Regioselective aromatic nucleophilic substitution in N-aryl-2- nitrosoanilines with oxygen and nitrogen nucleophiles

Article abstract of DOI:10.1055/s-0032-1316823

Aromatic nucleophilic substitution of halogens in N-aryl-2-nitrosoanilines with ammonia, alkylamines and alkoxide ions proceeds efficiently and highly regioselectively in the position para to the nitroso group. When two halogen atoms ortho and para are pr

Full text of DOI:10.1055/s-0032-1316823

PAPER
▌127
paper
Regioselective Aromatic Nucleophilic Substitution in N-Aryl-2-nitrosoanilines
with Oxygen and Nitrogen Nucleophiles
Nucleophilic Substitution in N-Aryl-2-nitrosoanilines
Zbigniew Wróbel,* Karolina Stachowska, Andrzej Kwast
Institute of Organic Chemistry, Polish Academy of Sciences, ul. Kasprzaka 44, 01-224 Warsaw, Poland
Fax +48(22)6326681; E-mail: zbigniew.wrobel@icho.edu.pl
Received: 16.10.2012; Accepted after revision: 10.11.2012
reaction proceeds efficiently with nitroarenes of sufficient
Abstract: Aromatic nucleophilic substitution of halogens in N-
electrophilic activity, however, it does not proceed if the
aryl-2-nitrosoanilines with ammonia, alkylamines and alkoxide
nitroarenes contain electron-donating substituents, such
as NR2, OR and particularly NHR or OH, that form anions
ions proceeds efficiently and highly regioselectively in the position
para to the nitroso group. When two halogen atoms ortho and para
are present, the latter is substituted exclusively. Oxidative substitu- under the reaction conditions. Since N-aryl-2-nitrosoani-
tion of hydrogen at the unsubstituted ortho position of the nitro-
soaniline ring does not compete with substitution of para halogen
atoms. The reaction allows the synthesis of N-aryl-2-nitrosoanilines
cles, it was of interest to expand our methods to these ni-
which cannot be obtained according to known methods.
lines with such electron-donating substituents can be
starting materials in the synthesis of valuable heterocy-
trosoanilines. It is well known that the nitroso group is a
strong electron-withdrawing substituent, even stronger
than the nitro group. Thus, we expected that it would be
Key words: arenes, amines, nucleophilic aromatic substitution, re-
gioselectivity, nitroso group
possible to introduce alkylamino, alkoxy and similar sub-
stituents into N-aryl-2-nitrosoanilines, obtained from
The main reaction pathway between nucleophilic agents
electron-deficient nitroarenes, via nucleophilic substitu-
and electron-deficient arenes is addition to the ring in ac-
tion of hydrogen or halogen atoms.
tivated positions. If there is a nucleofugal group X (Cl,
Despite the strong electron-withdrawing effect of the ni-
OMe, etc.) in one of such positions, the addition can result
troso group, nucleophilic substitution of halogen (SNAr
in the formation of σH- and σX-adducts. It has been unam-
reaction) or hydrogen (SNHAr) in nitrosoarenes has only
biguously shown that the rate of the former process is fast-
been sporadically reported.10–12 Indeed, nitrosoarenes are
rather unstable, due to their facile dimerization and redox
er than formation of σX-adducts. Since the addition is
associated with dearomatization of the ring, the σ-adducts
processes, they are not readily available and nucleophiles
tend to restore aromaticity. Fast departure of X– from σX-
tend to add to the nitrogen of the nitroso group.13
adducts results in nucleophilic aromatic substitution
(SNAr).1,2 Spontaneous departure of H– from σH-adducts
does not occur but these adducts can be transformed into
products of nucleophilic substitution of hydrogen (SNHAr)
in several ways,1c,3,4 and under suitable circumstances this
process dominates over the conventional SNAr reaction.4
Since N-aryl-2-nitrosoanilines have two activated posi-
tions, the 3- and 5-positions (ortho and para to the nitroso
group, respectively), nucleophilic agents can add to the
ring at both of them, regardless what substituents are pres-
ent at these positions. Addition at the position bearing any
leaving group would result in replacement of this group
with the nucleophile (SNAr reaction), while addition to the
unsubstituted ring position, which seems to be faster than
to any substituted position, may result in oxidative substi-
tution of hydrogen. All these reaction pathways, reported
for halonitrosoarenes,10–13 are also likely in the case of N-
aryl-2-nitrosoanilines (Scheme 1).
A few years ago we described nucleophilic substitution of
hydrogen in the reaction of nitroarenes with anilines in the
presence of a strong base. The reaction, in which σH-ad-
ducts are converted into substituted nitrosoarenes accord-
ing to an intramolecular redox stoichiometry, allowed for
the synthesis of a wide range of N-aryl-2-nitrosoanilines.5
The reaction is a general and practical method for the
preparation of these compounds5–9 which are otherwise
difficult to obtain. This simple and one-step synthesis of
N-aryl-2-nitrosoanilines is of great value because such
compounds are versatile starting materials for the synthe-
sis of a plethora of heterocyclic systems, for example,
phenazines,6 benzimidazoles7 and quinoxalinones.8
Preliminarily studied reactions of three differently substi-
tuted N-aryl-2-nitrosoanilines 1 that contain chlorine in
one or both activated positions with nucleophiles, such as
methoxide ion and alkylamines, revealed a striking differ-
ence in reactivity of the 3- and 5-positions in the substitu-
tion of halogen, and a low tendency to substitute
hydrogen. In the reaction of 1a (X = Cl, Y = H, Ar = 4-
ClC6H4), only substitution of the 5-chlorine was observed.
Substitution of the 3-chlorine in 1b (X = H, Y = Cl,
Ar = 2,6-Me2C6H3) occurred with methoxide ion to give
N-(2,6-dimethylphenyl)-3-methoxy-2-nitrosoaniline,
whereas the reactions with amines gave mixtures of un-
identified products. The reactions of dichloro compound
Although the scope of the nucleophilic substitution of hy-
drogen in nitroarenes with anilines to form N-aryl-2-nitro-
soanilines is rather wide, there are some limitations. The
SYNTHESIS 2013, 45, 0127–0133
Advanced online publication: 29.11.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0032-1316823; Art ID: SS-2012-T0815-OP
© Georg Thieme Verlag Stuttgart · New York

128
Z. Wróbel et al.
PAPER
1c (X = Y = Cl, Ar = 4-EtOC6H4) with all examined nu- reactions carried out in the potassium carbonate/methanol
cleophiles proceeded selectively with substitution of the system (Table 1, entries 1 and 16). In a few other reactions
5-chlorine, and no reaction at the nitroso group was ob- of 1 carried out under such conditions, this cyclization
served.
was also observed, but amounts of the resultant phen-
azines were rather insignificant.
Nu
O–
The cyclization of N-aryl-2-nitrosoanilines in the pres-
ence of potassium carbonate in methanol has been de-
scribed previously, and is an efficient method for the
synthesis of certain phenazine derivatives.6 Interestingly,
if 2-nitrosoaniline is N-substituted with a condensed, bi-
cyclic aromatic system (1-naphthalene or 8-quinoline) the
cyclization is so fast that possible substitution of 4-chlo-
rine was not observed.6 Detailed studies on the reactivity
and selectivity of the cyclization under various conditions
are currently in progress.
N
X
H
Y
N
Ar
final
products
O
O–
O
N
N
X
N
H
H
H
N
Y
Nu
Y
N
N
Nu
Ar
Ar
Ar
_
Nu
The results given in Table 1 confirmed the main feature of
the reaction which was revealed in the introductory exam-
ination, i.e. the high preference for the substitution of the
halogen located para to the nitroso group, over that locat-
ed ortho. When both the 3- and 5-positions were occupied
by chlorine atoms, only the latter was replaced (Table 1,
entries 4–6, and 14 and 15). This regioselectivity of the
substitution in 1 is consistent and was observed for all nu-
cleophiles studied (neutral alkylamines and alkoxide
ions), hence it is apparently an inherent feature of the
ortho-aminonitrosobenzene system. It seems to be caused
by efficient conjugation of the lone electron pair of the
ortho-amine nitrogen of the N-aryl-2-nitrosoanilines with
the strong electron-withdrawing nitroso group (Figure 1).
In the favored quinoid structure, the 3- and 5-positions are
markedly differentiated regarding their electrophilic ac-
tivity, and addition of a nucleophile occurs preferentially
to the 5-position.
X
X
1
ortho σ-adduct
X, Y = H, Hal
O–
O
N
H
N
N
H
N
Y
Y
Ar
Ar
Nu
X
Nu
para σ-adduct
Scheme 1 Possible ways of nucleophilic addition to N-aryl-2-nitro-
soanilines
The high regioselectivity in the nucleophilic substitution
of 1 may be advantageous for the synthesis of a variety of
substituted 2-nitrosoanilines. In order to examine the po-
tential value of the method, several N-aryl-2-nitrosoani-
lines 1a–j, possessing one or two halogen atoms in the 3-
and/or 5-position activated by the nitroso group, were
subjected to the reaction with ammonia, and primary and
secondary amines, as well as alcohols (Table 1). The reac-
tions with alcohols, used also as the solvent, were promot-
ed by potassium carbonate. Amines were used in a
fivefold excess and the reactions were carried out in ace-
tonitrile. For introduction of the unsubstituted amino
group, a 4 M ethanolic solution of ammonia was used. All
the reactions proceeded at ambient temperature, for the
time specified in Table 1.
_
O
O
N
N
+
NHAr
NHAr
_
Nu
Figure 1
Similar directing effects caused by the conjugation of
electron pairs of heteroatoms with a nitro group in ni-
troarenes have been observed previously in reactions of
carbanions with 2,4-dinitrophenolates,14 2,4-dinitroani-
line derivatives15 and N-substituted 2-nitropyrroles16
(Figure 2). In all these cases, reorganization of the elec-
tronic structure of the substrate, caused by conjugation,
led to selective or preferential addition of carbanions of
aryl chloromethyl sulfones to the most electrophilic posi-
tion of the ring.
Substitution of 5-fluoro and 5-chloro derivatives with alk-
oxides and secondary amines gave products 2 in high
yields. Relatively less nucleophilic primary alkylamines
reacted slower, much more efficiently with 5-fluoro- than
with 5-chloro-N-aryl-2-nitrosoanilines. On the other
hand, more reactive morpholine was able to substitute the
5-methoxy group in 1e, although after long reaction time.
Noteworthy, condensation of primary amines with the ni-
troso group was never observed.
The known literature data dealing with nucleophilic sub-
stitution in nitrosoarenes give rather limited information
on the regioselectivity of the reaction. In polyhalogenated
The only serious side process observed was cyclization of
1a and 1g with formation of phenazine derivatives in the
Synthesis 2013, 45, 127–133
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Nucleophilic Substitution in N-Aryl-2-nitrosoanilines
129
Table 1 Reaction of N-Aryl-2-nitrosoanilines 1 with Nucleophiles
NO
H
NO
H
N
Y
N
Y
base
R
R
NuH
+
Nu
X
1a,c–j
2a–r
Entry
X
Y
R
1
NuH
Conditions
Timea (h)
2
Yieldb (%)
1
Cl
Cl
Cl
Cl
Cl
Cl
F
H
H
H
Cl
Cl
Cl
H
H
H
H
H
H
H
Cl
Cl
H
4-Cl
4-Cl
4-Cl
4-OEt
4-OEt
4-OEt
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
H
a
a
a
c
c
c
d
d
d
d
d
a
e
f
MeOH
K2CO3, MeOH, r.t.
MeCN, r.t.
2
a
b
c
d
e
f
27c
85
86
81
85
74
84
95
87
85
90
81
74
88
78
53d
96
86
76
90
81
2
pyrrolidine
n-BuNH2
MeOH
2
3
MeCN, r.t.
7 d
2
4
K2CO3, MeOH, r.t.
MeCN, r.t.
5
pyrrolidine
n-BuNH2
n-BuNH2
morpholine
BnNH2
1
6
MeCN, r.t.
44
2
7
MeCN, r.t.
c
g
h
i
8
F
MeCN, r.t.
1
9
F
Et3N, MeCN, r.t.
MeCN, r.t.
7
10
11
12
13
14
15
16
17
18
19
20
21
F
HO(CH2)2NH2
NH3
2
F
EtOH, r.t.
24
2
j
Cl
morpholine
morpholine
morpholine
MeOH
MeCN, r.t.
g
g
k
l
OMe
Cl
Cl
Cl
Cl
F
MeCN, r.t.
22 d
24
4
MeCN, r.t.
f
K2CO3, MeOH, r.t.
K2CO3, MeOH, r.t.
K2CO3, MeOH, r.t.
K2CO3, glycol, r.t.
MeCN, r.t.
g
h
i
MeOH
3
m
n
o
p
q
r
OMe
H
H
MeOH
2
4-F
HO(CH2)2OH
CH2=CHCH2NH2
pyrrolidine
MeOH
2
F
H
4-F
i
2
Cl
Cl
OMe
OMe
4-OEt
4-OEt
j
MeCN, r.t.
3
j
K2CO3, MeOH, r.t.
7
a Not optimized; d = days.
b Yield of isolated products.
c Additionally, 2,6-dichlorophenazine (28%) was formed.
d Additionally, 2-chlorophenazine (22%) was formed.
nitrosobenzenes, substitution of both ortho10 and para11 In conclusion, the presented method allows the synthesis
halogens with nucleophiles was observed. Noteworthy, of N-aryl-2-nitrosoanilines which are difficult or impossi-
when the halonitrosoarene possesses an activated unsub- ble to obtain directly by nucleophilic substitution of hy-
stituted position, spontaneous oxidative substitution of drogen in nitroarenes with anions of anilines.5 It extends
hydrogen was much faster than the SNAr reaction of halo- the scope of available compounds potentially useful in the
gens.10,12
synthesis of many important heterocyclic systems. Aro-
matic nucleophilic substitution of halogens in activated
positions of N-aryl-2-nitrosoanilines proceeds efficiently
with various neutral and anionic nucleophiles under very
mild conditions; moreover, it is highly regioselective.
When two halogens ortho and para to the nitroso group
As indicated by the results in Table 1, substitution of hy-
drogen at the unoccupied 3-position in 1 was not ob-
served, even when an inactive nucleofugal group such as
methoxy was present at the 5-position (Table 1, entry 13).
© Georg Thieme Verlag Stuttgart · New York
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130
Z. Wróbel et al.
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1H NMR (500 MHz, CDCl3): δ = 6.55–6.60 (m, 1 H), 6.68–6.78 (m,
1 H), 7.11–7.17 (m, 2 H), 7.20–7.24 (m, 2 H), 8.83 (br s, 1 H), 12.11
(br s, 1 H).
_
_
NO2
NO2
Nu
13C NMR (125 MHz, CDCl3): δ = 99.5 (d, JC-F = 27 Hz), 107.5 (d,
J
C-F = 25 Hz), 116.8 (d, JC-F = 24 Hz), 127.1 (d, JC-F = 7 Hz), 132.3,
NO2
NO2
135.9, 145.0, 154.8, 161.2 (d, JC-F = 246 Hz), 168.1 (d, JC-F = 260
Hz).
NMe2
NMe2
+
MS (EI, 70 eV): m/z (%) = 234 (19), 220 (30), 217 (100), 203 (97).
HRMS (EI): m/z calcd for C12H8N2OF2: 234.0605; found:
234.0601.
_
NO2
Reaction of N-Aryl-2-nitrosoanilines 1 with Alcohols; General
Procedure
N
+
Me
NO2
N
Me
A N-aryl-2-nitrosoaniline 1 (0.5 mmol) was dissolved in the appro-
priate alcohol (5 mL), anhyd K2CO3 (953 mg, 6.8 mmol) was added
and the mixture was stirred magnetically at r.t. for the time specified
in Table 1. The mixture was then poured into H2O (50 mL) and ex-
tracted with EtOAc (3 × 50 mL). The combined extracts were
washed with H2O (100 mL) and brine (70 mL), then dried with
Na2SO4, and the solvent was evaporated. The crude product was pu-
rified by silica gel column chromatography (hexane–EtOAc, 4:1 to
1:1, unless otherwise specified) to obtain pure 2.
_
Nu
Figure 2
are present, the para halogen is substituted exclusively.
Oxidative substitution of hydrogen at activated, but un-
substituted, positions of the nitrosoarene ring, common in Reaction of N-Aryl-2-nitrosoanilines 1 with Amines; General
Procedure
reactions of polyhalonitrosoarenes, does not compete with
substitution of para halogens. As a consequence, the reac-
tion is clean and high-yielding.
A N-aryl-2-nitrosoaniline 1 (0.5 mmol) was dissolved in MeCN (10
mL) and the appropriate amine (2.5 mmol) was added, except for
benzylamine (64 mg, 0.6 mmol) added along with Et3N (121 mg,
1.2 mmol). The mixture was stirred at r.t. for the time specified in
Table 1. After the reaction was complete, the mixture was poured
into H2O (50 mL) and extracted with EtOAc (3 × 50 mL). The com-
bined extracts were washed with H2O (100 mL) and brine (50 mL),
then dried with Na2SO4, and the solvent was evaporated. The crude
product was purified by silica gel column chromatography (hex-
ane–EtOAc, 4:1 → 1:1, unless otherwise specified) to obtain pure 2.
1
Melting points are uncorrected. H and 13C NMR spectra were re-
corded on a Varian VNMRS 500 instrument (500 MHz for 1H and
125 MHz for 13C spectra) at 298 K (except for 2i, which were ob-
tained at 353 K). Chemical shifts (δ) are expressed in ppm referred
to TMS; coupling constants are in hertz. Mass spectra (EI, 70 eV)
were obtained on an AMD-604 spectrometer. Silica gel 60 (Merck,
230–400 mesh) was used for column chromatography. MeCN was
dried over CaH2, distilled and stored over molecular sieves. THF
was distilled from a sodium benzophenone ketyl solution. Known
N-aryl-2-nitrosoanilines 1 were obtained following procedures pub-
lished previously.5
Reaction of N-Aryl-2-nitrosoaniline 1d with Ammonia
N-(4-Chlorophenyl)-5-fluoro-2-nitrosoaniline (1d; 150 mg, 0.6
mmol) was dissolved in 4 M NH3 in EtOH (7 mL) and the reaction
mixture was kept at r.t. for 24 h, then diluted with H2O (50 mL) and
extracted with EtOAc (3 × 50 mL). The combined extracts were
washed with H2O (100 mL) and brine (80 mL), then dried with
Na2SO4, and the solvent was evaporated. The crude product was pu-
rified by silica gel column chromatography (hexane–EtOAc, 2:1) to
obtain pure 2j; yield: 133 mg (90%).
N-Aryl-2-nitrosoanilines 1b and 1i; General Procedure
To a cooled soln of t-BuOK (695 mg, 6.2 mmol) in anhyd THF (10
mL) was added dropwise at –70 to –78 °C a soln of the aniline (1.77
mmol) in THF (2 mL), then the nitroarene (1.77 mmol) in THF (2
mL). The mixture was stirred at that temperature for 30 min, then
poured into sat. aq NH4Cl (100 mL) and extracted with EtOAc
(3 × 50 mL). The combined extracts were washed with H2O (100
mL) and brine (80 mL), then dried with Na2SO4, and the solvent was
evaporated. The product was isolated by column chromatography.
N-(4-Chlorophenyl)-5-methoxy-2-nitrosoaniline (2a)
Chromatography eluent: CH2Cl2–EtOAc, 4:1.
Dark solid; yield: 35 mg (27%); mp 110–111 °C.
1H NMR (500 MHz, CDCl3): δ = 3.81 (s, 3 H), 6.34 (br s, 1 H),
6.59–6.65 (m, 1 H), 7.20–7.24 (m, 2 H), 7.37–7.41 (m, 2 H), 8.56–
8.64 (m, 1 H), 12.77 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 55.9, 93.8, 109.3, 126.1, 129.9,
131.8, 135.6, 136.7, 143.1, 153.8, 167.2.
3-Chloro-N-(2,6-dimethylphenyl)-2-nitrosoaniline (1b)
Chromatography eluent: CH2Cl2–hexane, 1:10 → 2:1.
Dark green solid; yield: 194 mg (42%); mp 110–111 °C.
1H NMR (500 MHz, CDCl3): δ = 2.07 (s, 6 H), 6.27 (dd, J = 8.9, 1.0
Hz, 1 H), 7.01 (dd, J = 7.4, 1.0 Hz, 1 H), 7.12–7.15 (m, 2 H), 7.17–
7.22 (m, 2 H), 12.58 (s, 1 H).
MS (EI, 70 eV): m/z (%) = 262 (30), 245 (100), 216 (16), 202 (13).
HRMS (EI): m/z calcd for C13H11N2O235Cl: 262.0509; found:
262.0510.
13C NMR (125 MHz, CDCl3): δ = 18.0, 115.0, 118.0, 128.1, 128.7,
133.2, 135.3, 135.7, 138.6, 144.7, 152.5.
N-(4-Chlorophenyl)-2-nitroso-5-(pyrrolidin-1-yl)aniline (2b)
Green solid; yield: 128 mg (85%); mp 200–202 °C.
MS (EI, 70 eV): m/z (%) = 260 (49), 245 (100), 228 (73), 194 (67).
HRMS (EI): m/z calcd for C14H13N2O35Cl: 260.0716; found:
260.0730.
1H NMR (500 MHz, CDCl3): δ = 2.01–2.07 (m, 4 H), 3.2–3.7 (m, 4
H), 5.86 (d, J = 2.2 Hz, 1 H), 6.38 (dd, J = 9.3, 2.2 Hz, 1 H), 7.21–
7.25 (m, 2 H), 7.32–7.36 (m, 2 H), 8.15 (d, J = 9.3 Hz, 1 H), 13.12
(s, 1 H).
5-Fluoro-N-(4-fluorophenyl)-2-nitrosoaniline (1i)
Chromatography eluent: hexane–EtOAc, 4:1.
13C NMR (125 MHz, CDCl3): δ = 25.2, 48.3, 89.1, 107.7, 125.7,
129.6, 130.6, 136.9, 138.9, 142.1, 151.8, 153.5.
Green solid; yield: 246 mg (59%); mp 100–101 °C.
Synthesis 2013, 45, 127–133
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PAPER
Nucleophilic Substitution in N-Aryl-2-nitrosoanilines
131
MS (EI, 70 eV): m/z (%) = 301 (81), 287 (100), 285 (21), 270 (39).
HRMS (EI): m/z calcd for C16H16N3O35Cl: 301.0982; found:
13C NMR (125 MHz, CDCl3): δ = 44.7, 66.2, 90.9, 106.8, 126.0,
129.8, 131.2, 136.2, 137.9, 142.3, 152.3, 156.0.
301.0985.
MS (EI, 70 eV): m/z (%) = 317 (100), 300 (72), 228 (36).
HRMS (EI): m/z calcd for C16H16N3O235Cl: 317.0931; found:
317.0926.
N1-Butyl-N3-(4-chlorophenyl)-4-nitrosobenzene-1,3-diamine
(2c)
Dark solid; yield: 130 mg (86%); mp 167–168 °C.
N1-Benzyl-N3-(4-chlorophenyl)-4-nitrosobenzene-1,3-diamine
(2h)
Dark solid; yield: 147 mg (87%); mp 194–196 °C.
1H NMR (500 MHz, CDCl3): δ = 4.36 (d, J = 5.4 Hz, 2 H), 5.30 (br
s, 1 H), 5.87 (d, J = 2.2 Hz, 1 H), 6.34 (dd, J = 9.1, 2.2 Hz, 1 H),
6.95–7.01 (m, 2 H), 7.22–7.25 (m, 3 H), 7.32–7.41 (m, 4 H), 8.20
(d, J = 9.1 Hz, 1 H), 13.20 (br s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 0.94 (t, J = 7.7 Hz, 3 H), 1.36–
1.44 (m, 2 H), 1.58–1.64 (m, 2 H), 3.12–3.18 (m, 2 H), 5.31 (br s, 1
H), 5.89 (d, J = 2.1 Hz, 1 H), 6.27–6.31 (m, 1 H), 7.19–7.23 (m, 2
H), 7.32–7.36 (m, 2 H), 8.08 (d, J = 9.1 Hz, 1 H), 13.35 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.7, 20.0, 31.0, 42.9, 87.7,
109.6, 125.9, 129.6, 130.9, 136.4, 139.9, 141.7, 151.9, 155.7.
MS (EI, 70 eV): m/z (%) = 303 (100), 286 (78), 229 (77), 209 (29).
13C NMR (125 MHz, CDCl3): δ = 47.5, 125.7, 127.2, 128.0, 128.5,
128.8, 129.0, 129.6, 130.9, 136.2, 136.6, 138.8, 142.1, 152.4, 154.8.
HRMS (EI): m/z calcd for C16H18N3O35Cl: 303.1138; found:
303.1135.
MS (EI, 70 eV): m/z (%) = 337 (80), 320 (34), 91 (100).
HRMS (EI): m/z calcd for C19H16N3O35Cl: 337.0982; found:
337.0987.
3-Chloro-N-(4-ethoxyphenyl)-5-methoxy-2-nitrosoaniline
(2d)5b
Dark solid; yield: 124 mg (81%).
2-({3-[(4-Chlorophenyl)amino]-4-nitrosophenyl}amino)ethan-
1-ol (2i)
Dark solid; yield: 124 mg (85%); mp 165–167 °C.
1H NMR (500 MHz, DMSO-d6, 353 K):17 δ = 3.22 (t, J = 5.8 Hz, 2
H), 3.57 (t, J = 5.8 Hz, 2 H), 4.57 (br s, 1 H), 6.11 (br s, 1 H), 6.45
(br s, 1 H), 7.32–7.44 (m, 4 H), 7.61 (br s, 1 H), 7.96 (br s, 1 H),
13.06 (br s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 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 = 2.4 Hz, 1 H), 6.65 (d,
J = 2.4 Hz, 1 H), 6.91–6.95 (m, 2 H), 7.12–7.16 (m, 2 H), 13.55 (br
s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.8, 56.0, 63.8, 92.9, 110.4,
115.5, 126.9, 128.6, 140.0, 146.1, 149.6, 157.9, 166.8.
MS (EI, 70 eV): m/z (%) = 306 (66), 289 (80), 261 (100), 246 (42).
13C NMR (125 MHz, DMSO-d6, 353 K):17 δ = 44.9, 59.1, 88.0,
108.2, 124.8, 128.9, 137.1, 140.9, 151.6, 156.5.
HRMS (EI): m/z calcd for C15H15N2O335Cl: 306.0771; found:
306.0762.
MS (EI, 70 eV): m/z (%) = 291 (100), 274 (68), 229 (65).
HRMS (EI): m/z calcd for C14H14N3O235Cl: 291.0774; found:
291.0780.
3-Chloro-N-(4-ethoxyphenyl)-2-nitroso-5-(pyrrolidin-1-yl)ani-
line (2e)
Dark solid; yield: 147 mg (85%); mp 170–172 °C.
N3-(4-Chlorophenyl)-4-nitrosobenzene-1,3-diamine (2j)
Dark red solid; yield: 133 mg (90%); mp 197 °C.
1H NMR (500 MHz, DMSO-d6): δ = 4.71 (s, 2 H), 5.99 (d, J = 2.2
Hz, 1 H), 6.32 (dd, J = 9.0, 2.2 Hz, 1 H), 7.17–7.21 (m, 2 H), 7.34–
7.38 (m, 2 H), 8.28 (d, J = 9.0 Hz, 1 H), 12.95 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 91.7, 108.9, 126.3, 129.7,
131.4, 136.1, 138.8, 143.3, 152.8, 155.1.
1H NMR (500 MHz, CDCl3): δ = 1.43 (t, J = 6.8 Hz, 3 H), 1.98–
2.06 (m, 4 H), 3.06–3.66 (m, 4 H), 4.04 (q, J = 6.8 Hz, 2 H), 5.61
(d, J = 2.4 Hz, 1 H), 6.50 (d, J = 2.4 Hz, 1 H), 6.87–6.91 (m, 2 H),
7.13–7.17 (m, 2 H), 13.49 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 14.8, 25.1, 48.2, 63.7, 88.1,
108.1, 115.2, 126.6, 130.0, 141.7, 145.7, 147.9, 153.0, 157.1.
MS (EI, 70 eV): m/z (%) = 345 (100), 331 (29), 300 (58), 285 (19).
HRMS (EI): m/z calcd for C18H20N3O235Cl: 345.1244; found:
345.1235.
MS (EI, 70 eV): m/z (%) = 247 (56), 230 (100), 216 (54).
HRMS (EI): m/z calcd for C12H10N3O35Cl: 247.0512; found:
247.0506.
N1-Butyl-5-chloro-N3-(4-ethoxyphenyl)-4-nitrosobenzene-1,3-
diamine (2f)
3-Chloro-N-(4-chlorophenyl)-5-(morpholin-4-yl)-2-nitrosoani-
line (2k)
Dark brown solid; yield: 128 mg (74%); mp 172–175 °C.
Brown solid; yield: 154 mg (88%); mp 210 °C.
1H NMR (500 MHz, CDCl3): δ = 0.92 (t, J = 7.3 Hz, 3 H), 1.32–
1.41 (m, 2 H), 1.43 (t, J = 7.0 Hz, 3 H), 1.53–1.61 (m, 2 H), 3.05–
3.12 (m, 2 H), 4.04 (q, J = 7.0 Hz, 2 H), 5.10 (br s, 1 H), 5.67 (d,
J = 2.2 Hz, 1 H), 6.39–6.42 (m, 1 H), 6.89–6.93 (m, 2 H), 7.12–7.16
(m, 2 H), 13.72 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 13.7, 14.8, 20.0, 30.9, 42.9, 63.7,
87.0, 109.5, 115.3, 126.7, 129.6, 142.6, 145.3, 147.9, 155.0, 157.4.
1H NMR (500 MHz, CDCl3): δ = 3.37–3.40 (m, 4 H), 3.77–3.81 (m,
4 H), 5.96 (d, J = 2.5 Hz, 1 H), 6.71 (d, J = 2.5 Hz, 1 H), 7.16–7.20
(m, 2 H), 7.34–7.39 (m, 2 H), 13.40 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 46.7, 66.1, 89.8, 107.6, 126.4,
129.9, 131.8, 135.8, 139.4, 146.9, 148.2, 155.7.
MS (EI, 70 eV): m/z (%) = 351 (100), 334 (37), 320 (27), 262 (46).
HRMS (EI): m/z calcd for C16H15N3O235Cl2: 351.0541; found:
351.0536.
MS (EI, 70 eV): m/z (%) = 347 (59), 333 (100), 302 (45), 290 (68).
HRMS (EI): m/z calcd for C18H22N3O235Cl: 347.1401; found:
347.1403.
3-Chloro-N-(4-chlorophenyl)-5-methoxy-2-nitrosoaniline (2l)
Brown solid; yield: 115 mg (78%); mp 131–132 °C.
N-(4-Chlorophenyl)-5-(morpholin-4-yl)-2-nitrosoaniline (2g)
Dark solid; yield: 151 mg (95%); mp 191–192 °C.
1H NMR (500 MHz, CDCl3): δ = 3.39–3.42 (m, 4 H), 3.78–3.82 (m,
4 H), 6.11 (d, J = 2.2 Hz, 1 H), 6.59 (dd, J = 9.4, 2.2 Hz, 1 H), 7.18–
7.22 (m, 2 H), 7.34–7.38 (m, 2 H), 8.33 (d, J = 9.4 Hz, 1 H), 12.90
(s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 3.78 (s, 3 H), 6.20 (d, J = 2.5 Hz,
1 H), 6.71 (d, J = 2.5 Hz, 1 H), 7.17–7.21 (m, 2 H), 7.39–7.42 (m, 2
H), 13.40 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 56.2, 93.0, 110.5, 126.6, 130.0,
132.5, 135.1, 138.3, 146.9, 149.7, 167.1.
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Z. Wróbel et al.
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MS (EI, 70 eV): m/z (%) = 296 (73), 279 (100), 265 (30), 231 (24).
HRMS (EI): m/z calcd for C13H10N2O235Cl2: 296.0119; found:
13C NMR (125 MHz, CDCl3): δ = 14.8, 25.1, 48.2, 56.0, 63.6, 83.0,
86.7, 115.1, 126.4, 130.7, 141.8, 145.2, 155.5, 156.7, 163.6.
296.0120.
MS (EI, 70 eV): m/z (%) = 341 (20), 327 (100), 323 (14).
HRMS (EI): m/z calcd for C19H23N3O3: 341.1739; found: 341.1735.
5-Methoxy-2-nitroso-N-phenylaniline (2m)
Chromatography eluent: hexane–toluene, 1:1.
N-(4-Ethoxyphenyl)-3,5-dimethoxy-2-nitrosoaniline (2r)
Brown solid; yield: 122 mg (81%); mp 165–167 °C.
Green solid; yield: 60 mg (53%); mp 66–68 °C.
1H NMR (500 MHz, CDCl3): δ = 3.79 (s, 3 H), 6.41 (br s, 1 H),
6.57–6.62 (m, 1 H), 7.26–7.29 (m, 3 H), 7.40–7.44 (m, 2 H), 8.56
(d, J = 8.7 Hz, 1 H), 12.93 (br s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 1.43 (t, J = 7.0 Hz, 3 H), 3.73 (s,
3 H), 4.05 (q, J = 7.0 Hz, 2 H), 4.05 (s, 3 H), 5.83 (AB, J = 2.4 Hz,
2 H), 6.90–6.94 (m, 2 H), 7.13–7.17 (m, 2 H), 13.97 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 55.9, 93.7, 109.5, 124.8, 126.5,
13C NMR (125 MHz, CDCl3): δ = 14.8, 55.8, 56.4, 63.7, 85.8, 89.8,
129.7, 136.9, 137.4, 142.6, 153.6, 167.2.
115.3, 126.7, 129.3, 140.4, 147.0, 157.6, 164.3, 169.5.
MS (EI, 70 eV): m/z (%) = 228 (26), 211 (100).
MS (EI, 70 eV): m/z (%) = 302 (100), 285 (61), 257 (80), 242 (50).
HRMS (EI): m/z calcd for C16H18N2O4: 302.1267; found: 302.1262.
HRMS (EI): m/z calcd for C13H12N2O2: 228.0899; found: 228.0889.
3,5-Dimethoxy-2-nitroso-N-phenylaniline (2n)
Dark solid; yield: 123 mg (96%); mp 126–128 °C.
N-(2,6-Dimethylphenyl)-3-methoxy-2-nitrosoaniline (3)
Dark solid; yield: 84.5 mg (66%); mp 144–146 °C.
1H NMR (500 MHz, DMSO-d6): δ = 3.80 (s, 3 H), 4.01 (s, 3 H),
6.02 (d, J = 2.3 Hz, 1 H), 6.12 (d, J = 2.3 Hz, 1 H), 7.27–7.30 (m, 1
H), 7.36–7.39 (m, 2 H), 7.43–7.48 (m, 2 H), 13.61 (br s, 1 H).
1H NMR (500 MHz, CDCl3): δ = 2.08 (s, 6 H), 4.14 (s, 3 H), 5.85
(dd, J = 8.9, 0.8 Hz, 1 H), 6.28 (dd, J = 7.9, 0.8 Hz, 1 H), 7.11–7.19
(m, 3 H), 7.21–7.26 (m, 1 H), 12.85 (s, 1 H).
13C NMR (125 MHz, DMSO-d6): δ = 56.1, 56.5, 88.1, 90.2, 124.6,
13C NMR (125 MHz, CDCl3): δ = 18.1, 56.4, 97.4, 106.2, 127.8,
126.2, 129.7, 136.7, 137.2, 146.8, 164.3, 169.5.
128.5, 133.9, 135.6, 135.8, 141.0, 150.2, 163.5.
MS (EI, 70 eV): m/z (%) = 258 (100), 241 (73), 227 (41), 198 (23).
HRMS (EI): m/z calcd for C14H14N2O3: 258.1004; found: 258.1015.
MS (EI, 70 eV): m/z (%) = 256 (24), 241 (100), 225 (35), 210 (58).
HRMS (EI): m/z calcd for C15H16N2O2: 256.1212; found: 256.1213.
2-{3-[(4-Fluorophenyl)amino]-4-nitrosophenoxy}ethan-1-ol
(2o)
Dark green solid; yield: 119 mg (86%); mp 120–121 °C.
Acknowledgment
The authors are deeply grateful to Professor M. Mąkosza for fruitful
discussion, encouragement and valued assistance during prepara-
tion of the manuscript.
1H NMR (500 MHz, CDCl3): δ = 3.95 (t, J = 4.6 Hz, 2 H), 4.06 (t,
J = 4.6 Hz, 2 H), 6.26 (br s, 1 H), 6.64 (d, J = 8.2 Hz, 1 H), 7.09–
7.16 (m, 2 H), 7.19–7.26 (m, 2 H), 8.60 (d, J = 8.2 Hz, 1 H), 12.69
(br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 60.9, 69.9, 94.6, 109.0, 116.7 (d,
Supporting Information for this article is available online at
JC-F = 23 Hz), 127.1 (d, JC-F = 8.6 Hz), 132.7, 137.4, 143.1, 153.8,
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
161.0 (d, JC-F = 246.1 Hz), 166.2.
MS (EI, 70 eV): m/z (%) = 276 (100), 262 (64), 259 (59).
References
HRMS (EI): m/z calcd for C14H13N2O3F: 276.0910; found:
(1) (a) Bunnet, J. F.; Zahler, R. E. Chem. Rev. 1951, 49, 273.
(b) Miller, J. Aromatic Nucleophilic Substitution; Elsevier:
Amsterdam, 1968. (c) Terrier, F. Nucleophilic Aromatic
Displacement: The Influence of the Nitro Group; J. Wiley &
Sons: New York, 1991.
(2) (a) Crampton, M. R.; Emokpae, T. A.; Isanbor, C. Eur. J.
Org. Chem. 2007, 1378. (b) Crampton, M. R.; Emokpae, T.
A.; Isanbor, C. J. Phys. Org. Chem. 2006, 19, 75.
(c) Mancini, P. M.; Fortunato, G. G.; Vottero, L. R. J. Phys.
Org. Chem. 2004, 17, 138.
276.0916.
N3-(4-Fluorophenyl)-4-nitroso-N1-(prop-2-en-1-yl)benzene-1,3-
diamine (2p)
Dark red solid; yield: 103 mg (76%); mp 115–116 °C.
1H NMR (500 MHz, CDCl3): δ = 3.76–3.82 (m, 2 H), 5.17–5.26 (m,
2 H), 5.38–5.44 (m, 1 H), 5.78–5.88 (m, 2 H), 6.30 (dd, J = 9.2, 2.3
Hz, 1 H), 7.04–7.11 (m, 2 H), 7.19–7.24 (m, 2 H), 8.11 (d, J = 9.2
Hz, 1 H), 13.25 (br s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 45.7, 88.5, 109.2, 116.3 (d, JC-F
=
(3) (a) Chupakhin, O. N.; Charushin, V. N.; van der Plas, H. C.
Nucleophilic Aromatic Substitution of Hydrogen; Academic
Press: San Diego, 1994. (b) van der Plas, H. C. Adv.
Heterocycl. Chem. 2004, 86, 1. (c) Gulevskaya, A. V.;
Pozharskii, A. F. Adv. Heterocycl. Chem. 2007, 93, 57.
(d) Charushin, V. N.; Chupakhin, O. N. Mendeleev
Commun. 2007, 17, 249.
(4) (a) Mąkosza, M.; Wojciechowski, K. Chem. Rev. 2004, 104,
2631. (b) Mąkosza, M. Synthesis 2011, 2341. (c) Mąkosza,
M. Chem. Soc. Rev. 2010, 39, 2855.
(5) (a) Wróbel, Z.; Kwast, A. Synlett 2007, 1525. (b) Wróbel,
Z.; Kwast, A. Synthesis 2010, 3865.
(6) Kwast, A.; Stachowska, K.; Trawczyński, A.; Wróbel, Z.
Tetrahedron Lett. 2011, 52, 6484.
(7) Wróbel, Z.; Stachowska, K.; Grudzień, K.; Kwast, A. Synlett
2011, 1439.
22.4 Hz), 117.8, 126.8 (d, JC-F = 8.3 Hz), 133.0, 133.5, 140.2, 141.7,
152.2, 155.4, 160.5 (d, JC-F = 247.1 Hz).
MS (EI, 70 eV): m/z (%) = 271 (100), 257 (72), 199 (58), 216 (41).
HRMS (EI): m/z calcd for C15H14N3OF: 271.1121; found:
271.1117.
N-(4-Ethoxyphenyl)-3-methoxy-2-nitroso-5-(pyrrolidin-1-
yl)aniline (2q)
Chromatography eluent: acetone.
Dark red solid; yield: 153 mg (90%); mp 168–169 °C.
1H NMR (500 MHz, CDCl3): δ = 1.43 (t, J = 7.0 Hz, 3 H), 1.90–
2.04 (m, 4 H), 3.2–3.7 (m, 4 H), 4.01 (s, 3 H), 4.03 (q, J = 7.0 Hz, 2
H), 5.42 (d, J = 2.1 Hz, 1 H), 5.56 (d, J = 2.1 Hz, 1 H), 6.86–6.90
(m, 2 H), 7.15–7.18 (m, 2 H), 13.84 (br s, 1 H).
Synthesis 2013, 45, 127–133
© Georg Thieme Verlag Stuttgart · New York

PAPER
(8) Gościk, A.; Królikiewicz, M.; Kwast, A.; Pawłowski, R.;
Nucleophilic Substitution in N-Aryl-2-nitrosoanilines
Org. Chem. 2010, 46, 1639. (c) Gornostaev, L. M.;
133
Stachowska, K.; Turska, I.; Wróbel, Z. Helv. Chim. Acta
2012, in press, DOI: 10.1002/hlca.201200304.
Bocharova, E. A.; Dolgushina, L. V.; Bagryanskaya, I. Yu.;
Gatilov, Yu. V. Russ. J. Org. Chem. 2010, 46, 693.
(13) Zumman, P.; Shah, B. Chem. Rev. 1994, 94, 1621.
(14) Mąkosza, M.; Ludwiczak, S. J. Org. Chem. 1984, 49, 4562.
(15) Mąkosza, M.; Voskresensky, S.; Białecki, M.; Kwast, A.
Pol. J. Chem. 1999, 73, 1969.
(16) Mąkosza, M.; Kwast, E. Tetrahedron 1995, 51, 8339.
(17) Due to low solubility of 2i in other deuterated solvents, the
spectra were recorded in DMSO-d6. While a complex
mixture of isomeric forms was observed in this solvent at
room temperature, acceptable spectra could be obtained at
80 °C, although two 13C signals were not visible.
(9) Wirth, S.; Wallek, A. U.; Zernickel, A.; Feil, F.; Sztiller-
Sikorska, M.; Lesiak-Mieczkowska, K.; Bräuchle, Ch.;
Lorenz, I.-P.; Czyż, M. J. Inorg. Biochem. 2010, 104, 774.
(10) Lipilin, D. L.; Churakov, A. M.; Ioffe, S. L.; Strelenko, Y.
A.; Tartakovsky, V. A. Eur. J. Org. Chem. 1999, 29.
(11) (a) Bolton, R.; Sandall, P. B. J. Chem. Soc., Perkin Trans. 2
1978, 1288. (b) Burdon, J.; Thomas, D. F. Tetrahedron
1965, 21, 2389.
(12) (a) Gornostaev, L. M.; Bocharova, E. A.; Geets, N. V. Russ.
J. Org. Chem. 2006, 42, 1289. (b) Bocharova, E. A.;
Gornostaev, L. M.; Gritsan, N. P.; Gurova, T. N. Russ. J.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 127–133