A novel practical cleavage of tert-butyl esters and carbonates using fluorinated alcohols

Article abstract of DOI:10.1016/j.tetlet.2010.02.100

Thermolytic cleavage of t-butyl esters and t-butyl carbonates was accomplished using TFE (2,2,2-trifluoroethanol) or HFIP (hexafluoroisopropanol) as solvent. Thus, a practical method to cleanly convert t-butyl esters and carbonates into the corresponding carboxylic acids, decarboxylated products, or alcohols in nearly quantitative yields was developed. The product is recovered by a simple solvent evaporation. The practicality of this methodology was demonstrated on alkyl, aryl, and heteroaromatic esters.

Full text of DOI:10.1016/j.tetlet.2010.02.100

Tetrahedron Letters 51 (2010) 2244–2246
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Tetrahedron Letters
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A novel practical cleavage of tert-butyl esters and carbonates using
fluorinated alcohols
*
Jason Choy, Saul Jaime-Figueroa , Teresa Lara-Jaime
Roche Palo Alto, 3431 Hillview Ave., Palo Alto, CA 94304, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Thermolytic cleavage of t-butyl esters and t-butyl carbonates was accomplished using TFE (2,2,2-trifluo-
roethanol) or HFIP (hexafluoroisopropanol) as solvent. Thus, a practical method to cleanly convert t-butyl
esters and carbonates into the corresponding carboxylic acids, decarboxylated products, or alcohols in
nearly quantitative yields was developed. The product is recovered by a simple solvent evaporation.
The practicality of this methodology was demonstrated on alkyl, aryl, and heteroaromatic esters.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 21 January 2010
Revised 16 February 2010
Accepted 18 February 2010
Available online 23 February 2010
Among various protecting groups for carboxylic acids, the tert-
butyl (t-Bu) group is perhaps the most widely used due to its
exceptional stability toward a variety of reagents and reaction con-
ditions.1 As a result, cleavage of the t-butyl group on esters remains
to be of prime importance in organic synthesis. Deprotection of
t-butyl esters is generally achieved by employing strong protic
acids such as trifluoroacetic and hydrochloric acids1,2, or Lewis
acid-catalyzed conditions using ZnBr23a, CeCl33b, and SiO2.3c In cer-
tain circumstances, highly activated t-butyl esters can be cleaved
under basic conditions using LiOH.3d Methods involving the ther-
molytic neat-cleavage (>200 °C) of t-butyl esters have also been
reported4, but these are very harsh conditions for many substrates.
Similarly, t-butyl carbonates, which are more reactive than t-
butyl esters, can be deprotected using trifluoroacetic acid3g or
hydrochloric acid.1b On the other hand, basic conditions using
KOH1b or Na2CO33e,3f to give the corresponding alcohols have been
also reported. Additionally, the cleavage of both the t-butyl carbon-
ates and t-butyl esters has been achieved with the use of relatively
mild TMSOTf-lutidine conditions.5
is recovered by simple solvent evaporation without any work up
and, in some cases, no further purification is needed.
Compared to other solvents, TFE (bp = 73 °C) and HFIP (bp =
58 °C) are unique due to their high ionizing powers, strong hydro-
gen bond donor abilities, mild acidic characters (pKa = 12.4 and
pKa = 9.3, respectively)7, and low nucleophilicity for transesterifi-
cation. These outstanding features encouraged us to explore their
use in the cleavage of t-butyl esters and carbonates. Initially, the
cleavages were conducted at the solvent reflux temperature.
Although the deprotection process was successful under these con-
ditions, long reaction times were often required (Scheme 1). In
order to shorten the reaction times, the cleavages were also exam-
ined under microwave-assisted conditions8 and the results are
shown in Scheme 1. These results suggest that although micro-
wave heating is not essential in this process, the reactions are
significantly accelerated with this protocol.
In an effort to explore the role of the solvent in this deprotection
process, tert-butyl ester 3 was subjected to experiments in differ-
ent solvents. Thus, TFE and HFIP were replaced with solvents such
Because each of these methods requires the use of specific
reagents and/or suffers drawbacks due to substrate sensitivity to
acids, attempts to find alternative practical conditions are still
desirable. Herein, we report a practical method to cleanly convert
t-butyl esters and carbonates into the corresponding carboxylic
acids, decarboxylated products, or alcohols in high yields.
We reported recently a new method to deprotect N-Boc-amines
using 2,2,2-trifluoroethanol (TFE) or hexafluoroisopropanol (HFIP)
as a solvent in quantitative yields.6 We now wish to report the
expansion of this methodology to the cleavage of t-butyl esters
and carbonates. The reaction conditions are neutral and do not re-
quire additional reagents apart from the solvent. Thus, the product
O
O
H
O
Trifluoroethanol
H
reflux temp. / 2h
or
O
O
OH
1
mw, 100 oC / 20 min
2 (> 95 % conversion)
O
O
Hexafluoroisopropanol
O
OH
reflux temp. / 2 days
or
Br
Cl
Br
Cl
mw, 100 oC / 2 h.
3
4 (> 95 % conversion)
* Corresponding author. Tel.: +1 973 235 7643; fax: +1 973 235 6263.
E-mail address: saul.jaime@roche.com (S. Jaime-Figueroa).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.100

J. Choy et al. / Tetrahedron Letters 51 (2010) 2244–2246
2245
as chloroform, acetone, acetonitrile, and tetrahydrofuran under the
trifluoroethanol
same conditions as those indicated in Scheme 1 (microwave,
100 °C/2 h). Using these solvents or neat conditions, unreacted
tert-butyl ester 3 was cleanly recovered in most cases, and the for-
mation of product 4 was not detected by NMR. When non-fluori-
nated alcohols such as MeOH and EtOH were used as solvents,
the unreacted tert-butyl ester 3 was again the main component
in the resulting crude mixture with some of the deprotected prod-
uct (<10% by NMR). Furthermore, in these cases the corresponding
methyl or ethyl esters were also observed as side products.
In order to study the generality and scope of this methodology,
the deprotection of a series of alkyl, aryl, and heteroaromatic t-bu-
tyl esters and carbonates was initiated. First, the deprotection of a
series of t-butyl carbonates was performed, varying the nature of
the substituents on the Boc-hydroxy moiety. In all cases, the prod-
uct was obtained in essentially quantitative yields; the results are
summarized in Table 1. It was confirmed that these reaction condi-
tions are compatible with silicon-protecting groups such as
–OTBDMS (Table 1, entry 5). More importantly, compounds that
are sensitive to typical acidic conditions, such as compounds 5
and 7 gave the corresponding deprotected product in excellent
yields (Table 1, entry 2 and 3). It is reported in the literature9 that
the use of trifluoroacetic acid (TFA) on substrate 5 gives a 6:4 mix-
ture of the desired product 6 and 4-t-butyl-2,6-dimethylphenol as
a side product. These results suggest that our conditions suppress
the side reactions produced by tert-butyl cation formation.
For the cleavage of tert-butyl esters it was found that HFIP is a
better solvent than TFE. Thus, the use of HFIP over TFE as a solvent
on the same substrate under similar conditions consistently re-
duced the reaction times (Scheme 2).
reflux temp. / 4 days
or
O
mw, 100 oC / 8 h.
( > 85 % conversion)
O
OH
O
Br
Cl
Br
Cl
4
hexafluoroisopropanol
3
reflux temp. / 2 days
or
o
mw, 100 C / 2 h.
( > 95 % conversion)
Scheme 2.
In general, the cleavage of t-butyl esters using HFIP under
microwave-assisted conditions proceeds cleanly; the results are
shown in Table 2. In all cases, the corresponding carboxylic acids10
were obtained in excellent yields. In appropriately functionalized
substrates such as entries 4 and 5 (Table 2), subsequent decarbox-
ylation of the acid intermediate occurred readily under the reac-
tion conditions.
In summary, a practical and high-yielding method for the cleav-
age of t-butyl esters and t-butyl carbonates using TFE or HFIP has
been discovered. Under this protocol, the product is isolated by
simple solvent evaporation and minimal work up conditions. These
conditions are compatible with other protecting groups such as –
OTBDMS, –OBn, and with other functional groups such as boronic
esters and aldehydes. This methodology can be also utilized on
substrates that are sensitive to deprotection under typical acidic
conditions (TFA or HCl).
Table 1
Deprotection of various t-butylcarbonates using TFE as a solvent under microwave-assisted conditions at 100 °C11
Entry
t-Butylcarbonate
Time (h)
Product
Yielda (%)
O
O
H
H
O
1
1
5
0.5
2
6
98
OH
O
O
O
2
3
1
1
96b
OH
O
O
O
B
O
B
O
O
O
7
9
8
96
O
O
OH
CF3
CF3
O
4
1
1
10
95b
O
O
OH
O
O
NH
NH
N
N
Si
Si
O
O
O
O
O
5
11
12
97
O
O
O
OH
O
HO
HO
a
Isolated yield.
b
Calculated by NMR of the crude (product has low boiling point).

2246
J. Choy et al. / Tetrahedron Letters 51 (2010) 2244–2246
Table 2
Cleavage of various t-butyl esters using HFIP as a solvent under microwave-assisted conditions12
Entry
1
t-Butylester
Temp/Time (h)
Product
Yielda (%)
96a
O
O
Br
Br
Br
Br
O
OH
3
100 °C/2
4
Cl
O
Cl
O
O
OH
2
3
4
13
100 °C/3
100 °C/2
14
95
N
N
Bn
N
Bn
N
O
O
15
16
85b
N
N
O
OH
O
O
O2N
O2N
O2N
O2N
O
82
71
17
19
100 °C/4 or 150 °C/1
100 °C/1
18
20
O
CO2Me
CO2Me
CN
O
5
96
O
CN
a
Isolated yield.
Estimated yield by NMR.
b
Shahidan, R. J. Macromol. Sci. Part A: Pure Appl. Chem. 2007, 44, 651; (c) Alcázar,
J.; Diels, G.; Schoentjes, B. Mini-Rev. Med. Chem. 2007, 7, 345.
Acknowledgments
9. Hansen, M. M.; Riggs, J. R. Tetrahedron Lett. 1998, 39, 2705.
We thank Dr. Joseph Muchowski and Dr. Robert Greenhouse for
the helpful discussion.
10. (a) Suryakiran, N.; Prabhakar, P.; Venkateswarlu, Y. Synth. Commun. 2008, 38,
177; (b) Augustine, J. K.; Arthoba, N. Y.; Vairaperumal, V.; Narasimhan, S.
Tetrahedron 2009, 65, 134; (c) Anderson, K. W.; Ikawa, T.; Tundel, R. E.;
Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 10694; (d) Billingsley, K. L.; Barder,
T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 5359; (e) Nguyen, C.;
Kasinathan, G.; Leal-Cortijo, I.; Musso-Buendia, A.; Kaiser, M.; Brun, R.; Ruiz-
Perez, L. M.; Johansson, N. G.; Gonzalez-Pacanowska, D.; Gilbert, I. H. J. Med.
Chem. 2005, 48, 5942; (f) Cottet, F.; Marull, M.; Lefebvre, O.; Schlosser, M. Eur. J.
Org. Chem. 2003, 1559; (g) Myrboh, B.; Ila, H.; Junjappa, H. Synthesis 1981, 126;
(h) Kalir, A.; Mualem, R. Synthesis 1987, 514.
References and notes
1. (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 3rd ed.;
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ed.; Thieme: Stuttgart, 2000.
2. Li, B.; Berliner, B.; Buzon, R.; Chiu, C.; Colgan, S. T.; Kaneko, T.; Keene, N.; Kissel,
W.; Le, T.; Leman, K. R.; Marquez, B.; Morris, R.; Newell, L.; Wunderwald, S.;
Witt, M.; Weaver, J.; Zhang, Z.; Zhang, Z. J. Org. Chem. 2006, 71, 9045.
3. (a) Wu, Y.-q.; Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J.; Hamilton, G. S.
Tetrahedron Lett. 2000, 41, 2847–2849; (b) Bartoli, G.; Bosco, M.; Sambri, L. J.
Org. Chem. 2001, 66, 4430; (c) Jackson, R. W. Tetrahedron Lett. 2001, 42, 5163;
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Guillaumet, G. Tetrahedron Lett. 2006, 47, 8575; (f) Govek, S. P.; Overman, L. E. J.
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Wiley-VCH Verlag GmbH & Co.: KGaA, Weinheim, Germany, 2004; For a recent
review of the use of fluorinated alcohols as solvents in organic reactions see:
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11. Typical experimental procedure for the cleavage of t-butyl-carbonates: A solution of
the t-butylcarbonate 1 (0.222 g, 1 mmol) in TFE (2,2,2-trifluoroethanol) (5 mL)
was placed ina sealed microwave vial. The reaction mixture was heated at 100 °C
in a Biotage—Initiator™ Sixty microwave until the complete disappearance of
the starting material. After cooling to room temperature, the mixture was
evaporated to dryness under reduced pressure to provide the pure product 2; mp
115–117 °C (lit.10c 113–117 °C); 1H NMR (400 MHz, CDCl3) d 6.35 (br s, 1H), 6.99
(d, J = 8.59 Hz, 2H), 7.83 (d, J = 8.59 Hz, 2H), 9.87 (s, 1H); 13C NMR (400 MHz,
CDCl3) d 191.24, 161.59, 132.53, 129.90, 116.03; MS-ESI: m/z (%) 123 (M+H+,
100); Anal. Calcd for C7H6O2: C, 68.85; H, 4.95. Found: C, 68.84; H, 4.87.
12. Typical experimental procedure for the cleavage of t-butyl-esters: A solution of the
t-butyl ester 3 (0.291 g, 1 mmol) in HFIP (hexafluoroisopropanol) (5 mL) was
placed in a sealed microwave vial. The reaction mixture was heated to 100 °C
(see Table 2) in a Biotage—Initiator™ Sixty microwave instrument until the
complete disappearance of the starting material. After cooling to room
temperature, the mixture was evaporated to dryness under reduced pressure
to provide the pure product 4; mp 170–172 °C; 1H NMR (300 MHz, DMSO-d6) d
7.65 (dd, J = 8.69, 1.89 Hz, 1H), 7.74 (d, J = 8.31 Hz, 1H), 7.85 (d, J = 1.89 Hz, 1H),
13.59 (br s, 1H); 13C NMR (400 MHz, DMSO-d6) d 165.93, 132.99, 132.86,
132.41, 130.55, 130.39, 125.02; MS-ESI: m/z, 233 (MÀH)À; Anal. Calcd for
C7H4BrClO2: C, 35.71; H, 1.71. Found: C, 35.83; H, 1.42.
8. For recent reviews of microwave-assisted organic reactions, see: (a)
Mavandadi, F.; Pilotti, A. Drug Discovery Today 2006, 11, 165; (b) Man, A. K.;