2-Nitroso-N-arylanilines: Products of acid-promoted transformation of σH adducts of arylamines and nitroarenes

Article abstract of DOI:10.1055/s-2007-982534

Anions generated from arylamines react with substituted nitrobenzenes to form σ^H adducts, which, under protonation with acetic acid, undergo transformation to 2-nitroso-N-arylamines, susceptible to reduction, condensation and cyclization reactions. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-982534

LETTER
1525
2-Nitroso-N-arylanilines: Products of Acid-Promoted Transformation of
sH Adducts of Arylamines and Nitroarenes
2
-Nitroso-
N
-ary
b
lanilinesfro
i
m
H-
A
g
dducts niew Wróbel,* Andrzej Kwast
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44/52, 01-224 Warsaw, Poland
Fax +48(22)6318788; E-mail: wrobel@icho.edu.pl
Received 29 March 2007
formed in the position para to the nitro group, the corre-
Abstract: Anions generated from arylamines react with substituted
nitrobenzenes to form sH adducts, which, under protonation with
acetic acid, undergo transformation to 2-nitroso-N-arylamines,
susceptible to reduction, condensation and cyclization reactions.
sponding 4-nitrosodiarylamines can be obtained.9b,10
It should be mentioned here, that sH adducts of some tert-
alkylamines to nitrosoarenes undergo intermolecular oxi-
dation with the substrate, or with the external oxidant,
producing ortho and para N-(tert-alkyl)nitrosoanilines.11
Key words: nucleophilic, additions, arenes, amines, nitroso group
In order to acquire more information about the mechanism
of the complex reactions of nitroarenes with nucleophiles
leading to nitrogen heterocycles, we began to examine it
step by step, with special attention paid to the formation
of sH adducts and their interactions with proton or Lewis
acids. From several results of VNS and ONSH reactions
published by Mąkosza and co-workers it is known, that
under appropriate conditions, sH adducts of nucleophiles
to mononitroarenes can be formed in considerable con-
centration, and sometimes even almost quantitatively.4,12
The cine substitution of the nitro group by elimination of
HNO2 from the sH adducts of some carbanions and ni-
trobenzene derivatives, also requires their efficient forma-
tion as relatively stable intermediates.13 The elimination
proceeds upon acidification of sH adducts with strong
aqueous acids. On the other hand, definitely stable sH ad-
ducts were generated from nitroarenes and alkylmagne-
sium halides, which, when treated with hydrochloric acid,
underwent transformation to alkylated nitrosoarenes.14
The most general reaction of nucleophilic reagents with
nitroaromatics is their addition to the electron-deficient
positions ortho or para in the nitroarene with formation of
so-called s adducts.1 When a good leaving group is locat-
ed at such position it is often replaced by the nucleophile
in the well-known SNAr substitution process. Unsubstitut-
ed positions ortho or para in the nitroarene are more reac-
tive, but the corresponding sH adducts are not prone to
simple elimination of hydride anion in the SNAr process.
Nucleophilic substitution of hydrogen requires auxiliary
leaving groups located at the nucleophile [vicarious
nucleophilic substitution (VNS)]2 or at a side chain of the
nitroarene (cine and tele substitutions),1a,3 or presence of
external oxidants (oxidative nucleophilic substitution of
hydrogen) which causes that elimination of a proton
instead of a hydride ion takes place.1,4
In our studies on the synthesis of polycyclic nitrogen het-
erocycles, we investigated the reactions of carbanions and
other nucleophiles with nitroaromatic compounds, pro-
moted by the Lewis acids, leading to substituted quino-
line,5,6 1-hydroxyindole6 or 2,1-benzisoxazole7 and also
more complex polycyclic heterocyclic structures.8 The
common intermediates in these one-pot reactions seem to
be the sH adducts of the nucleophiles to the nitroarenes,
which supposedly undergo transformation to the corre-
sponding nitrosoarenes as a result of base-induced elimi-
nation of water, which can be assisted by a proton or a
Lewis acid. The whole process can be also considered as
a special case of the oxidative nucleophilic substitution of
hydrogen (ONSH), in which the intramolecular redox
process proceeds with reduction of the nitro group.
In this communication we would like to present the results
which show that anions of arylamines react with sub-
stituted nitrobenzenes to form sH adducts and the latter,
when protonated with acetic acid, undergo transformation
to nitroso compounds, isolated in reasonable yields
(Scheme 1).15
O–
+
O–
O
NO2
N
N
H
N
NHAr
t-BuOK
AcOH
DMF
Ar
ArNH2
+
H
DMF
R
R
R
H adduct
1a–e
2a–e
σ
3a–i
The similar Wohl–Aue reaction of an anilide anion with
nitroarenes, leading to phenazine derivatives, is also be-
lieved to proceed via cyclization of intermediate nitroso
compounds, although 2-nitrosodiarylamines have not
been detected.9 On the other hand, when sH adducts are
Scheme 1 Formation of nitrosoanilines 3a–i
The starting anilide anions were generated from aniline
derivatives 1a–e in the presence of an excess of t-BuOK
in DMF at –60 °C, and were subjected to the reaction with
substituted nitrobenzenes 2a–e. Then the sH adducts were
acidified with acetic acid. Usual workup and column
chromatography furnished pure products 3a–i (Table 1).
SYNLETT 2007, No. 10, pp 1525–1528
1
8
.0
6
.2
0
0
7
Advanced online publication: 07.06.2007
DOI: 10.1055/s-2007-982534; Art ID: G11407ST
© Georg Thieme Verlag Stuttgart · New York

1526
Z. Wróbel, A. Kwast
LETTER
Table 1 Formation of Nitrosoanilines 3 from Nitroarenes and Substituted Anilines
Entry
Arylamine
Ar
Nitroarene
R
2-Nitroso-N-arylaniline
Yield (%)a
1
1a
1b
1c
1d
1a
1d
1a
1b
1e
4-ClC6H4
4-EtOC6H4
3,4-diClC6H3
4-MeC6H4
4-ClC6H4
4-MeC6H4
4-ClC6H4
4-EtOC6H4
4-BrC6H4
2a
2a
2a
2a
2b
2c
2d
2e
2c
4-Cl
3a
3b
3c
3d
3e
3f
64
66
55
56
55b
72c
30
60
33
2
4-Cl
3
4-Cl
4
4-Cl
5
2,4-diCl
4-OMe
2-Cl-4-CF3
2-Cl-4-OMe
4-OMe
6
7
3g
3h
3i
8
9
a Isolated yield.
b Ortho chlorine substitution product (19%) was isolated.
c The starting nitroarene (12%) was recovered.
The para positions in all nitroarenes under investigations with the assumed ortho-nitrosoaniline structure and are
were, intentionally, occupied by substituents, thus there parallel to those described for N-(tert-butyl)-2-nitroso-
was no orientation issue in the formation of sH adducts anilines.11 While we believe that this is also valid for all
and consequently, only one regioisomer of each nitroso- products 3, additional spectral studies on their structure
amine 3 was formed.
and possible tautomerism are considered necessary.
Preliminary identification of products 3 was based on Up to date, 2-nitroso-N-arylanilines were reported in the
their high resolution mass spectra, which revealed the literature only as by-products in the photochemical
correct elemental composition for molecular ions. 1H and cyclization of N-acyl-2-nitroarylanilines,16a,b in the
13C NMR spectra of the ortho-substituted products (3e, Fisher–Hepp rearrangement16c and in a complex mixture
3g, 3h) are well recognized and are in accordance with the of products of the reaction of aryliminodimagnesium
assumed structures. On the other hand, almost all com- reagents with nitroarenes.16d The convenient method of
pounds with unsubstituted position ortho to the nitroso their synthesis, presented in this communication, allows
group (3a–d and 3i) show exceptionally broad or even to consider them as useful intermediates in organic syn-
undetectable signals for both ortho carbon atoms and also thesis, which can be demonstrated by a few representative
very broad signals for the aromatic ortho protons. A transformations (Scheme 2). For example, reduction of 3d
question that therefore arose was whether there was a was performed, depending on the applied conditions, with
possibility of nitroso/amine–oxime/imine tautomerism. preservation (Zn/AcOH) or removal of the halogen atom
For ortho nitrosoanilines reported in the literature, the (H2, Pd/C) from the aryl ring, which led to N-(2-amino-
structure is accepted as correct, although extensive exam- aryl)-N-arylamines 4a (yield 84%) and 4b (yield 75%),
inations have not been done.16 Much more inclusive spec- respectively.15 Acid-catalyzed cyclization of 3a resulted
tral analysis was completed for heterocyclic system of 4- in the formation of the expected 2,7-dichlorophenazine
nitroso-5-aminopyrazole17 and 6-amino-4-methylamino- 5.15 Characteristic reactivity of the nitroso group was re-
5-nitrosopyrimidine18 leading to the similar conclusion. vealed in the reaction of 3a with dimethyl malonate in the
On this basis, one can assume that the observed 1H and 13C presence of K2CO3, which led to 1-(4-chlorophenyl)-7-
NMR spectra of 3 could be explained considering the chloroquinoxalin-2(1H)-one (6) via the Ehrlich–Sachs
dynamic equilibrium between ArNO rotamers19 of the condensation followed by intramolecular acylation of the
ortho-aminonitrosoarenes. To support this hypothesis, for amine with the ester function.15
one of the products (3f) both 1H and 15N GHMBC experi-
The title nitrosoanilines can be of interest both for the syn-
ments were performed at lower temperature (–15 °C).
thesis of nitrogen-substituted arenes and nitrogen hetero-
They revealed the chemical shift values for 15N to be
cycles, and for the mechanistic elucidation of reactions of
–268.5 ppm and 334.0 ppm (relative to MeNO2). The
nitroarenes with anilides, if they are anticipated as inter-
former is situated in the nitroso group range, and the latter,
mediates. Our investigations in both these fields are now
showing one-bond N–H coupling (J = 91.9 Hz), proves
in progress.
the presence of the amino group, hence both are in accord
Synlett 2007, No. 10, 1525–1528 © Thieme Stuttgart · New York

LETTER
2-Nitroso-N-arylanilines from sH Adducts
1527
CDCl3 at 273 K. Mass spectra (EI, 70 eV) were obtained on
an AMD-604 spectrometer. Silica gel Merck 60 (230–400
mesh) was used for column chromatography.
O
NH2
NH2
N
NHAr
NHAr
NHAr
Zn/AcOH
H2 Pd/C
2-Chloro-4-trifluoromethylonitrobenzene20 (2d) and 4-
chloro-2-methoxynitrobenzene21 (2e) were obtained
according to the literature. All other reagents are
Ar = p-Tol
Ar = p-Tol
4b
Cl
Cl
commercially available.
3
4a
Preparation of 2-Nitroso-N-arylanilines 3a–i; General
Procedure
Ar = 4-ClC6H4
H2C(CO2Me)2
AcOH
COOMe
O
reflux
K2CO3
To a cooled solution of t-BuOK (6 mmol, 672 mg) in DMF
(2 mL) was added dropwise at –60 °C a solution of aniline 1
(2 mmol) in DMF (1 mL) and nitroarene 2 (2 mmol) in DMF
(1 mL). The mixture was stirred at this temperature for 2–5
min, and then a cooled mixture of AcOH (1.5 mL) and DMF
(1.5 mL) was added in one portion. The cooling bath was
removed and the mixture was allowed to reach the ambient
temperature, then it was poured into H2O (ca. 50 mL) and
extracted with EtOAc. The extract was washed with H2O
and brine, and dried with Na2SO4. After evaporation, the
crude product mixture was subjected to column
N
N
Cl
N
Ar
Cl
N
Cl
5
6
Scheme 2 Reactions of 2-nitroso-N-arylanilines 3
chromatography (SiO2, hexane–benzene) to obtain products
3a–i. The representative examples of 3 are described below.
3a: Brown solid; mp 124–125 °C. 1H NMR: d = 7.09 (dd,
J = 1.4, 10.2 Hz, 1 H), 7.05 (d, J = 1.7, 8.8 Hz, 1 H), 7.17–
7.24 (m, 2 H), 7.39–7.45 (m, 2 H), 8.68 (br s, 1 H), 11.82 (br
s, 1 H). 13C NMR: d = 114.0, 119.1, 126.1, 130.0, 132.2,
135.0, 140.4 (br), 144.8, 154.9, one signal not observed. MS
(EI): m/z (%) = 268 (7), 266 (11), 251 (66), 249 (100), 237
(18), 235 (26), 201 (22). HRMS (EI): m/z [M]+ calcd for
C12H8ON235Cl2: 266.0014; found: 266.0024.
References and Notes
(1) (a) Terrier, F. Nucleophilic Aromatic Displacement – The
Influence of the Nitro Group; Verlag Chemie: Weinheim,
1991. (b) Chupakhin, O. N.; Charushin, V. N.; van der Plas,
H. C. Nucleophilic Aromatic Substitution of Hydrogen;
Academic Press: San Diego, 1994. (c) Mąkosza, M. Russ.
Chem. Bull. 1996, 45, 491.
3d: Brown solid; mp 96–97 °C (hexane–benzene). 1H NMR:
d = 2.38 (s, 3 H), 6.93 (d, J = 8.6 Hz, 1 H), 7.05 (d, J = 2.0
Hz, 1 H), 7.13 (br d, J = 8.2 Hz, 2 H), 7.23 (br d, J = 8.2 Hz,
2 H), 8.67 (br s, 1 H), 12.08 (br s, 1 H). 13C NMR: d = 114.4,
118.5, 120.2, 124.9, 130.4, 133.4, 136.9, 141.8 (very br),
144.6, 154.9, one signal not observed. MS (EI): m/z (%) =
245 (6), 231 (42), 229 (100), 214 (22), 180 (25). HRMS
(LSI): m/z [M + H]+ calcd for C13H12ON235Cl: 247.0632;
found: 247.0621.
(2) (a) Mąkosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20,
282. (b) Mąkosza, M.; Wojciechowski, K. Liebigs Ann./
Recl. 1997, 1805. (c) Mąkosza, M.; Kwast, A. J. Phys. Org.
Chem. 1998, 11, 341.
(3) Suwiński, J.; Świerczek, K. Tetrahedron 2001, 57, 1639.
(4) (a) Mąkosza, M.; Staliński, K. Pol. J. Chem. 1999, 73, 151.
(b) Mąkosza, M.; Staliński, K. Tetrahedron 1998, 54, 8797.
(c) Mąkosza, M.; Staliński, K. Chem. Eur. J. 2001, 7, 2025.
(d) Adam, W.; Mąkosza, M.; Zhao, C. G.; Surowiec, M. J.
Org. Chem. 2000, 65, 1099.
(5) (a) Wróbel, Z. Tetrahedron Lett. 1997, 38, 4913.
(b) Wróbel, Z. Tetrahedron 1998, 54, 2607.
(6) Wróbel, Z. Eur. J. Org. Chem. 2000, 521.
(7) Wróbel, Z. Pol. J. Chem. 1998, 72, 2384.
(8) Wróbel, Z. Synlett 2004, 1929.
3f: Brown solid; mp 106–107 °C. 1H NMR (500 MHz,
CDCl3, –15 °C): d = 2.37 (s, 3 H), 3.76 (s, 3 H), 6.35 (d, J =
2.1 Hz, 1 H), 6.57 (dd, J = 2.1, 9.2 Hz, 1 H), 7.17–7.25 (m,
4 H), 8.48 (d, J = 9.2 Hz, 1 H), 12.97 (br s, 1 H). 13C NMR:
d = 20.9, 55.7, 93.5, 109.3, 124.7, 130.2, 133.9, 136.4, 137.7,
142.4, 153.6, 167.0. 15N NMR (GHMBC, CDCl3, d relative
to MeNO2, 273 K): d = –286.5 (N=O), 334 (JNH = 91.9 Hz,
NH). MS (EI): m/z (%) = 242 (16), 241 (15), 225 (100), 210
(15), 196 (15), 182 (21). HRMS (EI): m/z [M]+ calcd for
C14H14O2N2: 242.1055; found: 242.1051.
(9) (a) Wohl, A.; Aue, W. Ber. Dtsch. Chem. Ges. 1901, 34,
2442. (b) Wohl, A. Ber. Dtsch. Chem. Ges. 1903, 36, 4135.
(c) Serebryanyi, S. B. Ukr. Khim. Zh. (Russ. Ed.) 1955, 21,
350.
Reduction of 3d with Zn/AcOH: To a solution of 2-nitroso-
N-(4-tolyl)aniline 3d (0.15 mmol, 37.2 mg) in AcOH (1
mL), powdered Zn (150 mg) was added and the mixture was
stirred at ambient temperature, while monitored by TLC.
After the substrate had disappeared (ca. 1.5 h), the mixture
was diluted with EtOAc (10 mL), filtered, washed with H2O,
sat. NaHCO3 and H2O, and then dried with Na2SO4. The
solvent was evaporated and the crude product was purified
by column chromatography (SiO2, hexane–EtOAc, 5:1) to
give 4a (26.2 mg, 75%).
(10) (a) Stern, M. K.; Hileman, F. D.; Bashkin, J. K. J. Am. Chem.
Soc. 1992, 114, 9237. (b) Beska, E.; Toman, P.; Fiedler, K.;
Hronec, M.; Pinter, J. US Patent 6388136, 2002.
(11) Lipilin, D. L.; Churakov, A. M.; Ioffe, S. L.; Strelenko, Y.
A.; Tartakowsky, V. A. Eur. J. Org. Chem. 1999, 29.
(12) Lemek, T.; Mąkosza, M.; Stephenson, D. S.; Mayr, H.
Angew. Chem. Int. Ed. 2003, 42, 2793.
(13) Błażej, S.; Kwast, A.; Mąkosza, M. Tetrahedron Lett. 2004,
45, 3193.
(14) (a) Bartoli, G.; Rosini, G. Synthesis 1976, 270. (b) Bartoli,
G.; Leardini, R.; Medici, A.; Rosini, G. J. Chem. Soc.,
Perkin Trans. 1 1978, 692.
4a: Brown solid; mp 65–66 °C(hexane) [Lit.22 66.5–67.5 °C
(PE)]. 1H NMR: d = 2.68 (s, 3 H), 3.64 (br s, 2 H), 5.10 (br
s, 1 H), 6.69 (d, J = 8.4 Hz, 1 H), 6.72–6.76 (m, 2 H), 6.89
(dd, J = 2.3, 8.4 Hz, 1 H), 7.04–7.08 (m, 3 H). 13C NMR:
d = 20.6, 116.9, 117.0, 121.7, 123.7, 123.8, 129.9, 130.0,
131.5, 138.6, 141.3. MS (EI): m/z (%) = 232 (100), 217 (59).
HRMS (EI): m/z [M]+ calcd for C13H13N235Cl: 232.0767;
found: 232.0772.
(15) Melting points are uncorrected. 1H and 13C NMR spectra
were recorded on a Varian Mercury 400 instrument (400
MHz for 1H NMR and 100 MHz for 13C NMR spectra) in
CDCl3. Chemical shifts (d) are expressed in ppm referred to
TMS, and coupling constants are given in Hz. 15N GHMBC
experiment was performed on a Bruker 500 instrument in
Synlett 2007, No. 10, 1525–1528 © Thieme Stuttgart · New York

1528
Z. Wróbel, A. Kwast
LETTER
diluted with MeCN, filtered and evaporated. The crude
Catalytic Hydrogenation of 3d: 2-Nitroso-N-(4-
tolyl)aniline 3d (0.22 mmol, 55 mg), suspended (partially
soluble) in MeOH (1 mL), Et3N (0.44 mmol, 44 mg) and Pd/
C (10%, 25 mg) were stirred under H2 at r.t. for 30 min. The
catalyst was filtered off and the solution was evaporated to
dryness. The residue was diluted with EtOAc (10 mL) and
H2O (5 mL), and the organic layer was separated, washed
with H2O and dried with Na2SO4. After evaporation of the
solvents, the crude product was purified by column
chromatography (SiO2, hexane–EtOAc, 4:1) to deliver 4b
(37 mg, 84%).
product was purified by column chromatography (SiO2,
hexane–EtOAc, 5:1) to obtain pure 6 (20 mg, 85%).
6: Yellowish crystals; mp 160–161 °C. 1H NMR: d = 4.03 (s,
3 H), 6.71 (d, J = 2.2 Hz, 1 H), 7.23–7.27 (m, 2 H), 7.35 (dd,
J = 2.2, 8.6 Hz, 1 H), 7.60–7.65 (m, 2 H), 7.92 (d, J = 8.6 Hz,
1 H). 13C NMR: d = 55.3, 115.2, 125.2, 129.5, 130.2, 130.9,
132.1, 132.8, 135.5, 136.3, 138.9, 148.8, 151.8, 163.4. MS
(EI): m/z (%) = 350 (31), 348 (48), 263 (67), 261 (100), 226
(24), 191 (21). HRMS (EI): m/z [M]+ calcd for
C16H10N2O335Cl2: 348.0068; found: 348.0076.
4b: Brown solid; mp 77 °C(hexane). 1H NMR: d = 2.26 (s, 3
H), 3.67 (br s, 2 H), 5.26 (br s, 1 H), 6.65 (m, 2 H), 6.71–6.76
(m, 1 H), 6.78 (dd, J = 1.2, 7.8 Hz, 1 H), 6.95–7.00 (m, 1 H),
(16) (a) Fasani, E.; Pietra, S.; Albini, A. Heterocycles 1992, 33,
573. (b) Fasani, E.; Mella, M.; Albini, A. J. Chem. Soc.,
Perkin Trans. 1 1992, 2689. (c) Titova, S. P.; Arinich, A.
K.; Gorelik, M. V. J. Org. Chem. USSR (Eng. Transl.) 1986,
1407. (d) Okubo, M.; Inatomi, Y.; Taniguchi, N.; Imamura,
K. Bull. Chem. Soc. Jpn. 1988, 61, 3581.
(17) Holschbach, M. H.; Sanz, D.; Claramunt, R. M.; Infantes, L.;
Motherwell, S.; Raithby, P. R.; Jimeno, M. L.; Herrero, D.;
Alkorta, I.; Jagerovic, N.; Elguero, J. J. Org. Chem. 2003,
68, 8831.
7.00–7.05 (m, 2 H), 7.08 (dd, J = 1.4, 7.8 Hz, 1 H). 13
C
NMR: d = 20.4, 115.8, 116.1, 119.1, 123.8, 125.0, 128.8,
129.4, 129.8, 141.3, 142.62. MS (EI): m/z (%) = 198 (100),
183 (64), 91 (18). HRMS (EI): m/z [M]+ calcd for C13H14N2:
198.1157; found: 198.1147.
Cyclization of 3a to 2,7-Dichlorophenazine (5): 2-Nitroso-
N-(4-chlorophenyl)aniline 3a (0.1 mmol, 25 mg) in AcOH
(3 mL) was refluxed for 1.5 h. After cooling down, the
mixture was diluted with H2O and the precipitated crude
product was filtered off. Recrystallization from EtOH gave
pure 5 (20 mg (80%).
(18) Urbelis, G.; Susvilo, I.; Tumkevicius, S. J. Mol. Model.
2007, 13, 219.
(19) Buckley, P. D.; Furness, A. R.; Jolley, K. W.; Pinder, D. N.
Austr. J. Chem. 1974, 27, 21.
5: Pale yellow solid; mp 265–266 °C (Lit.23 266–268 °C).
MS (EI): m/z (%) = 250 (64), 248 (100), 213 (33).
Condensation of 3a with Methyl Malonate: 2-Nitroso-N-
(4-chlorophenyl)aniline 3a (0.067 mmol, 18 mg), methyl
malonate (0.14 mmol, 18 mg) and K2CO3 (75 mg) were
stirred in MeCN (1 mL) at r.t. for 30 min. The mixture was
(20) Tsui, K.; Nakamura, K.; Konishi, N.; Okumura, H.; Matsuo,
M. Chem. Pharm. Bull. 1992, 40, 2399.
(21) Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chem.
Eur. J. 1965, 397.
(22) Mangini, A. Gazz. Chim. Ital. 1935, 65, 1191.
(23) Vivian, D. L. J. Am. Chem. Soc. 1951, 73, 457.
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