A mild method for cleavage of N-Tos protected amines using mischmetal and TiCl4

Article abstract of DOI:10.1016/j.tetlet.2007.12.098

The para-toluenesulfonyl (Tos) protecting group is removed efficiently and quickly under neutral conditions from the corresponding protected primary and secondary amines using mischmetal in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2007.12.098

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1373–1375
A mild method for cleavage of N-Tos protected
amines using mischmetal and TiCl4
Eerold Vellem a¨ e, Oleg Lebedev, Uno M a¨ eorg *
Institute of Organic and Bioorganic Chemistry, University of Tartu, Jakobi 2, 51014 Tartu, Estonia
Received 20 September 2007; revised 10 December 2007; accepted 18 December 2007
Abstract
The para-toluenesulfonyl (Tos) protecting group is removed efficiently and quickly under neutral conditions from the corresponding
protected primary and secondary amines using mischmetal in moderate to excellent yields.
Ó 2007 Elsevier Ltd. All rights reserved.
4
Keywords: Amines; Mischmetal; TiCl ; Tos; Deprotection
8
9
1
. Introduction
Sulfonamides, including para-toluenesulfonamide, are
HClO in AcOH, HF–pyridine in anisole, 48% HBr and
4
1
0
phenol and 30% HBr in AcOH.
Thus, classical deprotection methods requiring harsh
reaction conditions cannot be considered as convenient
for cleavage of the Tos group. To prevent side reactions,
several new methods have been reported in recent years
wherein the Tos group has been cleaved under mild condi-
tions using the following approaches: Li–naphthalenide in
1
one of the most stable and widely used protecting groups
for reactive NH groups in organic synthesis. This group is
stable under various experimental conditions such as cata-
lytic hydrogenation and treatment with acids, bases or
reductants commonly used for the removal of other pro-
tecting groups. This stability contributes to its usefulness,
but also makes it difficult to remove.
Most often, to remove the Tos protecting group, a solu-
tion of metallic sodium or, alternatively, a solution of lith-
ium in liquid ammonia is necessary. Consequently, with
such drastic conditions being used, serious side reactions
have been reported and the yields of regenerated com-
pounds with free NH group(s) are sometimes poor. The
Tos group has also been cleaved by employing NaAl-
1
1
12
13
THF, Li and di-t-butylbiphenyl in THF, Na in IPA,
2
14
15
Mg in MeOH with sonication, Na(Hg) in MeOH and
1
6
Li/TiCl in THF.
3
Most of these methods still utilize alkali metals or highly
reactive compounds such as LiAlH , which do not tolerate
3
,4
4
molecules that include easily reducible moieties. Moreover,
to complete the deprotection reaction without significant
formation of side products, these methods typically require
cooling of the reaction mixture—Li–naphthalenide or Li
with di-t-butylbiphenyl in THF, need to be cooled to
À78 °C; alternatively, they need high temperatures and/
or long reaction times to accomplish the deprotection.
For example, when using NaAlH (OCH CH OCH ) for
5
6
H (OCH CH OCH ) or LiAlH in toluene. Another
2
2
2
3
4
1
1
widely used strategy for cleavage of the Tos group is based
on acid hydrolysis, however, this requires a high concentra-
tion of mineral acid at elevated temperatures for extended
2
2
2
3
7
periods of time. These approaches include HBr and P,
Tos cleavage, the reaction requires approximately 20 h at
6
reflux in toluene. Some of the recently reported methods
allowing removal of the Tos group at room tempera-
ture require long reaction times for complete cleavage.
*
Corresponding author. Tel.: +372 7 375243; fax: +372 7 375245.
E-mail address: uno@chem.ut.ee (U. M a¨ eorg).
For example, when using Li and TiCl in THF it takes
3
0
040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.098

1374
E. Vellem a¨ e et al. / Tetrahedron Letters 49 (2008) 1373–1375
1
6
approximately 18 h in THF at room temperature.
Another method that allows rapid removal of the Tos
mately 6 equiv of mischmetal and 4.9 equiv of TiCl were
4
used (Table 1, entry 10).
1
4
group at room temperature has also been reported. How-
ever, this procedure can only be used when another activat-
ing protecting group like Boc, Z or Ac is present at the
same nitrogen and does not work with simple Tos-pro-
Having optimized the deprotection conditions, various
Tos-protected aromatic amines, aliphatic amines, hydra-
zines and amino acids were prepared according to modified
methods published previously and subjected to the depro-
tection reaction using the conditions described above
(Table 1, entry 10). The results are outlined in Table 2. It
can be seen that the reaction proceeded smoothly to furnish
the corresponding amines or other compounds generally, in
good to excellent yields.
2
0
1
4,17
tected aromatic and aliphatic amines.
Recently, numer-
ous papers have been published where lanthanides and
1
8
their salts have been adapted for use in organic synthesis,
1
9
including Tos group cleavage. Regardless of the good
yields with some of the previous methods, some reagents
1
9
15
employed are rather expensive (SmI2) or toxic (Na/Hg).
When employing the MM/TiCl4 system Tos group
cleavage proceeded usually within 3–4 h at reflux in THF.
Another very important advantage of this method is that
Thus, the aim of our work was to find a fast, safe, cheap
and easily reproducible method for removing the Tos
group from the corresponding protected amines, hydra-
zines and amino acids under mild conditions. Herein, we
report the results of our work where we utilize mischmetal
MM/TiCl enables Tos group cleavage from non-activated
4
or slightly activated primary and secondary aliphatic
amines and also from aromatic amines under neutral reac-
tion conditions.
1
8
(
MM), (50% Ce, 25% La, 16% Nd, 6% Pr) for this pur-
pose (Scheme 1).
We found that the activated mischmetal in THF was
capable of removing the Tos group in the presence of other
common functional groups such as MeO and Ph. However,
the cleavage was not very selective. When other widely used
protecting groups, such as Boc, Troc, Z (Cbz) and Ac
(Table 1) were present, those groups were also removed
under our reaction conditions.
We also discovered that it was possible to accelerate
cleavage of the Tos group from aromatic amines in two
ways. Acceleration was observed if the aromatic ring
included an electron donating group, such as MeO or if
the same nitrogen atom was bonded to a strong electron-
withdrawing group, such as Boc or Troc (Table 2, see
entries 3–5). Thus, it should be possible to increase the rate
of the cleavage even further if more potent electron-with-
drawing groups are present.
As the first step of optimization of this process, we
applied the same reaction conditions reported in our previ-
1
8
ous work. However, the results were not satisfactory
because the deprotection reaction usually required reflux-
ing the mixture for at least 48 h. To accelerate the reaction,
the influence of different activators were studied, for
example, TiCl , SnCl and 1,2-dibromoethane. The most
4
4
efficient Tos group cleavage was observed when approxi-
R1
O
MM/TICl4
H
N
N
S
R1
R2
reflux in dry THF
R2
O
1
R = p-CH O-C H , n-Bu, Ph, Ph-NH, Ph-CH ,p-MeO-C H -CH -CH , L-Pro
3
6
4
2
6
4
2
2
2
R = H, Boc, Troc, Me, n-Bu
The behaviour of mischmetal under these conditions is
interesting. Considering that the Tos group is generally
Scheme 1.
Table 1
Optimization of the reaction conditions
a
c
Entry
Compound
Time (h)
Activator (equiv)
Product
Conversion (%)
1
2
3
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
3
3
3
3
3
3
3
3
3
3
O–C
O–C
O–C
O–C
O–C
O–C
O–C
O–C
O–C
O–C
6
6
6
6
6
6
6
6
6
6
H
H
H
H
H
H
H
H
H
H
4
4
4
4
4
4
4
4
4
4
–NH–Tos
–NH–Tos
–NH–Tos
–NH–Tos
–NH–Tos
–NH–Tos
–NH–Tos
–NH–Tos
–NH–Tos
–NH–Tos
5
48
24
5
24
4
4
4
4
2.5
3
TMSCl (9.3)
TMSCl (18.2)
TMSCl (18.2)
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
p-CH
—
3
3
3
3
3
3
3
3
3
3
O–C
O–C
O–C
O–C
O–C
O–C
O–C
O–C
O–C
O–C
6
H
6
H
6
H
6
H
6
H
6
H
6
H
6
H
6
H
6
H
4
4
4
4
4
4
4
4
4
4
–NH
–NH
–NH
–NH
–NH
–NH
–NH
–NH
–NH
–NH
2
2
2
2
2
2
2
2
2
2
<10
>90
0
Traces
0
0
0
50
>90
>99
Dec.
Dec.
<99
<99
0
b
4
5
6
7
8
9
0
1
2
3
4
5
a
TMSCl, Br–CH
Br–CH –CH –Br (5.2)
TiCl , Br–CH –CH –Br (4.1; 5.2)
SnCl
2
–CH
2
–Br (6.1; 5.2)
2
2
4
2
2
4
(3.9)
(2.1)
(4.1)
(4.9)
(4.9)
(4.9)
(4.9)
(4.9)
TiCl
TiCl
TiCl
TiCl
TiCl
TiCl
TiCl
TiCl
4
4
4
4
4
4
4
4
1
1
1
1
1
1
d
Boc–NH–NH–Tos
Z-NH–NH–Troc
n-Bu–NH–Tos
Ph–NH–Ac
d
3
—
1.5
1.5
24
n-Bu–NH
Ph–NH
Ph–NH
2
2
Ph–NH–Ac
2
:H O (4.9:1)
2
All reactions were performed at reflux in dry THF under argon atmosphere and 6.1 equiv of MM was used.
In entry 3, 1,4-dioxane was used instead of THF.
Extent of conversion was monitored by TLC.
b
c
d
The product decomposes.

E. Vellem a¨ e et al. / Tetrahedron Letters 49 (2008) 1373–1375
1375
Table 2
Deprotection of the Tos group with mischmetal/TiCl
4
in dry THF
Reaction time (h)
a
b
Entry
Starting material
Product
Yield (isolated) (%)
1
2
3
4
5
6
7
8
9
Ph–NH–NH–Tos
Ph–NH–Tos
Ph–N(Boc)–Tos
Ph–N(Troc)–Tos
3
8
5
4
2.5
3
3
6
2.5
3
Ph–NH–NH
2
4
23
99
50
97
80
23
Ph–NH
Ph–NH
Ph–NH
2
2
2
c
6
p-MeO–C H
4
–NH–Tos
6
p-MeO–C H
–NH
2
Ph–CH
Ph–CH
Ph–CH
2
2
2
–NH–Tos
–NH–Tos
–N–(Me)–Tos
Ph–CH
Ph–CH
Ph–CH
2
2
2
–NH
–NH
2
c
2
40
–NH–Me
2 2 2
–CH –CH –NH
45
40
78
83
p-MeO–C
(n-Bu) –N–Tos
N-Tos-(L)proline
6
H
4
–CH
2
–CH
2
–NH–Tos
p-MeO–C
(n-Bu) –NH
HN(L)proline
6
H
4
1
1
0
1
a
2
2
3
The spectral data of the starting compounds in entries 1–11 are presented in the supplementary data.
Yield after purification of the crude product by column chromatography.
% NaCl was used for washing the extract instead of distilled H O.
2
b
c
5
1
1–13
removed via reductive elimination,
we propose that
Supplementary data
lanthanide chlorides formed during activation of the mis-
chmetal act as mediators in the deprotection of the Tos
group. The mischmetal essentially acts as an electron
donor. In the presence of water, these salts can be hydro-
lyzed, effectively quenching the reaction. This could be
the reason why the reaction must be conducted in a
water-free environment (Table 1, see entry 15).
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.
2007.12.098.
References and notes
In conclusion, we have described a new, mild and cheap
method for the cleavage of Tos groups by using the misch-
1
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Synthesis 1990, 925–930.
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1987, 17, 1185–1187.
4
metal/TiCl system in dry THF. The reactions are rela-
4
3
tively fast and typically provide high yields.
3
4
2
2
. Experimental
1
General procedure: 456 mg (3.2 mmol) of freshly, man-
6
7
ually filed mischmetal (from Redel–de Haen, for applica-
tions see Ref. 21) powder (grain size 0.1–0.3 mm) was
added to 10 ml of dry THF and activated with 0.24 ml
8
(
2.18 mmol) of TiCl by refluxing for 20–30 min under an
4
argon atmosphere. Then Tos-protected starting material
0.53 mmol) was added and the mixture refluxed for the
9. Oppolzer, W.; Bienayme, H.; Genovois-Borella, A. J. Am. Chem. Soc.
991, 113, 9660–9661.
0. Weisblat, D. I.; Magerlein, B. J.; Myers, D. R. J. Am. Chem. Soc.
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4. Nyasse, B.; Grehn, L.; Ragnarsson, U. Chem. Commun. 1997, 1017–
018.
15. Chavez, F.; Sherry, A. D. J. Org. Chem. 1989, 54, 2990–2992.
1
(
1
1
indicated period of time (see Table 2). The progress of
the deprotection reaction was monitored by TLC (EtOAc:
hexane, usually 2:1, the sample was neutralized with 2 M
NaOH prior to running the TLC). When the reaction
was complete, the mischmetal powder was filtered off and
the resulting filtrate was neutralized with 30 ml of 2 M
NaOH aqueous solution, stirred for 5 min and then
extracted with dichloromethane (5 Â 15 ml). The combined
organic layers were washed twice with distilled water (or
1
1
9
1
1
4
1
1
1
6. Nayak, S. K. Synthesis 2000, 1575–1578.
7. Sridhar, M.; Kumar, A.; Narender, R. Tetrahedron Lett. 1998, 39,
5
% NaCl solution) and dried over anhydrous Na SO .
2 4
The mixture was then filtered and the solvent removed by
rotary evaporation under reduced pressure. The products
were identified using GC and NMR.
2
847–2850.
1
8. Vellem a¨ e, E.; Lebedev, O.; M a¨ eorg, U. J. Chem. Res. 2006, 3, 685–687
and references therein.
1
2
9. Vedejs, E.; Lin, S. J. Org. Chem. 1994, 59, 1602–1603.
0. M a¨ eorg, U.; Pehk, T.; Ragnarsson, U. Acta Chem. Scand. 1999, 53,
Acknowledgement
1
127–1133.
1. Lannou, M. I.; H e´ lion, F.; Namy, J. L. Tetrahedron 2003, 59, 10551–
0565.
2
We thank the Estonian Science Foundation for financial
support (Grant No. 6706).
1