Indium-mediated facile cleavage of the t-butoxycarbonyl group from di-t-butylimidodicarbonate

Article abstract of DOI:10.1016/S0040-4039(01)02374-7

Di-t-butylimidodicarbonates are selectively and efficiently deprotected to the corresponding mono-BOC protected amines in high yields using indium or zinc metal in refluxing methanol. Simple BOC and CBz protected amines are unaffected by these conditions.

Full text of DOI:10.1016/S0040-4039(01)02374-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1549–1551
Indium-mediated facile cleavage of the t-butoxycarbonyl group
from di-t-butylimidodicarbonate
J. S. Yadav,* B. V. S. Reddy, K. Srinivasa Reddy and K. Bhaskar Reddy
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 27 July 2001; revised 6 December 2001; accepted 14 December 2001
Abstract—Di-t-butylimidodicarbonates are selectively and efficiently deprotected to the corresponding mono-BOC protected
amines in high yields using indium or zinc metal in refluxing methanol. Simple BOC and CBz protected amines are unaffected by
these conditions. © 2002 Elsevier Science Ltd. All rights reserved.
Protection of amines with appropriate protecting
groups plays an important role in multi-step synthesis
and also in peptide synthesis. Among various amine-
protecting groups, carbamate protecting groups are
widely used during the synthesis of amino acids, pep-
tides and other natural products.1 The t-butoxycar-
bonyl group is one of the most frequently used
amine-protecting groups in organic synthesis due to its
chemical stability to basic and mildly acidic conditions
and its ease of removal under specific conditions. Fur-
ther, di-t-butylimidodicarbonates are very useful as
phthalimide substitutes in Mitsunobu2 and Gabriel-type
processes3 in the synthesis of several bioactive
molecules and are found to be essential for the success
of the reaction.4 However, the final stage of the chemi-
cal process frequently requires their cleavage so as to
regenerate the parent compounds. Generally, the
removal of the t-BOC group is achieved by strong acid
catalysis.5,6 However, most of these procedures are of
limited synthetic scope due to lower selectivity for e.g.
the removal of both BOC groups by conc. HCl6a or
HBr6b and incompatibility with other acid sensitive
functional groups.5,6 Therefore, the development of a
neutral alternative would extend the scope of the di-
BOC protective group in peptide synthesis.7 Recently,
metal mediated reactions have attracted much interest
in organic synthesis because of their high reactivity,
stability and selectivity. Particularly, indium metal has
gained more popularity,8 owing to its unique reactivity
and stability in aqueous media. However, there are no
reports on the partial deprotection of di-t-butylimido-
dicarbonate using indium or zinc metal. In the course
of our studies on the synthesis of biologically interest-
ing compound sphingosine, we required the selective
removal of the t-butoxycarbonyl group from N-BOC
protected carbamates and sulfonamides in the presence
of THP, trityl, TBDMS and TBDPS ethers.
In this report we describe a new and efficient procedure
for the selective removal of the t-butoxycarbonyl group
from N-BOC protected carbamates using indium or
zinc metal under mild and neutral conditions (Scheme
1).
The cleavage of di-BOC protected amides was effected
by indium metal in methanol at reflux temperature.
This method is highly selective for cleavage of the
t-BOC group from N-BOC protected cabamates and
leaves simple BOC protected amines unaffected. The
deprotection of t-butylimidodicarbonates proceeded
smoothly to give exclusively mono-BOC protected
amines in excellent yields. Such selectivity can be
applied in synthetic sequences in which two BOC
groups must be unmasked at different stages of the
synthesis. It should be noted that the N(BOC)2 deriva-
tives bearing a-stereogenic centers gave the mono-BOC
protected amines with complete retention of the origi-
nal configuration.9 The removal of t-BOC from a N-
BOC protected sulfonamide was achieved with high
selectivity (Table 1, entry m). There are many advan-
tages in the use of indium metal for this cleavage which
Keywords: indium; carbamates; sulfonamides; a-amino acids.
* Corresponding author. E-mail: yadav@iict.ap.nic.in
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02374-7

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J. S. Yada6 et al. / Tetrahedron Letters 43 (2002) 1549–1551
Table 1. Metal-mediated conversion of di-BOC to mono-BOC

J. S. Yada6 et al. / Tetrahedron Letters 43 (2002) 1549–1551
1551
include the selective removal of a mono-t-BOC group
from di-t-BOC protected carbamates and sulfonamides
in the presence of other acid sensitive functional groups.
Another advantage of this procedure is the selective
removal of a t-BOC group in the presence of highly acid
sensitive protecting groups such as THP, TBDMS and
trityl ethers who do not survive TFA or conc. HCl.
Other functional groups such as esters, carbamates,
ethers and olefins are unaffected by these conditions.
Furthermore, the compatibility of this procedure is
illustrated by the selective removal of the t-BOC group
without affecting mono-BOC, CBz and sulfonamides. In
terms of efficiency and selectivity, this procedure is
superior to the reported methods where protic acids such
as TFA, conc. HBr and HCl are used. These reagents
sequentially remove both BOC groups from di-BOC
protected amides whereas mono BOC protected amines
survive under the present reaction conditions. It is of
interest to note that both t-BOC and ester groups were
hydrolyzed when the reaction was carried out with 2
equiv. of sodium hydroxide in methanol at ambient
temperature. Similarly, 2 equiv. of sodium metal in
methanol or sodium methoxide also cleaved both acid
and amine protective groups. In contrast, indium metal
in methanol being a mild base (pH of the reaction media
approximately 7.2) selectively cleaved mono-BOC from
di-t-BOC protected amides leaving both acid and base
labile functional groups intact.
2. (a) Koppel, I.; Koppel, J.; Degerback, F.; Grehn, L.;
Ragnarsson, U. J. Org. Chem. 1991, 56, 7172; (b) Henry,
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Engl. 1968, 7, 919; (b) Ragnarsson, U.; Grehn, L. Acc.
Chem. Res. 1991, 24, 285.
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M. J.; Allen, J. G. J. Org. Chem. 1997, 62, 7054; (c)
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Tetrahedron Lett. 1993, 34, 7873.
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R. D.; Johnston, G. A.; Kazlauskas, R.; Tran, H. W. J.
Chem. Soc., Perkin Trans. 1 1983, 2983; (c) Degerbeck, F.;
Fransson, B.; Grehn, L.; Ragnarsson, B. J. Chem. Soc.,
Perkin Trans. 1 1992, 245.
7. (a) Gunnarsson, K.; Grehn, L.; Ragnarsson, U. Angew.
Chem., Int. Ed. Engl. 1988, 27, 400; (b) Carpino, L. A.;
Mansour, E. M. E.; El-Faham, A. J. Org. Chem. 1993, 58,
4162.
8. (a) Li, C.-J.; Chan, T.-H. Tetrahedron 1999, 55, 11149; (b)
Cintas, P. Synlett. 1995, 1087; (c) Yadav, J. S.; Reddy, B.
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The results illustrated in Table 1 indicate the scope and
generality of the reaction with respect to various t-BOC
protected amino acids. Similar results were also obtained
with zinc metal in refluxing methanol (Table 1). The use
of metal grade zinc powder makes the procedure inexpen-
sive and offers advantages over existing methods.
Finally, mono-t-BOC and CBz protected amines are
unaffected under similar conditions (entries o and p).
This procedure has strengthened the utility of di-BOC
protection in organic synthesis, which allows application
in peptide synthesis.
9. Experimental procedure: A mixture of t-butyl imidodicar-
bonate (5 mmol), indium or zinc powder (10 mmol) in
methanol (15 ml) was stirred under reflux for an appropri-
ate time. After complete conversion, as indicated by TLC,
the solvent was removed under reduced pressure, diluted
with water (15 ml) and extracted with ethyl acetate (2×15
ml). The combined organic layers were dried over anhy-
drous Na2SO4, concentrated in vacuo and purified by
column chromatography on silica gel (Merck, 60–120 mesh,
ethyl acetate:hexane, 2:8) to afford mono-BOC protected
amines. Spectral data for compound 1c: [h]2D5=12.8 (c 1.0,
CHCl3); 1H NMR (CDCl3): l 0.88 (d, 3H, J=6.8 Hz), 1.18
(d, 3H, J=6.8 Hz), 1.50 (s, 18H), 2.42–2.50 (m, 1H), 3.78
(s, 3H), 4.48 (d, 1H, J=6.8 Hz). Compound 2c: [h]2D5=
−20.8 (c 1.1, MeOH); (lit.,4 [h]D25=−21.2 (c 1.1, MeOH); 1H
NMR (CDCl3): l 0.85 (d, 3H, J=6.8 Hz), 0.90 (d, 3H,
J=6.8Hz), 1.50 (s, 9H), 2.02–2.18 (m, 1H), 3.75 (s, 3H),
4.23 (m, 1H), 4.95 (brs, NH). Compound 1j: [h]2D5=−35.57
In conclusion, we have demonstrated a novel and highly
efficient protocol for the selective removal of the t-BOC
group from N-BOC protected amides using indium or
zinc metal under mild conditions. Due to its high
chemoselectivity, efficiency and simplicity, this method
may find wide applications in solid-phase peptide synthe-
sis.
1
(c 1.0, CHCl3); H NMR (CDCl3): l 1.48 (s, 18H), 2.10 (s,
Acknowledgements
3H), 2.43–2.60 (m, 4H), 3.78 (s, 3H), 5.05 (dd, 1H J=9.0,
4.5 Hz,). Compound 2j: [h]2D5=24.3 (c 2.8, CHCl3); (lit.,4
1
[h]2D5=24.6 (c 2.84, CHCl3).; H NMR (CDCl3): l 1.33 (s,
B.V.S., K.S.R. and K.B.R. thank CSIR New Delhi for
the award of fellowships.
9H), 1.78–1.90 (m, 2H), 1.98 (s, 3H), 2.41 (t, 2H, J=7.3
Hz), 3.65 (s, 3H), 4.32–4.41 (m, 1H), 5.23 (brs, NH).
Compound 1k: [h]D25=−37.02 (c 2.15, CHCl3) (lit.,4 [h]2D5=
−37.2) (c 2.15, CHCl3); 1H NMR (CDCl3): l 1.50 (s, 18H),
2.18 (m, 1H), 2.40 (m, 2H), 2.45 (m, 1H), 3.68 (s, 3H), 3.75
(s, 3H), 4.95 (dd, 1H, J=9.0, 4.3 Hz). Compound 2k:
[h]D25=+12.7 (c 2.00, CHCl3), (lit.,4 [h]2D5=+12.9) (c 2.00,
References
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1
CHCl3); H NMR (CDCl3): l 1.40 (s, 9H), 1.90 (m, 1H),
2.15 (m, 1H), 2.39 (m, 2H), 3.65 (s, 3H), 3.70 (s, 3H), 4.30
(bs, 1H), 5.15 (brs, NH).