Hg cathode-free electrochemical detosylation of N,N-disubstituted p-toluenesulfonamides: mild, efficient, and selective removal of N-tosyl group

Article abstract of DOI:10.1016/j.tetlet.2009.11.056

Hg cathode-free electrochemical detosylation of N,N-disubstituted p-toluenesulfonamides was successfully carried out by a constant current electrolysis using an undivided cell equipped with a platinum cathode and a magnesium anode in the presence of an arene mediator. The deprotection proceeded efficiently and selectively under neutral and mild conditions with a stoichiometric amount of electricity without the use of an Hg cathode to obtain the corresponding secondary amines in good to excellent yields.

Full text of DOI:10.1016/j.tetlet.2009.11.056

Tetrahedron Letters 51 (2010) 435–438
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Tetrahedron Letters
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Hg cathode-free electrochemical detosylation of N,N-disubstituted
p-toluenesulfonamides: mild, efficient, and selective removal of N-tosyl group
*
Hisanori Senboku , Kazuo Nakahara, Tsuyoshi Fukuhara, Shoji Hara
Laboratory of Organic Reaction, Division of Chemical Process Engineering, Graduate School of Engineering, Hokkaido University, Sapporo 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Hg cathode-free electrochemical detosylation of N,N-disubstituted p-toluenesulfonamides was success-
fully carried out by a constant current electrolysis using an undivided cell equipped with a platinum cath-
ode and a magnesium anode in the presence of an arene mediator. The deprotection proceeded efficiently
and selectively under neutral and mild conditions with a stoichiometric amount of electricity without the
use of an Hg cathode to obtain the corresponding secondary amines in good to excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 14 September 2009
Revised 9 November 2009
Accepted 13 November 2009
Available online 18 November 2009
Arenesulfonyl groups, particularly a p-toluenesulfonyl (tosyl,
Ts) group, are useful and important protecting groups for primary
and secondary amines and have been widely used for organic
transformations.1 Due to the stability of the resulting arenesulf-
onamides, desulfonylation reaction is frequently troublesome and
harmful reagents or harsh reaction conditions have been required
for reproducing amine function. Desulfonylation of benzene- or p-
toluenesulfonamides has been classically performed by using re-
agents such as strong acids,2 sodium or lithium metal in liquid
ammonia,2a,3 sodium amalgam,4 and sodium naphthalenide and
the related arenides.2b,5 Various efforts have been made to improve
the utilities of arenesulfonyl groups as protecting groups. For
example, efforts have been made to modify arenesulfonyl groups
to make the resulting amides more labile. Consequently, 2- or 4-ni-
tro-,6 2,4-dinitro-,7 and electron-donating group-substituted ben-
zenesulfonyl groups,8 2,2,5,7,8-pentamethylchloman-6-sulfonyl
group9 and heteroarene-2-sulfonyl groups10 were developed as
alternative arenesulfonyl groups. Efforts have also been made to
develop new and efficient methods for desulfonylation of conven-
tional benzene- and p-toluenesulfonamides under milder condi-
tions than the classical conditions. Several reagents such as
Bu3SnH/AIBN,11 SmI2,12 TMSI,13 TiCl4/Zn,11b TiCl4/mischmetal,14
TiCl3/Li,15 Mg/MeOH,16 Me3CoLi, Me3FeLi and Me3MnLi with
Mg,17 Ni(0)acac/i-PrMgCl,18 photolysis,19 TBAF,20 phase-transfer
catalyst,21 alkali metals on silica gel,22 and microwave irradiation
in the presence of acid23 were found to be applicable for desulfony-
lation. However, many of these reagents were effective only for
arenesulfonamides having an activating group such as a phenyl,
acyl, and Boc group on nitrogen, and were ineffective for stable
amides such as N,N-dialkyltosylamides. Electrochemical reduction
of tosylamides is also known to be a useful method for detosylation
under mild conditions and has been extensively studied.2a,10a,24,25
However, in most cases the electrolysis has been performed by
using mercury as a cathode and/or a divided cell. The use of mer-
cury is unfavorable nowadays from the viewpoint of green chem-
istry and a divided cell sometimes gives rise to complications in
choice of diaphragm and its structure. The divider usually increases
the cell resistance and the power loss (dissipated as heat) in the
cell sometimes causes the problem of undesirable reactions taking
place at the counter electrode. Therefore, powerful, efficient, and
selective detosylation under mild conditions without harmful
and toxic reagents has been still desirable. During the course of
our studies on electrochemical reduction in organic transforma-
tions,26 we recently found that electrolysis of N,N-disubstituted
tosylamides using an undivided cell, which is easier to construct
and to apply to large-scale synthesis, in the presence of an arene
mediator resulted in efficient detosylation of the amides without
the use of a mercury electrode to obtain secondary amines in high
yields. In this communication, we report mild, efficient, and Hg
electrode-free electrochemical detosylation of N,N-disubstituted
tosylamides in the presence of an arene mediator.
A constant current electrolysis of N,N-dihexyltosylamide (1a)
was carried out in DMF containing 0.1 M Et4NBr as a supporting
electrolyte by using a test tube-like undivided cell equipped with
a platinum plate cathode and a magnesium rod anode. The results
of optimization of reaction conditions are partly shown in Table 1.
Electrolysis of 1a with a stoichiometric amount of electricity (2 F/
mol) without any mediator gave dihexylamine (2) in 77% yield
along with 13% of recovered 1a (Table 1, entry 1). The yield of 2 in-
creased to 87% when 5 F/mol of electricity was passed. However, a
trace amount of 1a remained (Table 1, entry 2). On the other hand,
1a was consumed completely with 2 F/mol of electricity and amine
2 was obtained in 88% yield when the electrolysis was carried out
in the presence of 1.0 equiv of naphthalene as an electron-transfer
mediator (Table 1, entry 3). Even 0.5 equiv of naphthalene effec-
tively played a role of mediator to give 2 in 90% yield (Table 1, en-
try 4). Biphenyl was also usable as a mediator, though there was a
* Corresponding author. Tel./fax: +81 11 706 6555.
E-mail address: senboku@eng.hokudai.ac.jp (H. Senboku).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.056

436
H. Senboku et al. / Tetrahedron Letters 51 (2010) 435–438
Table 1
Table 2
Optimization of reaction conditions
Scope of Hg cathode-free electrochemical detosylation
R1
R2
R1
R2
Hex
Hex
Hex
Hex
Pt
Mg
Pt
Mg
N
Ts
N
H
N
Ts
N
H
0.1 M Et4NBr - DMF
5 mA/cm2, 2 F/mol, 0 ºC
naphthalene (0.5 equiv.)
0.1 M Et4NBr - DMF
5 mA/cm2, 0 ºC
mediator
3
4
1a
2
Entry
1
Substrate, product, and yielda
Entry
Mediator (equiv)
Electricity (F/mol)
Yielda (%)
1
2
3
4
5
—
—
2.0
5.0
2.0
2.0
3.0
77b
87
88
90
80
3a; X = Ts
96%
Naphthalene (1.0)
Naphthalene (0.5)
Biphenyl (0.5)
N
X
4a; X = H
3b; X = Ts
4b; X = H
a
All reactions were performed on a 1 mmol scale. The yields refer to isolated
amine 2.
90%
2
3
N
X
b
Amide 1a was recovered in 13% yield.
3c; X = Ts
4c; X = H
97%
87%
slight decrease in the yield (Table 1, entry 5). Although pyren25j
and anthracene25g have already been used as an electron-transfer
mediator in electrochemical detosylation, naphthalene, and biphe-
nyl are more convenient and also works as a mediator. These re-
sults indicated that neither a mercury electrode nor a divided
cell is critical for the efficient electrochemical detosylation. We
also found that detosylation can be accomplished more easily
and friendly than a conventional method by using the present elec-
trochemical detosylation. It should also be noted that naphthalene,
used as an electron-transfer mediator, could be recovered quanti-
tatively by usual work up including extraction followed by column
chromatography on silica gel, and could also be reused as a
mediator.
Desulfonylation of other representative arenesulfonamides was
next investigated, and the results are summarized in Scheme 1. A
similar electrolysis of benzenesulfonamide 1b with 2 F/mol of elec-
tricity gave deprotected amine 2 in 88% yield. In the case of 4-
bromobenzenesulfonamide (brosylate) 1c, probably due to com-
petitive reduction with a C–Br bond, 6 F/mol of electricity was nec-
essary for consumption of amide 1c to obtain 2 in 78% yield. These
results also showed that the present desulfonylation is effective for
benzene- and 4-bromobenzenesulfonamides.
N
X
O
3d; X = Ts
4d; X = H
4
N
X
MeO
MeO
3e; X = Ts
4e; X = H
3f; X = Ts
5b
84%
N
X
Me
6b
7
N
82%
80%
90%
X
11
4f; X = H
3g; X = Ts
Bu
Bu
Bu
N
4g; X = H
3h; X = Ts
X
Bu
8
N
4h; X = H
X
THPO
PivO
4
9
N
X
11
3j; X = Ts
4j; X = H
4
70%
10
N
X
11
The results of the present electrochemical detosylation of vari-
ous N,N-disubstituted tosylamides 3 are shown in Table 2. In all
cases, detosylation proceeded efficiently under neutral and mild
conditions to afford the corresponding secondary amines 4 in good
to excellent yields. Thus, dicyclohexylamine (4a), tetrahydroquino-
line (4b), indole (4c), and 3,4-dihydro-2H-1,4-benzoxazine (4d)
were obtained in 96%, 90%, 97%, and 87% yields, respectively, from
the corresponding tosylamides 3a, 3b, 3c, and 3d (Table 2, entries
1–4). When electrolysis of N-tosyltetrahydroisoquinoline (3e) and
N-dodecyl-N-methyltosylamide (3f) was carried out in DMF under
similar conditions, detosylation also took place efficiently and
amines were surprisingly obtained as the corresponding forma-
mides.27 Instead of DMF, the use of acetonitrile as a solvent re-
sulted in exclusive formation of 4e and 4f in 84% and 82% yields,
Ph
3k; X = Ts
11b,c
12d
13c
94%
71%
N
Ph
X
4k; X = H
3l; X = Ts
Boc
N
X
11
4l; X = H
Ts
N
3m; X = Ts
4m; X = H
X
95%
11
a
All reactions were performed on a 1 mmol scale. The yields refer to isolated
amine 4.
b
Instead of DMF, acetonitrile was used as a solvent.
2.5 F/mol of electricity was passed.
Electrolysis was carried out in the presence of 1.0 equiv of naphthalene.
c
d
Hex
Hex
Hex
O
Hex
O
N
H
N
S
respectively (Table 2, entries 5 and 6). N-Tosylaziridines 3g and
3h could also be deprotected efficiently without isomerization of
the stereochemistry and ring opening to give cis- and trans-dialky-
laziridines 4g–h in 80% and 90% yields, respectively (Table 2, en-
tries 7 and 8). Chemoselective detosylation was also achieved by
using tosylamides 3i–l having a functional group such as tetrahy-
dropyranyl ether, pivalate, N-benzyl or N-Boc group to afford func-
tionalized amines 4i–l in good yields (Table 2, entries 9–12).
Notably, selective mono-detosylation of N-dodecyl-di-tosylamide
Pt
Mg
0.1 M Et4NBr - DMF
2
5 mA/cm2, 0 ºC
naphthalene (0.5 equiv.)
1a: R = Me
1b: R = H
1c: R = Br
90% from 1a (2 F/mol)
88% from 1b (2 F/mol)
78% from 1c (6 F/mol)
R
Scheme 1. Desulfonylation of arenesulfonamides.

H. Senboku et al. / Tetrahedron Letters 51 (2010) 435–438
437
present selective
present
detosylation
R1
R2
H
Ts
R1
H
mono-detosylation
alkylation
with
1-X
alkylation
with
2-X
N
Ts
N
Ts
N
R
R
H
A
B
C
Scheme 2. New protocol for the synthesis of N,N-dialkylamine.
H
N
H
N
H
N
H
N
Pt
Mg
Ts
N
Ts
Ts
Ts
N
H
Ts
0.1 M Et4NBr - DMF
5 mA/cm2, 3 F/mol, 0 ºC
naphthalene (0.5 equiv.)
93% conversion
5
6
66%
(71% based on reacted 5)
Scheme 3. Selective detosylation of triamide 5.
2. (a) Roemmele, R. C.; Rapoport, H. J. Org. Chem. 1988, 53, 2367; (b) Alonso, D. A.;
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(3m) was found to proceed efficiently under similar conditions to
give N-dodecyltosylamide (4m) in 95% yield (Table 2, entry 13).
It has been shown that mono-detosylation of N-alkyl-di-tosyla-
mides required harsh reaction conditions,28 whereas mono-
detosylation of N-aryl derivatives could take place under relatively
mild conditions.20b,29 The present method enables selective mono-
detosylation of N-alkyl-di-tosylamides under neutral and quite
mild conditions without a mercury electrode to afford N-alkylto-
sylamides in high yields. These accomplishments of detosylation
should enable the establishment of a new general protocol for
the synthesis of N,N-dialkylamines as shown in Scheme 2. Thus,
alkylation of a commercial ditosylamide A gives N-alkyl-di-tosyla-
mide, which can be selectively mono-detosylated by the present
method (entry 13 in Table 2) to give N-alkyltosylamide B. Succes-
sive alkylation of the resulting B gives N,N-dialkyltosylamide,
which can also be detosylated by the present method (entry 6 in
Table 2) to produce N,N-dialkylamine in high yield.
Finally, selective detosylation of N,N-disubstituted tosylamide
in the presence of N-mono-substituted tosylamide was attempted,
and the results are shown in Scheme 3. Electrolysis of triamide 5 in
the presence of 0.5 equiv of naphthalene with 3.0 F/mol of electric-
ity30 resulted in selective detosylation of disubstituted tosylamide
to give a high yield of amino ditosylamide 6, which is a useful com-
ponent for the synthesis of polyaza macrocycles and was prepared
by four steps.31 By using the present method, 6 could be prepared
from commercially available 5 in one step. Moreover, it should be
noted that this selective detosylation cannot be achieved by re-
ported conventional methods.
In conclusion, Hg cathode-free electrochemical detosylation has
been accomplished under neutral and mild conditions. Efficient
detosylation of N,N-disubstituted tosylamides was successfully
carried out by a constant current electrolysis using an undivided
cell equipped with a Pt cathode and an Mg anode in the presence
of naphthalene as an electron-transfer mediator. The present
method also enabled selective detosylation of N,N-disubstituted
tosylamide in the presence of N-mono-substituted tosylamides.
Consequently, it should become a powerful tool for synthesis of
various nitrogen-containing organic compounds.
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Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.11.056.
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