Chemoselective O-tert-butoxycarbonylation of hydroxy compounds using NaLaTiO4 as a heterogeneous and reusable catalyst

Article abstract of DOI:10.1016/j.tetlet.2008.04.149

A facile, efficient and chemoselective protocol for O-tert-butoxycarbonylation of various hydroxy compounds has been developed using NaLaTiO₄ (layered perovskite) as a novel catalyst. The catalyst showed remarkable activity and reusability affording high yields of the desired products under mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2008.04.149

Tetrahedron Letters 49 (2008) 4249–4251
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Tetrahedron Letters
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Chemoselective O-tert-butoxycarbonylation of hydroxy compounds
using NaLaTiO4 as a heterogeneous and reusable catalyst
*
Savita J. Singh, Radha V. Jayaram
Department of Chemistry, Institute of Chemical Technology (Autonomous), N. Parekh Marg, University of Mumbai, Matunga, Mumbai 400 019, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A facile, efficient and chemoselective protocol for O-tert-butoxycarbonylation of various hydroxy com-
pounds has been developed using NaLaTiO4 (layered perovskite) as a novel catalyst. The catalyst showed
remarkable activity and reusability affording high yields of the desired products under mild reaction
conditions.
Received 7 February 2008
Revised 19 April 2008
Accepted 26 April 2008
Available online 1 May 2008
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
O-Boc-protection
Organic carbonates
Perovskite
NaLaTiO4
Heterogeneous catalyst
Organic carbonates constitute an important class of compounds
having pharmacological and chemical importance.1 They are used
as alkylating agents in organic reactions, as lubricating oils, pesti-
cides and also in medicinal and pharmaceutical chemistry. Tradi-
tionally these compounds are prepared by various methods such
as phosgenation, oxidative carbonylation and alkylation of metal
carbonates with alkyl halides. However, these methods either
involve toxic materials, gaseous reagents or lack simplicity and
efficiency.1a Di-tert-butyl dicarbonate (Boc2O) is an easily available
commercial reagent which is a better choice for preparing unsym-
metrical organic carbonates by direct coupling with hydroxy com-
pounds in the presence of a catalyst.2 Although the application of
Boc2O has been significant for the protection of amino groups,3
its use for the synthesis of organic carbonates has been limited
and is still a fertile area of research.4 Houlihan et al. have employed
a phase transfer protocol for the protection of alcohols and phenols
as their O-Boc derivatives (unsymmetrical organic carbonates).4a
There are a few reports on the preparation of organic carbonates
in the presence of catalysts such as 4-(dimethylamino)pyridine4b,c
and zinc acetate.4d More recently, oxomolybdenum5 and oxovana-
dium6 species were introduced as amphoteric catalysts for nucleo-
philic acyl substitutions of anhydrides and dicarbonates. However,
most of the methods reported above employ either homogeneous
media or homogeneous catalysts, which are not reusable. As per
our knowledge, there is only one report on the synthesis of organic
carbonates employing diethyl carbonate and an alcohol in the
presence of a heterogeneous catalyst under an inert atmosphere
at 125 °C.7 Thus, there was a need to develop an efficient catalytic
protocol that could overcome the above disadvantages and facili-
tate O-tert-butoxycarbonylation of various hydroxy compounds
under milder reaction conditions.
Perovskites are a class of compounds with robust structure and
varied physicochemical properties.8 There are several catalytic
applications of perovskites for various vapour phase reactions.9
However, the catalytic activity of this class of material has not been
explored fully in organic synthesis. There are a few reports demon-
strating the use of perovskites as catalysts for organic reactions
such as catalytic transfer hydrogenation,10 Ullmann and Sonogash-
ira reactions11 and Suzuki couplings.12 Layered perovskites can be
structurally described as two-dimensional perovskite slabs that are
separated by ion-exchangeable interlayer cations. NaLaTiO4 is one
such layered perovskite,13 which has not been explored as a cata-
lyst to date. NaLaTiO4 has the general formula A0 ½Anꢀ1BnO3nþ1ꢁ,
2
where A0 = alkali metal, A = alkaline earth or rare earth metal,
B = transition metal. The high metal content, insolubility in water
and common organic solvents and stability at high temperatures
make NaLaTiO4 a promising heterogeneous catalyst for liquid
phase organic transformations.14
Thus, in continuation of our previous work on the catalytic
activity of perovskites,10 we herein report a simple method for
the synthesis of unsymmetrical organic carbonates by O-tert-but-
oxycarbonylation of various hydroxy compounds using NaLaTiO4
as a heterogeneous and reusable catalyst under mild reaction
conditions (Scheme 1).
* Corresponding author. Tel.: +91 22 24145616; fax: +91 22 24145614.
E-mail addresses: savi2381@yahoo.co.in (S. J. Singh), rvjayaram@udct.org (R. V.
Jayaram).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.04.149

4250
S. J. Singh, R. V. Jayaram / Tetrahedron Letters 49 (2008) 4249–4251
Table 2
O
NaLaTiO4
, reflux
NaLaTiO4-catalyzed O-tert-butoxycarbonylation of hydroxy compoundsa
O
O
RO
O
ROH
+
CH2Cl2
O
O
O
Entry Hydroxy
compound
Time Product
(h)
Yieldb
(%)
R = alkyl, aryl
O
Scheme 1. O-tert-Butoxycarbonylation of hydroxy compounds.
98, 97, 96,
95, 95, 94c
OH
7
O
O
1
O
O
Table 1
OH
Influence of catalysta
O
O
2
3
4
7.3
92 (88)
97
MeO
Cl
Yieldb (%)
MeO
Entry
Catalyst
O
1
2
3
4
5
None
—
OH
5.5
O
NaLaTiO4
HLaTiO4
TiO2
92
90
37
20
Cl
O
La2O3
OH
7
O
O
83
a
O2N
Reaction conditions: 4-methoxybenzyl alcohol = 1 mmol; Boc2O = 1.1 mmol;
catalyst = 0.1 mmol; solvent = CH2Cl2 (1 mL); reflux; time = 7.3 h.
O2N
b
Yield determined by GC and GC–MS analysis.
O
5
6
6.85
7
77
70
OH
O
O
O
In order to investigate the influence of catalyst on the reaction
system, the reaction of 4-methoxybenzyl alcohol with Boc2O was
chosen as a model (Table 1). Initially, the reaction was performed
under catalyst-free conditions and no product formation was
observed.
OH
O
O
O
OH
7
8
9
7.5
7
72
O
O
O
15
The use of 10 mol % of NaLaTiO4 or HLaTiO4 (prepared by
exchanging the Na+ ions of NaLaTiO4 with H+ ions) catalysts affor-
ded 92% and 90% yields of the desired products, respectively.
The observed similar activity of NaLaTiO4 and HLaTiO4 can be
explained on the basis of their structural features as both consist
of single layers of TiO6 octahedra that are separated in alternate
layers by monovalent cations, which are ion-exchangeable and
La3+, which is non-exchangeable. Thus, the activity may be due
to the anionic moiety [LaTiO4]ꢀ which is the same for both the
catalysts. This was further proved when the influence of the com-
ponent metal oxides on the reaction was studied. It was observed
that both the component metal oxides (Table 1, entries 4 and 5)
provided lower yields compared to the perovskites indicating that
the actual catalytic activity resides in the perovskite structure.
Thus using NaLaTiO4 (10 mol %) as the catalyst, O-tert-butoxy-
carbonylation of various structurally and electronically diverse ali-
phatic and aromatic hydroxy compounds was carried out in
dichloromethane at reflux (Table 2, entries 1–18).16,17 The reaction
of benzyl alcohol with Boc2O provided a 98% yield of the desired
product within 7 h (Table 2, entry 1). Benzyl alcohols possessing
electron-donating and electron-withdrawing groups such as
OMe, Cl and NO2 afforded excellent yields of the desired products
(Table 2, entries 2–4). Primary and secondary aliphatic alcohols
also reacted smoothly under the present conditions giving the cor-
responding O-Boc derivatives in moderate to good yields (Table 2,
entries 5–10). Unsaturated alcohols such as cinnamyl alcohol and
crotyl alcohol also underwent facile Boc-protection without affect-
ing the ethylenic bond and afforded 92% and 89% yields of the
desired products, respectively (Table 2, entries 11 and 12). Thus,
both primary and secondary alcohols were viable partners for this
transformation.
O
89
OH
O
O
6.5
50
OH
O
O
O
O
10
11
12
13
14
15
7.25
23
OH
O
O
OH
6
92
O
O
O
O
O
6.75
89
OH
O
O
8
95
O
OH
H3C
Cl
H3C
O
8
78
OH
O
O
Cl
O
7.5
88 (83)
OH
O
O
O
O
16
17
18
7.5
84 (80)
80
OH
O
Cl
Cl
O2N
O2N
In order to explore the generality of the protocol, we also stud-
ied the protection of aryl alcohols under the same reaction condi-
tions (Table 2, entries 13–18). The reaction of phenol with Boc2O
afforded a 95% yield of phenyl tert-butyl carbonate within 8 h
(Table 2, entry 13). Phenols having functional groups such as Me,
Cl and NO2 were well tolerated affording their corresponding O-
Boc derivatives in excellent yields. The presence of substituents
at the ortho or para positions of the phenol did not have much
effect on the reaction (Table 2, entries 15 and 16). The O-tert-
butoxycarbonylation of a bulky phenol, such as 2-naphthol also
O
8
OH
O
O
O
6.6
91
OH
O
O
a
Reaction conditions: hydroxy compound = 1 mmol; Boc2O = 1.1 mmol; NaLa-
TiO4 = 0.1 mmol; solvent = CH2Cl2 (1 mL); reflux.
b
Yield determined by GC and GC–MS analysis. Yields in parentheses are of
isolated products.
c
Yield after sixth cycle.

S. J. Singh, R. V. Jayaram / Tetrahedron Letters 49 (2008) 4249–4251
4251
O
O
100%
0%
OH
OH
O
O
O
O
O
1 mmol
1 mmol
NaLa TiO4 (10 mol%)
CH2Cl2, reflux
+
O
O
O
1 mmol
O
Scheme 2. NaLaTiO4-mediated chemoselective O-tert-butoxycarbonylation of hydroxy compounds.
Bosco, M.; Carlone, A.; Dalpozzo, R.; Locatelli, M.; Melchiorre, P.; Palazzi, P.;
Sambri, L. Synlett 2006, 2104–2108.
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3729–3732.
proceeded smoothly under the present reaction conditions provid-
ing 2-naphthyl tert-butyl carbonate in 91% yield within 6.6 h
(Table 2, entry 18). Thus, the methodology was able to tolerate
both steric and electronic variations on the aryl alcohols under
the adopted reaction conditions.
We further investigated the reusability of the catalyst by sepa-
rating it from the reaction mass by filtration. After separation, the
catalyst was washed with acetone followed by diethyl ether and
heated at 150 °C for 2 h before the next cycle. The catalyst was
found to be reusable for up to six consecutive cycles with no signif-
icant loss in activity (Table 2, entry 1).
The scope of this methodology was further extended by inves-
tigating the possible chemoselectivity of the NaLaTiO4-mediated
O-tert-butoxycarbonylation by carrying out competitive reactions
of alcohols and phenol (Scheme 2). It was found that phenol
reacted exclusively in the presence of n-octyl alcohol or cyclohexyl
alcohol which was confirmed by GC and GC–MS analysis of the
reaction mixture. Thus, the protocol may be useful in the multistep
synthesis of bulky organic molecules wherein phenolic hydroxy
groups are to be protected selectively in the presence of saturated
alcoholic hydroxy functionalities, which either do not contain aryl
substituents or have them at remote sites.
7. Veldurthy, B.; Figueras, F. Chem. Commun. 2004, 734–735.
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14. Typical procedure for the preparation of NaLaTiO4: Stoichiometric amounts of
La2O3 (preheated at 900 °C for 12 h), TiO2 and 20% excess of Na2CO3 were
mixed and heated slowly up to 800 °C in
a platinum crucible and the
temperature was kept constant for 12 h in air. The resulting powder was
ground and heated at 900 °C for 2 days with two intermittent grindings and
In conclusion, we have developed a simple, efficient and chemo-
selective protocol for the O-tert-butoxycarbonylation of hydroxy
compounds using NaLaTiO4 as a novel heterogeneous catalyst.
The methodology offers several advantages such as use of a heter-
ogeneous and reusable catalyst, high chemoselectivity, greater
substrate compatibility, high reaction rates, operational simplicity
and mild reaction conditions. Further work is in progress to
explore this novel catalyst for use in other organic transformations.
cooled in
a furnace. Twenty percent excess of Na2CO3 was added while
grinding to compensate for the loss of the volatile sodium component. The
resulting product was washed with distilled water and dried at 120 °C.
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16. General procedure for the O-tert-butoxycarbonylation of hydroxy compounds: To a
dried 10 mL round-bottomed flask containing 1 mmol of alcohol was added
1.1 mmol of Boc2O followed by 0.1 mmol of NaLaTiO4 and finally 1 mL of
CH2Cl2. The mixture was stirred under reflux. The reaction was monitored by
TLC and GC. After the appropriate time, the reaction mixture was cooled to
room temperature and the catalyst was separated by filtration. The products
were characterized using GC/GC–MS.
References and notes
17. Spectral data of selected products: Table 2, entry 2: 1H NMR (300 MHz, CDCl3,
25 °C) d = 1.47 (s, 9H), 3.78 (s, 3H), 5.02 (s, 2H), 6.86 (d, J = 6.6 Hz, Ar 2H), 7.30
(d, J = 6.6 Hz, Ar 2H). 13C NMR (75 MHz, CDCl3, 25 °C) d = 27.7, 55.2, 68.5, 82,
113.8, 127.7, 130.2, 153.5, 159.7. MS (EI, 70 eV): 238 (10) (M+), 181 (24), 137
(52), 121 (100), 57 (30). Table 2, entry 15: 1H NMR (300 MHz, CDCl3, 25 °C)
d = 1.46 (s, 9H), 7.03 (d, J = 7.1 Hz, Ar 2H), 7.24 (d, J = 6.6 Hz, Ar 2H). 13C NMR
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J = 7.8 Hz, Ar 1H). 13C NMR (75 MHz, CDCl3, 25 °C) d = 27.4, 83.9, 123.3, 126.9,
127.7, 130.2, 147.1, 150.7. MS (EI, 70 eV): 228 (3) (M+), 128 (35), 111 (16), 57
(100).
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