Efficient and selective cleavage of the t-butoxycarbonyl group from di-t-butylimidodicarbonate using catalytic bismuth(III) bromide in acetonitrile

Article abstract of DOI:10.1016/j.tetlet.2009.06.104

Di-t-butylimidodicarbonates can be chemoselectively and efficiently deprotected to the corresponding mono-BOC-protected amines in high yields using a catalytic amount of bismuth(III) bromide in acetonitrile at room temperature. This method is mild and compatible with the presence of a wide range of functional and other protecting groups in the substrates, such as TBDMS, MOM and mono-BOC or Cbz-protected amines, etc. The method has advantages of ease of operation and use of nontoxic and inexpensive catalyst.

Full text of DOI:10.1016/j.tetlet.2009.06.104

Tetrahedron Letters 50 (2009) 5094–5097
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient and selective cleavage of the t-butoxycarbonyl group from
di-t-butylimidodicarbonate using catalytic bismuth(III) bromide in acetonitrile
Jianlong Zheng a, Biaolin Yin b, Wenming Huang a, Xiaopeng Li a, Hequan Yao c, Zhaogui Liu a,
Jiancun Zhang a, Sheng Jiang a,
*
a Laboratory of Regenerative Biology, Guangzhou Institute of Biomedicine and Health, CAS, Guangzhou, Guangdong 510663, PR China
b School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, Guangdong 510640, PR China
c School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 210009, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Di-t-butylimidodicarbonates can be chemoselectively and efficiently deprotected to the corresponding
mono-BOC-protected amines in high yields using a catalytic amount of bismuth(III) bromide in acetoni-
trile at room temperature. This method is mild and compatible with the presence of a wide range of func-
tional and other protecting groups in the substrates, such as TBDMS, MOM and mono-BOC or Cbz-
protected amines, etc. The method has advantages of ease of operation and use of nontoxic and inexpen-
sive catalyst.
Received 11 March 2009
Revised 12 June 2009
Accepted 19 June 2009
Available online 25 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The strategy to protection and deprotection of a functional
group plays an important role in multi-step synthesis of many
complex natural products and pharmaceutical intermediates.
Among various amine-protecting groups, the t-butoxycarbonyl
group is one of the most widely used amine-protecting groups dur-
ing the synthesis of amino acids, peptides, and other biologically
interesting molecules, due to its chemical stability over a pH range
and its ease of removal under specific conditions.1 Di-t-butylimid-
odicarbonates are very useful as phthalimide substitutes in Mits-
unobu2 and Gabriel-type processes3 in the synthesis of several
bioactive molecules and are found to be essential to the success
of the reaction.4 Typical conditions for acid-catalyzed removal of
the t-BOC include conc. HCl5a or HBr,5b trifluoroacetic acid/DCM,5c
Mg(ClO4)2,5d,4f indium, or zinc/refluxing methanol.5e However,
many of these reaction conditions involve strong acids, corrosive
reagents, or elevated temperatures which are difficult to handle
especially on a large scale.
Recently, considerable effort has been focused on developing
mild, selective methods for the removal of BOC group from di-t-
butylimidodicarbonate. Several methods have been reported for
cleaving BOC group from di-t-butylimidodicarbonate under nearly
neutral conditions, wherein mild Lewis acids are often adopted in-
stead of strong acids. For example, CeCl3ꢀ7H2O–NaI in acetonitrile
and Montmorillonite K-10 in CH2Cl2 can deprotect BOC group from
di-t-butylimidodicarbonate efficiently.6 Bismuth(III) reagents are
specially attractive since they have suitable acidity, and are non-
toxic, easy to handle, and are inexpensive, thereby making the pro-
cess economically viable and environmentally benign.7
We report herein that bismuth(III) bromide in acetonitrile is a
highly efficient catalytic system and practical method for selective
deprotection of a N-Boc group in N-Boc-N-acyl-protected amines
and a-amino acids, and leaves simple BOC-protected amines with-
out any detectable racemization.8 Since very few mild methods ex-
ist for the selective deprotection of BOC group from di-t-
butylimidodicarbonate, we examined the use of this system on a
variety of other functionalities. We found that the method was
highly efficient and easy to apply. Furthermore, chemoselective
deprotection of BOC group was achieved in the presence of other
functional protecting groups, such as TBMDS, MOM, and mono-
BOC and Cbz. The reaction proceeded very smoothly in acetonitrile
with a catalytic amount of bismuth(III) bromide at room tempera-
ture (Scheme 1).9
As shown in Table 1, deprotection of the BOC group from di-t-
butylimidodicarbonate was achieved in excellent yields, leaving
simple BOC-protected amines unaffected (entries a–j) and afford-
ing the corresponding N-Boc amino derivatives. The procedure
was found to be highly general. When another carbamoyl-based
protecting group, such as Cbz, was used, the cleavage of the Boc
group was accomplished cleanly and selectively, yielding the cor-
NHBoc
OCH3
N(Boc)2
OCH3
BiBr3 (10 mol%)
MeCN, rt
R
R
O
O
* Corresponding author. Tel.: +86 20 32290439; fax: +86 20 32290606.
E-mail address: jiang_sheng@gibh.ac.cn (S. Jiang).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.104

J. Zheng et al. / Tetrahedron Letters 50 (2009) 5094–5097
5095
Table 1
Selective removal of BOC from BOC-protected amides using BiBr3 in MeCN
Entrya
Substrate (1)
Time (h)
Conditionsb
A
Product (2)
Yieldc (%)
82
O
O
a
2
N(Boc)2
NHBoc
OMe
EtO
Ph
EtO
O
O
b
12
A
86
OMe
N(Boc)2
Ph
NHBoc
N(Boc)2
OMe
NHBoc
OMe
c
2
2
A
A
90
94
O
O
O
O
MeO
MeO
d
OMe
N(Boc)2
OMe
NHBoc
O
O
O
O
e
2
A
A
A
A
A
A
88
83
83
93
90
87
OMe
N(Boc)2
OMe
NHBoc
O
O
f
2
OMe
N(Boc)2
OMe
NHBoc
N(Boc)2
OMe
NHBoc
OMe
MeO
O
MeO
O
g
h
i
2
O
O
O
O
O
O
OCH3
OCH3
NHBoc
24
12
2
N(Boc)2
N
H
N
H
S
S
OEt
OEt
(Boc)2N
BocHN
N
N
O
O
O
O
S
S
j
OMe
OMe
N(Boc)2
NHBoc
O
O
k
l
2
3
A
A
83
93
TBSO
OMe
N(Boc)2
O
TBSO
OMe
NHBoc
O
MOMO
OMe
N(Boc)2
MOMO
OMe
NHBoc
(continued on next page)

5096
J. Zheng et al. / Tetrahedron Letters 50 (2009) 5094–5097
Table 1 (continued)
Entrya
Substrate (1)
Time (h)
Conditionsb
Product (2)
Yieldc (%)
O
O
m
n
o
p
q
r
2
A
81
BocS
OMe
N(Boc)2
HS
HO
OMe
NHBoc
O
O
12
12
12
12
2
B
B
B
B
A
A
82
89
70
78
93
96
OMe
N(Boc)2
OM
NHBoc
HO
OH
OH
N(Boc)2
NHBoc
O
O
HO
OMe
N(Boc)2
HO
OMe
NHBoc
O
O
MeO
MeO
OMe
NCbzBoc
OMe
NHCbz
O
O
N(Boc)2
NHBoc
O
O
s
1
N(Boc)2
NHBoc
a
All substrates and products were fully characterized by spectroscopic methods.
(A) CH3CN, room temperature; (B) CH3CN, 65 °C.
Isolated yields.
b
c
responding N-Cbz amino derivative (entry q). TBDMS (entry k) and
MOM (entry l) groups, which are highly acid sensitive groups, were
also stable under this reaction conditions. However, the Boc group
of Cys (entry m) was simultaneously cleaved using this protocol.
When a hydroxyl group is present in the substrate, the reactions
need to proceed with longer time and higher temperature (entries
n–p), which was reasoned that this behavior is presumably related
to the chelate complex of hydroxyl with bismuth(III) ion. In addi-
tion, the cleavage of the mono Boc group from N,N-di-Boc-pro-
tected benzylamine and aromatic amine was achieved with high
selectivity and good yield (entries r and s). The reaction rate de-
creased when the preferred solvent (MeCN) was replaced with
CH2Cl2. Significant quantities of unreacted starting materials were
indicated by TLC monitoring. It is noteworthy that the reaction
could be accelerated by a catalytic amount of H2O, and could be re-
duced to 1 h or shorter. However, under these conditions the reac-
tion system is weakly acidic. It should be emphasized that in most
cases virtually pure samples were obtained after simple filtration
and removal of solvents.
thereby leaving acid- and base-labile protecting groups intact.
Advantages of this method include the simplicity of the procedure
and the use of inexpensive, nontoxic catalyst.
Acknowledgments
This project was supported by the National Natural Science
Foundation (Grant No. 20802078), National Basic Research Pro-
gram of China (973 Program, Grant No. 2009CB940900), the
Guangdong Natural Science Foundation (Grant No. 8151066
302000008), and NN-CAS Research Foundation (Grant No.
NNCAS-2008-8).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.104.
In summary, we have demonstrated that the use of catalytic
(10 mol %) amount of bismuth(III) bromide in acetonitrile at room
temperature provides a mild and effective protocol for selective
cleavage of a Boc group in N-Boc-N-acyl-diprotected amines in
high yield. This reagent system operates under neutral conditions
References and notes
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.

J. Zheng et al. / Tetrahedron Letters 50 (2009) 5094–5097
5097
2. (a) Koppel, I.; Koppel, J.; Degerback, F.; Grehn, L.; Ragnarsson, U. J. Org. Chem.
1991, 56, 7172; (b) Henry, J. R.; Marcin, L. R.; McIntosh, M. C.; Scola, P. M.; Harris,
G. D.; Weinreb, S. M. Tetrahedron Lett. 1989, 30, 5709; (c) Campbell, J. A.; Hart, D.
J. J. Org. Chem. 1993, 58, 2900.
3. (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.
temperature for 0.5 h. Then water (0.36 mmol) was added, the reaction mixture
was stirred at room temperature until all starting material had disappeared, and
was then quenched by adding 1 ml of saturated aqueous NaHCO3. The layers
were separated, and the aqueous layer was extracted with ethyl acetate
(2 ꢁ 20 mL). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo to afford pure mono-BOC-
4. (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; (d) Jia, Y.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2007, 9, 2401; (e) Padrón, J.
M.; Kokotos, G.; Martín, T.; Markidis, T.; Gibbons, W. A.; Martín, V. S.
Tetrahedron: Asymmetry 1998, 9, 3381–3394; (f) Burkhart, F.; Hoffmann, M.;
Kessler, H. Angew. Chem., Int. Ed. 1997, 36, 1191.
5. (a) Carpino, L. A. J. Org. Chem. 1964, 29, 2820; (b) Allan, R. D.; Johnston, G. A.;
Kazlauskas, R.; Tran, H. W. J. Chem. Soc., Perkin Trans. 1 1983, 2983; (c) Brosse, N.;
Pinto, M.-F.; Gregoire, B.J. Tetrahedron Lett.2000, 41, 205; (d)Stafford, J. A.;Brackeen,
M. F.; Karanewsky, D. S.; Valvano, N. L. Tetrahedron Lett. 1993, 34, 7873; (e) Yadav, J.
S.; Reddy, B. V. S.; Reddy, K. S.; Reddy, K. B. Tetrahedron Lett. 2002, 43, 1549.
6. (a) Yadav, J. S.; Reddy, B. V. S.; Reddy, K. S. Synlett 2002, 468; (b) Hernández, J. N.;
Crisóstomo, F. R. P.; Martín, T.; Martín, V. S. Eur. J. Org. Chem. 2007, 5050.
7. (a) Nicholas, M. L.; Laura, C. W.; Ram, S. M. Tetrahedron 2002, 58, 8373–8397; (b)
Cong, X.; Hu, F.; Liu, K.-G.; Liao, Q.-J.; Yao, Z.-J. J. Org. Chem. 2005, 70, 4514.
protected amine. Spectroscopic data of 1b: ½a D25
ꢂ
ꢃ89.3 (c 0.7, CHCl3); (lit.,5e a 2D5
½ ꢂ
ꢃ90.3 (c 0.7, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.27–7.16 (m, 5H), 5.13 (dd,
J = 10.3, 4.9 Hz, 1H), 3.73 (s, 3H), 3.41 (dd, J = 14.0, 4.9 Hz, 1H), 3.19 (dd, J = 14.0,
10.4 Hz, 1H), 1.37 (s, 18H) ppm. 2b: ½a D25
ꢂ
+60.0 (c 0.8, CHCl3); (lit.,5e a 2D5
½ ꢂ +44.3 (c
1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d 7.33–7.13 (m, 5H), 4.98 (d, J = 5.3 Hz,
1H), 4.59 (d, J = 6.0 Hz, 1H), 3.71 (s, 3H), 3.08 (m, 2H), 1.42 (s, 9H) ppm. 1g: ½a D25
ꢂ
ꢃ36.5 (c 2.2, CHCl3); (lit.,5e
½
a 2D5
ꢂ
ꢃ37.2 (c 3.5, CHCl3); 1H NMR (400 MHz,
CDCl3):d 4.93 (dd, J = 9.6, 4.8 Hz, 1H), 3.71 (s, 3H), 3.67 (s, 3H), 2.49–2.39 (m,
3H), 2.18 (m, 1H), 1.49 (s, 18H) ppm. 2g: ½a D25
ꢂ
+12.8 (c 2.0, CHCl3), 1H NMR
(400 MHz, CDCl3): d 5.13 (br s, 1H), 4.31 (br s, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 2.39
(m, 2H), 2.14 (m, 1H), 1.92 (m, 1H), 1.41 (s, 9H) ppm. Compound 1i: ½a D25
ꢂ
+3.6 (c
1.0, CH3OH); 1H NMR (400 MHz, CDCl3): d 8.10 (s, 1H), 5.73 (q, J = 7.0 Hz, 1H),
4.40 (q, J = 7.0 Hz, 2H), 1.85 (d, J = 6.8 Hz, 3H), 1.46 (s, 18H), 1.26 (t, J = 7.0 Hz,
3H) ppm. Compound 2i: ½a D25
ꢂ
+40.7 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3): d
8.08 (s, 1H), 5.20 (br s, 1H), 5.10 (br s, 1H), 4.41 (q, J = 7.0 Hz, 2H), 1.62 (d,
J = 6.8 Hz, 3H), 1.38 (s, 9H), 1.29 (t, J = 7.0 Hz, 3H) ppm. Compound 1j: ½a D25
ꢂ
8. Comparative analysis of N-Boc-protected
a
-amino acids and similar materials
ꢃ39.0 (c 2.8, CHCl3); (lit.,5e
½
a 2D5
ꢂ
ꢃ35.57 (c 1.0, CHCl3); 1H NMR (400 MHz,
obtained by the di-t-butylimidodicarbonate and further N-Boc cleavage
sequence using the present methodology provided compounds with identical
specific rotations.
CDCl3): d 5.04 (dd, J = 8.6, 5.3 Hz, 1H), 3.70 (s, 3H), 2.54 (m, 2H), 2.45 (m, 1H),
2.13 (m, 1H), 2.10 (s, 3H), 1.48 (s, 18H) ppm. Compound 2j: ½a D25
ꢂ
+23.1 (c 0.8,
CHCl3); (lit.,5e a D25 +24.3 (c 2.8, CHCl3); 1H NMR (400 MHz, CDCl3): d 5.11 (br s,
½ ꢂ
9. Experimental procedure:
A
mixture of di-BOC derivative (3.3 mmol) and
1H), 4.41 (br s, 1H), 3.8 (s, 3H), 2.53 (t, J = 7.5 Hz, 2H), 2.14 (m, 1H), 2.10 (s, 3H),
bismuth(III) bromide (0.33 mmol) in acetonitrile (10 mL) was stirred at room
1.93 (m, 1H), 1.44 (s, 9H) ppm.