Efficient and selective cleavage of t-butoxycarbonyl group from carbamates and amides by CeCl3·7H2O-NaI

Article abstract of DOI:10.1055/s-2002-20467

A highly selective cleavage of the t-butoxycarbonyl group has been achieved in high yields using CeCl₃·7H₂O-NaI in acetonitrile at ambient temperature under neutral conditions. This method is mild and compatible with a wide range of

Full text of DOI:10.1055/s-2002-20467

4
68
LETTER
Efficient and Selective Cleavage of t-Butoxycarbonyl Group from Carbamates
and Amides by CeCl 7H O-NaI
3
2
E
J
ffi ci ent
a
.
nd s el ective
S
C
l eavage of
t
-
.
B
utoxycarbo
Y
nyl
G
roup adav,* B. V. Subba Reddy, K. Srinivasa Reddy
Organic Chemistry Division-I, Indian Institute of Chemical Technology, Hyderabad-500 007, India
Fax +91(40)7170512; E-mail: yadav@iict.ap.nic.in
Received 31 October 2001
Abstract: A highly selective cleavage of the t-butoxycarbonyl
group has been achieved in high yields using CeCl 7H O-NaI in
3
2
acetonitrile at ambient temperature under neutral conditions. This
method is mild and compatible with a wide range of functional
groups such as THP, TBDMS, TBDPS, trityl ethers, mono-BOC or
Cbz protected amines, acetamide, sulfonamide and benzamide etc.,
present in the substrate.
Scheme 1
Key words: cerium reagents, carbamates, amides -amino acids
high chemoselectivity. The combination of cerium(III)
chloride with NaI selectively cleaved a t-butoxycarbonyl
group from di-BOC protected amides leaving other func-
tional groups intact. Such selectivity can be applied in
synthetic sequences in which two BOC groups must be
unmasked at different stages of the synthesis. This method
is highly chemoselective for removal of a t-BOC group
from di-BOC or BOC protected amides and carbamates
The strategy of protection and deprotection of a functional
group is frequently used in the multi-step synthesis of
1
many complex natural products. The t-butoxycarbonyl
group is one of the most widely used amine-protective
groups during the synthesis of amino acids, peptides and
2
other biologically interesting molecules. In addition, di- without affecting the mono-BOC or Cbz protected
t-butylimidodicarbonates are very useful as phthalimide amines. It should be noted that the N(BOC) derivatives
2
3
4
substitutes in Mitsunobu and Gabriel-type processes in bearing -stereogenic centres gave mono-BOC protected
the synthesis of several bio-active compounds and are amines with complete retention of the original configura-
tion.10 Further, the removal of a t-BOC group from N-
found to be essential for the success of the reaction.5
a
However, the final stage of the chemical process requires BOC protected acetamide, benzamide and sulfonamides
was also achieved with high selectivity (entry f, g, k). The
major advantage of this cleavage is in the selective remov-
al of t-BOC group in the presence of highly acid sensitive
trityl, TBDMS and THP ethers, which do not survive ei-
ther in TFA or HBr in acetic acid.6 Furthermore, the
compatibility of this procedure is illustrated by the selec-
their cleavage so as to regenerate the parent compounds.
In consequence, several procedures have been reported
for the selective cleavage of mono-BOC from di-BOC
protected amides using strong acid catalysis. However,
many of these reagents or solvents used are corrosive or
toxic, expensive and difficult to handle especially on large
6
,7
,7
scale. In addition, some of these methods are of limited tive removal of t-BOC group without affecting mono-
synthetic scope due to the lack of selectivity and incom- BOC or Cbz group and sulfonamide. In terms of selectiv-
patibility with other acid sensitive functional groups. ity and efficiency, this procedure is superior than reported
Therefore, there is a need to develop a mild and efficient methods where protic acids such as HCl, TFA and HBr
procedure for the removal of BOC group from t-BOC pro- are used. These reagents sequentially remove both BOC
tected amides.
groups from di-BOC protected amides whereas mono-
BOC protected amides survive under the present reaction
conditions. The reactions are clean and complete with in
8
Lanthanide salts are unique Lewis acids that are currently
of great research interest. Among these catalysts cerium
4
–6.5 hours. Due to mild reaction conditions, a number of
9
halides are relatively non-toxic, readily available at low
functional groups, albeit being capable of reacting with
CeCl 7 H O, remain intact. There are many advantages in
cost and are fairly stable to water. We wish to report that
cerium(III)chloride-NaI is an efficient reagent system for
the selective removal of mono-BOC from di-BOC pro-
tected amides under neutral conditions (Scheme 1).
3
2
the use of cerium(III)chloride for this cleavage, which
avoids the use of strongly acidic or basic conditions. In
addition, this method does not require the use of expen-
sive reagents or anhydrous solvents and no precautions
need to be taken to exclude moisture from the reaction
system. Thus, the present method is efficient and mild,
tolerating a wide range of functional groups. As evident
from the Table the acid sensitive protecting groups such
as trityl, THP, TBDMS, TBDPS, BOC, Cbz group and
The cleavage was affected by equimolar ratio of
CeCl 7H O-NaI in acetonitrile at ambient temperature.
3
2
The deprotection proceeded efficiently in high yields with
Synlett 2002, No. 3, 04 03 2002. Article Identifier:
1
©
437-2096,E;2002,0,03,0468,0470,ftx,en;D21401ST.pdf.
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214
sulfonamide are compatible with CeCl 7H O-NaI in ace-
3
2

LETTER
Efficient and Selective Cleavage of t-Butoxycarbonyl Group
469
tonitrile at ambient temperature. The cleavage may be af-
fected through the activation of carbonyl groups in the
BOC protected amides by cerium(III)chloride resulting in
–
the formation of oxonium ion which is attacked by I nu-
cleophile to afford the corresponding amide and t-BuI as
identified by spectral analysis (Scheme 2).
Scheme 2
Table Selective Removal of BOC from BOC protected amides by
Finally, we have examined the possibility of CeCl 7 H O
3 2
functioning catalytically or at least, in less than stoichio-
metric amounts. However best results were obtained with
–
CeCl 7 H O-Na
3
2
Entry Substrate (1)
Product (2)
Time
Yield
(%)
equimolar ratio of CeCl 7H O-NaI. In the absence of
(
h)
3
2
NaI, the deprotection by CeCl alone in acetonitrile at am-
3
a
4.5
91
bient temperature took longer to achieve complete con-
version. This clearly indicates that the addition of 1
equivalent of NaI is crucial in the deprotection to obtain
high yields of mono-BOC protected amines.
b
4.0
89
In summary, this paper describes a method for the selec-
tive removal of a single BOC group from di-BOC protect-
ed amides using a cheap and readily available reagent
system that operates under neutral conditions thereby
leaving acid- and base-labile protecting groups intact. The
high levels of chemoselectivity in this process combined
with a simple operation, high yields and ready availability
of reagents will facilitate wider use of di-BOC protection
in organic synthesis.
c
5.0
6.0
93
95
d
e
f
4.0
4.0
85
83
Acknowledgement
BVS and KSR thank CSIR, New Delhi for the award of fellowship.
g
h
i
5.0
6.0
6.5
87
91
92
References
(1) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd ed.; John Wiley and Sons: New
York, 1999. (b) Kocienski, P. J. Protecting Groups;
Thieme: Stuttgart, 1994.
(
2) (a) Gunnarsson, K.; Grehn, L.; Ragnarsson, U. Angew.
Chem., Int. Ed. Engl. 1988, 27, 400. (b) Carpino, L. A.;
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j
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6.5
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85
95
89
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3) (a) Campbell, J. A.; Hart, D. J. J. Org. Chem. 1993, 58,
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(
(
(
2
k
l
U. J. Org. Chem. 1991, 56, 7172.
4) (a) Gibson, M. S.; Bradshaw, R. W. Angew Chem., Int. Ed.
Engl. 1968, 7, 919. (b) Ragnarsson, U.; Grehn, L. Acc.
Chem. Res. 1991, 24, 285.
5) (a) Kokotos, G.; Padron, J. M.; Martin, T.; Gibbons, W. A.;
Martin, V. S. J. Org. Chem. 1998, 63, 3741. (b)Burk, M. J.;
Allen, J. G. J. Org. Chem. 1997, 62, 7054. (c) Sugawara,
N.; Stevens, E. S.; Bonora, G. M.; Toniolo, C. J. Am. Chem.
Soc. 1980, 102, 7044.
m
(
6) (a) Connell, R. D.; Rein, T.; Akermark, B.; Helquist, P. J.
Org. Chem. 1988, 53. (b) Brosse, N.; Pinto, M.-F.;
Gregoire, B. J. Tetrahedron Lett. 2000, 41, 205.
7) (a) Allan, R. D.; Johnston, G. A.; Kazlauskas, R.; Tran, H.
W. J. Chem. Soc., Perkin Trans. 1 1983, 2983. (b) Carpino,
L. A. J. Org. Chem. 1964, 29, 2820. (c) Stafford, J. A.;
Brackeen, M. F.; Karanewsky, D. S.; Valvano, N. L.
Tetrahedron Lett. 1993, 34, 7873.
n
6.0
91
(
o
p
10.0
12.0
–
–
(
8) (a) Kobayashi, S. Synlett 1994, 689. (b) Kobayashi, S. Eur.
J. Org. Chem. 1999, 15.
Synlett 2002, No. 3, 468–470 ISSN 0936-5214 © Thieme Stuttgart · New York

4
70
J. S. Yadav et al.
LETTER
Hz), 4.05 (dd, 1 H, J = 5.8, 13.7 Hz), 4.30 (m, 1 H), 5.23
(
9) (a) Bartoli, G.; Bosco, M.; Marcantoni, E.; Sambri, L.;
Torregiani, E. Synlett 1998, 209. (b) Bartoli, G.; Bellucci,
M. C.; Bosco, M.; Cappa, A.; Marcantoni, E.; Sambri, L.;
Orregiani, E. J. Org. Chem. 1999, 64, 5696.
2
5
1
(brd, NH, J = 7.8 Hz). 1d: [ ]D = –11.8 (c 1.5, CHCl ). H
3
NMR (CDCl3): = 1.03 (s, 9 H), 1.43 (s, 18 H), 3.62 (s, 3
H), 4.18 (dd, 2 H, J = 5.7, 13.8 Hz), 5.23 (dd, 1 H, J = 5.7,
10.3 Hz), 7.38–7.40 (m, 6 H), 7.58–7.65 (m, 4 H). 2d:
(
c) Marcantoni, E.; Nobili, F.; Bartoli, G.; Bosco, M.;
Sambri, L. J. Org. Chem. 1997, 62, 4183. (d) Yadav, J. S.;
Reddy, B. V. S. Synlett 2000, 1275.
2
5
1
[ ]D = +14.2 (c 1.5, CHCl ). H NMR (CDCl ): = 1.0 (s,
3
3
9 H), 1.45 (s, 9 H), 3.78 (s, 3 H), 3.98 (dd, 2 H, J = 5.7, 13.8
Hz), 4.38 (m, 1 H), 5.32 (br d, NH, J = 8.3 Hz), 7.28–7.43
(
10) Experimental Procedure: A mixture of di-BOC derivative
5 mmol), CeCl 7 H O (5 mmol) and sodium iodide (5
2
5
(
(m, 6 H), 7.5–7.63 (m, 4 H). 1h: [ ] = –35.57 (c 1.0,
3
2
D
1
mmol) in acetonitrile (10 mL) was stirred at ambient
temperature for an appropriate time (Table). After complete
conversion, as indicated by TLC, the reaction mixture was
diluted with water (25 mL) and extracted with ethyl acetate
CHCl ). H NMR (CDCl ): = 1.48 (s, 18 H), 2.10 (s, 3 H),
3
3
2.43–2.60 (m, 4 H), 3.78 (s, 3 H), 5.05 (dd, 1 H, J = 9.0 and
2
5
5
25
4.5 Hz). 2h: [ ]D = 24.3 (c 2.8, CHCl ), (ref. [ ] = 24.6
3
D
1
(c 2.84, CHCl )). H NMR (CDCl ): = 1.33 (s, 9 H), 1.78–
3
3
(
2
20 mL). The combined organic layers were washed with
1.90 (m, 2 H), 1.98 (s, 3 H), 2.41 (t, 2 H, J = 7.3 Hz), 3.65 (s,
2
5
brine, dried over anhyd Na SO and concentrated in vacuo,
and the resulting product was purified by column
3 H), 4.32–4.41 (m, 1 H), 5.23 (br s, NH). 1j: [ ] = +12.8
2
4
D
1
(c 1.0, CHCl ). H NMR (CDCl ): = 0.88 (d, 3 H, J = 6.8
3
3
chromatography on silica gel (Merck, 100-200 mesh, ethyl
acetate–hexane, 2:8) to afford pure mono-BOC protected
Hz), 1.18 (d, 3 H, J = 6.8 Hz), 1.50 (s, 18 H), 2.42–2.50 (m,
2
5
1 H), 3.78 (s, 3 H), 4.48 (d, 1 H, J = 6.8 Hz). 2j: [ ] = –
D
2
5
5
25
1
amine. Spectroscopic Data of 1a: [ ]D = –38.2 (c 1.5,
20.8 (c 1.1, MeOH) (ref. [ ] = –21.2 (c 1.1, MeOH)). H
D
1
CHCl ). H NMR (CDCl ): = 1.45 (s, 18 H), 3.60 (dd, 2 H,
NMR (CDCl3): = 0.85 (d, 3 H, J = 6.8 Hz), 0.90 (d, 3 H,
3
3
J = 5.5, 13.6 Hz), 3.65 (s, 3 H), 5.38 (dd, 1 H, J = 5.5, 10.3
J = 6.8 Hz), 1.50 (s, 9 H), 2.02–2.18 (m, 1 H), 3.75 (s, 3 H),
2
5
25
Hz), 7.28–7.42 (m, 15 H). 2a: [ ]D = +11.3 (c 1.5, CHCl3).
4.23 (m, 1 H), 4.95 (brs, NH). 1l: [ ] = –37.2 (c 2.15,
D
1
5
25
1
H NMR (CDCl3): = 1.40 (s, 9 H), 3.38 (dd, 2 H, J = 5.5,
CHCl ), (ref. [ ] = –37.2 (c 2.15, CHCl )). H NMR
3
D
3
1
3.6 Hz), 3.75 (s, 3 H), 4.38 (m, 1 H), 5.35 (brd, NH, J = 8.0
(CDCl ): = 1.50 (s, 18 H), 2.18 (m, 1 H), 2.40 (m, 2 H),
3
2
5
Hz), 7.10–7.40 (m, 15 H). 1b: [ ]D = –29.789 (c 1.5,
CHCl ). H NMR (CDCl ): = 0.03 (s, 6 H), 0.85 (s, 9 H),
2.45 (m, 1 H), 3.68 (s, 3 H), 3.75 (s, 3 H), 4.95 (dd, 1 H,
1
25
5
J = 9.0 and 4.3 Hz). 2l: [ ] = +12.7 (c 2.00, CHCl ), [ref.
3
3
D
3
2
5
1
1
5
1
.48 (s, 18 H), 3.67 (s, 3 H), 4.10 (dd, 2 H, J = 5.8, 13.7 Hz),
.10 (dd, 1 H, J = 5.8 and 10.5 Hz). 2b: [ ]D = +17.684 (c
.5, CHCl ). H NMR (CDCl ): = 0.02 (s, 6 H), 0.84 (s, 9
[ ]D = +12.9 (c 2.00, CHCl )]. H NMR (CDCl ): = 1.40
3
3
2
5
(s, 9 H), 1.90 (m, 1 H), 2.15 (m, 1 H), 2.39 (m, 2 H), 3.65 (s,
3 H), 3.70 (s, 3 H), 3.40 (br s, 1 H), 5.15 (br s, NH). IICT
Commun. No: 01/x/10.
1
3
3
H), 1.43 (s, 9 H), 3.75 (s, 3 H), 3.80 (dd, 1 H, J = 5.8, 13.7
Synlett 2002, No. 3, 468–470 ISSN 0936-5214 © Thieme Stuttgart · New York