N-nitrosation of secondary amines using supported perchloric acid on silica gel and stereoselectivity study of nitrosated products

Article abstract of DOI:10.1002/jccs.201300136

N-Nitrosation of different types of secondary amines has been proceeded using supported perchloric acid on silica gel and sodiume nitrite under heterogeneous conditions. The operational system is simple and high pure products can be easily isolated with good to high yields.

Full text of DOI:10.1002/jccs.201300136

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
N-Nitrosation of Secondary Amines Using Supported Perchloric Acid on Silica Gel
and Stereoselectivity Study of Nitrosated Products
Hamid Goudarziafshar,* Arash Ghorbani-Choghamarani* and Laila Hadian
Department of Chemistry, Faculty of Science, Ilam University, P.O. Box 69315516, Ilam, Iran
(Received: Mar. 14, 2013; Accepted: May 13, 2013; Published Online: Jul. 11, 2013; DOI: 10.1002/jccs.201300136)
N-Nitrosation of different types of secondary amines has been proceeded using supported perchloric acid
on silica gel and sodiume nitrite under heterogeneous conditions. The operational system is simple and
high pure products can be easily isolated with good to high yields.
Keywords: N-Nitrosation; Secondary amines; Heterogeneous; Perchloric acid; Sodium nitrite.
INTRODUCTION
In the last few years, supported reagents on the solid
and sodium nitrite with good to excellent yields (Scheme
I).
bases have become increasingly used in organic reac-
tions,1-4 mainly because the reactions are carried out under
mild conditions and the organic products are easily isolated
from the reaction media.
Scheme I N-Nitrosation of secondary amines
Nitrosation reactions are of wide and varied signifi-
cance. N-Nitrosation of amines is an important and well-es-
tablished reaction in organic reactions; nitrosation chemis-
try has been a fruitful area for mechanistic organic and bio-
logical chemists.5 N-Nitrosamine is a class of carcinogenic,
mutagenic, and teratogenic compounds.6 These compounds
are of biological interest and are used as ‘transnitrosating
agents’, i.e. NO-donor drugs.7
Initially, to optimize the reaction conditions, different
molar ratio of sodium nitrite and supported perchloric acid
on silica gel reacted with dibenzylamine in dichlorometh-
ane at room temperature. The best ration was 2.5 mmol of
NaNO2 and 0.838 grams of HClO4-SiO2 (50% w/w). Under,
obtained optimize conditions secondary amines were con-
verted into N-nitrosoamines, which the results has been
summarized in Table 1.
Even though a variety of literature procedures were
examined for this transformation,8-15 most of these proce-
dures suffer from one or more of the following drawbacks:
harsh reaction conditions, long reaction times, low yields
of products, heavy metal contamination, and side reactions.
Supported perchloric acid on silica gel (HClO4-SiO2) as an
efficient and heterogeneous solid acid has been previously
used in some organic reactions.16-17 Therefore, in order to
develop the scope of this solid acid we decided to apply that
for the nitrosation of secondary amines.
N-Nitrosation reactions has been readily carried out
via mixing of supported perchloric acid on silica gel (50%
w/w) and sodium nitrite with an amine at room temperature.
And the resulting nitrosoamine could be purified by short
column chromatography. Because of mild and heteroge-
neous conditions of described system, there was no nitra-
tion product observed for aromatic rings of amines (Table
1, entries 1-4 and 6).
It is of interest that dinitrosation of piperazine oc-
curred, with the appropriate molar ratio of the reagents (en-
try 12), but unfortunately any attempt to produce mono
nitrosopiperazine was failed. However, the mixtures of
mono and di nitroso piperazine were observed on TLC
when the reactions carried out by even one equivalent of
the nitrosating reagents. We believed that self trans-nitro-
sation of mono nitrosopiperazine is the main reason for this
RESULTS AND DISCUSSION
Therefore we decided to design a new heterogeneous
system for the chemoselctive N-nitrosation of secondary
amines by in situ generation of nitrosoniume ion (NO+).
Consequently, different types of secondary amines
has been converted into corresponding N-nitrosoamines
using supported perchloric acid on silica gel (50% w/w)
* Corresponding author. Tel./Fax: +98 841 2227022; E-mail: hamid_gafshar@yahoo.com (H. Goudarziafshar;
a.ghorbani@mail.ilam.ac.ir (A. Ghorbani-Choghamarani)
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N-Nitrosation of Secondary Amines
Scheme III N-Nitroso amines isomers
Table 1. N-Nitrosation of secondary amines to the corresponding
N-nitrosamines via combination of supported perchloric
acid on silica gel (50% w/w) and sodium nitrite in di-
chloromethane at room temperaturea
Time Yield
(Min) (%b)
Entry
Substrate
Product
Therefore, 1H and 13C-NMR spectra of the symmetri-
cal dialkyl N-nitroso amines (Table 1, entries 6-12) give
two distinct signals with equal intensity for each proton or
carbon (for example 1H and 13C-NMR of N-nitroso diben-
zylamine is outlined in Fig. 1). The higher frequency peaks
are attributed to the proton and carbon of the trans group
the nitroso oxygen.22,23
In the other hand, 1H and 13C-NMR spectra of the un-
symmetrical N-nitroso amines (Table 1, entries 1-5) give
two distinct signals with unequal intensity for protons and
carbons (for example 1H-NMR spectra of N-nitrosoalkyl-
benzylamines is outlined in Fig. 2).
N
N
H
1
2
5
5
91
93
NO
N
H
N
NO
N
H
N
3
4
5
5
89
93
NO
N
H
N
NO
NO
H
N
N
5
6
7
5
5
5
88
99
87
N
H
N
NO
N
N
H
N-Nitroso amines with different alkyl moieties show
two proton signals with different intensity, which the inten-
sity of protons are depend on the steric effect of N-nitro-
soamines. Therefore we can determine the ratio of two iso-
NO
PhH2C
NH
PhH2C
N NO
8
5
5
5
92
96
99
O
O
N
NH
NO
9
H3C(H2C)5
(CH2)5CH3
H3C(H2C)5
(CH2)5CH3
1
N
N
H
10
mers of N-nitroso compound easily using their H-NMR
NO
NO
N
spectra. The ratio of the rotamers for the N-nitrosoalkyl-
benzylamines are summarized in Table 2.
H
N
11
12
5
5
99
93
Table 2 clearly shows that the percent of B isomer
rises with increasing the bulk of alkyl group.
ON
N
HN
N
NO
NH
Molar ratio of reagents: substrate/HClO4-SiO2/NaNO2 for entries
1-11 = 1 mmol : 0.838 g : 2.5 mmol; for entry 12 = 1 mmol :
1.676 g : 5 mmol. b Yield refers to high pure product, which
obtained by the short column chromatography.
In order to prove that two forms of N-nitroso amine
subject (Scheme II), which is in close agreemnet with pre-
viously reported works.10,12,13
Self trans-nitrosation of mono nitroso-
piperazine
Scheme II
NMR study of N-nitrosoamines
The most interesting feature of this project is the 1H
and 13C-NMR spectra of N-nitroso products. They clearly
show, in all cases the diastereotopic nature of the adjacent
N–CH protons and carbons which is due to the bent nature
of the N=O bond and its mutual exchange (Scheme III).
Fig. 1. 1H and 13C-NMR spectra of N-nitrosodiben-
zylamine.
J. Chin. Chem. Soc. 2013, 60, 1272-1276
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Article
Goudarziafshar et al.
Table 2. Ratio of the rotamers for the N-nitrosoalkylbenzyl-
amines, which determine by 1H-NMR spectroscopy
O
O
N
N
N
N
C
H
R
C
H
R
2
2
A
B
Entry
R
Ratio of A:B (%)
1
2
3
4
CH3
CH2CH3
77 : 23
53 : 47
26 : 74
0 : 100
CH(CH3)2
C(CH3)3
not arise from the configurational inversion of the SP3 ni-
1
trogen, we run HNMR of Nnitroso-iso-propylbenzyl-
Fig. 2. 1H and 13C-NMR spectra of N-nitrosoalkylben-
amine (as typical example) at different temperatures, (As
we know configurational inversion of SP3 nitrogen is de-
pendent of temperature) surprisingly we observed that the
molar ratio of two isomers was no changed in different tem-
peratures (Fig. 3).
zylamines.
In order to assess the capability of the present meth-
odology with respect to the reported procedures for the
N-nitrosation of secondary amines, we compared our ob-
tained results for the N-nitrosation of dibenzylamine (as
typical examples) with the best of the well-known data
from the literature as shown in the Table 3.
EXPERIMENTAL
General. The chemicals and solvents were supplied by
Fluka, Merck and Aldrich chemical companies.
N-Nitrosation of dibenzyl amine by HClO4-SiO2 and
Fig. 3. 1H-NMR of N-nitroso-iso-propylbenzylamine
at different temperatures.
Table 3. Comparison of the different methods used for the N-nitrosation of dibenzyl-
amine with different reagents
Time
Yield (%)a Reference
(Min)
Entry
Reagents
1
2
3
4
HClO4-SiO2
Citric acid/NaNO2/wet SiO2
[P4-Me]NO2
5
99
97
95
88
This work
35
10
40
10
18
8
1-Butyl-3-methylimidazolium nitrite
Alumina-methanesulfonic acid
(AMA)/NaNO2
5
25
89
19
6
[NO+.Crown.H(NO3)2 ]
5
100b
98
20
15
15
15
21
21
-
7
Al(HSO4)3/NaNO2
30
+
-
NH2(CO)NH3 HSO4 /NaNO2
8
30
94
+
-
9
NH2(CS)NH3 HSO4 /NaNO2
H2SO4-SiO2/NaNO2
60
98
10
11
300
300
80
H3PO4-SiO2/NaNO2
91
a Isolated yield. b Conversion
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N-Nitrosation of Secondary Amines
NaNO2. A suspension of dibenzyl amine (0.197 g, 1 mmol), sup-
ported perchloric acid (0.838 g) and NaNO2 (0.228 g, 2.5 mmol)
in dichloromethane (5 mL) was stirred at room temperature for 5
min (reaction progress was monitored by TLC) and then filtered
into short column chromatoghraphy. The column was washed by
CH2Cl2 (as eluent). Finally dichloromethane was evaporated and
N-nitroso dibenzylamine obtained in 99% yield (0.223 g).
Selected spectral data
(m, 2H), 1.19-1.24 (m, 12H), 0.77-0.82 (m, 6H), ppm; 13C NMR
(75 MHz, CDCl3): d = 52.2, 43.5, 31.2, 31.1, 28.2, 26.8, 26.1,
25.9, 22.4, 22.3, 13.9, 13.9 ppm. N-Nitrosodicyclohexylamine:
1H NMR (300 MHz, CDCl3): d = 4.77-4.85 (m, 1H), 3.64-3.71 (m,
1
1H), 1.26-1.87 (m, 20H), ppm. 1,4-Dinitrosopiperazine: H
NMR (400 MHz, DMSO-D6): d = 4.53 (s, 1H), 4.47 (t, J = 5.6,
2H), 3.91 (t, J = 5.6, 2H), 3.77 (s, 1H) ppm; 13C NMR (100 MHz,
DMSO-D6): d = 49.4, 46.2, 42.2, 38.3 ppm.
N-Nitrosomethylbenzylamine: 1H NMR (300 MHz,
CDCl3): d = 7.25-7.38 (m, 5H), 5.29 and 4.79 (s and s, 2H), 3.67
and 2.93 (s and s, 3H), ppm; 13C NMR (75 MHz, CDCl3): d =
134.5, 133.8, 129.1, 128.9, 128.6, 128.3, 128.1, 127.9, 57.5, 47.7,
CONCLUSIONS
In summary, an effective N-nitrosation procedure us-
ing supported perchloric acid on silica gel (HClO4-SiO2)
and sodium nitrite (NaNO2) has been delineated. The ad-
vantages of this heterogeneous procedure are high effi-
ciency, manipulative simplicity, high yields of products,
short reaction times and absence of by-product such as ni-
tro and nitroso products.
1
38.5, 30.1 ppm. N-Nitrosoethylbenzylamine: H NMR (300
MHz, CDCl3): d = 7.12-7.39 (m, 5H), 5.27 and 4.83 (s and s, 2H),
4.12 and 3.52 (q and q, J = 7.2 and 7.2, 2H), 1.37 and 0.98 (t and t,
J = 7.2 and 7.2, 3H), ppm; 13C NMR (75 MHz, CDCl3): d = 134.8,
134.2, 129.0, 12.8, 128.5, 128.2, 128.1, 127.8, 55.8, 46.6, 45.7,
1
38.3, 13.9, 11.0 ppm. N-Nitroso-iso-propylbenzylamine: H
NMR (300 MHz, CDCl3): d = 7.06-7.31 (m, 5H), 5.23 and 4.76 (s
and s, 2H), 4.90-4.95 and 4.16-4.53 (sep and sep, J = 6.8 and 6.8,
1H), 1.40 and 0.98 (d and d, J = 6.8 and 6.8, 3H), ppm; 13C NMR
(75 MHz, CDCl3): d = 136.6, 135.1, 128.8, 128.7, 128.1, 127.8,
127.6, 127.5, 55.1, 52.8, 45.6, 45.4, 21.8, 19.1 ppm. N-Nitroso-
t-butylbenzylamine: 1H NMR (300 MHz, CDCl3): d = 7.00-7.27
(m, 5H), 4.85 (s, 2H), 1.56 (s, 9H), ppm; 13C NMR (75 MHz,
CDCl3): d = 135.8, 128.6, 127.0, 126.8, 61.9, 44.6, 29.3 ppm.
N-Nitrosomethylcyclohexylamine: 1H NMR (300 MHz,
CDCl3): d = 5.29 and 4.30 (m and m, 1H), 3.59 and 2.93 (s and s,
3H), 1.17-1.93 (m, 10H), ppm; 13C NMR (75 MHz, CDCl3): d =
63.0, 51.3, 34.9, 31.1, 29.0, 28.5, 25.2, 25.1 ppm. N-Nitro-
sodibenzylamine:1H NMR (300 MHz, CDCl3): d = 7.07-7.41 (m,
10H), 5.23 (s, 2H), 4.69 (s, 2H), ppm; 13C NMR (75 MHz,
CDCl3): d = 134.5, 133.9, 129.1, 128.9, 128.6, 128.5, 128.4,
127.9, 55.0, 44.9 ppm. N-Nitrosoazepane: 1H NMR (300 MHz,
CDCl3): d = 4.31 (t, J = 5.5, 2H), 3.63 (t, J = 5.9, 2H), 1.80-1.86
(m, 2H), 1.73-1.76 (m, 2H), 1.58-1.59 (m, 4H), ppm; 13C NMR
(75 MHz, CDCl3): d = 52.1, 46.3, 29.3, 28.6, 28.0, 24.5 ppm.
4-Benzyl-1-nitrosopiperidine: 1H NMR (300 MHz, CDCl3): d =
7.14-7.32 (m, 5H), 4.96-5.01 (m, 1H), 4.66-4.71 (m, 1H), 3.56-
3.57 (m, 1H), 2.45-2.58 (m, 3H), 1.87-1.92 (m, 2H), 1.69-1.73 (m,
1H), 1.06-1.38 (m, 3H), ppm; 13C NMR (75 MHz, CDCl3): d =
139.6, 129.1, 128.4, 126.3, 50.0, 42.4, 38.9, 37.9, 32.3, 30.7 ppm.
N-Nitrosomorpholine: 1H NMR (300 MHz, CDCl3): d = 4.20 (t,
ACKNOWLEDGEMENTS
Financial support for this work by the research affairs
of Ilam University, Ilam, Iran is gratefully acknowledged.
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