Chemoselective N-nitrosation of secondary amines under mild and heterogeneous conditions

Article abstract of DOI:10.1081/SCC-100000524

A combination of iodic or periodic acids 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-100000524

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CHEMOSELECTIVE N-NITROSATION OF SECONDARY
AMINES UNDER MILD AND HETEROGENEOUS
CONDITIONS
Mohammad Ali Zolfigol a , Arash Ghorbani Choghamarani a , Farhad Shirini b , Hassan
Keypour a & Sadegh Salehzadeh a
a Chemistry Department, College of Science, Bu-Ali Sina University, Hamadan, 65174,
Iran
b Chemistry Department, College of Science, Gilan University, Rasht, Iran
Published online: 09 Nov 2006.
To cite this article: Mohammad Ali Zolfigol , Arash Ghorbani Choghamarani , Farhad Shirini , Hassan Keypour & Sadegh
Salehzadeh (2001): CHEMOSELECTIVE N-NITROSATION OF SECONDARY AMINES UNDER MILD AND HETEROGENEOUS
CONDITIONS, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 31:3, 359-365
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SYNTHETIC COMMUNICATIONS, 31(3), 359–365 (2001)
CHEMOSELECTIVE N-NITROSATION OF
SECONDARY AMINES UNDER MILD AND
HETEROGENEOUS CONDITIONS
Mohammad Ali Zolfigol,1,∗ Arash Ghorbani
Choghamarani,1 Farhad Shirini,2 Hassan Keypour,1
and Sadegh Salehzadeh1
1Chemistry Department, College of Science, Bu-Ali Sina
University, Hamadan 65174, Iran
2Chemistry Department, College of Science,
Gilan University, Rasht, Iran
ABSTRACT
A combination of iodic or periodic acids and sodium nitrite
in the presence of wet SiO2 was used as an effective nitrosating
agent for the nitrosation of secondary amines to their correspond-
ing nitroso derivatives under mild and heterogeneous conditions in
excellent yields.
N-Nitrosation chemistry of amines is an important and well-established
reaction in organic synthesis. Many nitrosating agents have been examined in-
cluding alkyl nitrites, nitrosothiols, nitrogen oxides, nitrosyl salts, etc., and a
number of catalysts identified and quantified (1,2). The most general reagent
is nitrous acid, generated from sodium nitrite and mineral acid in water or in
mixed alchohol–water solvents (1). Other nitrosating agents, such as Fremy’s salt,
∗Corresponding author. E-mail: Zolfi@basu.ac.ir
359
Copyright ꢀ 2001 by Marcel Dekker, Inc.
www.dekker.com
C

ORDER
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ZOLFIGOL ET AL.
bis(triphenylphosphine)nitrgen(1+) nitrite, N-haloamides, and sodium nitrite un-
der phase-transfer conditions, oxyhyponitrite, oxalic acid dihydrate, or inorganic
acidic salts and sodium nitrite have been also used (3,4).
Very recently, we among many others have demonstrated that heterogeneous
reagent systems have many advantages, such as simple experimental procedures,
mild reaction conditions, and minimization of chemical wastes compared to the
liquid phase counterparts. It has been shown also that any carrier of NO+ would
I or II
R1R2NH
R1R2N N O
III
1
2
R1=R2
1 or 2
R1=R2
1 or 2
Et
CH2 CHCOOH
CH2
a
e
f
b
c
iso-Pr
O
N CH2CH2
O
g
O
N CH2CH2CH2
O
h
d
R1
O
R2
O
N CH2CH2CH2
O
N CH2CH2
i
O
Scheme 1.

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REPRINTS
N-NITROSATION OF SECONDARY AMINES
361
Table 1. Nitrosation of Secondary Amines (1) to Their Corresponding
Nitrosoamines (2) with a Combination of H5IO6 (I) or HIO3 (II), NaNO2
(III) and Wet SiO2 (50 wt%) in Dichloromethane at Room Temperature
(Reagent/Substrate)a
Yieldb
Entry
Substrate
Product
I
II
III
Time (h)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1a
1a
1b
1b
1c
1c
1c
1c
1d
1d
1e
1e
1f
2a
2a
2b
2b
2c
2c
2c
2c
2d
2d
2e
2e
2f
2
–
2
–
2
–
–
–
1.25
–
2
–
2
1.25
–
1.25
–
1
2
2
–
2
–
2
–
2
2
2
–
2
–
2
–
–
2
–
2
–
–
–
–
2
–
2
2
2
2
2
2
2
2
2
1.25
2
2
2
2
1.25
2
1.25
2
1
2
2
0.5
1
0.25
0.5
0.5
1
93
85
85
84
98
98
24c
24e
0.75
0.5
1.25
2
–
–
d
d
95
91
96
90
93
92
92
94
95
82c
59c
40
56
99
99
98
1
1f
1f
2f
2f
1.75
2.5
4
3.5
15.5
13.5
2
1
2
2.5
0.75
1g
1g
1h
1h
1h
1h
1h
1i
2g
2g
2h
2h
2h
2h
2h
2i
1
–
1.25
–
1
2
1.25
2
1i
2i
aWet SiO2: substrate (0.2 g:1 mmol).
bIsolated yields.
cIn the absence of both dry and wet SiO2.
d Reaction did not occur.
eIn the presence of dry SiO2.
suffice for the nitrosation reaction of suitable compounds such as thiols (5,6),
urazoles (7–9), dihydropyridines (10–12), and phenols (13). 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 NO+IO−X (X = 3
and 4 as an efficient heterogeneous nitrosating agents) by the strongly acidic solid
inorganic acid H5IO6 (dihydrated form) and its milder analogue HIO3 (pKa ≈ 1)
and sodium nitrite for the nitrosation of secondary amines. We report a simple,

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362
ZOLFIGOL ET AL.
NO
N
H
N
OCH3
OCH3
I or II
+
+
III
NO
0%
3
100%
Scheme 2.
chemoselective, and convenient method for the effective nitrosation of secondary
amines under mild and heterogeneous conditions.
Different types of secondary amines (1) were subjected to the nitrosation
reaction in the presence of H5IO6 (I) or HIO3 (II), NaNO2 (III) and wet SiO2
(50 wt%) in dichloromethane (Sch. 1). The nitrosation reactions were performed
under mild and completely heterogeneous conditions at room temperature and take
place with excellent yields (Table 1).
This nitrosation reaction can be readily carried out by placing solid acid (I or
II), NaNO2 (III), amine (1), wet SiO2 (50 wt%), and CH2Cl2 as the inert solvent
in a reaction vessel and efficiently stirring the resulting heterogeneous 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
Table 1.
To demonstrate the chemoselectivity of this method, a competitive reaction
was performed between dibenzylamine (1f) and anisole (3). It was observed that
amine nitrosation occurred exclusively, whereas anisole remained intact in the
reaction mixture after 2 h (Sch. 2).
The nitrosation reaction of diphenylamine further shows the chemoselectiv-
ity of the method as the N-nitrosodiphenylamine is the only product. This system
thus behaves differently from some reported methods (14,15) in that nitrosonium
ion (NO+) attacks the nitrogen sites of the secondary amines even where an aro-
matic moiety is connected directly to the nitrogen atom (Sch. 3).
H
N
H
N
NO
N
I or II
+
III
ON
0%
100%
Scheme 3.

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N-NITROSATION OF SECONDARY AMINES
363
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 (Sch. 1, Table 1, Entries 11 and 12). L-Nitrosoproline (2e) is a precursor of
mesoionic moieties in an important class of dipolar heterocyclic compounds with
special properties (16).
Some of the amines used are very important precursors for the synthesis
of symmetrical and asymmetrical tripodal tetraamines (Table 1, Entries 16–24),
(17–20). We therefore believe that their nitroso derivatives also may be useful for
synthesis of special NO releasing complexes.
The HIO3/NaNO2 system is more convenient and also milder than its anal-
ogous H5IO6/NaNO2, and does not affect amide units in the substrate (Table 1,
Entries 14–22).
The reaction with H5IO6 (dihydrated form) occurred in the absence of wet
SiO2 overamuchlongerperiodoftime, butthereactionwithHIO3 doesnotproceed
under the same conditions (Table 1, Entries 7, 8, 20, and 21). This observation
suggests that the water molecule is essential for such processes. The presence
of wet SiO2 thus provides an effective heterogeneous surface area for in situ
generation of HNO2. It also eases the reaction work-up.
In conclusion, the cheapness and availability of the reagents, easy and clean
work-up, chemoselectivity, and high yields make this method attractive for large-
scale operations. This simple procedure is highly selective, and contamination
by deprotection and C-nitrosation side-products is avoided. Moreover, the new
element here is that the reaction is heterogeneous. This could be worthwhile in an
industrial setting. The scope and limitations of this method are under investigation
in our laboratory.
EXPERIMENTAL
General. Chemicals were purchased from Fluka, Merck, and Aldrich
chemical companies. Yields refer to isolated pure products. The nitrosation prod-
ucts were characterized by comparison of their spectral (IR, 1H NMR, 13C NMR,
and TLC) and physical data with the authentic samples.
General Procedure for N-Nitrosation of Secondary Amines. A suspen-
sion of sodium nitrite, solid acid (the molar ratio of solid acid and sodium nitrite
to the substrate 1 was optimized, see Table 1), amine (1, 5 mmol), and wet SiO2
(50 wt%) in dichloromethane (10 mL for Entries 1–13 and 50 mL for Entries 14–
22) was vigorously stirred magnetically at room temperature. The progress of the
reaction was followed by TLC. The reaction mixture was filtered after completion
of the reaction. The residue was washed with CH2Cl2 (2 × 5 mL). Then anhydrous
Na2SO4 (10 g) was added to the filtrate and filtered after 20 min. The solvent was

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ZOLFIGOL ET AL.
evaporated and the N-nitroso compounds (2) were obtained (Table 1). If further
purification is needed, flash chromatography on silica gel [eluent: acetone/petro-
leum ether (10:90)] provides pure 2.
A Typical Procedure for N-Nitrosation of Protected Amine (1 g) with
H5IO6 (I), NaNO2 (III), and Wet SiO2. A suspension of compound 1g (0.670 g,
2 mmol), I (0.568 g 2.5 mmol), wet SiO2 (50 wt%, 0.4 g), and III (0.172 g,
2.5 mmol) in dichloromethane (10 mL) was stirred at room temperature for 4 h
(the progress of the reaction was monitored by TLC) and then filtered. Anhydrous
Na2SO4 (5 g) was added to the filtrate. After 15 min the resulting mixture was
also filtered. Dichloromethane was removed by water bath (35–40◦C) and simple
distillation. The yield was 0.681 g, (94%) of crystalline pale yellow solid (2g),
m.p. 183–185◦C.
ACKNOWLEDGMENTS
Financial support for this work by the research affairs of Bu-Ali Sina
University, Hamadan, Iran, and also Gilan University, Rasht, Iran, are gratefully
acknowledged.
REFERENCES
1. Williams, D.L.H. Supplement F2: The Chemistry of Amino, Nitroso, Nitro
and Related Groups; John Wiley & Sons, Ltd.: London, 1996; 665–682.
2. Keefer, L.K.; Williams, D.L.H. Methods in Nitric Oxide Reseach; John Wiley
& Sons, Ltd.: London, 1996; 509–519.
3. Zolfigol, M.A. Synth. Commun. 1999, 29, 905.
4. Zolfigol, M.A.; Ghaemi, E.; Madrakian, E.; Kiany-Borazjani, M. Synth.
Commun. 2000, 30, 2057.
5. Zolfigol, M.A.; Nematollahi, D.; Mallackpour, S.E. Synth. Commun. 1999,
29, 2277.
6. Zolfigol, M.A. Synth. Commun. 2000, 30, 1593.
7. Zolfigol, M.A.; Mallackpour, S.E. Synth. Commun. 1999, 29, 4061.
8. Zolfigol, M.A.; Kiany-Borazjani, M.; Mallackpour, S.E.; Nassr-Isfahani, H.
Synth. Commun. 2000, 30, 2573.
9. Zolfigol, M.A.; Madrakian, E.; Ghaemi, E. Indian J. Chem. 2000, 39B, 308.
10. Zolfigol, M.A.; Kiany-Borazjani, M.; Sadeghi, M.M.; Mohammadpoor-
Baltork, I.; Memarian, H.R. Synth. Commun. 2000, 30, 551.
11. Zolfigol, M.A.; Kiany-Borazjani, M.; Sadeghi, M.M.; Memarian, H.R.;
Mohammadpoor-Baltork, I. Synth. Commun. 2000, 30, 2945.

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365
12. Zolfigol, M.A.; Kiany-Borazjani, M.; Sadeghi, M.M.; Mohammadpoor-
Baltork, I.; Memarian, H.R. Synth. Commun. 2000, 30, 3919.
13. Zolfigol, M.A.; Ghaemi, E.; Madrakian, E. Synth. Commun. 2000, 30, 1689.
14. Vogels Text Book of Practical Organic Chemistry, 4th Edn.; Longman:
London, 1986.
15. Sheriner, R.L.; Reynold, T.L.; Fuson, C.; Curtin, D.Y.; Morrill, T.C. The
Systematic Identification of Organic Compounds, 6th. Edn.; John Wiley &
Sons: New York, 1980; 220–223.
16. Turnbull, K. J. Heterocycl. Chem. 1985, 22, 965.
17. Keypour, H.; Stotter, D.A. Inorg. Chim. Acta 1979, 33, 149.
18. Keypour, H.; Pritchard, R.G.; Parish, R.V. Transition Met. Chem. 1998,
23, 609.
19. Keypour, H.; Pritchard, R.G.; Parish, R.V. Transition Met. Chem. 1998,
23, 121.
20. Keypour, H.; Salehzadeh, S. Transition Met. Chem. 2000, 25, 205.
Received in the UK January 19, 2000

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