Nucleophilic substitution of halogens with amines in 2- and 4-nitrophenols

Article abstract of DOI:10.1055/s-2006-958946

Fluorine and chlorine in halonitrophenols are efficiently replaced with alkylamines in acetonitrile or in an excess of the amine at elevated temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-958946

PAPER
259
Nucleophilic Substitution of Halogens with Amines in 2- and 4-Nitrophenols
Substitution of
H
b
alogens wi
i
th
A
min
g
e
s
in
N
itrop
n
henols iew 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 11 October 2006; revised 25 October 2006
Y
N
Y
Abstract: Fluorine and chlorine in halonitrophenols are efficiently
replaced with alkylamines in acetonitrile or in an excess of the
amine at elevated temperature.
OH
OH
R1
R2
MeCN
reflux
HN
+
Z
Z
Key words: amines, nucleophilic aromatic substitutions, phenols,
arenes
X
R1
R2
5
6
Y = NO2 Z = H
Y = H Z = NO2
4a–f
1
2
3
X = F Y = NO2 Z = H
X = Cl Y = H
Z = NO2
The nucleophilic substitution of halogens, mainly fluo-
rine, located in positions ortho and para to the nitro group,
is one of the most versatile methods for the synthesis of
substituted nitrobenzenes.1 The reaction is strongly affect-
ed by other groups bound to the aromatic ring, and can be
inhibited when strong electron-donating substituents, es-
pecially negatively charged substituents conjugated with
the nitro group, are present. This is the case with 2- and 4-
nitrophenols when the reaction conditions or the nucleo-
phile are sufficiently basic. Taking into account the acidi-
ty of 5-fluoro-2-nitrophenol (1) (pKa 6.07 in EtOH–H2O)2
and the acidity of secondary amine conjugated acids (e.g,
pKa 8.78 in H2O for morpholine),3 replacing fluorine with
such amines seems to be a bold idea since one would ex-
pect proton transfer as the sole reaction.
X = Cl Y = NO2 Z = H
Equation 1
22.4,9 whereas that of protonated morpholine only from
pKa 8.36 to 16.61.10
Thus, the reaction of 1 with various primary and second-
ary alkylamines (2.5-fold excess) was carried out in re-
fluxing acetonitrile for one hour giving almost
quantitative yields of substitution products 5 (Table 1).
Less reactive aniline derivatives, however, reacted poorly
under these conditions. Increasing the temperature to 125
°C and replacing acetonitrile with a large excess of the
amine slightly improved the result (Table 1).
Nucleophilic substitution of chlorine is more difficult then
that of fluorine even when located in the more activated
ortho position to the nitro group. As a result, 3-chloro-4-
nitrophenol (2) and 5-chloro-2-nitrophenol (3) required
harsher conditions for the displacement of chlorine atom
with alkylamines (Table 2). Reaction of 2 with five equiv-
alents of morpholine (4a) in acetonitrile at 60 °C gave
only a 36% yield of product 6a after two days, while when
2 was refluxed in excess of 4a used as a solvent (25 equiv,
bp 129 °C) the reaction was complete within 30 minutes.
Similarly the reaction of 2 with 1-methylpiperazine (bp
138 °C) (4e) was complete within one hour, while the re-
action with benzylamine (4c) required heating for five
hours at 120 °C. Reaction or 2 with lower-boiling butyl-
amine (bp 78 °C) required reflux for 96 hours to go to
completion.
Since the nitration of 3-aminophenols seems to be effec-
tive only for the N-acylated derivatives,4 the number of di-
rect methods for the synthesis of aminonitrophenols is
very limited; the substitution of fluorine with amines in O-
silylated fluoronitrophenols5 and with hydroxide ion in
fluoronitroanilines have been reported.6
The aforementioned substitution of halogens in halonitro-
phenols with amines was, however, observed as an unex-
pected side process in the Mannich condensation of 5-
fluoro-2-nitrophenol (1) or 3-fluoro-4-nitrophenol with
piperidine in boiling ethanol, which gave the correspond-
ing substitution products in rather moderate and low
yields of 54% and 7% respectively;7 there are only a few
isolated reports of similar reactions.8 In this paper we
would like to present the results of a more regular exami-
nation of the scope of the reaction.
The presented results show, that fluoronitrophenols can be
excellent substrates for the direct preparation of the de-
sired aminonitrophenols in reactions with alkyl amines.
The corresponding chloronitrophenols are less reactive,
although under appropriate conditions they give satisfac-
tory yields of products. While high temperature and large
excess of the amine significantly lower the reaction time,
in the cases of costly amines, much slower reactions in
boiling acetonitrile with only 2.5 equivalents of the amine
may be more suitable.
We decided to use aprotic solvents as the reaction medi-
um, which should decrease the acidity of nitrophenols
compared to the protonated alkylamines. According to lit-
erature data, changing the solvent from water to acetoni-
trile reduces the acidity of 2-nitrophenol from pKa 7.2 to
SYNTHESIS 2007, No. 2, pp 0259–0262
x
x
.
x
x
.2
0
0
7
Advanced online publication: 14.12.2006
DOI: 10.1055/s-2006-958946; Art ID: Z20206SS
© Georg Thieme Verlag Stuttgart · New York

260
Z. Wróbel, A. Kwast
PAPER
Table 1 Reaction of Amines with 5-Fluoro-2-nitrophenol (1)
Amine
NR1R2
Conditions
Time (h)
Product
5a
Yielda (%)
4a
morpholin-4-yl
NHBu
amine (2.5 equiv), MeCN, reflux
amine (2.5 equiv), MeCN, reflux
amine (2.5 equiv), MeCN, reflux
amine (2.5 equiv), MeCN, reflux
amine (2.5 equiv), MeCN, reflux
amine (2.5 equiv), MeCN, reflux
amine (12.5 equiv), 125 °C
1
1
97
97
98
99
87
5
4b
5b
4c
NHBn
1
5c
4d
pyrrolidin-1-yl
4-methylpiperazin-1-yl
4-ClC6H4NH
4-ClC6H4NH
1
5d
4e
1
5e
4f
24
72
5f
4f
5f
16
a Isolated yield.
Table 2 Reaction of 3-Chloro-4-nitrophenol (2) and 5-Chloro-2-nitrophenol (3) with Amines 4
Substrate
Amine
4a
NR1R2
Conditions
Temp (°C) Time (h)
Product
Yielda (%)
3
3
3
3
2
2
2
2
2
morpholin-4-yl
morpholin-4-yl
pyrrolidin-1-yl
4-methylpiperazin-1-yl
morpholin-4-yl
morpholin-4-yl
NHBu
amine (2.5 equiv), MeCN
amine (12.5 equiv)
amine (12.5 equiv)
amine (2.5 equiv), MeCN
amine (2.5 equiv), MeCN
amine (12.5 equiv)
amine (12.5 equiv)
amine (12.5 equiv)
amine (12.5 equiv)
82
120
87
24
1.5
5a
5a
5d
5e
6a
6a
6b
6c
6e
83
85
72
67
36
95
66
75
69
4a
4d
48
30
48
4e
82
4a
60
4a
129
78
0.5
4b
96
5
4c
NHBn
120
138
4e
4-methylpiperazin-1-yl
1
a Isolated yield.
Melting points are uncorrected. NMR spectra were recorded on a
Varian Mercury 400 (400 MHz for 1H and 100 MHz for 13C) instru-
ment in DMSO-d6. MS spectra (EI, 70 eV) were obtained on an
AMD-604 spectrometer. Silica gel Merck 60 (230–400 mesh) was
used for column chromatography.
mL) and a small amount of H2O was added, enough to obtain two
separable layers. The inorganic layer was extracted with EtOAc, the
combined organic extracts were washed with small volume of brine,
dried (Na2SO4), and worked up further as usual.
5-(Morpholin-4-yl)-2-nitrophenol (5a)
Yellow crystals; mp 144–145 °C.
1H NMR: d = 10.70 (br s, 1 H), 7.85 (d, J = 9.0 Hz, 1 H), 6.50 (d,
J = 2.6 Hz, 1 H), 6.45 (dd, J = 9.0, 2.6 Hz, 1 H), 3.00–2.96 (m, 4
H), 2.52–2.49 (m, 4 H).
3-Chloro-4-nitrophenol (2) and 5-chloro-2-nitrophenol (3) were ob-
tained according to literature procedures.11 All other reagents are
commercially available. The amines 4a, 4b, and 4d were addition-
ally dried by distillation and stored over KOH pellets.
Amino-Substituted Nitrophenols 5 and 6; General Procedure
The nitrophenol 1–3 (0.2 mmol) was mixed with the appropriate
amine (0.5 mmol for reactions in MeCN, or 2.5 mmol for reactions
carried out without solvent) and, when applicable, with anhyd
MeCN (4 mL), then stirred at elevated temperature for the time
specified in Tables 1 and 2. After cooling, the mixture was poured
into dil HCl (1:10, 50 mL), then extracted with EtOAc (3 × 20 mL).
The combined extracts were washed with brine, dried (Na2SO4),
and evaporated. The crude product was purified by column chroma-
tography (silica gel, hexane–EtOAc). Analytically pure samples
were obtained by recrystallization (hexane–EtOAc).
13C NMR: d = 156.6, 156.4, 127.0, 124.7, 106.7, 99.3, 65.7, 46.3.
MS (EI): m/z (%) = 224 (96), 166 (100), 136 (22), 108 (11), 65 (13).
Anal. Calcd for C10H12N2O4: C, 53.57; H, 5.39; N, 12.49. Found: C,
53.35; H, 5.44; N, 12.53.
5-(Butylamino)-2-nitrophenol (5b)
Yellow crystals; mp 91–98 °C.
1H NMR: d = 11.28 (br s, 1 H), 7.79 (d, J = 9.4 Hz, 1 H), 7.55 (ap-
parent t, 1 H), 6.32 (dd, J = 9.4, 2.6 Hz, 1 H), 6.05 (d, J = 2.6 Hz, 1
H), 3.11–3.17 (m, 2 H), 1.49–1.57 (m, 2 H), 1.32–1.42 (m, 2 H),
0.92 (t, J = 7.3 Hz, 3 H).
In the case of reactions with 1-methylpiperazine (4e), as the prod-
ucts are reasonably basic, a better workup procedure was as follows:
the mixture was evaporated in vacuo, then mixed with EtOAc (20
13C NMR: d = 157.9, 156.7, 127.1, 122.9, 108.1, 95.2, 42.1, 30.3,
19.6, 13.6.
Synthesis 2007, No. 2, 259–262 © Thieme Stuttgart · New York

PAPER
Substitution of Halogens with Amines in Nitrophenols
261
MS (EI): m/z (%) = 211 (3), 210 (26), 168 (9), 167 (100), 122 (2),
121 (18), 120 (2).
Anal. Calcd for C10H12N2O4: C, 53.57; H, 5.39; N, 12.49. Found: C,
53.51; H, 5.41; N, 12.51.
Anal. Calcd for C10H14N2O3: C, 57.13; H, 6.71; N, 13.32. Found: C,
57.15; H, 6.66; N, 13.22.
3-(Butylamino)-4-nitrophenol (6b)
Yellow crystals; mp 100–101 °C.
5-(Benzylamino)-2-nitrophenol (5c)
Yellow crystals; mp 122–124 °C.
1H NMR: d = 11.16 (br s, 1 H), 8.05 (apparent t, 1 H), 7.80 (d,
J = 9.4 Hz, 1 H), 7.26–7.39 (m, 5 H), 6.38 (dd, J = 9.4, 2.4 Hz, 1
H), 6.08 (d, J = 2.4 Hz, 1 H), 4.42 (d, J = 6.0 Hz, 1 H).
13C NMR: d = 157.7, 156.5, 138.2, 128.5, 127.3, 127.2, 123.4,
108.1, 96.5, 45.9.
1H NMR: d = 10.90 (br s, 1 H), 8.25 (t, J = 4.9 Hz, 1 H), 7.97 (d,
J = 9.3 Hz, 1 H), 6.20 (d, J = 2.3 Hz, 1 H), 6.17 (dd, J = 9.3, 2.3 Hz,
1 H), 3.21–3.29 (m, 2 H), 1.56–1.66 (m, 2 H), 1.33–1.45 (m, 2 H),
0.90–0.96 (m, 3 H).
13C NMR: d = 165.0, 147.8, 129.0, 124.7, 106.3, 96.8, 41.9, 30.2,
19.7, 13.6.
MS (EI): m/z (%) = 210 (39), 167 (100), 149 (17), 134 (12), 122
(28), 109 (38), 94 (17).
MS (EI): m/z (%) = 245 (8), 244 (55), 243 (6), 197 (2), 167 (3), 91
(100).
Anal. Calcd for C10H14N2O3: C, 57.13; H, 6.71; N, 13.32. Found: C,
57.02; H, 6.69; N, 13.34.
Anal. Calcd for C13H12N2O3: C, 63.93; H, 4.95; N, 11.47. Found: C,
63.87; H, 4.89; N, 11.41.
3-(Benzylamino)-4-nitrophenol (6c)
Yellow crystals; mp 193–196 °C (dec).
2-Nitro-5-(pyrrolidin-1-yl)phenol (5d)
Yellow crystals; mp 137–139 °C.
1H NMR: d = 10.75 (br s, 1 H), 8.77 (t, J = 6.0 Hz, 1 H), 7.97 (d,
J = 9.5 Hz, 1 H), 7.32–7.39 (m, 4 H), 7.24–7.31 (m, 1 H), 6.16 (dd,
J = 9.3, 2.4 Hz, 1 H), 6.10 (d, J = 2.4 Hz, 1 H), 4.54 (d, J = 6.0 Hz,
2 H).
13C NMR: d = 164.7, 147.6, 138.4, 129.0, 128.6, 127.1, 126.9,
125.0, 106.4, 97.7, 45.8.
1H NMR: d = 11.19 (br s, 1 H), 7.87 (d, J = 9.7 Hz, 1 H), 6.33 (dd,
J = 9.7, 2.6 Hz, 1 H), 6.04 (d, J = 2.6 Hz, 1 H), 3.38–3.42 (m, 4 H),
1.94–2.00 (m, 4 H).
13C NMR: d = 156.9, 153.7, 127.2, 123.1, 106.9, 97.1, 47.9, 24.8.
MS (EI): m/z (%) = 209 (12), 208 (100), 207 (92), 191 (2), 180 (5),
162 (8), 161 (17), 153 (6), 152 (11), 150 (5).
MS (EI): m/z (%) = 244 (27), 226 (18), 210 (11), 197 (12), 196 (19),
105 (76), 91 (100).
HRMS (EI): m/z [M]+ calcd for C13H12N2O3: 244.0848; found:
244.0855.
Anal. Calcd for C10H12N2O3: C, 57.69; H, 5.81; N, 13.45. Found: C,
57.70; H, 5.70; N, 13.39.
5-(4-Methylpiperazin-1-yl)-2-nitrophenol (5e)
Yellow crystals; mp 90–93 °C.
1H NMR: d = 10.9 (br s, 1 H), 7.87 (d, J = 9.7 Hz, 1 H), 6.66 (dd,
J = 9.7, 2.7 Hz, 1 H), 6.42 (d, J = 2.7 Hz, 1 H), 3.44–3.48 (m, 4 H),
2.38–2.42 (m, 4 H), 2.21 (s, 3 H).
13C NMR: d = 156.8, 156.2, 127.0, 124.2, 107.0, 99.2, 54.1, 46.1,
45.5.
3-(4-Methylpiperazin-1-yl)-4-nitrophenol (6e)
Yellow crystals; mp 199–200 °C.
1H NMR: d = 10.70 (br s, 1 H), 7.85 (d, J = 9.0 Hz, 1 H), 6.50 (d,
J = 2.6 Hz, 1 H), 6.45 (dd, J = 9.0, 2.6 Hz, 1 H), 2.90–3.00 (m, 4
H), 2.49–2.52 (m, 4 H), 2.27 (s, 3 H).
13C NMR: d = 163.3, 149.1, 133.4, 129.3, 108.7, 106.0, 54.4, 50.9,
45.6.
MS (EI): m/z (%) = 238 (14), 237 (100), 236 (11), 222 (7), 195 (7),
176 (5), 166 (19).
MS (EI): m/z (%) = 237 (41), 207 (21), 202 (19), 190 (63), 147 (66),
135 (88), 43 (100).
Anal. Calcd for C11H15N3O3: C, 55.69; H, 6.37; N, 17.71. Found: C,
55.51; H, 6.28; N, 17.59.
Anal. Calcd for C11H15N3O3: C, 55.69; H, 6.37; N, 17.71. Found: C,
55.63; H, 6.31; N, 17.63.
5-(4-Chlorophenylamino)-2-nitrophenol (5f)
Brown solid; mp 195–197 °C.
1H NMR: d = 11.04 (br s, 1 H), 9.35 (br s, 1 H), 7.91 (d, J = 9.2 Hz,
1 H), 7.40–7.44 (m, 2 H), 7.22–7.27 (m, 2 H), 6.52–6.57 (m, 2 H).
13C NMR: d = 156.8, 151.8, 138.8, 129.4, 127.7, 127.1, 126.3,
122.7, 108.0, 100.0.
References
(1) Terrier, F. Nucleophilic Aromatic Displacement — The
Influence of the Nitro Group; Feuer, H., Ed.; VCH
Publishers: Weinheim, 1991.
(2) Hancock, C. K.; Clague, A. D. H. J. Am. Chem. Soc. 1964,
86, 4942.
(3) Castro, E. A.; Saavedra, C.; Santos, J. G.; Umana, M. I. J.
Org. Chem. 1999, 64, 5401.
(4) (a) Reppe, W. Justus Liebigs Ann. Chem. 1955, 596, 158.
(b) Costerousse, G.; Cagniant, A.; Teutsch, G. Bull. Soc.
Chim. Fr. 1988, 151.
(5) Donaghy, M. J.; Stanford, S. P. Tetrahedron 1999, 55, 1441.
(6) Hodgson, H. H.; Nicholson, D. E. J. Chem. Soc. 1941, 766.
(7) Barlin, G. B.; Ireland, S. J.; Nguyen, T. M. T.; Kotecka, B.;
Rieckmann, K. H. Aust. J. Chem. 1994, 47, 1553.
(8) (a) Cowart, M.; Kowaluk, E. A.; Daanen, J. F.; Kohlhaas, K.
L.; Alexander, K. M.; Wagenaar, F. L.; Kerwin, J. F. J. Med.
Chem. 1998, 41, 2636. (b) Welmaker, G. S.; Nelson, J. A.;
Sabalski, J. E.; Sabb, A. L.; Potoski, J. R.; Graziano, D.;
Kagan, M.; Coupet, J.; Dunlop, J.; Mazandarani, H.;
MS (EI): m/z (%) = 264 (100), 218 (18), 206 (9), 154 (13).
Anal. Calcd for C12H9ClN2O3: C, 54.46; H, 3.43; N, 10.58. Found:
C, 53.43; H, 3.54; N, 10.25.
3-(Morpholin-4-yl)-4-nitrophenol (6a)
Yellow crystals; mp 194–197 °C (dec).
1H NMR: d = 7.89 (d, J = 9.0 Hz, 1 H), 6.52 (d, J = 2.5 Hz, 1 H),
6.49 (dd, J = 9.0, 2.5 Hz, 1 H), 3.68–3.74 (m, 4 H), 2.92–2.98 (m,
4 H).
13C NMR: d = 163.2, 149.1, 133.7, 129.3, 109.0, 106.0, 66.1, 51.5.
MS (EI): m/z (%) = 225 (9), 224 (65), 223 (12), 208 (12), 207 (100),
206 (4), 191 (6), 190 (32), 189 (31), 178 (7), 177 (52), 163 (11), 162
(10), 161 (61), 149 (51).
Synthesis 2007, No. 2, 259–262 © Thieme Stuttgart · New York

262
Z. Wróbel, A. Kwast
PAPER
(9) Magoński, J.; Pawlak, Z.; Jasiński, T. J. Chem. Soc.,
Faraday Trans. 1993, 89, 119.
(10) Coetzee, J. F.; Padmanabhan, G. R. J. Am. Chem. Soc. 1965,
87, 5005.
Rosenzweig-Lipson, S.; Sukoff, S.; Zhang, Y. Bioorg. Med.
Chem. Lett. 2000, 10, 1991. (c) Quan, M. L.; Lam, P. Y. S.;
Han, Q.; Pinto, D. J. P.; He, M. Y.; Li, R.; Ellis, C. D.; Clark,
C. G.; Teleha, C. A.; Sun, J.-H.; Alexander, R. S.; Bai, S.;
Luettgen, J. M.; Knabb, R. M.; Wong, P. C.; Wexler, R. R.
J. Med. Chem. 2005, 48, 1729.
(11) Mąkosza, M.; Sienkiewicz, K. J. Org. Chem. 1998, 63, 4199.
Synthesis 2007, No. 2, 259–262 © Thieme Stuttgart · New York