Unusual and unexpected reactivity of t-butyl dicarbonate (Boc2O) with alcohols in the presence of magnesium perchlorate. A new and general route to t-butyl ethers

Article abstract of DOI:10.1021/ol047704o

(Chemical Equation Presented) A new mild method for protecting alcohols as t-butyl ethers is reported. The reaction proceeds with Mg(ClO₄) ₂ and Boc₂O and shows general applicability. The deprotection of t-butyl ethers has also been revisited. Preliminary results indicate the CeCl₃·7H₂O/Nal system is a very suitable catalyst for their removal.

Full text of DOI:10.1021/ol047704o

ORGANIC
LETTERS
2005
Vol. 7, No. 3
427-430
Unusual and Unexpected Reactivity of
t-Butyl Dicarbonate (Boc2O) with
Alcohols in the Presence of Magnesium
Perchlorate. A New and General Route
to t-Butyl Ethers
Giuseppe Bartoli,* Marcella Bosco, Manuela Locatelli, Enrico Marcantoni,†
Paolo Melchiorre, and Letizia Sambri*
Dipartimento di Chimica Organica “A. Mangini”, V.le Risorgimento 4,
I-40136 Bologna, Italy
giuseppe.bartoli@unibo.it; letizia.sambri@unibo.it
Received November 8, 2004
ABSTRACT
A new mild method for protecting alcohols as t-butyl ethers is reported. The reaction proceeds with Mg(ClO4)2 and Boc2O and shows general
applicability. The deprotection of t-butyl ethers has also been revisited. Preliminary results indicate the CeCl3
‚7H2O/NaI system is a very
suitable catalyst for their removal.
In the past few years, metal perchlorates have been widely
exploited as Lewis acid promoters in various organic
transformations. In particular, perchlorate salts have shown
a high ability to activate 1,3-dicarbonyl systems and have
found considerable application in various acylation1 and
esterification2 procedures, in the synthesis of â-enamino
esters,3 and in the protection of amines as N-Boc derivatives.4
We now report that, surprisingly, the reaction of 1-octanol
1a (Scheme 1) with tert-butyl dicarbonate (Boc2O, 1.5 equiv)
Scheme 1
† Present address: Universita` di Camerino (MC), Italy.
(1) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Rinaldi,
S.; Sambri, L. Tetrahedron Lett. 2002, 34, 6331. (b) Bartoli, G.; Bosco,
M.; Dalpozzo, R.; Marcantoni, E.; Massaccesi, M.; Rinaldi, S.; Sambri, L.
Synlett 2003, 39. (c) Bartoli, G.; Bosco, M.; Dalpozzo, R.; Marcantoni, E.;
Massaccesi, M.; Sambri, L. Eur. J. Org. Chem. 2003, 4611. (d) Chakraborti,
A. K.; Gulhane, R.; Shivani Synlett 2003, 1805. (e) Chakraborti, A. K.;
Sharma, L.; Gulhane, R.; Shivani Tetrahedron 2003, 59, 7661. (f) Lu, K.-
C.; Hsieh, S.-Y.; Patkar, L. N.; Chen, C.-T.; Lin, C.-C. Tetrahedron 2004,
60, 8967.
(2) (a) Gooâen, L.; Do¨hring, A. AdV. Synth. Catal. 2003, 345, 943. (b)
Bartoli, G.; Boeglin, J.; Bosco, M.; Locatelli, M.; Massaccesi, M.;
Melchiorre, P.; Sambri, L. AdV. Synth. Catal. 2005, in press.
(3) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Melchiorre,
P.; Sambri, L. Synlett 2004, 239.
in the presence of anhydrous Mg(ClO4)2 does not give the
corresponding Boc-derivative 2a, as expected, but rather a
mixture of t-butyl octyl ether 3a (66%) and unreacted alcohol
(30%) after 18 h at room temperature.
(4) Bartoli, G.; Bosco, M.; Locatelli, M.; Marcantoni, E.; Massaccesi,
M.; Melchiorre, P.; Sambri, L. Synlett 2004, 1794.
10.1021/ol047704o CCC: $30.25
© 2005 American Chemical Society
Published on Web 01/06/2005

Similar behavior was observed with an aromatic substrate
such as phenol (1b), which can be easily converted in the
corresponding t-butyl ether 3b in 84% yield. These prelimi-
nary results seemed extremely interesting, as they represented
a potential solution to a longstanding problem in organic
synthesis, namely, t-butyl ether formation. The t-butyl ether
in fact is “one of the most underused alcohol protecting
groups”,5 although it is one of the few ethers stable under
strongly basic conditions.6 Its scarce employment in organic
synthesis is probably due to the conditions required for its
formation. Most of the known methodologies5,6 in fact require
harsh conditions based on the reaction of an alcohol with
isobutylene in the presence of a strong acidic catalyst.
Moreover, the reaction involves the formation of a t-butyl
carbocationic intermediate, thus avoiding the application of
these methodologies to the protection of aromatic alcohols,7
which predominantly undergo a Friedel-Crafts alkylation.
Thus, the peculiar observed reactivity prompted us to
optimize the reaction conditions to develop a new route to
t-butyl ethers. A series of experiments carried out on 1a and
1b (Table 1) indicated that the best yields were obtained in
Table 2. Protection of Alcohols as tBu-Ethers by Reaction
with Boc2O (2.3 equiv) in the Presence of 10 mol % Mg(ClO4)2
at 40 °C
Table 1. Reaction of 1-Octanol (1a) and Phenol (1b) with
Boc2O, under Various Conditions, in the Presence of 10 mol %
Mg(ClO4)2, unless Otherwise Mentioned
entry ROH Boc2O solvent time (h) T (°C) yield % of 3
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1.5
1.5
1.5
2.3
1.5
2.3
1.5
2.3
2.3
1.5
/
18
7
7
rt
40
40
40
rt
40
40
40
40
40
66
65
79
82
CH2Cl2
/
/
/
/
/
/
7
144
18
21
21
13
125
0 (13)a
72b
84
93
90
CH2Cl2
/
10
0 (95)a
a Reaction carried out without catalyst; the yield in parentheses refers to
the recovered carbonate 2. b Reaction carried out with 10% mol Zn(ClO4)2‚
6H2O as the catalyst.
the presence of 10 mol % anhydrous Mg(ClO4)2 and 2.3
equiv of Boc2O at 40 °C in CH2Cl2 or under neat conditions.
Although Zn(ClO4)2‚6H2O is usually more active than
Mg(ClO4)2,1c in this particular reaction, lower yields were
obtained in the presence of hydrated zinc perchlorate,
probably due to the presence of water (Table 1, entry 6). In
the absence of the perchlorate salt, both alkyl and aromatic
substrates reacted with Boc2O, giving only the t-butyl
carbonate 2 after prolonged reaction times (Table 1, entries
5 and 10).
The procedure succeeded in the synthesis of a large variety
of t-butyl ethers. The best obtained results are reported in
Table 2. The etherification process worked well with primary,
secondary, benzylic, allylic, and homoallylic alcohols, and
(5) Greene, T. W.; Wuts, P. G. M. In ProtectiVe Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999; pp 65-67.
(6) Kocienski, P. J. In Protecting Groups, 3rd ed.; Thieme: Stuttgart,
2004; pp 59-61.
(7) (a) Wright, S. W.; Hageman, D. L.; Wright, A. S.; McClure, L. D.
Tetrahedron Lett. 1997, 38, 7345. (b) Holcombe, J. L.; Livinghouse, T. J.
Org. Chem. 1986, 51, 111.
428
Org. Lett., Vol. 7, No. 3, 2005

neither isomerization of the substrate (entries 11 and 13) nor
racemization (entries 3, 12, and 16) were observed. Unfor-
tunately, tertiary alcohols failed to give the desired ether,
only the starting material being recovered after prolonged
reaction times.
Scheme 2. Possible Mechanistic Explanation for the
Formation of t-Butyl Ethers
Notably, the reaction gave excellent results with a large
variety of aromatic alcohols. Various substituted phenols
(entries 6-8) and 1- and 2-naphthol (entries 9 and 10) can
be converted into the corresponding t-butyl ethers in high
yields, and no product derived from an eletrophilic addition
to the aromatic ring was ever detected.
The reaction is highly chemoselective. In fact, other
functionalities present in the alcohol such as a carbonyl, an
ester, and a nitro group, a carbon-carbon double bond or a
fluoride, a chloride, and a bromide survived under the
adopted reaction conditions.
The compatibility of some typical protecting groups with
the reaction conditions was also evaluated. Benzyl and
(i-Pr)3Si (TIPS) ether derivatives were almost completely
unaffected (entries 17 and 18). Concerning the amine
function, the N-Boc-derivative is compatible with the reaction
conditions; in fact, the expected protected amino-ether was
obtained in high yield (entry 19).
Some preliminary experiments were carried out in order
to understand the reaction mechanism for the formation of
t-butyl ethers. We found that Boc2O alone decomposes in
the presence of Mg(ClO4)2 to give CO2, t-BuOH, and
isobutylene. The formation of a t-butyl carbocation inter-
mediate can be therefore assumed. This carbocation could
be in some way captured by the alcohol present in the
reaction mixture to give the t-butyl ether. But this hypothesis
must be excluded since it is well-known that phenols undergo
electrophilic substitution at the aromatic ring in the presence
of a t-butyl carbocation,7 and we never observed any addition
product, even with highly activated p-methoxy phenol8 (Table
2, entry 6). However, the fact that Boc2O decomposes in
the presence of Mg(ClO4)2 can explain why an excess of
Boc2O is required to obtain good yields in t-butyl ethers,
since its decomposition is a competitive reaction.
On the other hand, the formation of the carbonate 2 as a
reaction intermediate can be excluded. In fact, t-butyl octyl
carbonate 2a, prepared according to a known procedure,9
and the commercially available t-butyl phenyl carbonate 2b
react in the presence of Mg(ClO4)2 to give 1-octanol 1a and
phenol 1b, respectively, without any trace of t-butyl ethers
3a and 3b.
According to the previously reported procedure,10 we
synthesized the t-butyl cyclopentyl dicarbonate 4d as a
mixture with the corresponding carbonate. Upon treating this
inseparable mixture with Mg(ClO4)2, formation of the
corresponding t-butyl ether 3d was detected. Studies are in
progress to produce further evidence of this hypothesis.
The cleavage of t-butyl ethers to deprotected alcohols
requires strongly acidic conditions5,6 that are generally “not
mild enough to accommodate acid-sensitive functional
groups”.6
Recently, we reported11 that the CeCl3‚7H2O/NaI system
is able to cleave the carbon-oxygen bond of ethers (R′O-
R) provided that the substrates feature particular structural
properties, i.e., when the R framework bonded to oxygen is
able to stabilize a positive charge.12 Since the t-butyl group13
can generate a stable tertiary carbocation, we successfully
tested the CeCl3‚7H2O/NaI procedure using the t-butyl ethers
we just obtained.
Preliminary experiments gave very satisfactory results
(Table 3). Both alkyl and aromatic t-butyl ethers can be
Table 3. Deprotection of t-Bu-Ethers in the Presence of
CeCl3‚7H2O (1 equiv) and NaI (1 equiv) in CH3CN
entry
reagent
t (h)
T (°C)
yield of 1 (%)
1
2
3
1-octyl-OtBu 3a
Ph-OtBu 3b
(R)-menthyl-OtBu 3e
8
8
17
70
40
70
94
93
>98
It has been reported10 that in the synthesis of RO-Boc
from R-OH and Boc2O catalyzed by DMAP, a mixed
dicarbonate intermediate like 4 is formed (Scheme 2). On
this basis, a reasonable mechanistic hypothesis could invoke
the initial formation of the mixed dicarbonate 4, which,
coordinated by the catalyst, decomposes to the tert-butyl
ether 2 and CO2 through a concerted cyclic mechanism.
reconverted into the corresponding alcohols simply by
heating in CH3CN in the presence of 1 equiv of CeCl3‚7H2O/
NaI. Studies are in progress to extend this procedure to
(11) Bartoli, G.; Marcantoni, E.; Sambri, L. Synlett 2003, 2101
(12) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.; Torregiani,
E. Synlett 1998, 209. (b) Bartoli, G.; Bellucci, M. C.; Cappa, A.; Bosco,
M.; Marcantoni, E.; Sambri, L.; Torregiani, E. J. Org. Chem. 1999, 64,
5696. (c) Bartoli, G.; Cupone, G.; Dalpozzo, R.; De Nino, A.; Maiuolo, L.;
Marcantoni, E.; Procopio, A. Synlett 2001, 1897. (d) Yadav, J. S.; Reddy,
B. V. S. Synlett 2000, 1275. (e) Sabitha, G.; Babu, R. S.; Rajkumar, M.;
Srividya, R.; Yadav, J. S. Org. Lett. 2001, 3, 1149.
(8) In addition, we carried out a decomposition test of Boc2O with
Mg(ClO4)2 also in the presence of anisole as the carbocation scavenger.
We did not observe the formation of any tert-butyl anisole, not even in
trace amounts.
(9) Marshall, J. A.; Yanik, M. M. J. Org. Chem. 1999, 64, 3798.
(10) Basel, Y.; Hassner, A. J. Org. Chem. 2000, 65, 6368.
Org. Lett., Vol. 7, No. 3, 2005
429

functionalized substrates and to check its consistency with
other protecting groups.
procedure here proposed will increase if combined with a
general and simple deprotection step.
In conclusion, the Mg(ClO4)2-promoted procedure we have
presented here provides a very good method for obtaining
t-butyl ethers from alcohols, since it works under mildly
acidic conditions and many functional groups survive the
protection process.
Moreover, all side products of the reaction are volatile
compounds, so that the purification of the products is very
simple and convenient. Typically, t-butyl ethers have to be
separated only from the residual starting materials.
Finally, a simple and mild method for deprotecting t-butyl
ethers based on the CeCl3‚7H2O/NaI system gives very
satisfactory preliminary results. The value of the protection
Acknowledgment. Work was carried out in the frame-
work of the National Project “Stereoselezione in Sintesi
Organica. Metodologie e Applicazioni” supported by MIUR,
Rome, by the University of Bologna, and in the framework
of “Progetto di Finanziamento Pluriennale, Ateneo di Bo-
logna” and supported by National project FIRB “Progettazi-
one, preparazione e valutazione biologica e farmacologica
di nuove molecole organiche quali potenziali farmaci”.
Supporting Information Available: Experimental pro-
cedures, full characterization, and copies of both proton and
carbon NMR spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(13) Bartoli, G.; Bosco, M.; Marcantoni, E.; Massaccesi, M.; Sambri,
L.; Torreggiani, E. J. Org. Chem. 2001, 66, 4430.
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Org. Lett., Vol. 7, No. 3, 2005