs.
of CO2 and tert-butanol. MgO–ZrO2 catalysts participate in all
these steps by weakening the chemical bonds of reactants and
subsequently lowering the activation energy.
In order to prove that the reaction is heterogeneous, a standard
leaching experiment was conducted by the filtration method. The
model reaction of phenol and Boc anhydride proceeded for
10 min in the presence of the MgO–ZrO2 at 60ꢀC. The reaction
mixture was then filtered under suction to remove the catalyst.
The filtered reaction mixture was then stirred without catalyst for
12 h. Notably, no formation of O-Boc corresponding product was
observed even after 12 h, indicating that no homogeneous catalyst
was involved. The reusability of catalyst was tested for the reaction
of phenol and Boc anhydride under solvent-free conditions at 60ꢀC.
After completion of reaction the catalyst was filtered off, washed
with ethyl acetate two to three times, and then dried at 120ꢀC in
an oven for 3 h, then again used for the next cycle. The catalytic
activity slightly decreased even after six cycles (Fig. 2).
Acknowledgements
Manoj B. Gawande thanks FCT, Lisbon, Portugal, for the award of
a research grant (SFRH/BPD/64934/2009) and financial assistance.
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