Simple synthesis of N-aryl-2-nitrosoanilines in the reaction of nitroarenes with aniline anion derivatives

Article abstract of DOI:10.1055/s-0030-1258230

Anions generated from primary arylamines react with substituted nitrobenzenes to form ^H-adducts, which, under basic reaction conditions, undergo transformation to N-aryl-2-nitroso?amines. Competitive substitution of reactive halogens in the nit

Full text of DOI:10.1055/s-0030-1258230

PAPER
3865
Simple Synthesis of N-Aryl-2-nitrosoanilines in the Reaction of Nitroarenes
with Aniline Anion Derivatives
S
imple Synthes
b
is of
N
-Aryl-
i
2-nitro
g
soanilines 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 7 July 2010; revised 13 July 2010
nitroaryl)anilines,7a,b in a few exceptional examples of the
Abstract: Anions generated from primary arylamines react with
substituted nitrobenzenes to form sH-adducts, which, under basic
reaction conditions, undergo transformation to N-aryl-2-nitroso-
amines. Competitive substitution of reactive halogens in the nitro-
Fisher–Hepp rearrangement7c,d and in a complex mixture
of products of the reaction of aryliminodimagnesium re-
agents with nitroarenes.7e One example of apparently di-
arenes, which is observed in certain cases, can be controlled by the rect C-nitrosation of 1,3,5-tris(phenylamino)benzene has
also been reported.7f None of these reactions could be re-
solvent selected.
garded as a useful method for practical synthesis.
Key words: nucleophilic additions, arenes, amines, nitroso group
In our preliminary communication we have shown that
anions of arylamines react with substituted nitrobenzenes
to form, after protonation with acetic acid, N-aryl-2-ni-
trosoanilines, which could be isolated in acceptable
yields.8
A fundamental reaction of nitroaromatic compounds with
anionic nucleophiles is addition of the latter to the ni-
troarene ring at its activated positions with formation of s-
adducts.1 Nucleophilic aromatic substitution (SNAr) of
halogens and some other leaving groups is a well-known
result of the addition of the nucleophiles at positions oc-
cupied by such substituents. Formation of sH-adducts at
unoccupied positions of the nitroarene, although usually
faster, does not produce definite products until certain re-
quirements are met. The presence of oxidizing agents in
the reaction medium (oxidative nucleophilic substitution
of hydrogen, ONSH)1,2 or leaving groups in the nucleo-
phile molecule (vicarious nucleophilic substitution,
VNS)3 are, among other, beneficial circumstances that al-
low the sH-adducts to convert into stable products. Anoth-
er possible transformation of sH-adducts is the formal
intramolecular redox process, resulting in substitution of
hydrogen with parallel reduction of the nitro group to the
nitroso group.1a,4 In such reactions of carbanions, howev-
er, the so-formed substituted nitrosoarenes remain hypo-
thetical intermediates as they were not isolated. Their
formation was anticipated from the final products of sub-
sequent transformations, usually leading to fused hetero-
cycles.4 As a rule, protic medium or the presence of Lewis
acids are required for such reactions to occur. The Wohl–
Aue reaction of anilines with nitroarenes in the presence
of a base leading to phenazine derivatives is also believed
to proceed via cyclization of nitroso compounds, although
intermediate N-aryl-o-nitrosoanilines have not been de-
tected.5 On the other hand, when sH-adducts are formed in
the position para to the nitro group the corresponding 4-
nitrosodiarylamines can be obtained.5b,6
Their convenient synthesis permits them to be considered
as useful intermediates in organic synthesis and this was
demonstrated by a few representative transformations: re-
duction to 2-(arylamino)anilines, acid-catalyzed cycliza-
tion to give substituted phenazines, and reaction with
dimethyl malonate in the presence of potassium carbonate
to give quinoxalin-2(1H)-one derivatives. Beneficial use
of N-aryl-2-nitrosoanilines for the synthesis of these and
other types of heterocyclic compounds, which are current-
ly under investigation, prompted us to examine the title re-
action from both a synthetic and a mechanistic point of
view. During the preparation of this manuscript, an appli-
cation of our method for the synthesis of some N-aryl-2-
nitrosoanilines as N,N¢-chelate ligands in rhenium com-
plexes was reported.9
In this paper, we would like to present further examples of
the reaction of arylamine anions with nitroarenes, explor-
ing its scope and limitations. They were chosen with spe-
cial regard to the orientation of the reaction (ortho and
para positions in the nitroarene) and competition between
the formation of nitrosoarenes and other possible process-
es that could be an effect of the nitroarene–aniline anion
interactions under the applied conditions. The results, in-
cluding those obtained earlier (entries 1–9), are collected
in Table 1.
Initial examination of the selected base/solvent/quench
systems was performed, which revealed important fea-
tures of the reactions of preparative and mechanistic val-
ue. Formerly, searching for favorable conditions for the
reaction, we found that the best yields of N-aryl-2-ni-
trosoanilines 3 were obtained when at least three equiva-
lents of potassium tert-butoxide were used in the reaction,
thus such an excess of the base was applied in the prepar-
ative experiments presented in the preliminary paper. This
fact is, however, difficult to explain if 3 is formed, accord-
N-Aryl-2-nitrosoanilines have been reported in the litera-
ture in the photochemical rearrangements of N-acyl-N-(2-
SYNTHESIS 2010, No. 22, pp 3865–3872
x
x.
x
x
.
2
0
1
0
Advanced online publication: 25.08.2010
DOI: 10.1055/s-0030-1258230; Art ID: Z17410SS
© Georg Thieme Verlag Stuttgart · New York

3866
Z. Wróbel, A. Kwast
PAPER
ing to our tentative supposition depicted in Scheme 1, via complete formation of the latter, and as a result also of the
transformations of the protonated sH-adducts. An final product 3. In order to clarify this discrepancy, addi-
equimolar amount of the base seems to be sufficient for tional experiments were performed.
Table 1 Synthesis of N-Aryl-2-nitrosoanilines 3 in the Reaction of Nitroarenes 1 with Aniline Derivatives 2a
O
N
NO2
NH2
H
N
t-BuOK
solvent
R1
R2
+
4, 5, or 6
+
R2
R1
3
1
2
Entry
1e
R1
R2
Solvent
DMF
Procedure, time (min)b Nitrosoaniline Yieldc (%) Other productsd
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
A, 3
A, 3
A, 3
A, 3
A, 3
A, 5
A, 3
A, 5
A, 3
B, 10
C
3af
3b
3c
64
66
55
56
55
72
30
60
33
84
60
47
36
63
34
56
14
67
33
66
41/12
43
0
2e
4-OEt
3,4-Cl2
4-Me
4-Cl
DMF
3e
DMF
4e
DMF
3df
3e
5e
2,4-Cl2
4-OMe
DMF
4e (19)
6e
4-Me
4-Cl
DMF
3ff
3g
7e
4-Cl-2-CF3
DMF
8e
4-Cl-2-OMe
4-OMe
4-Cl
4-OEt
4-Br
DMF
3hg
3i
9e
DMF
10
11
12
13
14
15
16
17
18
19
20
21
22
23
2,6-Me2
2,6-Me2
4-OEt
4-Cl
DMF–THF
DMF–THF
DMF–THF
DMF
3j
2,4-Cl2
2,4-Cl2
H
3k
3l
A, 60
B, 15
B, 60
A, 5
C
4l (8)
3m
3m
3n
3o
5m (13)
H
4-Cl
THF
2-Cl-4-OMe
4-OMeh
4-F
4-OEt
4-Cl
DMF
4n (17)
5p (70)
DMF–THF
DMF
2,6-Me2
2,6-Me2
4-Cl
C
3p
3p
3q
3q
3r/3si
3t
4-F
THF
C
4-F
DMF
B, 5
B, 15
C
5m (37)
5m (4)
4-F
4-Cl
THF
2-NH2-5-NO2
2-Cl
4-Cl
DMF
4-Cl
THF
B, 30
A, 15
4t (15)
4-Cl
Hj
DMF–THF
3u
6 (32/60)k
a Numbering of R group positions corresponds to starting materials 1 and 2.
b Reaction conditions. A: –60 °C, 5–60 min, quenched with AcOH at –60 °C; B: –60 °C, 10–60 min, then poured into acidified H2O; C: –60
°C, 5 min, warmed to r.t. then poured into acidified H2O.
c Isolated yield.
d The structures shown on Figure 1. Yields (%) in parentheses.
e Reported in the preliminary communication.8
f Compounds fully characterized in the preliminary communication.8 See also ref.9
g This compound was earlier described erroneously as 2-chloro-4-methoxy isomer.8
h 1-Nitro-4-methoxynaphthalene.
i Two isomers, the structures shown on Figure 1.
j N-Methyl compound.
k Yields of the reactions with an equimolar amount or with a 2-fold excess of 1-chloro-4-nitrobenzene, respectively.
Synthesis 2010, No. 22, 3865–3872 © Thieme Stuttgart · New York

PAPER
Simple Synthesis of N-Aryl-2-nitrosoanilines
3867
O–
O–
aqueous ammonium chloride solution, or even into water,
followed by neutralization. Importantly, the chromato-
graphically determined yields of 3j were virtually equal in
each case.
O
N+
NO2
N
NHAr
NHAr
H+
t-BuOK
DMF
ArNH2
+
H
2
R
R
R
σH adduct
Moreover, when the reaction mixture was allowed to
warm up to room temperature for a period of one hour
then quenched, 3j was obtained in a yield only slightly
lower than that obtained when the reaction was finished at
–60 °C. It is not expected that the sH-adducts would be
stable at room temperature.
3
1
Scheme 1 Formation of nitrosoanilines 3
In order to use convenient gas chromatography analysis of
the reaction mixtures, 2,6-dimethylaniline was chosen for
the model reaction with nitroarenes. N-Aryl-2-nitroso-
anilines are quite stable compounds and they can be stored
at room temperature for extended periods without detect-
able degradation. However, they were found to be unsta-
ble at higher temperatures and, thus, monitoring of their
formation by gas chromatography was impossible. Fortu-
nately, nitrosoanilines derived from 2,6-dimethylaniline
showed much higher thermal stability, for which both
steric hindrance in the vicinity of the nitroso group and/or
the presence of substituents at ortho positions in the N-
aryl moiety that prevent potential cyclization processes,
could be responsible. Thus, 1-chloro-4-nitrobenzene was
reacted with 2,6-dimethylaniline in N,N-dimethylform-
amide at –60 °C using various amounts of potassium tert-
butoxide and the yield of 5-chloro-N-(2,6-dimethylphe-
nyl)-2-nitrosoaniline (3j) formed was measured by gas
chromatography using internal standards. All reactions
were performed by adding the nitroarene to a solution of
2,6-dimethylaniline and potassium tert-butoxide, so an
excess of the base/anilide was maintained during the addi-
tion of 1-chloro-4-nitrobenzene.
All the observations above indicate that the reaction is
more complex and that Scheme 1 does not reflect the ac-
tual course of the reaction. They suggest that the final
product is formed in the reaction mixture prior to the final
quench, the latter being nothing more than protonation of
the anionic form of the nitrosoaniline. Thus, the base is
also involved in the reaction step leading to the nitroso-
arene, possibly as depicted in Scheme 2.
A more detailed examination of the mechanistic aspects of
the reaction is in progress and will be published else-
where.
Most of the reactions under investigation were complete
in 5–15 minutes after mixing of the reagents at –60 °C.
For certain substrates, however, when the reaction mix-
ture was allowed to warm up to room temperature, the
yields were noticeably higher. Essentially, two solvents,
N,N-dimethylformamide and tetrahydrofuran, were used
for their different polarity. Usually, the reactions carried
out in tetrahydrofuran required a longer time to go to com-
pletion. Occasionally a N,N-dimethylformamide–tetrahy-
drofuran (2:1) mixture was applied for its behavior at low
temperatures, much better than that of N,N-dimethylform-
amide itself near its freezing point, while maintaining
dipolar properties of the latter.
The reaction was first conducted on a preparative scale us-
ing three equivalents of potassium tert-butoxide (Table 1,
entry 10), nitrosoaniline 3j was isolated in 84% yield,
characterized, and used to prepare the calibration mix-
tures.
The results collected in Table 1 show, that the reaction has
quite general character. Numerous anilines 2 enter the re-
action, provided their acidity allows for effective deproto-
nation by potassium tert-butoxide and, on the other hand,
nucleophilicity of their anions is sufficient for efficient
addition to the nitroarene. The choice of anilines, howev-
er, seems to be limited to primary ones. N-Methylaniline
reacted readily with 1-chloro-4-nitrobenzene, but the ex-
pected nitrosoaniline was not isolated. Instead, the ONSH
product of ortho hydrogen with the aniline was formed
(Table 1, entry 23).
It was found, that the yield of 3j was strongly depended on
the amount of the base used and after 10 minutes of the re-
action the yields, which did not change noticeably when
the reaction was continued, were 32%, 68%, and 92% at
one, two, and three equivalents of potassium tert-butox-
ide, respectively.
Another important observation was made: 3j was pro-
duced in the reaction not only when the reaction mixture
was acidified with acetic acid at low temperatures, as
practiced previously, but also when it was quenched by
pouring into dilute hydrochloric acid, dilute acetic acid,
The results seem to be in accord with the revised mecha-
nistic scheme, indicating that in the absence of the hydro-
_
O
O–
O–
O–
O–
N+
N
N
H
N
NHAr
N
– OH–
H+
t-BuOK
t-BuOK
Ar
Ar
1 + 2
3
H
R
R
R
σH adduct
nitroaniline dianion
Scheme 2 Revised scheme of the formation of nitrosoanilines from the sH-adducts
Synthesis 2010, No. 22, 3865–3872 © Thieme Stuttgart · New York

3868
Z. Wróbel, A. Kwast
PAPER
gen atom at the ortho amino group, formation of the furan the nitroso product 3p was formed exclusively
nitroso group becomes problematic, or much slower than (Table 1, entry 18).
the competitive oxidation of the intermediate dianion. The
oxidation process occurs most probably by means of the
starting nitroarene, as the yield of 6 can be significantly
improved when an excess of 2 is used.
When both, ortho and para positions in the nitroarene are
unsubstituted, sH-adducts at both these positions can be
formed. In highly polar, aprotic solvents, addition of nu-
cleophiles at the ortho position is usually faster than at the
Nitrobenzene and its substituted derivatives enter the re- para position,1,10 but when the equilibration of the sH-ad-
action with selectivity that is strongly dependent on the ducts take place, formation of the products of the reaction
substituents as well as on the solvent used. Nitroarenes at para position could also be expected. Indeed, in the re-
substituted in the para position formed 2-nitrosoanilines action of nitrobenzene with anion of 4-chloroaniline in
efficiently, and formation of ONSH products at the ortho N,N-dimethylformamide formation of sH-adducts at both
position was not observed. However, when the nitroarene positions occurred, but only the ortho isomer of nitroso-
possesses halogen atoms, or other leaving group at anoth- aniline 3m was isolated. The sH-adducts formed at the para
er activated position of the aromatic ring (ortho or para to position underwent an oxidation reaction, leading to the
the nitro group), substitution of this group with anilide corresponding 4-nitrodiarylamine 5m. In tetrahydrofuran,
(SNAr) can be a serious competing reaction. It is known, the latter was not observed and 3m was formed exclusive-
that addition of nucleophiles to the aromatic ring occurs, ly in good yield (entries 13 and 14). This seems to confirm
as a rule, much faster to the activated unsubstituted carbon the anticipated role of the hydrogen atom at the ortho
atom than to that substituted with potential leaving amino group in the transformation of sH-adducts into
groups, including even the most reactive halogens.1 This nitrosoanilines (Scheme 2).
statement was frequently confirmed in carbanion chemis-
Reaction of 4-chloroaniline with 2,4-dinitroaniline (entry
try, but in cases of hetero nucleophiles, the rule seems to
21) required an additional equivalent of base, since the lat-
be less rigid. In the reactions of substituted nitroarenes
ter is a strong N–H acid, thus under basic conditions exists
with aniline anions, competitive SNAr substitution of
in an anionic form. Nevertheless, due to the two nitro
chlorine was observed only when it was located at the po-
groups present in the aromatic ring it retains significant
electrophility. The structure of the ring exhibits cyclo-
hexadienoid character, originated from strong conjuga-
tion of the negatively charged amine nitrogen with the
sition ortho to the nitro group (entries 5, 12, 15, and 22).
In the reaction of 4-chloroaniline with 2,4-dichloro-1-ni-
trobenzene in N,N-dimethylformamide or N,N-dimethyl-
formamide–tetrahydrofuran mixture, the nitrosoaniline 3e
nitro groups. Thus, the addition of nucleophiles occurs as
was the major product and only ortho halogen was re-
a rule selectively at C3, i.e. at a position between the nitro
placed by the anilide to give 4e. Changing the order of
addition of the reagents, the solvent from N,N-dimethyl-
formamide to tetrahydrofuran, and also the amount of the
base, had little influence on the products ratio 3e/4e,
which varied from 3.2 to 4.6 depending on particular re-
action conditions.
groups.11 The reaction with 4-chloroaniline also follows
this rule, even so two isomeric nitroso compounds were
obtained depending on the nitro groups reduced (entry
21). The structure of the main product 3r shown in
1
Figure 1 was confirmed by standard H and 13C NMR
spectra, but those taken for the minor product 3s were not
Reaction of more sterically demanding 2,6-dimethyl- diagnostic due to extremely broad signals of protons and
aniline with 2,4-dichloro-1-nitrobenzene led to the ni- carbon atoms of the nitrosoaromatic ring, thus, the struc-
trosoarene 3k almost exclusively (entry 11). Substitution ture of 3s remains tentative.
of fluorine is much easier, thus it is observed also when
the halogen is located in the para position (entries 17–20).
1-Fluoro-4-nitrobenzene reacted with the anion of 4-chlo-
roaniline yielding both nitrosoaniline 3q and SNAr prod-
uct 5m in ratio 0.9. Impressive increase of this ratio to 16
was achieved by changing the solvent used from N,N-
dimethylformamide to tetrahydrofuran. The latter is
known to promote nucleophilic addition of carbanions
and other anionic nucleophiles selectively to the ortho po-
sition in nitroarenes.3
NO2
NO
Me
NO2
H
N
H
N
N
Cl
Cl
NO
NO2
NH2
NH2
Cl
3r
3s
6
NO2
R1
NO2
H
N
Analogous reaction of 1-fluoro-4-nitrobenzene with 2,6-
dimethylaniline carried out in N,N-dimethylformamide or
N,N-dimethylformamide–tetrahydrofuran gave mainly
substitution of the para-fluorine substituent (3p/5p 0.2),
which again proves the importance of steric hindrance in
the formation of sH-adducts, in this case due to the two ad-
jacent methyl groups in the 2,6-dimethylaniline. On the
other hand, in the same reaction carried out in tetrahydro-
R2
HN
R2
R1
4
5
4e R1 = 4-Cl, R2 = 4-Cl
4l R1 = 4-Cl, R2 = 4-OEt
4n R1 = 4-OMe, R2 = 4-OEt
4t R1 = H, R2 = 4-Cl
5m R1 = H, R2 = 4-Cl
5p R1 = H, R2 = 2,6-Me2
Figure 1
Synthesis 2010, No. 22, 3865–3872 © Thieme Stuttgart · New York

PAPER
Simple Synthesis of N-Aryl-2-nitrosoanilines
3869
5-Chloro-N-(3,4-dichlorophenyl)-2-nitrosoaniline (3c)
Red solid; mp 155 °C subl. (hexane).
ried out at low temperature in N,N-dimethylformamide or 1H NMR (400 MHz, CDCl3): d = 7.01 (m, 2 H), 7.14 (d, J = 8.4, 2.5
In summary, the nucleophilic substitution of ortho hydro-
gen in nitroarenes with anions of aniline derivatives car-
Hz, 1 H), 7.38 (d, J = 2.5 Hz, 1 H), 7.51 (d, J = 8.4 Hz, 1 H), 8.66
(br s, 1 H), 11.60 (br s, 1 H).
13C NMR (100 MHz, CDCl3):14 d = 114.0, 119.6, 124.0, 126.5,
130.5, 131.5, 133.8, 136.2, 145.0, 154.9.
tetrahydrofuran leads to N-aryl-substituted ortho-nitroso-
anilines in acceptable yields. This simple, one-step proce-
dure, starting with easily available materials, seems to be,
so far, the only convenient method of practical synthesis
of such bifunctional compounds, which are potentially
useful building blocks, suitable for synthesis of many
types of nitrogen heterocyclic structures. Our investiga-
tion on this, so far unexplored, field are now in progress.
MS (EI): m/z (%) = 302 (10), 301 (11), 300 (11), 299 (10), 285 (97),
283 (100), 271 (24), 269 (25), 237 (23), 235 (36), 200 (31).
HRMS (EI): m/z [M]+ calcd for C12H735Cl3N2O: 299.9624; found:
299.9630.
3,5-Dichloro-N-(4-chlorophenyl)-2-nitrosoaniline (3e)
Brown crystals; mp 183 °C.
1H NMR (400 MHz, CDCl3): d = 6.90 (d, J = 2.0 Hz, 1 H), 7. 09 (d,
J = 2.0 Hz, 1 H), 7.14–7.19 (m, 2 H), 7.40–7.45 (m, 2 H), 12.68 (br
s, 1 H).
13C NMR (100 MHz, CDCl3): d = 113.8, 119.7, 126.7, 130.2, 133.1,
133.8, 134.2, 144.9, 146.9, 150.9.
1
Melting points are uncorrected. H and 13C NMR spectra were re-
corded on a Bruker (500 MHz) (500 MHz for 1H and 125 MHz for
13C spectra), Varian-NMR-vnmrs600 (600 MHz for 1H spectra) and
a Varian Mercury 400 (400 MHz for 1H and 100 MHz for 13C spec-
tra) instruments at 298 K or 233 K in the case of 3e. Mass spectra
(EI, 70 eV) were obtained on an AMD-604 spectrometer. Silica gel
Merck 60 (230–400 mesh) was used for column chromatography.
THF was distilled from Na/benzophenone ketyl prior to use. DMF
was dried over CaH2, distilled and stored over molecular sieves.
MS (EI): m/z (%) = 302 (21), 301 (8), 300 (22), 285 (96), 283 (100),
271 (38), 269 (39), 237 (31), 235 (48).
HRMS (EI): m/z [M]+ calcd for C12H735Cl3N2O: 299.9624; found:
299.9612.
2-Chloro-4-(trifluoromethyl)-1-nitrobenzene,12 4-chloro-2-meth-
oxy-1-nitrobenzene,13 were obtained according to the literature. All
other reagents are commercially available.
3-Chloro-N-(4-chlorophenyl)-2-nitroso-5-(trifluorometh-
yl)aniline (3g)
Red solid; mp 110–112 °C.
1H NMR (400 MHz, CDCl3): d = 7.15–7.19 (m, 2 H), 7.19–7.21 (m,
1 H), 7.28 (d, J = 1.9 Hz, 1 H), 7.44–7.47 (m, 2 H), 12.51 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 113.1 (q, JC-F = 4.3 Hz), 115.1 (q,
JC-F = 4.3 Hz), 122.4 (q, JC-F = 272.6 Hz), 126.6, 130.3, 132.0,
133.4, 134.0, 138.6 (q, JC-F = 32.8 Hz), 147.1, 151.5.
N-Aryl-2-nitrosoanilines 3; General Procedures
Procedure A: To a cooled soln of t-BuOK (6 mmol, 672 mg) in the
specified solvent (12 mL) was added dropwise at –60 °C a soln of
aniline 1 (2 mmol), then nitroarene 2 (2 mmol) in the appropriate
solvent (2 mL each). The mixture was stirred at this temperature for
5–60 min (Table 1), and a cooled mixture of AcOH (1.5 mL) and
DMF (1.5 mL) was added in 1 portion. The cooling bath was re-
moved and the mixture was allowed to reach r.t., then it was poured
into H2O (ca. 50 mL) and extracted with EtOAc. The extract was
washed with H2O and brine and dried (Na2SO4). After evaporation,
the crude product mixture was subjected to column chromatography
(silica gel, hexane–EtOAc, hexane–CH2Cl2, or hexane–benzene).
MS (EI): m/z (%) = 336 (9), 334 (14), 319 (64), 317 (100), 303 (34),
269 (37).
HRMS (EI): m/z [M]+ calcd for C13H735Cl2F3N2O: 333.9887; found:
333.9874.
Procedure B: The reaction was carried out and worked up according
to the procedure A, except that after stirring of the reaction mixture
at –60 °C for the time specified (Table 1), the mixture was poured
into dilute aq HCl (ca. 50 mL) and extracted with EtOAc.
5-Chloro-N-(4-ethoxyphenyl)-3-methoxy-2-nitrosoaniline (3h)
Brown solid; mp 156–157 °C.
1H NMR (400 MHz, CDCl3): d = 1.43 (t, J = 7.0 Hz, 3 H), 4.05 (t,
J = 7.0 Hz, 2 H), 4.12 (s, 3 H), 6.26 (d, J = 1.8 Hz, 1 H), 6.48 (d,
J = 1.8 Hz, 1 H), 6.90–6.94 (m, 2 H), 7.09–7.14 (m, 2 H), 13.24 (br
s, 1 H).
Procedure C: The reaction was carried out and worked up accord-
ing to the procedure A, except that after 5 min of stirring of the re-
action mixture at –60 °C the cooling bath was removed and the
mixture was allowed to reach r.t., then it was poured into dilute aq
HCl (ca. 50 mL) and extracted with EtOAc.
13C NMR (100 MHz, CDCl3): d = 14.7, 56.8, 63.7, 99.4, 106.2,
115.4, 126.8, 128.3, 135.8, 146.8, 148.2, 157.9, 163.7.
Products 3a, 3d, and 3f were fully characterized in the preliminary
communication,8 and also in ref.9
MS (EI): m/z (%) = 308 (25), 306 (72), 289 (100), 261 (75), 246
(42), 232 (14).
5-Chloro-N-(4-ethoxyphenyl)-2-nitrosoaniline (3b)
Brown solid; mp 106–107 °C.
1H NMR (400 MHz, CDCl3): d = 1.44 (t, J = 7.1 Hz, 3 H), 4.06 (q,
J = 7.1, 2 H), 6.88–6.98 (m, 4 H), 7.11–7.18 (m, 2 H), 8.66 (br s, 1
H), 12.10 (br s, 1 H).
HRMS (EI): m/z [M]+ calcd for C15H1535ClN2O3: 306.0771; found:
306.0781.
N-(4-Bromophenyl)-5-methoxy-2-nitrosoaniline (3i)
Dark green solid; mp 138 °C.
13C NMR (100 MHz, CDCl3): d = 14.7, 63.7, 114.4, 115.5, 118.3,
1H NMR (400 MHz, CDCl3): d = 3.81 (s, 3 H), 6.36 (br s, 1 H), 6.62
(br d, J = 8.2 Hz, 1 H), 7.1–7.2 (m, 2 H), 7.5–7.6 (m, 2 H), 8.59 (br
d, J = 8.2 Hz, 1 H), 12.76 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 55.9, 93.8, 109.4, 119.6, 126.4,
132.8, 136.2, 136.5, 143.1, 153.8, 167.2.
126.7, 128.4, 134.3 (br), 141.9 (br), 144.5, 154.9, 157.9.
MS (EI): m/z (%) = 276 (18), 261 (33), 259 (100), 233 (34), 231
(84), 216 (29), 154 (29).
HRMS (EI): m/z [M]+ calcd for C14H1335ClN2O2: 276.0666; found:
276.0658.
MS (EI): m/z (%) = 308 (27), 306 (28), 291 (97), 289 (100), 227
(17), 182 (30), 154 (40).
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HRMS (EI): m/z [M]+ calcd for C13H1179BrN2O2: 306.0004; found:
MS (EI, 70 eV): m/z (%) = 306 (62) [M+], 289 (74), 261 (100), 246
305.9989.
(31), 218 (18).
HRMS (EI): m/z calcd for C15H1535ClN2O3: 306.0771; found:
306.0761.
5-Chloro-N-(2,6-dimethylphenyl)-2-nitrosoaniline (3j)
Yellow-green solid; mp 55–58 °C.
1H NMR (500 MHz, CDCl3): d = 2.10 (s, 6 H), 6.30 (d, J = 1.7 Hz,
1 H), 6.93 (d, J = 7.5 Hz, 1 H), 7.14–7.18 (m, 2 H), 7.19–7.23 (m, 1
H), 8.78 (br s, 1 H), 11.75 (br s, 1 H).
N-(4-Chlorophenyl)-4-methoxy-1-nitrosonaphthalen-2-amine
(3o)
Dark-green solid; mp 166–169 °C.
13C NMR (150 MHz, CDCl3): d = 18.0, 114.1, 118.3, 128.2, 128.8,
1H NMR (400 MHz, CDCl3): d = 3.88 (s, 3 H), 6.13 (s, 1 H), 7.15–
7.22 (m, 2 H), 7.40–7.45 (m, 2 H), 7.45–7.50 (m, 1 H), 7.59–7.65
(m, 1 H), 7.98 (dd, J = 8.1, 0.7 Hz, 1 H), 8.80 (dd, J = 8.1, 0.7 Hz,
1 H).
13C NMR (100 MHz, CDCl3): d = 56.2, 90.4, 121.6, 122.9, 123.0,
125.5, 127.0, 129.8, 130.8, 132.1, 133.8, 137.9, 144.4, 147.0, 165.2.
133.2, 134.6 (br), 135.9, 142.3 (br), 144.9, 155.0.
MS (EI, 70 eV): m/z (%) = 260 (2) [M+], 245 (100), 228 (7).
HRMS (EI): m/z calcd for C14H1335ClN2O: 260.0716; found:
260.0722.
3,5-Dichloro-N-(2,6-dimethylphenyl)-2-nitrosoaniline (3k)
Dark solid; mp 92–95 °C.
MS (EI, 70 eV): m/z (%) = 312 (100) [M+], 295 (44), 281 (17), 266
(22).
1H NMR (400 MHz, CDCl3): d = 2.08 (s, 6 H), 6.24 (d, J = 2.0 Hz,
1 H), 7.02 (d, J = 2.0 Hz, 1 H), 7.15–7.18 (m, 2 H), 7.20–7.25 (m, 1
H), 12.46 (br s, 1 H).
HRMS (EI): m/z calcd for C17H1335ClN2O2: 312.0666; found:
312.0655.
N-(2,6-Dimethylphenyl)-5-fluoro-2-nitrosoaniline (3p)
Dark-green solid; mp 75–77 °C.
13C NMR (100.6 MHz, CDCl3): d = 18.0, 113.9, 118.9, 128.5,
128.9, 132.7, 135.6, 135.7, 144.9, 146.5, 151.0.
1H NMR (400 MHz, CDCl3): d = 2.11 (s, 6 H), 5.91 (dd, JC-C = 2.2
Hz, JC-F = 11.5 Hz, 1 H), 6.70 (br s, 1 H), 7.12–7.23 (m, 3 H), 8.87
(br s, 1 H), 11.93 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 18.0, 99.3 (d, JC-F = 25.8 Hz),
107.1 (d, JC-F = 24.0 Hz), 128.14, 128.8, 133.3, 135.8, 137.2 (br),
144.6 (br), 154.8, 168.2 (JC-F = 264.7 Hz).
MS (EI, 70 eV): m/z (%) = 294 (8) [M+], 279 (100), 248 (7), 228
(10), 214 (6).
HRMS (EI): m/z calcd for C14H1235Cl2N2O: 294.0327; found:
294.0335.
3,5-Dichloro-N-(4-ethoxyphenyl)-2-nitrosoaniline (3l)
Brown solid; mp 79–81 °C.
MS (EI, 70 eV): m/z (%) = 244 (2) [M+], 229 (100), 212 (4), 198 (9).
1H NMR (400 MHz, CDCl3): d = 1.44 (t, J = 7.0 Hz, 3 H), 4.05 (q,
J = 7.0 Hz, 2 H), 6.86 (d, J = 2.0 Hz, 1 H), 6.92–6.97 (m, 2 H), 6.99
(d, J = 2.0 Hz, 1 H), 7.08–7.13 (m, 2 H), 12.87 (br s, 1 H).
HRMS (EI): m/z calcd for C14H13FN2O: 244.1012; found:
244.1020.
N-(4-Chlorophenyl)-5-fluoro-2-nitrosoaniline (3q)
Green crystals; mp 125–128 °C.
1H NMR (400 MHz, CDCl3): d = 6.68 (dd, JC-C = 2.2 Hz, JH-F
11.5 Hz, 1 H), 6.72–6.80 (m, 1 H), 7.18–7.22 (m, 2 H), 7.38–7.43
(m, 2 H), 8.70 (br s, 1 H), 12.06 (br s, 1 H).
13C NMR (100 MHz, CDCl3):12 d = 99.6 (d, JC-F = 25 Hz), 107.8 (d,
JC-F = 25 Hz), 126.1, 130.0, 132.3, 135.1, 144.5 (br), 154.8, 168.1
(JC-F = 263 Hz).
13C NMR (100 MHz, CDCl3): d = 14.7, 63.8, 114.3, 115.6, 118.8,
126.9, 127.6, 135.5, 144.4, 146.2, 150.7, 158.2.
=
MS (EI, 70 eV): m/z (%) = 310 (35) [M+], 293 (99), 265 (100), 251
(39), 217 (39), 188 (30).
HRMS (EI): m/z calcd for C14H1235Cl2N2O2: 310.0276; found:
310.0287.
N-(4-Chlorophenyl)-2-nitrosoaniline (3m)
Brown solid; mp 102–105 °C.
MS (EI, 70 eV): m/z (%) = 250 (5) [M+], 233 (100), 219 (41), 198
(8), 184 (38).
1H NMR (500 MHz, CDCl3): d = 7.04 (app. t, J = 7.5 Hz, 1 H), 7.12
(app. d, J = 8.4 Hz, 1 H), 7.20–7.23 (m, 2 H), 7.36–7.40 (m, 3 H),
8.71 (br s, 1 H), 11.83 (br s, 1 H).
HRMS (EI): m/z calcd for C12H835ClFN2O: 250.0309; found:
250.0300.
13C NMR (125 MHz, CDCl3):14 d = 114.8, 118.2, 125.9, 129.8,
3-Amino-N-(4-chlorophenyl)-6-nitro-2-nitrosoaniline (3r)
Dark brown solid; mp 210–211 °C.
1H NMR (400 MHz, DMSO-d6): d = 6.39 (d, J = 9.7 Hz, 1 H), 7.13–
7.18 (m, 2 H), 7.27–7.31 (m, 2 H), 8.05 (d, J = 9.7 Hz, 1 H), 8.66
(br s, 1 H), 10.41 (br s, 1 H), 11.01 (br s, 1 H).
13C NMR (100 MHz, CDCl3):14 d = 109.4, 119.8, 122.3, 124.3,
127.5, 128.7, 135.4, 141.8, 148.0.
MS (EI, 70 eV): m/z (%) = 292 (5) [M+], 291 (6), 275 (100), 258
131.6, 135.8, 138.0, 156.7.
13C NMR (125 MHz, 233 K, CDCl3): d = 114.5, 118.3, 125.8,
129.6, 131.3, 131.6, 134.7, 138.5, 140.7, 156.0.
MS (EI, 70 eV): m/z (%) = 232 (10) [M+, 215 (100), 201 (35), 179
(6), 167 (41), 139 (10).
HRMS (EI): m/z calcd for C12H935Cl N2O: 232.0403; found:
232.0397.
(87), 240 (19), 228 (17), 215 (12).
HRMS (ESI): m/z [M – H]– calcd for C12H8ClN4O3: 291.0279;
3-Chloro-N-(4-ethoxyphenyl)-5-methoxy-2-nitrosoaniline (3n)
Yellow-green solid; mp 130–137 °C.
found: 291.0271.
1H NMR (400 MHz, CDCl3): d = 1.44 (t, J = 7.0 Hz, 3 H), 3.74 (s,
3 H), 4.05 (q, J = 7.0 Hz, 2 H), 6.13 (d, J = 2.5 Hz, 1 H), 6.39 (d,
J = 2.5 Hz, 1 H), 6.91–6.95 (m, 2 H), 7.11–7.16 (m, 2 H), 13.57 (br
s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.7, 56.0, 63.7, 92.8, 110.4,
115.4, 126.8, 128.5, 140.0, 146.0, 149.5, 157.9, 166.7.
3-Amino-N-(4-chlorophenyl)-2-nitro-6-nitrosoaniline (3s)
Brown solid; mp 230–245 °C.
1H NMR (400 MHz, DMSO-d6):14 d = 6.54 (br s, 1 H), 7.13–7.21
(m, 2 H), 7.32–7.40 (m, 2 H), 8.32 (br s, 2 H).
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Simple Synthesis of N-Aryl-2-nitrosoanilines
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13C NMR (100 MHz, CDCl3):14 d = 110.4, 122.3, 129.0, 152.6.
MS (EI, 70 eV): m/z (%) = 292 (34) [M+], 291 (34), 275 (100), 259
HRMS (EI): m/z calcd for C12H935ClN2O2: 248.0353; found:
248.0347.
(24), 258 (23), 257 (70), 244 (19), 227 (33).
4-Chloro-N-(4-nitrophenyl)aniline (5m)
Pale brown crystals; mp 182–183 °C (Lit.17 180–181 °C).
HRMS (EI): m/z calcd for C12H9ClN4O3: 292.0363; found:
292.0356.
1H NMR (500 MHz, CDCl3): d = 6.91–6.94 (m, 2 H), 7.13–7.17 (m,
2 H), 7.33–7.37 (m, 2 H), 8.11–8.15 (m, 2 H).
MS (EI, 70 eV): m/z (%) = 248 (100) [M+], 218 (22), 167 (72).
3-Chloro-N-(4-chlorophenyl)-2-nitrosoaniline (3w)
Red solid; mp 134–136 °C.
1H NMR (500 MHz, CDCl3): d = 6.96 (d, J = 8.8 Hz, 1 H), 7.08 (d,
J = 7.4 Hz, 1 H), 7.18 (d, J = 8.5 Hz, 2 H), 7.25–7.30 (m, 1 H), 7.39
(d, J = 8.5 Hz, 2 H), 12.72 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 114.7, 119.0, 126.5, 129.9, 132.5,
133.1, 134.9, 138.6, 145.3, 152.5.
MS (EI, 70 eV): m/z (%) = 266 (19) [M+], 249 (100), 235 (36), 201
(37).
HRMS (EI): m/z calcd for C12H835Cl2N2O: 266.0014; found:
266.0020.
5-Chloro-2-nitro-N-methyl-N-phenylaniline (6)
Oil (Lit.18 50–53 °C).
1H NMR (400 MHz, CDCl3): d = 3.31 (s, 3 H), 6.80–6.84 (m, 2 H),
7.13 (dd, J = 9.1, 2.2 Hz, 1 H), 7.20–7.25 (m, 3 H), 7.32 (d, J = 2.2
Hz, 1 H), 7.76 (d, J = 8.8 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 262 (73) [M+], 245 (39), 215 (100), 180
(30).
HRMS (EI): m/z calcd for C13H1135ClN2O2: 262.0509; found:
262.0502.
5-Chloro-N-(4-chlorophenyl)-2-nitroaniline (4e)
Yellow solid; mp 158–159 °C (Lit.15 158–158.5).
References
1H NMR (500 MHz, CDCl3): d = 6.96 (dd, J = 9.2, 2.2 Hz, 1 H),
7.09 (d, J = 2.2 Hz, 1 H), 7.20–7.24 (m, 2 H), 7.40–7.45 (m, 2 H),
8.17 (d, J = 9.2 Hz, 1 H), 9.47 (br s, 1 H).
MS (EI, 70 eV): m/z (%) = 282 (100) [M+], 248 (25), 235 (20), 201
(34).
(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.
HRMS (EI): m/z calcd for C12H835Cl2N2O2: 291.9963; found:
(2) (a) Mąkosza, M.; Staliński, K. Pol. J. Chem. 1999, 73, 151.
(b) Mąkosza, M.; Staliński, K. Tetrahedron 1998, 54, 8797.
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(d) Adam, W.; Mąkosza, M.; Zhao, C. G.; Surowiec, M.
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Recl. 1997, 1805. (c) Mąkosza, M.; Kwast, A. J. Phys. Org.
Chem. 1998, 11, 341.
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(b) Wróbel, Z. Tetrahedron 1998, 54, 2607. (c) Wróbel, Z.
Eur. J. Org. Chem. 2000, 521. (d) Wróbel, Z. Pol. J. Chem.
1998, 72, 2384. (e) Wróbel, Z. Synlett 2004, 1929.
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(c) Serebryanyi, S. B. Uk. Khim. Zh. (Russ. Ed.) 1955, 21,
350.
281.9972.
5-Chloro-N-(4-ethoxyphenyl)-2-nitroaniline (4l)
Yellow solid; mp 128–131 °C.
1H NMR (400 MHz, CDCl3): d = 1.45 (t, J = 7.0 Hz, 3 H), 4.07 (q,
J = 7.0 Hz, 2 H), 6.66 (dd, J = 9.2, 2.2 Hz, 1 H), 6.93–6.99 (m, 3 H),
7.15–7.20 (m, 2 H), 8.14 (d, J = 9.2 Hz, 1 H), 9.44 (br s, 1 H).
13C NMR (100 MHz, CDCl3): d = 14.8, 63.8, 115.0, 115.7, 117.2,
127.3, 128.0, 130.1, 130.9, 142.5, 145.2, 157.8.
MS (EI, 70 eV): m/z (%) = 292 (100) [M+], 263 (58), 230 (14), 217
(18), 182 (12).
HRMS (EI): m/z calcd for C14H1335Cl N2O3: 292.0614; found:
292.0603.
N-(4-Ethoxyphenyl)-5-methoxy-2-nitroaniline (4n)
Yellow solid; mp 135–137 °C.
1H NMR (600 MHz, CDCl3): d = 1.44 (t, J = 7.0 Hz, 3 H), 3.70 (s,
3 H), 4.07 (t, J = 7.0 Hz, 2 H), 6.28 (dd, J = 9.5, 2.6 Hz, 1 H), 6.33
(d, J = 2.6 Hz, 1 H), 6.92–6.96 (m, 2 H), 7.18–7.21 (m, 2 H), 8.16
(d, J = 9.5 Hz, 1 H), 9.64 (br s, 1 H).
13C NMR (150 MHz, CDCl3): d = 14.8, 55.6, 63.7, 96.9, 106.1,
115.5, 126.9, 127.2, 128.9, 130.8, 147.0, 157.4, 165.6.
MS (EI, 70 eV): m/z (%) = 288 (100) [M+], 259 (63), 226 (11).
(6) (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 6388136, 2002.
(7) (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) Fischer, O.; Hepp, E. Justus
Liebigs Ann. Chem. 1889, 255, 145. (d) Titova, S. P.;
Arinich, A. K.; Gorelik, M. V. J. Org. Chem. USSR (Eng.
Transl.) 1986, 1407. (e) Okubo, M.; Inatomi, Y.; Taniguchi,
N.; Imamura, K. Bull. Chem. Soc. Jpn. 1988, 61, 3581.
(f) Jin, D.; Mandenhall, D. Tetrahedron Lett. 1996, 37, 4881.
(8) Wróbel, Z.; Kwast, A. Synlett 2007, 1525.
(9) Wirth, S.; Wallek, A. U.; Zernickel, A.; Feil, F.; Sztiller-
Sikorska, M.; Lesiak-Mieczkowska, K.; Bräuchle, C. h.;
Lorenz, I.-P.; Czyż, M. J. Inorg. Biochem. 2010, 104, 774.
(10) Mąkosza, M.; Lobanova, O.; Kwast, A. Tetrahedron 2004,
60, 2577.
HRMS (EI): m/z calcd for C15H16N2O4: 288.1110; found: 288.1118.
N-(4-Chlorophenyl)-2-nitroaniline (4u)
Orange crystals; mp 143–144 °C (EtOH) (Lit.16 142–144 °C).
1H NMR (400 MHz, CDCl3): d = 6.81 (ddd, J = 8.6, 7.0, 1.2 Hz, 1
H), 7.17 (dd, J = 8.6, 1.2 Hz, 1 H), 7.21–7.24 (m, 2 H), 7.36–7.41
(m, 3 H), 8.21 (dd, J = 8.6, 1.5 Hz, 1 H), 9.40 (br s, 1 H).
MS (EI, 70 eV): m/z (%) = 248 (100), M+, 214 (27), 201 (30), 167
(26).
(11) Mąkosza, M.; Voskresensky, S.; Białecki, M.; Kwast, A.
Pol. J. Chem. 1999, 73, 1969.
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PAPER
(12) Tsui, K.; Nakamura, K.; Konishi, N.; Okumura, H.; Matsuo,
M. Chem. Pharm. Bull. 1992, 40, 2399.
(13) Barluenga, J.; Fananas, F. J.; Sanz, R.; Fernandez, Y. Chem.
Eur. J. 1965, 397.
(14) Some signals very broad or invisible.
(15) Kottenhahn, A. P.; Seo, E. T.; Stone, H. W. J. Org. Chem.
1963, 28, 3114.
(16) Cross, B.; Williams, J. P.; Woodall, R. E. J. Chem. Soc. C
1971, 2085.
(17) Johnson, H. W. Jr.; Iwata, Y. J. Org. Chem. 1971, 36, 1921.
(18) Hunziker, F.; Kunzle, F.; Schmutz, J. Helv. Chim. Acta
1966, 49, 244.
Synthesis 2010, No. 22, 3865–3872 © Thieme Stuttgart · New York