Efficient procedure for chemoselective N-nitrosation of secondary amines with trichloromelamine-NaNO2

Article abstract of DOI:10.1134/S1070428007090229

A combination of trichloromelamine and sodium nitrite in the presence of wet silica gel was used as an effective nitrosating agent for the transformation of secondary amines into the corresponding N-nitroso derivatives under mild and heterogeneous conditions in good to excellent yields.

Full text of DOI:10.1134/S1070428007090229

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2007, Vol. 43, No. 9, pp. 1393–1396. © Pleiades Publishing, Ltd., 2007.
Published in Russian in Zhurnal Organicheskoi Khimii, 2007, Vol. 43, No. 9, pp. 1397–1400.
Efficient Procedure for Chemoselective N-Nitrosation
of Secondary Amines with Trichloromelamine–NaNO2*
A. Bamoniria, M. A. Zolfigolb, B. F. Mirjalilic, and F. Fallaha
a Department of Chemistry, College of Science, Kashan University, Kashan, 51167 Iran
e-mail: bamoniri@kashanu.ac.ir
b Chemistry Department, College of Science, Bu-Ali Sina University, Hamadan, Iran
c Department of Chemistry, College of Science, Yazd University, Yazd, Iran
Received April 14, 2005
Abstract—A combination of trichloromelamine and sodium nitrite in the presence of wet silica gel was used as
an effective nitrosating agent for the transformation of secondary amines into the corresponding N-nitroso
derivatives under mild and heterogeneous conditions in good to excellent yields.
DOI: 10.1134/S1070428007090229
Nitrosation chemistry has been a fruitful area for
mechanistic organic and biological chemists [1–3].
An effort has also been made to combine both syn-
thetic and mechanistic aspects of nitrosation or trans-
nitrosation [4, 5]. N-Nitrosation of amines is an im-
portant and well explored reaction in organic synthesis.
In the recent years N-nitroso amines have attracted
considerable interest due mainly to their strong muta-
genic and carcinogenic properties. They have also been
found to have vasorelaxant activity, and their use as
pesticides, antioxidants, and lubricant additives has
been described [6]. These compounds are also useful
synthetic intermediates for the preparation of various
N–N-containing functionalities. Furthermore, their easy
lithiation, followed by reaction with electrophiles and
subsequent denitrosation, ensures regio- and stereose-
lective electrophilic substitution at the α-carbon atom
[7]. Hindered rotation about the N–N bond owing to its
partially double character gives rise to many intriguing
stereochemical features of N-nitroso amines [8, 9]. The
most general reagent is nitrous acid generated from
sodium nitrite and mineral acid in water or mixed alco-
hol–water solvents [10, 11]. Other nitrosating agents,
such as Fremy’s salt [12], bis(triphenylphosphine)-
nitrogen(1+) nitrite [13], N-halo amides and sodium
nitrite under phase-transfer conditions [14] oxyhypo-
nitrite [15], dinitrogen tetraoxide and [NO+ ·crown·
H(NO3)2–] [16, 17], and solid acids or acetic anhydride
and sodium nitrite have also been used [18–22]. Very
recently, an excellent procedure was reported for the
selective N-nitrosation of amines, N-alkylamides, and
N-alkylureas by N2O4 supported on cross-linked poly-
vinylpyrrolidone (PVP–N2O4) [23]. Among many
other authors, we have recently demonstrated that
heterogeneous reagent systems have many advantages
such as simple experimental procedures, mild reaction
conditions, and minimization of chemical wastes com-
pared to the liquid-phase counterparts [18–22]. There-
fore, we tried to use a completely heterogeneous
system and examined nitrosation of secondary amines
under various conditions implying generation of HNO2
in situ from sodium nitrite and trichloromelamine.
A wide range of secondary amines I was subjected
to the nitrosation reaction in the presence of trichloro-
melamine (II), NaNO2, and wet silica gel (50 wt %) in
methylene chloride (Scheme 1). The reactions were
performed under mild and completely heterogeneous
conditions at room temperature, and they led to the
formation of the corresponding N-nitoso amines in
good to excellent yields (see table). The resulting
nitroso amines III can be isolated simply by filtration
and evaporation of the solvent. The reaction conditions
are given in table.
All our attempts to synthesize 1,3,5-tris(N-nitroso-
phenylamino)benzene were unsuccessful. In contrast to
the data reported in [24] on the nitrosation of 1,3,5-tris-
(phenylamino)benzene to give 1-nitroso-2,4,6-tris-
(phenylamino)benzene, among six possible nitrosation
products of N,N-diphenyl-1,4-phenylenediamine (Iaa)
* The text was submitted by the authors in English.
1393

BAMONIRI et al.
1394
Scheme 1.
NHCl
N
R1
N
II, NaNO2, SiO2/H2O
R1R2NH
N
N
O
R2
ClNH
NHCl
N
Ia–Iz
IIIa–IIIz
II
NO
H
N
N
NO
Ph
NH
Ph
N
Ph
N
Ph
N
N
N
ON
ON
NO
NO
IIIaa
IVaa
IIIab
IVab
H
N
NO
N
O
O
O
O
O
O
O
O
O
O
O
O
O
N
N
N
NO
IIIac
NO
NO
IIIаd
IVac
I, III, R = R′ = Me (a), Et (b), i-Pr (c); R = Me, R′ = cyclo-C6H11 (d); R = R′ = cyclo-C6H11 (e); RR′N = morpholino (f), piperi-
dino (g), 2-methylpiperidino (h), 4-hydroxypiperidino (i); RR′ = (CH2)6 (j), (CH2)4 (k); RR′N = 2,3-dihydro-1H-indol-1-yl (l),
1,2,3,4-tetrahydroquinolin-1-yl (m), 1,2,3,4-tetrahydroisoquinolin-2-yl (n), D-3-carboxy-1,2,3,4-tetrahydroisoquinolin-2-yl (o); R =
R′ = Ph (p); R = Ph, R′ = PhCH2 (q); R = R′ = PhCH2 (r); R = Ph, R′ = 2-naphthyl (s); R = Me, R′ = Ph (t); R = Ph, R′ = cyclo-
C6H11 (u); R = R′ = HOCH2CH2 (v); RR′N = 2-carboxypyrrolidin-1-yl (w), 2-carboxy-4-hydroxypyrrolidin-1-yl (x), 4-phenylpipera-
zin-1-yl (y), 4-(2-hydroxyethyl)piperazin-1-yl (z).
remained unchanged (see table). Amino acid deriva-
tives IVw, IVx, and IVo are precursors of mesoionic
moieties in an important class of dipolar heterocyclic
compounds with special properties [27]. Some N-ni-
troso amines reported in this paper (IVab, IVac) are
important models for mechanistic transnitrosation
studies. These compounds can also be useful in the
synthesis of special NO-releasing complexes [28].
No nitrosation occurred in the absence of wet silica
gel. This means that the presence of water molecules is
essential. Wet silica gel ensures a sufficient hetero-
geneous surface area for generation of HNO2 in situ
and facilitates work-up.
we isolated only N-mono- and N,N′-dinitroso deriva-
tives IIIaa and IVaa.
The nitrosation of N,N-diphenyl-1,4-phenylenedi-
amine (Iaa), piperazine (Iab), and diaza crown ether
Iac with 6 equiv of the reagent resulted in predominant
formation of the corresponding N,N′-dinitroso deriv-
atives IVaa–IVac, but we failed to effect selective
mononitrosation of these compounds. In all cases, mix-
tures of mono- and dinitroso compounds were formed,
and it was difficult to separate the products without
resorting to column chromatography. These findings
are consistent with the data reported by Singer et al.
[25, 26] on transnitrosation phenomena.
Thus the cheapness and availability of the reagents,
chemoselectivity, and high yields make the proposed
procedure attractive for organic chemists.
In order to demonstrate chemoselectivity of the
proposed procedure, a competitive reaction was per-
formed using diphenylamine (Ip) and anisole. After
30 min, the nitrosation of only secondary amine Ip was
observed, while anisole remained intact in the reaction
mixture. In the mitrosation of L-proline (Iw), 4-hy-
droxy-L-proline (Ix), and D-1,2,3,4-tetrahydroisoquin-
oline-3-carboxylic acid (Io), the chiral center also
EXPERIMENTAL
The initial compounds and reagents were com-
mercial products purchased from Fluka, Merck, and
Aldrich. The nitrosation products were characterized
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 43 No. 9 2007

EFFICIENT PROCEDURE FOR CHEMOSELECTIVE N-NITROSATION
1395
N-Nitrosation of secondary amines I with trichloromelamine (II)–NaNO2 in the presence of wet silica gel (50 wt %) in
methylene chloride at room temperature
II-to-I molar Time,
II-to-I molar Time,
Substrate
Producta
Yield,c % Substrate
Producta
IVr
IVs
IVt
IVu
IVv
IVw
IVx
IVy
IVz
IVaa, Vaa
Vaa
IVab, Vab
Vab
IVac, Vac
Vac
IVad
Yield,c %
ratiob
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
min
02
05
10
15
15
25
15
15
80
10
15
20
20
20
30
25
20
ratiob
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:3.5
1:6
min
15
25
25
20
20
60
90
25
60
30
25
15
10
25
20
00
d100d0
92
92
Ia
Ib
Ic
Id
Ie
If
Ig
Ih
Ii
Ij
Ik
Il
Im
In
Io
Ip
Iq
IVa
IVb
IVc
IVd
IVe
IVf
IVg
IVh
IVi
IVj
IVk
IVl
IVm
IVn
IVo
IVp
IVq
Ir
95
95
92
95
85
92
95
80
90
95
85
80
80
75
90
92
Is
It
Iu
Iv
Iw
Ix
Iy
90
90
85
70
70
85
75
Iz
20, 80
95
Iaa
Iaa
Iab
Iab
Iac
Iac
Iad
1:3.5
1:6
20, 80
95
1:3.5
1:6
25, 75
92
1:3.5
85
a
b
c
d
All of the isolated products are known compounds; their spectral and physical data have been reported in the literature [5–22].
Wet silica gel–substrate (I)–trichloromelamine molar ratio 4:1:1.
Yield of isolated products.
Conversion by chemical test (Cu2+).
by comparison of their spectral (1H and 13C NMR),
chromatographic (Rf), and physical data with those of
authentic samples [6, 8, 18–22].
CAUTION! All N-nitroso amines R1–N(NO)–R2
should be regarded as potentially powerful carcinogens
since most compounds of this type have been shown to
possess high activity in experimental animals [10].
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