Molybdate sulfuric acid/NaNO2: A novel heterogeneous system for the N-nitrosation of secondary amines under mild conditions

Article abstract of DOI:10.1002/hlca.200690261

Wet molybdate sulfuric acid (=dioxo[bis(sulfato-κO)]molybdenum; MSA), a new solid acid, can be used in combination with sodium nitrite (NaNO ₂) to transform a variety of secondary amines to the corresponding N-nitroso compounds under mild, heterogeneous conditions (Table). The process has several advantages: the reagents are inexpensive and non-hazardous, the reaction is clean, fast, and high-yielding, and MSA can be readily removed by filtration and re-used (after treatment with HCl) without loss of activity. Further, only N-nitrosation was observed, but no C- or O-nitrosation.

Full text of DOI:10.1002/hlca.200690261

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Helvetica Chimica Acta – Vol. 89 (2006)
Molybdate Sulfuric Acid/NaNO2: A Novel Heterogeneous System for the
N-Nitrosation of Secondary Amines under Mild Conditions
by Morteza Montazerozohori and Bahador Karami*
Department of Chemistry, Yasouj University, Yasouj 75918-74831, P. O. Box 353, Iran
(e-mail: karami@mail.yu.ac.ir)
Wet molybdate sulfuric acid (=dioxo[bis(sulfato-kO)]molybdenum; MSA), a new solid acid, can be
used in combination with sodium nitrite (NaNO2) to transform a variety of secondary amines to the cor-
responding N-nitroso compounds under mild, heterogeneous conditions (Table). The process has several
advantages: the reagents are inexpensive and non-hazardous, the reaction is clean, fast, and high-yield-
ing, and MSA can be readily removed by filtration and re-used (after treatment with HCl) without loss of
activity. Further, only N-nitrosation was observed, but no C- or O-nitrosation.
Introduction. – Currently, the search for and application of (new) heterogeneous
chemical systems is an active field both in industry and academia, especially in view
of simplified handling procedures, reduction of corrosion, avoidance of undesired by-
products, and clean, ecologically friendly reactions and workup procedures. With
regard to the wide application of acids as reagents or catalysts in organic chemistry,
the introduction of an inorganic solid acid can be useful in this direction. Several
solid acids such as silica sulfuric acid [1] and Nafion-H [2] have been used for a wide
variety of chemical transformations, e.g., preparation of disulfides from thiols, oxidation
of 1,4-dihydropyridines [3], N-nitrosation of secondary amines [4], acetal deprotection
[5], oxidation of alcohols [6], alkylation with olefins, alkyl halides, and alkyl esters, iso-
merization, transalkylation, acylation, nitration, ether and ester synthesis, acetal forma-
tion, and rearrangements [7].
In continuation of our recent studies [8] on the application of inorganic solid acids,
we herein present molybdate sulfuric acid (=dioxo[bis(sulfato-kO)]molybdenum;
MSA) as a new solid regent. MSA was prepared according to a previously published
protocol [8c], as shown in Scheme 1.
Scheme 1
To evaluate the synthetic utility of MSA, we turned to nitrosation reactions, espe-
cially because of the mutagenic and carcinogenic properties of N-nitrosamines [9]. N-
nitrosamines have been used as pesticides, lubricants, and antioxidants [10]. They play a
ꢀ 2006 Verlag Helvetica Chimica Acta AG, Zürich

Helvetica Chimica Acta – Vol. 89 (2006)
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key role in the preparation of various N,N’-bonded functionalities, and their easy lith-
iation, followed by denitrosative electrophilic reaction, can be applied for electrophilic
substitutions of secondary amines at the a-position [11]. Some nitrosating agents such
as Fremyꢁs salt [12], N-halogenoamides/NaNO2 under phase-transfer conditions [13],
nitrogen tetroxide, [14] oxyhyponitrite [15], and oxalic acid [16] have been reported
before. In situ generated HNO2 from NaNO2 and an inorganic acid in H2O or H2O/
alcohol mixtures is the most general reagent for nitrosations. In this paper we report
the new heterogeneous system MSA/NaNO2 for the in situ generation of HNO2 for
N-nitrosation reactions.
Results and Discussion. – First, we were interested to examine MSA as a H+ source
in combination with various oxidants in organic solvents. For this reason, we chose wet
10% (w/w) MSA/NaNO2 for the N-nitrosation of a series of secondary amines
(1a–14a), which were transformed to the corresponding N-nitrosamines (1b–14b) in
CH2Cl2. All reactions were run under mild, heterogeneous conditions at room temper-
ature and gave, in good-to-excellent yields, the expected N-nitrosamines (Table).
All nitrosation reactions were complete in short time (ca. 15–20 min), and without
formation of any by-products. The products were obtained by simple filtration and
evaporation of the solvent. A further advantage of the new system is that the solid
acid can be easily recovered and used again after treatment with dilute HCl. Thus,
recovered MSA from the nitrosation reaction of, e.g., 14a was reused in another reac-
tion with NaNO2, which afforded 14b in 88% yield (compared to 90% in the first run;
see Table).
In the amines 12a, 13a, and 14a, there are two or three positions susceptible to nitro-
sation. With two equivalent N-atoms present, as in 12a, double nitrosation took place in
good yield (85%) when using 2 equiv. of reagent. As expected, no selective mononitro-
sation was observed with only 1 equiv. of MSA/NaNO2. In 13a, theoretically both O-
and N-nitrosation could take place, but only N-nitrosation to 13b was observed
under the applied reaction conditions. This result is in accord with the well-known
observation that N-nitroso forms are thermodynamically distinctly more stable than
the corresponding O-nitroso isomers. Finally, in the case of diphenylamine (14a), N-
nitrosation took place without C-nitrosation at the Ph rings, further highlighting the
chemoselectivity of our method.
Based on other literature reports [4][17], we propose that the reactions proceed via
formation of NO+ upon reaction of wet MSA with NaNO2 according to Scheme 2.
Finally, it is noteworthy to point to the role of H2O in the MSA/NaNO2 system. We
decided to run a series of parallel reactions, one under anhydrous conditions (anh.
MSA), the other under hydrous conditions (wet MSA). The results clearly indicated
that H2O is essential for the generation of HNO2 (see Scheme 2), since no nitrosation
was observed under strictly anhydrous conditions.
Conclusions. – Molybdate sulfuric acid (MSA) is a versatile solid acid in heteroge-
neous reactions in which H+ acts as catalyst or reagent. MSA is an efficient H+ source,
can be readily prepared, is insoluble in all organic solvents, can be readily handled,
poses no problem during workup (filtration), is inexpensive, and gives rise to clean,
fast, high-yielding reactions, as exemplified by a novel method for the selective N-nitro-

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Table. Nitrosation of the Secondary Amines 1a–14a with MSA/NaNO2. Conditions: secondary amine (2
mmol), wet MSA (1 mmol), NaNO2 (2 mmol), CH2Cl2 (8 ml), r.t.
No.
Substrate (a)
Product (b)a)
Time [min]
Yield [%]b)
1
2
3
4
5
6
Me2NH
Et2NH
(i-Pr)2NH
(C6H11)(Me)NH
(C6H11)2NH
Me2NÀNO
15
15
15
15
15
15
90
90
95
90
90
95
Et2NÀNO
(i-Pr)2NÀNO
(C6H11)(Me)NÀNO
(C6H11)2NÀNO
7
8
15
15
95
95
9
15
16
90
84
10
11
12c)
(C6H5)(Me)NH
(C6H5)(Me)NÀNO
17
15
90
85
13
20
90
14
(C6H5)2NH
(C6H5)2NÀNO
15
90
a) Identified by comparison of the physical and spectroscopic data with those given in the literature
b
c
[1–7][17]. ) Yield of isolated compound. ) With 2 mmol of 12a, 2 mmol of wet MSA, and 4 mmol of
NaNO2.
Scheme 2

Helvetica Chimica Acta – Vol. 89 (2006)
2925
sation of secondary amines. Structural investigations of MSA and similar solid acids, as
well as other applications of these systems in various organic reactions, are currently
under investigation.
We gratefully acknowledge partial support of this work by the Yasouj University, Yasouj, Iran.
Experimental Part
General. The amines 1a–14a and all other chemicals were purchased from Merck, Fluka, and
Aldrich. All reactions were monitored by TLC. The products were identified by comparison of their phys-
ical and spectroscopic data with those of authentic samples prepared according to previous methods
[1–7][17]. IR Spectra were recorded on a Jasco 680 FT-IR spectrometer; in cmÀ1
.
1H-NMR Spectra
were obtained on a Bruker DPX-300 apparatus; d in ppm.
Preparation of Molybdate Sulfuric Acid (=Dioxo[bis(sulfato-kO]molybdenum; MSA). To chlorosul-
fonic acid (23.30 g, 0.2 mol) in a 250-ml round-bottom flask immersed in an ice bath, anh. sodium molyb-
date (20.58 g, 0.1 mol) was added gradually. After completion of the addition, the mixture was agitated
for 1 h, which gave rise to crude MSA as a bluish-white solid, which was filtered off and washed with cold
H2O. Yield: 28 g (87.5%).
General Procedure for the N-Nitrosation of Secondary Amines. To a soln. of the amine (2 mmol) in
CH2Cl2 (8 ml), wet MSA (1 mmol; 10% (w/w)) and NaNO2 (2 mmol) were added. The heterogeneous
mixture was stirred at r.t., and the reaction was monitored by TLC (SiO2; hexane/AcOEt). After com-
pletion of the reaction (ca. 15–20 min), the mixture was filtered and washed with CH2Cl2 (4 ml).
Then, anh. Na2SO4 was added to the filtrate, and after 10 min, the mixture was filtered and the
CH2Cl2 was removed on a water bath at 40–508. The products 1b–14b were purified by simple distillation
(Table) and, when necessary, further purified by flash chromatography (SiO2; hexane/AcOEt). Some
physical and spectroscopic data of selected products are given below.
N-Methyl-N-nitrosomethanamine (1b). B.p. 1528. IR: 2850–2950 (CH), 1450 (N=O), 1350 (CÀN),
1375 (Me). 1H-NMR (CDCl3): 2.95 (s, Me); 3.69 (s, Me).
N-Nitrosopyrrolidine (6b). B.p. 2148. IR: 2850–2950 (CH), 1430 (N=O and CH2), 1300 (CÀN), 1050
(NÀN). 1H-NMR (CDCl3): 4.07 (t, 2 H); 3 .3 5t(, 2 H); 1.85 (q, 2 H); 1.89 (q, 2 H).
N-Methyl-N-nitrosoaniline (11b). Solid, decomposing at 708. IR: 3050–3100 (arom. CH); 2900–3000
(aliph. CH); 1500, 1600 (arom. C=C); 1450 (N=O and CH2); 1320 (CÀN); 1050 (NÀN). 1H-NMR
(CDCl3): 7.44–7.51 (m, 5 arom. H); 1.69 (s, Me). 13C-NMR: 30.5 (Me); 141.7; 128.8; 126.6; 118.5.
1,4-Dinitrosopiperazine (12b). Isolated as a mixture of two isomers having either a plane of symme-
try (isomer A) or a C2-axis (isomer B). M.p. 156–1608. IR: 2850–2950 (CH), 1430 (N=O and CH2), 1350
(CÀN). 1H-NMR (CDCl3): 4.50 (s, 4 H of B); 4.40 (t, 4 H of A); 4.60 (s, 4 H of A); 3.83 (s, 4 H of B). 13C-
NMR: 37.2 (A); 40.5 (B); 46.6 (B); 49.2 (A).
2,2’-(Nitrosoimino)diethanol (13b). Solid, decomposing at 2008. IR: 3200–3400 (OH), 2850–2950
(CH), 1100–1350 (CÀO and CÀN), 1450 (N=O and CH2), 1350 (CÀN), 1050 (NÀN). 1H-NMR
(CDCl3): 7.3( s, OH); 4.37 (t, CH2); 4.09 (t, CH2); 3.9 (t, CH2); 3.8 (t, CH2).
N-Nitroso-N-phenylaniline (14b). M.p. 64–668. IR: 3050–3100 (arom. CH); 1500, 1600 (arom. C=
C); 1450 (N=O and CH2); 1300 (CÀN); 1050 (NÀN). 1H-NMR (CDCl3): 7.0–7.3( m, arom. H).
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Received May 19, 2006