N-nitrosation of secondary amines under mild and heterogeneous conditions

Article abstract of DOI:10.1081/SCC-100103999

A combination of potassium monopersulfate and sodium nitrite in the presence of wet SiO₂ was used as an effective nitrosating agent for the nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in excellent yields.

Full text of DOI:10.1081/SCC-100103999

This article was downloaded by: [University of California Santa Cruz]
On: 11 October 2014, At: 13:54
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
N-NITROSATION OF
SECONDARY AMINES UNDER
MILD AND HETEROGENEOUS
CONDITIONS
a
a
Mohammad Ali Zolfigol , Mojtaba Bagherzadeh
a
,
Arash Ghorbani Choghamarani , Hassan Keypour
a
a
&
Sadegh Salehzadeh
a
Chemistry Department , College of Science, Bu-
Ali Sina University , Hamadan, 65174, Iran
Published online: 09 Nov 2006.
To cite this article: Mohammad Ali Zolfigol , Mojtaba Bagherzadeh , Arash Ghorbani
Choghamarani , Hassan Keypour & Sadegh Salehzadeh (2001) N-NITROSATION OF
SECONDARY AMINES UNDER MILD AND HETEROGENEOUS CONDITIONS, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 31:8, 1161-1166, DOI: 10.1081/SCC-100103999
To link to this article: http://dx.doi.org/10.1081/SCC-100103999
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

SYNTHETIC COMMUNICATIONS, 31(8), 1161–1166 (2001)
N-NITROSATION OF SECONDARY
AMINES UNDER MILD AND
HETEROGENEOUS CONDITIONS
Mohammad Ali Zolfigol,* Mojtaba Bagherzadeh, Arash
Ghorbani Choghamarani, Hassan Keypour, and
Sadegh Salehzadeh
Chemistry Department, College of Science, Bu-Ali Sina
University, Hamadan, 65174, Iran
ABSTRACT
A combination of potassium monopersulfate and
sodium nitrite in the presence of wet SiO was used as an
2
effective nitrosating agent for the nitrosation of secondary
amines to their corresponding nitroso derivatives under mild
and heterogeneous conditions in excellent yields.
N-Nitrosation chemistry of amines is an important and well-estab-
1
,2
lished reaction in organic synthesis. The most general reagent is nitrous
acid, generated from sodium nitrite and mineral acid in water or in mixed
3
alcohol-water solvents. Other nitrosating agents, such as Fremy’s salt,
,4
5
6
bis(triphenylphosphine)nitrogen(1þ) nitrite, N-haloamides and sodium
7
nitrite under phase-transfer conditions, oxyhyponitrite, dinitrogen
8
*
Corresponding author. E-mail: Zolfi@basu.ac.ir
161
1
Copyright & 2001by Marcel Dekker, Inc.
www.dekker.com

1
162
ZOLFIGOL ET AL.
9
10
tetroxide, oxalic acid dihydrate, and sodium nitrite have also been used.
Very recently, we among many others have demonstrated that the hetero-
geneous reagent systems have many advantages, such as simple experi-
mental procedures, mild reaction conditions, and minimization of
1
0–13
chemical wastes, as compared to their liquid phase counterparts.
Therefore, we decided to apply a completely heterogeneous system and
we have investigated a number of different reaction conditions based upon
the in situ generation of HNO by relatively strong inorganic acidic salt, e.
2
g., potassium monopersulfate (KHSO , K ꢀ1), and sodium nitrite for the
5
p
a
nitrosation of secondary amines. We report a simple, cheap, and chemo-
selective method for the effective nitrosation of secondary amines under
mild and heterogeneous conditions.
Different types of secondary amines (1) were subjected to the nitrosa-
tion reaction in the presence of KHSO (I), NaNO (II) and wet SiO
2
5
2
(
50% w/w) in dichloromethane (Scheme). The nitrosation reactions were
performed under mild and completely heterogeneous conditions at room
temperature and took place with excellent yields (Tab.).
This present nitrosation reaction can be readily carried out by placing
KHSO (I), NaNO (II), amine (1), wet SiO (50% w/w), and CH Cl as the
5
2
2
2
2
inert solvent in a reaction vessel and efficiently stirring the resulting hetero-
geneous mixture at room temperature. The nitrosoamines (2) can be
obtained simply by filtration and evaporation of the solvent. The results
and reaction conditions are given in the Table.
To demonstrate the chemoselectivity of this method, a competitive
reaction was performed between dicyclohexylamine (1c) and anisole. It
was observed that amine nitrosation occurred exclusively, whereas anisole
remained intact in the reaction mixture after 2 h. The nitrosation reaction of
diphenylamine further shows the chemoselectivity of the method as the N-
nitrosodiphenylamine is the only product. This system thus behaves differ-
3
,4
þ
ently from some reported methods in that nitrosonium ion (NO ) attacks
the nitrogen sites of the secondary amines even where an aromatic moiety is
connected directly to the nitrogen atom.
Furthermore, the chiral center of L-proline (1e) also remained intact in
the course of the reaction so that L-nitrosoproline (2e) was obtained in
excellent yields (Table, Scheme 1, Entry 5). L-Nitrosoproline (2e) is a pre-
cursor of mesoionic moieties in an important class of dipolar heterocyclic
1
5
compounds with special properties.
Some of the amines used are very important precursors for the syn-
thesis of symmetrical and asymmetrical tripodal tetraamines (Table, Entries
1
6–18.
8
useful for synthesis of special NO-releasing complexes.
–10)
We therefore believe that their nitroso derivatives are also very

SECONDARY AMINE N-NITROSATION
1163
1
a
or 2
R ¼ R
1 or 2
R ¼ R
1
2
1
2
Et
f
b
c
iso-Pr
g
h
2 5
-(CH ) -
d
e
i
R1
R2
j
Scheme.
The nitrosation reaction did not occur in the absence of wet SiO This
2
.
observation suggests that the water molecule is essential for such processes.
The presence of wet SiO thus provides an effective heterogeneous surface
2
area for in situ generation of HNO (Scheme 4). It also eases the reaction
2
work-up.
In conclusion, the low cost and availability of the reagents, easy and
clean work-up, chemoselectivity, and high yields make this method attrac-
tive for large-scale operations. This simple procedure is highly selective, and
contamination by deprotection and C-nitrosation side-products is avoided.

1
164
ZOLFIGOL ET AL.
Table. Nitrosation of Secondary Amines (1) to Their Corresponding
Nitrosoamines (2) with a Combination of [KHSO .2KHSO .K SO ] (I), NaNO
II) and Wet SiO (50% w/w) in Dichloromethane at Room Temperature
4
5
2
4
2
(
2
b
(
Reagent/Substrate)
a
c
Time (h) Yield (%)
Entry Substrate Product
I
II
8
1
,9,14
4
1
2
3
4
5
6
7
8
9
0
1a
1b2b
1c
2a
13
1
1
13
13
1
13
1
0.75
3
3
0.5
2.5
92
1
1
94
98
7
2c
2d
3
,4
1d
1e
1f
1g
98
93
8
2e
7
2f
2g
2h
2i
3
3
3
2
3
2
92
9
,14
2.5
4.5
99
99
1
6–18
1h
99
97
1
6–18
1i
1j
13
1
1
6–18
1
2j
a
All of the isolated products are known and their spectra and physical data have
b
c
2
been reported in the literature; Wet SiO : substrate (0.2 g : 1mmol); Isolated yields.
Moreover, the new element here is that the reaction is heterogeneous. This
could be worthwhile in an industrial setting.
EXPERIMENTAL
General
Chemicals were purchased from Fluka, Merck, and Aldrich chemical
companies. The commercial potassium monopersulfate for synthesis [from
Merck company, chemical formula (KHSO ꢁ2KHSO ꢁK SO )] was used.
4
5
2
4
Yields refer to isolated pure products. The nitrosation products were char-
1
13
acterized by comparison of their spectral (IR, H NMR, C NMR), TLC,
and physical data with the authentic samples.
General Procedure for N-Nitrosation of Secondary Amines
A suspension of sodium nitrite, inorganic acidic salt (the molar ratio of
inorganic acidic salt and sodium nitrite to the substrate 1 was optimized; see
Table), amine (1, 5 mmol), and wet SiO (50% w/w) in dichloromethane
2
(
10 mL for Entries 1–7 and 50 mL for Entries 8–10) was stirred vigorously

SECONDARY AMINE N-NITROSATION
1165
magnetically at room temperature. The progress of the reaction was fol-
lowed by TLC. The reaction mixture was filtered after completion of the
reaction. The residue was washed with CH Cl (2ꢂ5 mL). Then anhydrous
2
2
Na SO (10 g) was added to the filtrate and filtered after 20 m. The solvent
2
4
was evaporated and the N-nitroso compounds (2) were obtained (Tab.). If
further purification is needed, flash chromatography on silica gel [eluent:
acetone/petroleum ether (10:90)] provides pure 2.
N-Nitrosation of Diphenyl Amine (1d) with [KHSO ꢁ2KHSO ꢁK SO ]
4
5
2
4
(
I), NaNO (II), and Wet SiO : A Typical Procedure
2 2
A suspension of compound 1d (0.338 g, 2 mmol), I (1.228 g, 2 mmol),
wet SiO (50% w/w 0.4 g), and II (0.414 g, 6 mmol) in dichloromethane
2
(
tion was monitored by TLC) and then filtered. Anhydrous Na SO (5 g) was
4 mL) was stirred at room temperature for 30 m (the progress of the reac-
2
4
added to the filtrate. After 15 m, the resulting mixture was also filtered.
ꢃ
ꢃ
Dichloromethane was removed by water bath (35 –40 C) and simple dis-
tillation. The yield was 0.358 g, (98%) of crystalline yellow solid (2d), m.p.
ꢃ ꢃ ꢃ
6
4 –66 C [Lit. m.p. 67 C].
ACKNOWLEDGMENTS
Financial support for this work by the Research Affairs of Bu-Ali Sina
University, Hamadan, Iran, is gratefully acknowledged.
REFERENCES
1
. Williams, D.L.H. Supplement F2: The Chemistry of Amino, Nitroso,
Nitro and Related Groups; John Wiley & Sons, Ltd.: New York, 1996;
6
65–682.
2
3
4
. Keefer, L.K.; Williams, D.L.H. Methods in Nitric Oxide Research;
John Wiley & Sons, Ltd.: New York, 1996; 509–519.
. Vogels, Text Book of Practical Organic Chemistry, 4th Ed.; Longman:
London and New York, 1986.
. Sheriner, R.L.; Reynold, T.L.; Fuson, C.; Curtin, D.Y.; Morrill, T.C.
The Systematic Identification of Organic Compounds, 6th Ed.; John
Wiley & Sons: New York, 1980; 220–223.
5
. Castedo, L.; Riguera, R.; Vezquez, M.P. J. Chem. Soc., Chem.
Commun. 1983, 301.

1
166
ZOLFIGOL ET AL.
6
. Fanning, J.C.; Keefer, L.K.; Larry, K. J. Chem. Soc., Chem. Commun.
987, 955.
. Nakajima, M.; Warner, J.C.; Anselme, J.P. Tetrahedron Lett. 1984, 25,
619.
1
7
2
8
. Chang, S.K.; Harrington, G.W.; Rothstein, M.; Shergalis, W.A.;
Swern, D.; Vohra, S.K. Cancer Res. 1979, 39, 3871.
. Makhova, N.N.; Karpov, G.A.; Mikhailyuk, A.N.; Bova, A.E.;
Khmel’nitskii, L.I.; Novikov, S.S. Izv. Akad. Nauk SSSR, Ser.
Khim. 1978, 1, 226.
9
10. Zolfigol, M.A. Synth. Commun. 1999, 29, 905.
11. Zolfigol, M.A.; Nematollahi, D.; Mallackpour, S.E. Synth. Commun.
1
999, 29, 2277.
2. Zolfigol, M.A.; Mallackpour, S.E. Synth. Commun. 1999, 29, 4061.
3. Zolfigol, M.A.; Kiany-Borazjani, M.; Sadeghi, M.M.;
Mohammadpoor-Baltork, I.; Memarian, H.R. Synth. Commun.
000, 30, 551.
1
1
2
1
4. Barton, S.D.; Ollis, W.D. Comprehensive Organic Chemistry;
Pergamon Press: Vol. 2, 363–370.
5. Turnbull, K. J. Heterocycl. Chem. 1985, 22, 965.
1
1
6. Keypour, H.; Pritchard, R.G.; Parish, R.V. Transition Met. Chem.
1
998, 23, 609.
7. Keypour, H.; Pritchard, R.G.; Parish, R.V. Transition Met. Chem.
998, 23, 121.
8. Keypour, H.; Salehzadeh, S. Transition Met. Chem. 2000, 25, 205.
1
1
1
Received April 26, 2000