Efficient detachment of N-benzyl carbamate group

Article abstract of DOI:10.1055/s-2002-32986

The efficient deprotection of N-benzyl carbamate (N-Cbz) group under the mild conditions with a combination of hard Lewis acid and soft nucleophile is described.

Full text of DOI:10.1055/s-2002-32986

LETTER
1283
Efficient Detachment of N-Benzyl Carbamate Group
E
T
fficient
D
etach
a
ment of
N
-
k
B
enzyl Carb
a
amate
G
rou
s
p
hi Tsujimoto, Akio Murai*1
Division of Chemistry, Graduate School of Science, Hokkaido University, Sapporo, 060-0810, Japan
Fax +81(11)7476963; E-mail: amurai@rmail.plala.or.jp
Received 15 May 2002
al of the N-Cbz group by using 3 (Table 1). Under the
usual conditions reported,2 the deprotection had the seri-
ous problems; detachment of the PMB and/or the TBS
ether under Lewis acidic conditions (entries 2–4), and
cleavage of the lactam ring under basic hydrolysis (entries
Abstract: The efficient deprotection of N-benzyl carbamate (N-
Cbz) group under the mild conditions with a combination of hard
Lewis acid and soft nucleophile is described.
,4
Key words: protecting groups, N-benzyl carbamate, diethylalu-
minium chloride, lactams, thioanisole
6
, 7). Fortunately, when thioanisole (MeSPh) as a less vol-
atile nucleophile was replaced to Me S, the reaction pro-
2
ceeded more smoothly to afford the desired lactam 4 in an
excellent yield, and the reaction completed only in the
shorter time (entry 5).
The N-benzyl carbamate (N-Cbz) group, as protection of
N-H in amine or amide, is widely used in the synthesis of
nitrogen-containing compounds. While the N-Cbz group
2
In order to clarify the efficiency of the Et AlCl–MeSPh
of amine is usually detached by means of hydrogenolysis,
of Lewis acid, of basic hydrolysis, or under conditions
2
6
system, we applied the conditions to other substrates
2
(
Table 2). The new system was found to be actually effec-
used in removal of benzyl ethers or esters, there has been
little precedent on selective deprotection of N-Cbz group
3
of amide or lactam. The conditions in the former cases
Table 1 Attempted Deprotection of N-Cbz Group in 3
were often rather drastic to apply to the highly functional-
ized complex compounds. We have investigated an alter-
nate general approach for detachment of N-Cbz group, the
results of which are described herein.
Me
OTBS
Me
OTBS
O
H
H
BMPO
BMPO
O
N
N
H
Et2AlCl (1.5 eq), CH2Cl2
78 °C, 10 min,
O
CBZ
O
O
-
3
4
N
OBn
NH
then Me2S (5 eq),
5 °C, 4 h
90% yield
En-
try
Reagents and Conditions
Yield of 4 Recovered3
2
(%)
(%)
1
2
1
Et AlCl (1.5 equiv), CH Cl ,
72
12
2
2
2
Scheme Deprotection of N-Cbz group – an initial approach.
–
78 °C, 15 min then Me2S
(
5 equiv), 25 °C, 4 h
Fuji and co-workers reported the combination of hard
Lewis acid and soft nucleophile for the useful detachment
of benzyl ethers and esters. We expected that the biden-
2a
TiCl (1.5 equiv), CH Cl ,
29
10
18
10
37
6
4
2
2
–
78 °C, 15 min then Me2S
4
(
5 equiv), 25 °C, 1 h
AlCl (1.5 equiv), CH Cl ,
2 2
tate Lewis acid, such as diethylaluminium chloride
Et AlCl), should cause the chelation smoothly with both 3a
(
3
2
5
–78 °C, 15 min then Me2S
the caboximide carbonyl groups. Resultingly, we found
the milder conditions for removal of the N-Cbz group in
amide or lactam as an initial approach (Scheme) as fol- 4a
lows: treatment of N-Cbz protected lactam 1 with 1.5
(
5 equiv), 25 °C, 1 h
BF OEt (1.5 equiv), CH Cl , 33
3
2
2
2
–78 °C, 15 min then Me
5 equiv), 25 °C, 4 h
S
2
(
equiv of Et AlCl at –78 °C for 15 minutes, followed by
2
addition of 5–10 equiv of dimethylsulfide (Me S) as a nu-
2
5
Et AlCl (1.5 equiv), CH Cl ,
90
29
2
2
2
cleophile, and further warming to 25 °C furnishes the N-
H lactam 2 in 90% yield. As further development, we ap-
plied the same conditions to the more functionalized com-
–
78 °C, 15 min then PhSMe
(2 equiv), 25 °C, 1 h
6b
LiOH (5 equiv), THF–H
O
25
29
6
2
pound 3 (Table 1, entry 1) and provided the desired
(
4:1), 0 °C, 1 h
lactam 4 in rather lower yield (72%). Accordingly, we ex-
amined various combinations or basic reagents for remov- 7b
K CO (1 equiv), MeOH, 0 °C, 36
2
3
1
h
a
Removal of the PMB and/or TBS ethers had occurred (~20–50%).
Cleavage of the lactam ring had occurred (~30%).
Synlett 2002, No. 8, Print: 30 07 2002.
Art Id.1437-2096,E;2002,0,08,1283,1284,ftx,en;Y07302ST.pdf.
b
©
Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1
284
T. Tsujimoto, A. Murai
LETTER
Table 2 Detachment of the N-Cbz Groups of Amide or Lactams
Table 3 Detachment of the N-Cbz Groups of Amines with Et AlCl–
2
MeSPh System
with Et AlCl–MeSPh System
2
Et2AlCl (1.5 eq)
CBZ CH2Cl2, 0 °C, 1 h
Et2AlCl (1.1 eq), CH2Cl2
O
O
O
-78 °C, 10 min,
R
NH2
Bn
H
R NH
R1
R1
then PhSMe (2.5 eq)
5 °C, 5 h
N
R2
O
N
then PhSMe (2 eq),
0 °C, 1 h
2
R2
Entry
1
Carbamate
Yield (%)
81
Recovered
Carbamate (%)
Entry Carbamate
Yield (%)
Recovered
Carbamate
(
%)
O
13
N
1
O
99
ND
OMe
Ph
CBZ
CBZ
N
2
3
89
74
ND
Me
N
Ph
OH
2
3
n = 1:94
n = 2:97
n = 3:92
2
ND
1
O
CBZ
O
15
CBZ
N
Ph
(
CH2)n
OMe
95
trace
ND
NHCBZ
O
Me
CBZ
Ph
N
References
4
Me
99
(
1) Present Address: 6-14-44 Asabu-Cho, Kita-Ku, Sapporo
01-0045, Japan
0
O
(
2) Reviews: (a) Greene, T. W.; Wuts, P. G. M. In Protecting
Groups In Organic Synthesis; John Wiley and Sons, Inc.:
New York, 1999. (b) Jakowski, K.; Kocienski, P. J. Chem.
Soc., Perkin Trans. 1 2001, 2109. (c) Jakowski, K.;
N
CBZ
CBZ
5
6
97
ND
O
Kocienski, P. J. Chem. Soc., Perkin Trans. 1 2000, 2495.
(d) Jakowski, K.; Kocienski, P. J. Chem. Soc., Perkin Trans.
N
1
1999, 1589.
(
3) Hungate, R. W.; Chen, J. L.; Starbuck, K. E.; Macaluso, S.
A.; Rubino, R. S. Tetrahedron Lett. 1996, 37, 4113.
n = 1:94
n = 2:90
n = 3:98
ND
ND
ND
OTBS
O
H
(4) (a) Fuji, K.; Ichikawa, K.; Node, M.; Fujita, E. J. Org. Chem.
1979, 44, 1661. (b) Fuji, K.; Kawabata, T.; Fujita, E. Chem.
Pharm. Bull. 1980, 28, 3662. (c) Node, M.; Ohta, K.;
TBDPSO
N
CBZ
Kajimoto, T.; Nishide, K.; Fujita, E.; Fuji, K. Chem. Pharm.
Bull. 1983, 31, 4178. (d) Sánchez, I. H.; López, F. J.; Soria,
J. J.; Larraza, M. I.; Flores, H. J. J. Am. Chem. Soc. 1983,
(CH2)n
1
05, 7640.
5) Evans, D. A.; Chapman, K. T.; Bisaha, J. Tetrahedron Lett.
984, 25, 4071.
6) The respective substrates of Tables 1 and 2 were prepared by
the Diels–Alder reactions of -exomethylene lactams with
the corresponding dienes: Tsujimoto, T.; Ishihara, J.; Horie,
M.; Murai, A. Synlett 2002, 399.
(
(
tive on the selective deprotection of N-Cbz group of acyc-
1
6
7
lic amide (entry 1) or lactams (entries 2–6). In the
respective cases of more complex lactams, the deprotec-
tion proceeded to give the desired products without any
trouble (entries 3–6). Especially, even in the presence of
Lewis acid sensitive functions, the reaction provided the
desired lactams in quantitative yields, respectively (entry
(
7) General Procedure: To a stirred solution of N-benzyl
carbamate 1 (112 mg, 0.5 mmol) in CH Cl (5.0 mL) was
2
2
added a solution of Et AlCl in hexane (1.0 M solution, 0.55
2
6
). Furthermore, it is to be noted that the conditions were
mL, 0.55 mmol) at –78 °C. After 10 min, MeSPh (1.1 mmol)
was added to this mixture, and the mixture was stirred at
able to be also useful in the cases of amines capable of
causing the chelation (Table 3). While a combination of
trimethylsilyl bromide (TMSBr) and MeSPh in trifluoro-
acetic acid (CF CO H) has been known for removing the
2
5 °C for 1 h. The mixture was then diluted with Et O (5
2
mL), and washed with sat. aq NaHCO (5 mL) and sat. brine
3
(5 mL). The combined aq layers were extracted twice with
EtOAc (5 mL). The combined extracts were dried over
3
2
8
N-Cbz groups of primary and secondary amines, our new
anhyd MgSO , filtered through Celite, and concentrated in
4
system doesn't require any protonic acid.
vacuo. The residue was purified by chromatography (SiO2,
50% EtOAc–hexane) to afford -valerolactam 2 (48 mg,
0.49 mmol, 97%) as yellow solids.
Thus, our results could provide a highly effective and gen-
eral procedure for selective removal of N-Cbz group in the
molecule having the other labile functional groups.
(
8) (a) Yajima, H.; Fuji, N.; Funakoshi, S.; Watanabe, T.;
Murayama, E.; Ozaka, A. Tetrahedron 1988, 44, 805.
(
b) Schmidt, U.; Leitenberger, V.; Griesser, H.; Schmidt, J.;
Meyer, R. Synthesis 1992, 1248.
Synlett 2002, No. 8, 1283–1284 ISSN 0936-5214 © Thieme Stuttgart · New York