N-nitrosation of secondary amines using p-TSA-NaNO2 as a novel nitrosating agent under mild conditions

Article abstract of DOI:10.1080/00397910903009448

A combination of p-toluenesulfonic acid (p-TSA) and sodium nitrite was used as a novel effective nitrosating agent for the N-nitrosation of secondary amines to their corresponding nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.

Full text of DOI:10.1080/00397910903009448

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N-Nitrosation of Secondary Amines Using
p-TSA-NaNO2 as a Novel Nitrosating
Agent Under Mild Conditions
Sanjay P. Borikar a & Vincent Paul a
a Division of Organic Chemistry, National Chemical Laboratory, Pune,
India
Version of record first published: 04 Feb 2010.
To cite this article: Sanjay P. Borikar & Vincent Paul (2010): N-Nitrosation of Secondary Amines Using
p-TSA-NaNO2 as a Novel Nitrosating Agent Under Mild Conditions, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 40:5, 654-660
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Synthetic Communications1, 40: 654–660, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903009448
N-NITROSATION OF SECONDARY AMINES USING
p-TSA-NaNO2 AS A NOVEL NITROSATING AGENT
UNDER MILD CONDITIONS
Sanjay P. Borikar and Vincent Paul
Division of Organic Chemistry, National Chemical Laboratory, Pune, India
A combination of p-toluenesulfonic acid (p-TSA) and sodium nitrite was used as a novel
effective nitrosating agent for the N-nitrosation of secondary amines to their corresponding
nitroso derivatives under mild and heterogeneous conditions in moderate to excellent yields.
Keywords: N-nitrosation; nitroso amines; secondary amines; p-toluenesulfonic acid
INTRODUCTION
N-Nitrosation chemistry has been an interesting area for mechanistic organic
and biological chemists.[1] An effort has been made to combine both the synthetic
and mechanistic aspects of nitrosation and transnitrosation.[2,3] However, N-nitroso
compounds have also been reported to have strong carcinogenic and mutagenic
properties.[4] The nitrosation of secondary (and tertiary) amines has been thoroughly
studied, mainly because of the possible in vivo formation of nitrosoamines from nat-
urally occurring secondary amines and sources of nitrous acid in the environment
(foods, water, atmosphere, etc.). They have been used as pesticides, lubricants,
and antioxidants.[5] The N-nitrosation of amines is an important and well-established
reaction in organic synthesis.
These compounds are useful synthetic intermediates for the preparation of
various N,N-bonded functionalities. Lithiation was followed by reaction with elec-
trophiles and subsequent denitrosation, which could be applied to the electrophilic
substitution of the secondary amines at the a-carbon in a regio- and stereoselective
manner.[6] A partial double bond between two adjacent nitrogens in nitroso com-
pounds, due to hindered rotation between the N-N single bond, results in many
intriguing stereochemical features.[7] N-Nitroso compounds are generally synthesized
by N-nitrosation of the corresponding NH-containing compounds (amines, amides,
urea, etc.) by reaction with nitrosating agents.[8] The most common reagent for the
synthesis of nitrosoamines is nitrous acid, generated from sodium nitrite and mineral
acid in water or in mixed alcohol–water solvents.[9] In acidic medium (pH < 4), the
main nitrosating species are nitrosonium ion, dinitrogen trioxide (N2O3) and nitrosyl
Received February 5, 2009.
Address correspondence to Vincent Paul, Organic Chemistry Division, National Chemical
Laboratory, Pune, 411008, India. E-mail: vp.swamy@ncl.res.in
654

N-NITROSATION OF SECONDARY AMINES
655
halides.[10,11] In basic or neutral medium, nitroprusside[12,10b,11] and alkyl nitrites[13]
are effective nitrosating agents. Other nitrosating agents, such as N-methyl-N-
nitroso-p-toluenesulfonamide (MNTS),[14] moist SiO2=NaNO2 in the presence of
an acid (mostly solid acids or inorganic halides),[15] [NOþ-crown-H(NO3)2ꢀ],[16]
and more recently charcoal impregnated with N2O4,[17] tin(IV) chloride,[18] combi-
nation of alumina with methane sulfonic acid (AMA),[19] tungstate sulfuric acid
(TSA),[20] and acetic anhydride,[21] have also been reported. Several other nitrosating
agents, such as Angeli’s salt,[12] have also been used. There are some disadvantages
such as poor yield, harsh reaction conditions, and the need for large amounts of
reagent or catalyst. In N-nitrosation with AMA, the reactivity of methane sulfonic
acid is low; therefore they were reported with the combination of alumina, and
the yield is very poor compared to our method.
With regard to wide application of p-toluenesulfonic acid as reagent or catalyst
in organic chemistry, the new nitrosating agent can be introduced and is useful in this
direction. We think that the p-toluenesulfonic acid would be a proton source
superior to all of the reported acidic solid supports or acidic resins such as poly-
styrene sulfonic acid and Naflon-H[22] for running reactions under heterogeneous
conditions. In recent years, heterogenation of chemical systems is an active field in
industrial and laboratorial chemistry because of simplification in handling proce-
dures, reduction of corrosion, green chemistry, avoidance of by-products, easy
and clean reaction, and simple workup.
RESULTS AND DISCUSSION
We hereby report a new nitrosating agent. The generation of NOþ in the nitro-
sation reaction is the well-known key step. We have found that p-toluenesulfonic
acid is a cheap, commercially and readily available reagent used in many organic
synthesis. Therefore, we decided to apply p-toluenesulfonic acid–sodium nitrite as
the new nitrosating agent for secondary amines. We report a simple and chemoselec-
tive method for the effective nitrosation of secondary amines under mild and hetero-
geneous conditions. Because, the N-nitrosoamines are highly toxic and carcinogenic,
their production and dispersion are of interest to organic and biological chemists
alike. A key feature of the present article is simple workup with easy removal of
nitroso adducts as a result of the heterogeneous nature of the reaction. The different
types of secondary amines 1 were subjected to the nitrosation reaction in the
presence of p-toluenesulfonic acid and sodium nitrite in dichloromethane at room
temperature (Scheme 1).
The nitrosation reaction was performed under mild and completely
heterogeneous conditions at room temperature with moderate to excellent yields.
Scheme 1. N-Nitrosation of secondary amines.

656

657

658
S. P. BORIKAR AND V. PAUL
Scheme 2. Chemoselective N-nitrosation of N-methyl aniline.
Scheme 3. Di-N-nitrosation of piperazine (1K).
This reaction can be efficiently carried out by placing sodium nitrite, secondary
amine, p-toluenesulfonic acid, and dichloromethane into a reaction vessel and
vigorous stirring the resulting heterogeneous mixture at room temperature. The N-
nitrosoamines 2 can be obtained simply by filtration and evaporation of the solvent.
The results and reaction conditions are given in Table 1.
To access the chemoselectivity of this method, a competitive reaction was
performed between N-methyl aniline and anisole. It was observed that the second-
ary amine nitrosation occurred exclusively, whereas anisole remained intact in the
reaction mixture after 1 h. The nitrosation reaction of N-methyl aniline further
shows the chemoselectivity of the method as N-nitroso-N-methyl aniline is the
only product. Thus, this system behaves differently than some other reported
methods.[19] The nitrosonium ion (NOþ) attacks only the nitrogen sites of the sec-
ondary amines even where an aromatic moiety is connected directly to nitrogen
atom (Scheme 2).
Dinitrosation of 11 occurred easily using the appropriate molar ratio of the
reagents, but unfortunately mononitrosation of this amine 11 could not be achieved
even after altering the molar ratio of the reactants (Scheme 3).
The nitrosation of L-proline 12 furnished L-nitrosoproline in good yield,
and the stereocenter remained intact. This reaction was very slow as compared to
others.
CONCLUSION
In conclusion, a mild and efficient methodology has been developed employing
an inexpensive, commercially and readily available p-toluenesulfonic acid. The
procedure is easy to operate, with clean workup. The high yield, highly chemo-
and regioselective reactions and lack of C-nitrosation side product make this
methodology simple and attractive for large-scale operations.

N-NITROSATION OF SECONDARY AMINES
659
EXPERIMENTAL
1
The NMR spectra were recorded on a Bruker system (200 MHz for H and
75 MHz for 13C) using tetramethylsilane (TMS) as an internal standard. The reaction
were monitored by thin-layer chromatography (TLC) using 0.25-mm Merck
silica-gel plates (60F-254), and the products were purified by column chromato-
graphy on silica gel (60–120 mesh) obtained from M=s Spectrochem India Ltd. IR
spectra were recorded on a Perkin-Elmer Fourier transform (FT)–IR 16 PC
spectrometer.
Typical Experimental Procedure for N-Nitrosation of
Secondary Amines
p-Toluenesulfonic acid (1.14 g, 6.0 mmol) was slowly added to a stirred suspen-
sion of sodium nitrite (0.416 g, 6.0 mmol) and morpholine (0.5 g, 5.7 mmol) in
CH2Cl2 (10 mL) at room temperature. The reaction mixture was efficiently stirred
for 5 min, and the completion of the reaction was monitored by TLC. After com-
pletion of the reaction, the insoluble solid was removed by filtration, and the filtrate
was concentrated under reduced pressure to afford N-nitrosomorpholine (0.630 g,
97% yield, mp 29ꢁC) as a pale yellow powder.
ACKNOWLEDGMENT
This work was carried out under Indo-Hungarian Inter-Governmental joint
project (P90807) and is gratefully acknowledged.
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