Alumina-methanesulfonic acid (AMA)/NaNO2 as an efficient procedure for the chemoselectivite N-nitrosation of secondary amines

Article abstract of DOI:10.1080/00397910600639927

A combination of alumina/methanesulfonic acid (AMA) and sodium nitrite was used as an effective nitrosating agent for the nitrosation of secondary amines under mild and heterogeneous conditions in good to excellent yields. Copyright Taylor & Francis Group, LLC.

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Alumina–Methanesulfonic Acid (AMA)/
NaNO2 as an Efficient Procedure for the
Chemoselectivite N‐Nitrosation of Secondary
Amines
Khodabakhsh Niknam a & Mohammad Ali Zolfigol b
a Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
b Department of Chemistry, College of Science, Bu‐Ali Sina University,
Hamadan, Iran
Published online: 22 Sep 2006.
To cite this article: Khodabakhsh Niknam & Mohammad Ali Zolfigol (2006) Alumina–Methanesulfonic Acid
(AMA)/NaNO2 as an Efficient Procedure for the Chemoselectivite N‐Nitrosation of Secondary Amines,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:16, 2311-2319, DOI: 10.1080/00397910600639927
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Synthetic Communicationsw, 36: 2311–2319, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600639927
Alumina–Methanesulfonic Acid
(AMA)/NaNO2 as an Efficient Procedure
for the Chemoselectivite N-Nitrosation
of Secondary Amines
Khodabakhsh Niknam
Department of Chemistry, Faculty of Sciences, Persian Gulf University,
Bushehr, Iran
Mohammad Ali Zolfigol
Department of Chemistry, College of Science, Bu-Ali Sina University,
Hamadan, Iran
Abstract: A combination of alumina/methanesulfonic acid (AMA) and sodium nitrite
was used as an effective nitrosating agent for the nitrosation of secondary amines under
mild and heterogeneous conditions in good to excellent yields.
Keywords: Alumina, methanesulfonic acid, N-nitrosation, secondary amines, sodium
nitrite
One of the most important objectives now is to adapt classical processes so
that pollution effects are kept to a minimum, with a reduction in both
energy and consumption of raw materials. In this respect, heterogeneous
systems are promising, and a new approach has been undertaken using
alumina/methanesulfonic acid (AMA) chemistry. Nitrosation chemistry has
been a fruitful area for mechanistic, organic, and biological chemists.[1] The
most general reagent is nitrous acid, generated from sodium nitrite and
mineral acid in water or in mixed alcohol–water solvents.[2] Other nitrosating
Received in the U.K. June 1, 2005
Address correspondence to Khodabakhsh Niknam, Department of Chemistry,
Faculty of Sciences, Persian Gulf University, Bushehr 75168, Iran. E-mail:
kh_niknam@yahoo.com or niknam@pgu.ac.ir
2311

2312
K. Niknam and M. A. Zolfigol
agents, such as Fremy’s salt,[3] bis(triphenylphosphine)nitrogen(1þ) nitrite,[4]
N-haloamides and sodium nitrite under phase-transfer conditions,[5] oxyhypo-
2
[7]
nitrite,[6] dinitrogen tetroxide and [NOþ crown H(NO3)2 ], solid acids or
acetic anhydide and sodium nitrite,[8] and N2O4 supported on cross-linked
polyvinylpyrrolidone (PVP-N2O4)[9] have been also used.
.
.
In recent years, we reported that a mixture of Al2O3/MeSO3H (AMA)
was an effective reagent for conversion of alcohols into corresponding
amides in nitrile solvents,[10] Fries rearrangement,[11] Beckmann rearrange-
ment,[12] hydration of nitriles into amides,[13] and synthesis of macrocyclic
polyester–diester compounds.[14]
Very recently, we, among many others, have demonstrated that the het-
erogeneous reagent systems have many advantages such as simple experimen-
tal procedures, mild reaction conditions, and minimization of chemical waste
as compared to the liquid-phase counterparts.[7,8] Therefore, we decided to
apply a heterogeneous system, and we have investigated a number of
different reaction conditions based upon the in situ generation of NOX
(X ¼ CH3SO23 ) by methanesulfonic acid and sodium nitrite for the nitrosation
of secondary amines.
A wide range of secondary amines (1) were subjected to the nitrosation
reaction in the presence of AMA (I), NaNO2 (II) and 2 drops of water in
dichloromethane (Table 1).
This present nitrosation reaction can be readily carried out by placing
AMA (I), NaNO2 (II), amine (1), 2 drops of water, and CH2Cl2 as the
solvent in a reaction vessel and efficiently stirring the resulting heterogeneous
mixture at room temperature. The nitrosoamines (2) can be isolated simply by
filtration and evaporation of the solvent. The results and reaction conditions
are given in Table 2.
Although selective dinitrosation of 1A and 1B has occurred easily by con-
trolling the molar ratio of the reagents, selective mono nitrosation of these
amines did not occur. Several attempts to produce pure mono nitrosoamines
2A1 and 2B1 as the sole products without any separation by column chromato-
graphy failed (Fig. 1). These mentioned results are in close agreement with the
transnitrosation phenomena reported by Singer et al.[15,16]
To demonstrate the chemoselectivity of this method, a competitive
reaction was performed between diphenylamine (1p) and anisole. It was
observed that only amine nitrosation occurred, whereas anisole remained
intact in the reaction mixture after 90 min. The nitrosation reaction of
N-arylamine and N,N-diarylamines further shows the chemoselectivity of
the method, as the N-nitrosoarylamine is the only product.
Furthermore, the chiral center of L-proline (1t), 4-hydroxy-L-proline
(1u), and D-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (1o) also
remained intact in the course of the reaction (Tables 1 and 2, entries 15, 20,
and 21). Amino acid derivatives (2t, 2u, and 2o) are a precursor of
mesoionic moieties in an important class of dipolar heterocyclic compounds
with special properties.[17]

Alumina–Methanesulfonic Acid
2313
Table 1. N-nitrosation of various secondary amines with a combination of AMA and
NaNO2
Compound 1 Structure of substrates Compound 2
Structure of products
a
b
c
Me2NH
Et2NH
a
b
c
Me2N-N55O
Et2N-N55O
(i-Pr)2N-N55O
(C6H11)CH3N-NO
(C6H11)2N-N55O
(i-Pr)2NH
(C6H11)CH3NH
(C6H11)2NH
d
e
d
e
f
f
g
g
h
h
i
i
j
j
k
l
k
l
m
n
m
n
(continued)

2314
K. Niknam and M. A. Zolfigol
Table 1. Continued
Compound 1 Structure of substrates Compound 2
Structure of products
o
o
p
q
r
s
Ph2NH
p
q
r
s
Ph2N-N55O
Ph(PhCH2)NH
(PhCH2)2NH
Ph(2-naph.)NH
Ph(PhCH2)N-N55O
(PhCH2)2N-N55O
Ph(2-naph.)N-N55O
t
t
u
u
v
v
A
A1
A2
B
Kryptofixw 22
B1
B2
Mononitroso Kryptofixw22
Dinitroso Kryptofixw22
Some of the N-nitrosoamines reported (2B2 Table 1) in this article are
very important precursors for the mechanistic transnitrosation studies. We
therefore believe that these nitrosoamines are also very useful for synthesis
of special NO-releasing complexes.[18]
The nitrosation reaction proceeded very slowly in the absence of water.
This observation suggests that the water molecule is essential for such
processes. The presence of water–AMA thus provides an effective hetero-
geneous surface area for in situ generation of NOX. It also eases the
reaction workup.
In conclusion, the low cost, the availability of the reagents, chemoselec-
tivity, and good to high yields make this method attractive for organic
chemists.

Alumina–Methanesulfonic Acid
2315
Table 2. Nitrosation of secondary amines (1) with a combination of AMA (I) and
NaNO2 (II) to their corresponding nitrosoamines (2) in CH2Cl2
Reagent/Substr.
(mmol)b
Time
(min)
Yieldc
(%)
Entry
Substrate
Producta
I
II
1
2
1a
1b
1c
1d
1e
1f
2a
2b
2c
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
5
5
100d
90
85
82
86
75
87
82
70
80
78
67
69
70
65
85
87
89
73
62
60
66
20
80
75
20
80
85
3
8
4
2d
2e
20
20
25
10
15
60
10
15
90
90
25
30
95
90
25
70
60
90
25
95
5
6
2f
2g
7
1g
1h
1i
8
2h
2i
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
1j
2j
1k
1l
2k
2l
1m
1n
1o
1p
1q
1r
1s
2m
2n
2o
2p
2q
2r
2s
1t
2t
1u
1v
1A
2u
2v
2A1
2A2
2A2
2B1
2B2
2B2
24
25
1A
1B
3
1
3
2
80
25
26
1B
3
3
20
aAll of the isolated products are known and their spectra and physical data have been
reported in the literature.[1–8,19–20]
bSubstrate: methanesulfonic acid–alumina (1 mmol: 1 mmol, 0.2 g).
cIsolated yields.
dConversion by chemical test (Cu2þ).
EXPERIMENTAL
General
Chemicals were purchased from Fluka, Merck, and Aldrich chemical
companies. IR spectra were run on a Shimadzu infrared spectroscope

2316
K. Niknam and M. A. Zolfigol
Figure 1. Self trans-nitrosation of mono nitroso amine 2B1.
IR-435. The 1H NMR and 13C NMR were run on Jeol NMR spectrometer FX
90Q. Melting-points were recorded on a melting point SMP1 apparatus in
open capillary tubes and are uncorrected. With TLC using silica-gel SILG/
UV 254 plates, the progress of reaction was followed. The nitrosation
1
products were characterized by comparison of their spectral (IR, HNMR),
TLC, and physical data with the authentic samples.[8,19,20]
Caution: All N-nitroso amines [R1-N(NO)-R2] should be regarded as
potentially powerful carcinogens, because most compounds of these types
have been shown to possess high activity in experimental animals.[2a]
General Procedure for N-Nitrosation of Secondary Amines
A suspension of AMA (I), sodium nitrite (II), (the molar ratio of AMA and
sodium nitrite to the substrate 1 was optimized as shown in Table 2), amine
1 (2 mmol), and 2 drops of water in dichloromethane (8 mL) was magnetically
stirred 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 ꢀ 10 mL), and then a solution of
sodium bicarbonate 10% (20 mL) was added and extracted. Then,
anhydrous Na2SO4 (3 g) was added to the filtrate, and the solution was
filtered after 15 min. The solvent was evaporated and the N-nitroso
compounds (2) were obtained (Table 2). If further purification is needed,
flash chromatography on silica gel [eluent: acetone/petroleum ether
(10:90)] provides pure 2.
N-Nitrosation of Diisopropylamine (1c) with AMA (I), NaNO2 (II):
A Typical Procedure
A suspension of compound 1c (0.202 g, 2 mmol), I (0.357 g, 2 mmol acid and
0.4 g alumina), II (0.28 g, 4 mmol), and 2 drops of water in dichloromethane

Alumina–Methanesulfonic Acid
2317
(8 mL) was stirred at room temperature (the progress of the reaction was
monitored by TLC). The reaction mixture was filtered after 8 min. The
residue was washed with CH2Cl2 (2 ꢀ 10 mL), and then a solution of
sodium bicarbonate 10% (20 mL) was added and extracted. Anhydrous
Na2SO4 (3 g) was added to the filtrate. After 15 min the resulting mixture
was also filtered. Dichloromethane was removed by simple distillation. The
yield was 0.221 g (85%) of crystalline pale yellow solid (2c), mp 43–458C
(lit.[8e] mp 47–488C).
N-Nitroso Diisopropyl Amine
IR, v cm21: 2850–2950 (C-H, aliph., stretch.), 1450 (N55O, stretch.) and
(CH2, bend.), 1375 (CH3, bend.), 1350 (C-N), 1040 (N-N, stretch.).
1H NMR (90 MHz), d (ppm:) 4.94 (h, 1H, H-b), 4.19 (h, 1H, H-a), 1.41
(d, 6H, CH3-d, J ¼ 6.9 Hz), 1.07 (d, 6H, CH3-c, J ¼ 6.9 Hz). 13C NMR
(22.5 MHz), d (ppm). 20.4 (C-c), 25.14 (C-d), 46.06 (C-e), 51.94 (C-f).
ACKNOWLEDGMENT
We are thankful to the Persian Gulf University Research Council for partial
support of this work.
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