Application of odorless thiols for the cleavage of 2- and 4-nitrobenzenesulfonamides

Article abstract of DOI:10.1080/00397910701866098

Several odorless or faint-smelling thiols were tested to cleave 2- and 4-nitrobenzenesulfonyl groups, which are widely utilized for selective protection and activation of amines. p-Mercaptobenzoic acid (7) was found to be the most useful thiol for cleavin

Full text of DOI:10.1080/00397910701866098

This article was downloaded by: [Florida International University]
On: 31 December 2014, At: 02:16
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Application of Odorless Thiols
for the Cleavage of 2‐ and
4
‐Nitrobenzenesulfonamides
a a
a
Manabu Matoba , Tetsuya Kajimoto & Manabu Node
a
Department of Pharmaceutical Manufacturing Chemistry , Kyoto
Pharmaceutical University , Kyoto, Japan
Published online: 17 Apr 2008.
To cite this article: Manabu Matoba , Tetsuya Kajimoto & Manabu Node (2008) Application of Odorless Thiols
for the Cleavage of 2‐ and 4‐Nitrobenzenesulfonamides, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:8, 1194-1200, DOI: 10.1080/00397910701866098
To link to this article: http://dx.doi.org/10.1080/00397910701866098
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”)
contained in the publications on our platform. However, Taylor & Francis, our agents, and our
licensors make no representations or warranties whatsoever as to the accuracy, completeness, or
suitability for any purpose of the Content. Any opinions and views expressed in this publication
are the opinions and views of the authors, and are not the views of or endorsed by Taylor &
Francis. The accuracy of the Content should not be relied upon and should be independently
verified with primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities
whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or
arising out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use
can be found at http://www.tandfonline.com/page/terms-and-conditions

w
Synthetic Communications , 38: 1194–1200, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701866098
Application of Odorless Thiols
for the Cleavage of 2-
and 4-Nitrobenzenesulfonamides
Manabu Matoba, Tetsuya Kajimoto, and Manabu Node
Department of Pharmaceutical Manufacturing Chemistry, Kyoto
Pharmaceutical University, Kyoto, Japan
Abstract: Several odorless or faint-smelling thiols were tested to cleave 2- and
4
-nitrobenzenesulfonyl groups, which are widely utilized for selective protection and
activation of amines. p-Mercaptobenzoic acid (7) was found to be the most useful
thiol for cleaving the o- and p-nosyl groups in terms of ease of separation of the
product from the workup residue, reaction temperature, and reaction time.
Keywords: Deprotection, 2- and 4-nitrobenzenesulfonamides, odorless thiol
2-Nitrobenzenesulfonyl (o-Nos, o-nosyl) and 4-nitrobenzenesulfonyl (p-Nos,
p-nosyl) groups have been used for both the protection and activation of amino
groups because of facile cleavability under mild conditions and the attainabil-
[1]
ity of selective protection of diamines, which was reported to be difficult.
For example, Fukuyama and his colleagues established a new method of
synthesizing secondary amines from primary amines by taking advantage of
[
2–5]
the ambident property of the nosyl groups
the synthesis of spider venom, HO-416 and Agel-489, as well as a macro-
and applied the method to
[6]
[7]
cyclic amine, from the skin mucus of grammitid fish, lipogrammistin-A.
Received July 4, 2007
Address correspondence to Manabu Node, Department of Pharmaceutical Manufac-
turing Chemistry, 21st Century COE Program, Kyoto Pharmaceutical University, 1
Shichono-cho, Misasagi, Yamashina-ku, Kyoto 607 8412, Japan. E-mail: node@mb.
kyoto-phu.ac.jp
1
194

Thiols Cleave 2- and 4-Nitrobenzenesulfonamides
1195
Because nosyl groups remain intact under the conditions that can cleave N-car-
boalkoxy protecting groups and possess selective cleavability with thiols, the
use of nosyl groups has been spreading in organic synthesis. 2-Mercaptoetha-
nol, benzenethiol, and a-mercaptoacetic acid have been utilized as thiols to
date; however, the malodorous stench on handling thiols for the cleavage
would degrade the benefits of nosyl groups. Katsumura’s group adopted dode-
canethiol, an odorless thiol, to avoid the generation of the malodorous smell
accompanying the deprotection of the nosyl group in the synthesis of a sphin-
[
8]
gomyelin analog. Although they reported that the use of a combination of
n-dodecanethiol and sodium hydride afforded a better result than that of benze-
nethiol and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), the method of cleaving
the nosyl groups on amino groups could be made more practical and usable by
changing the combination of thiol and base. Thus, we embarked on a search for
more suitable odorless thiols to cleave nosyl groups as part of our study on the
[9–17]
development of odorless thiols in organic synthesis.
In the beginning, nosylated N-(4-methoxybenzyl)-alkylamines (1a–f)
[18]
were prepared according to Fukuyama’s procedure
and chosen as the sub-
strates for denosylation reactions. Among many odorless or faint-smelling
thiols, n-dodecanethiol (2) was first employed to cleave the o- or p-nosyl
group from 1a–f using lithium hydroxide as a base. As expected, the
reactions proceeded smoothly at room temperature to give the desired
product (3a–c) in good yield (Table 1, entries 1–6). Moreover, the substrates
1
aromatic thiol i.e., p-dodecylbenzenethiol (4)
a–f were subjected to a reaction where either an odorless or faint-smelling
or p-tert-butylbenzenethiol
5) was used instead of 2 and lithium hydroxide was replaced with a weaker
[19,20]
(
[
2]
base, potassium carbonate. (The thiols 5–7 are purchased as commercially
available chemicals.) Fortunately, the reactions provided better results than
those achieved with 2 (Table 1, entries 7–18). However, the separation of
products (3a–c) from a workup residue containing o- or p-nitrophenyl
p-alkylphenyl sulfides required tedious chromatographic procedure.
Therefore, o-mercaptobenzoic acid (6) was employed to remove the
resulting sulfides facilely by extraction with alkaline aqueous solution and
organic solvent. Because both the electron-withdrawing property and steric
hinderance of the carboxylic group at the o-position caused a decrease in
nucleophilicity of the mercapto group, the reaction required a higher tempera-
ture (60 8C) and longer time (24 h) to yield the product in higher yield than
those with 2, 4, and 5 (Table 1, entries 19–24).
Finally, p-mercaptobenzoic acid (7), having a less hindered mercapto
group than 6, was tested as the deprotection agent, although the mesomery
effect still reduced the electron density or nucleophilicity of the thiol. The
reaction afforded excellent results in the case of substrates at a lower tempera-
ture (40 8C) and shorter reaction period (12 h) than those using 6 as a reagent
to cleave the nosyl group (Table 1, entries 25–30).
In conclusion, we found that p-mercaptobenzoic acid (7) was the most
useful thiol to cleave o- and p-nosyl groups within the tested thiols in terms

Table 1. Denosylation with odorless thiols
Substrate
0
Entry
R
X
Compound
R SH
Condition
Product
Yield (%)
0
1
2
3
4
5
6
7
8
9
Bn
3-Ph-Pr
n-Pr
o-Ns
o-Ns
o-Ns
p-Ns
p-Ns
p-Ns
o-Ns
o-Ns
o-Ns
p-Ns
p-Ns
p-Ns
1a
1b
1c
1d
1e
1f
R SH (2.0 eq) LiOH H
(2.0 eq) rt, 4 h
2
O
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
94
95
99
76
68
64
95
95
94
96
91
95
Bn
3-Ph-Pr
n-Pr
Bn
0
1a
1b
1c
1d
1e
1f
R SH (1.2 eq) K
(3.0 eq) rt, 4 h
2
CO
3
3-Ph-Pr
n-Pr
Bn
1
1
1
0
1
2
3-Ph-Pr
n-Pr

0
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Bn
3-Ph-Pr
n-Pr
o-Ns
o-Ns
o-Ns
p-Ns
p-Ns
p-Ns
o-Ns
o-Ns
o-Ns
p-Ns
p-Ns
p-Ns
o-Ns
o-Ns
o-Ns
p-Ns
p-Ns
p-Ns
1a
1b
1c
1d
1e
1f
R SH (1.2 eq) K
(3.0 eq) rt, 5 h
2
CO
3
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
3a
3b
3c
96
99
93
99
94
92
94
96
94
94
96
88
91
93
90
90
92
92
Bn
3-Ph-Pr
n-Pr
Bn
0
2 3
R SH (2.0 eq) K CO
1a
1b
1c
1d
1e
1f
3-Ph-Pr
n-Pr
Bn
(4.0 eq) 60 8C, 12–16 h
3-Ph-Pr
n-Pr
Bn
0
1a
1b
1c
1d
1e
1f
R SH (2.0 eq) K CO
2
3
3-Ph-Pr
n-Pr
Bn
(4.0 eq) 40 8C, 12 h
3-Ph-Pr
n-Pr

1
198
M. Matoba, T. Kajimoto, and M. Node
of ease of separation of the product from the workup residue, reaction temp-
erature, and reaction time.
EXPERIMENTAL
General Procedure (for 1a with 7)
p-Mercaptobenzoic acid (7) (90%, 1.41 g, 8.20 mmol) and potassium
carbonate (2.27 g, 16.4 mmol) were added to a solution of nosylamide 1b
(
1.81 g, 4.10 mmol) in DMF (20 mL), and the mixture was stirred at 40 8C
for 12 h. After the reaction, the organic solvent was removed in vacuo, and
the residue was extracted with diethyl ether. The organic layer was washed
with a saturated aqueous solution of sodium chloride, dried over potassium
carbonate, and condensed in vacuo. The residue was purified by silica-gel
column chromatography (CHCl and CHCl –MeOH ¼ 10:1) to afford the
3
3
amine 3b (974 mg, 93.0%).
Data
All of the starting materials (1a–1f) and the products (3a–3c) are known
compounds; however, no data except those for 1b and 3b appear in the litera-
[
ture. Thus, H NMR spectral data for 1a, 1c–f, 3a, and 3c are given here.
2]
1
1
Compound 1a. H NMR (200 MHz, CDCl ) d 3.78 (s, 3H), 4.40 and 4.44
3
(
each s, 2H), 6.77 (d, J ¼ 8.8 Hz, 2H), 7.00 (d, J ¼ 8.8 Hz, 2H), 7.05–7.16
(
m, 2H), 7.20–7.35 (m, 3H), 7.50–7.65 (m, 1H), 7.66–7.75 (m, 2H), 7.90–
7.95 (m, 1H).
1
Compound 1c. H NMR (200 MHz, CDCl ) d 0.73 (t, J ¼ 7.6 Hz, 3H), 1.42
3
(
sextet, J ¼ 7.6 Hz, 2H), 3.17 (t, J ¼ 7.6 Hz, 2H), 3.90 (s, 3H), 4.46 (s, 2H),
6
.83 (d, J ¼ 8.8 Hz, 2H), 7.19 (d, J ¼ 8.8 Hz, 2H), 7.58–7.72 (m, 3H), 7.95–
8.05 (m, 1H).
1
Compound 1d. H NMR (200 MHz, CDCl ) d 3.78 (s, 3H), 4.34 and 4.37
3
(
each s, 2H), 6.77 (d, J ¼ 8.8 Hz, 2H), 7.00 (d, J ¼ 8.8 Hz, 2H), 7.05–7.15
m, 2H), 7.22–7.30 (m, 3H), 7.92 (d, J ¼ 9.0 Hz, 2H), 8.29 (d, J ¼ 9.0 Hz,
(
2
H).
1
Compound 1e. H NMR (200 MHz, CDCl ) d 1.68 (quintet, J ¼ 7.6 Hz, 2H),
3
2
6
7
.45 (t, J ¼ 7.6 Hz, 2H), 3.13 (t, J ¼ 7.6 Hz, 2H), 3.80 (s, 3H), 4.29 (s, 2H),
.82 (d, J ¼ 8.8 Hz, 2H), 6.92–7.02 (m, 2H), 7.12 (d, J ¼ 8.8 Hz, 2H),
.13–7.30 (m, 3H), 7.91 (d, J ¼ 9.0 Hz, 2H), 8.31 (d, J ¼ 9.0 Hz, 2H).

Thiols Cleave 2- and 4-Nitrobenzenesulfonamides
1199
1
Compound 1f. H NMR (200 MHz, CDCl ) d 0.74 (t, J ¼ 7.3 Hz, 3H), 1.39
3
(
sextet, J ¼ 7.3 Hz, 2H), 3.11 (t, J ¼ 7.3 Hz, 2H), 3.80 (s, 3H), 4.33 (s, 2H),
6
.83 (d, J ¼ 8.8 Hz, 2H), 7.17 (d, J ¼ 8.8 Hz, 2H), 7.98 (d, J ¼ 9.0 Hz, 2H),
8
.34 (d, J ¼ 9.0 Hz, 2H).
1
Compound 3a. H NMR (200 MHz, CDCl ) d 3.75 and 3.797 (each s, 2H),
3
3
.804 (s, 3H), 6.87 (d, J ¼ 8.5 Hz, 2H), 7.23–7.35 (m, 7H).
1
Compound 3c. H NMR (200 MHz, CDCl ) d 0.92 (t, J ¼ 7.3 Hz, 3H), 1.56
3
(
sextet, J ¼ 7.3 Hz, 2H), 2.59 (t, J ¼ 7.3 Hz, 2H), 3.73 (s, 2H), 3.80 (s, 3H),
6
.86 (d, J ¼ 8.8 Hz, 2H), 7.24 (d, J ¼ 8.8 Hz, 2H).
ACKNOWLEDGMENTS
This research was financially supported in part by the Frontier Research
Program and the 21st Century Center of Excellence Program “Development
of Drug Discovery Frontier Integrated from Tradition to Proteome” of the
Ministry of Education, Culture, Science, Sports, and Technology, Japan.
REFERENCES
1. Fielder, W. J.; Hesse, M. Synthesis of selectively N-functionalized polyamine
derivatives. Helv. Chim. Acta 1993, 76, 1511–1519.
2
. Fukuyama, T.; Jow, C.-K.; Cheung, M. 2- and 4-nitrobenzenesulfonamides: excep-
tionally versatile means for preparation of secondary amines and protection of
amines. Tetrahedron Lett. 1995, 36, 6373–6374.
3
4
. Kan, T.; Fukuyama, T. Ns strategies: a highly versatile synthetic method for
amines. Chem. Commun. 2004, 353–359.
. Fukuyama, T.; Cheung, M.; Kan, T. N-Carboalkoxy-2-nitrobenzenesulfonamides:
a practical preparation of N-Boc-, N-Alloc-, and N-Cbz-protected primary amines.
Synlett 1999, 1301–1303.
5
6
. Kan, T.; Fukuyama, T. Highly versatile synthesis of nitrogen-containing
compounds by means of nitrobenzenesulfonamides. Syn. Org. Chem. Jpn. 2001,
59, 779–789.
. Hidai, Y.; Kan, T.; Fukuyama, T. Total synthesis of polyamine toxin HO-416b and
Agel-489 using a 2-nitrobenzenesulfonamide strategy. Chem. Pharm. Bull. 2000,
48, 1570–1576.
7. Fujiwara, A.; Kan, T.; Fukuyama, T. Total synthesis of lipogrammistin-A: efficient
macrocyclization with 2-nitrobenzenesulfonamide. Synlett 2000, 1667–1669.
8. Hakogi, T.; Taichi, M.; Katsumura, S. Synthesis of a nitrogen analogue of sphin-
gomyelin as a sphingomyelinase inhibitor. Org. Lett. 2003, 5, 2801–2804.
9. Node, M.; Kumar, K.; Nishide, K.; Ohsugi, S.; Miyamoto, T. Odorless substitutes
for foul-smelling thiols: Syntheses and applications. Tetrahedron Lett. 2001, 42,
9207–9210.

1
200
M. Matoba, T. Kajimoto, and M. Node
1
0. Nishide, K.; Miyamoto, T.; Kumar, K.; Ohsugi, S.; Node, M. Synthetic equivalents
of benzenethiol and benzyl mercaptan having faint smell: Odor reducing effect of
trialkylsilyl group. Tetrahedron Lett. 2002, 43, 8569–8572.
1
1
1. Nishide, K.; Ohsugi, S.; Fudesaka, M.; Kodama, S.; Node, M. New odorless
protocols for the Swern and Corey–Kim oxidations. Tetrahedron Lett. 2002, 43,
5
177–5180.
2. Ohsugi, S.; Nishide, K.; Oono, K.; Okuyama, K.; Fudesaka, M.; Kodama, S.;
Node, M. New odorless method for the Corey–Kim and Swern oxidations
utilizing dodecyl methyl sulfide (Dod-S-Me). Tetrahedron 2003, 59, 8393–8398.
3. Node, M. Development of odorless organosulfur reagents. Food Food Ingredients
J. Jpn. 2004, 209, 88–93.
1
1
4. Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.; Node, M. A
practical improvement of odorless Corey–Kim and Swern oxidations. Green
Chem. 2004, 6, 142–144.
1
5. Nishide, K.; Ohsugi, S.; Miyamoto, T.; Kumar, K.; Node, M. Development of
odorless thiols and sulfides and their applications to organic synthesis. Monatsh.
Chem. 2004, 135, 189–200.
1
1
1
6. Nishide, K.; Node, M. Development of odorless sulfur reagents and their appli-
cations. J. Synth. Org. Chem. Jpn. 2004, 62, 895–910.
7. Patra, P. K.; Nishide, K.; Fuji, K.; Node, M. Dod-S-Me and methyl 6-morpholino-
hexyl sulfide (MMS) as new odorless borane carriers. Synthesis 2004, 1003–1006.
8. Kurosawa, W.; Kan, T.; Fukuyama, T. Preparation of secondary amines from
primary amines via 2-nitrobenzenesulfonamides: N-(4-Methoxybenzyl)-3-phenyl-
propylamine [benzenepropanamine, N-[(4-methoxyphenyl)methyl]-]. Org. Synth.
2
002, 79, 186–195.
1
2
9. Kajimoto, T.; Ishioka, Y.; Katoh, T.; Node, M. Odorless benzenethiols in synthesis
of thioglycosides and its application for glycosylation reactions. Bioorg. Med.
Chem. Lett. 2006, 16, 5736–5739.
0. Kajimoto, T.; Ishioka, Y.; Katoh, T.; Node, M. Application of novel glycosides
prepared with odorless benzenethiols in glycosylation reaction. J. Carbohydr.
Chem. 2007, 26, 469–495.