4-(1-Benzotriazolyl)-5-nitrophthalonitrile as a highly active substrate in aromatic nucleophilic substitution reactions

Article abstract of DOI:10.1070/MC2002v012n02ABEH001538

The title compound was synthesised, and its derivatives were prepared in high yields using the selective substitution of O-, S- and N-nucleophiles for the nitro group; an activating effect of the benzotriazolyl moiety on the above reactions was found.

Full text of DOI:10.1070/MC2002v012n02ABEH001538

Mendeleev Commun., 2002, 12(2), 72–74
4-(1-Benzotriazolyl)-5-nitrophthalonitrile as a highly active substrate in aromatic
nucleophilic substitution reactions
Alexey V. Smirnov, Igor G. Abramov,* Vladimir V. Plakhtinskii and Galina G. Krasovskaya
Department of Organic Chemistry, Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation.
Fax: +7 0852 44 0729; e-mail: abramov.orgchem@staff.ystu.yar.ru
10.1070/MC2002v012n02ABEH001538
The title compound was synthesised, and its derivatives were prepared in high yields using the selective substitution of O-, S- and
N-nucleophiles for the nitro group; an activating effect of the benzotriazolyl moiety on the above reactions was found.
Previously,1–6 we studied the activated aromatic nucleophilic
O
substitution for the nitro group in 4-nitrophthalonitrile and for
N
N
H2N
the bromine atom and the nitro group in 4-bromo-5-nitro-
phthalonitrile using various O-, S- and N-nucleophiles. Benzo-
triazole is widely used in SNAr reactions as a nitrogen-containing
nucleophile.7–9 The procedure for preparing 4-(1-benzotriazolyl)-
5-nitrophthalonitrile 1 in 48% yield was reported earlier.3 The
yield of the mono-substituted product was increased up to 59%
by decreasing reaction temperature and using another alkaline
agent. However, we failed to prevent the formation of disubsti-
tuted products 2a,b (Scheme 1).
Et3N
NaNO2
O
1
BNPN
PriOH
MeCOOH
NH
H2N
NH2
N
Scheme 2
The synthesised substrate is of interest because a benzene
ring bears four electron-acceptor substituents: two cyano groups
and a benzotriazole moiety in the ortho position with respect to
the nitro group. Although the reactions of substitution for the
nitro group were studied in detail,10 reactions with the partici-
pation of the above compound were not described in the litera-
ture. Substitution for the benzotriazole moiety was described for
only aliphatic systems.
O
N
N
N
K2CO3
O
N
DMF, 20 °C
N
H
Br
N
BNPN
R
N
O
N
N
N
N
N
N
N
N
O
N
N
O
N
N
OH
N
N
K2CO3
1
R
N
75% aq. DMF
N
N
N
1
2a
3a–l
a
b
c
g
h
i
R = H
R = 3,4-Me
R = 4-Cl
R = 4-cyclohexyl
R = 4-COMe
R = 4-F
N
N
N
N
N
N
d R = 4-Br
e
f
j R = 4-Cl-3,5-Me
k
l
N
N
R = 4-(4-MeC6H4)
R = 4-Ph
R = 4-Cl-3-Me
R = 3-COMe
Scheme 3
2b
Scheme 1
We found that the presence of a comparatively strong electron-
acceptor benzotriazole substituent increases the probability of a
nucleophilic attack on the carbon atom bound to the nitro group.
Moreover, this carbon atom is activated by two cyano groups;
thus, the nitro group becomes more labile. Because of this, only
the nitro group in compound 1 can be readily replaced by various
O-, S- and N-nucleophiles under mild reaction conditions. Thus,
compound 1 reacted with substituted phenols (Scheme 3) in a
75% aqueous DMF solution in the presence of potassium car-
bonate within 30 min even at room temperature (20 °C). Reaction
products 3a–l‡,†† precipitated from the reaction mixture and did
not require further purification. The reaction of 1 with bisphenols
occurred under analogous conditions with the formation of, for
example, compound 4§,†† (Scheme 4). The above nucleophiles
can replace the nitro group1 in 4-nitrophthalonitrile only at 60 °C,
whereas substitution for the heterocyclic moiety in 4-benzotri-
azolylphthalonitrile did not occur at a higher temperature.3 We
Therefore, we developed a two-step procedure (Scheme 2) to
prepare chromatographically pure compound 1. This procedure
allowed us to synthesise the target product in 83% yield on a
basis of starting 4-bromo-5-nitrophthalonitrile.† At the first step,
4-bromo-5-nitrophthalonitrile readily reacted with o-phenylene-
diamine in boiling isopropanol in the presence of triethylamine
to form 4-(2-aminoanilino)-5-nitrophthalonitrile.2 The second step
consisted in the diazotisation of the isolated product on heating
in acetic acid to result in the target compound.
†
4-(1-Benzotriazolyl)-5-nitrophthalonitrile 1. 4-(2-Aminoanilino)-5-nitro-
phthalonitrile (31.00 g, 0.11 mol) was dissolved in 300 ml of acetic acid.
A solution of 7.60 g (0.11 mol) of NaNO2 in 50 ml of water was added
to the resulting solution. The reaction mixture was stirred at 70 °C for
3 h. The precipitate formed after cooling was filtered off, washed with
20 ml of acetic acid, and dried at 70 °C.
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Mendeleev Commun., 2002, 12(2), 72–74
with water. For comparison, note that the nitro group in 4-nitro-
phthalonitrile can be replaced3 with benzotriazole only at 70 °C
in anhydrous DMF to result in a mixture of 1- and 2-substituted
derivatives in the ratio 1.4:1.
O
N
OH
OH
N
N
K2CO3
O
N
2
75% aq. DMF
The substrate under consideration can also react with ambident
nucleophiles such as thiourea and the nitrite ion.
N
N
O
N
N
S
Et3N
PriOH
O
N
2
1
H2N
NH2
N
N
N
N
N
N
N
1
N
N
N
N
N
O
O
N
N
N
N
S
N
N
N
N
N
N
4
N
Scheme 4
6
Scheme 6
partially replaced the benzotriazole unit by phenoxide (according
to LC data) only in compound 2 upon refluxing the correspond-
ing parent compounds in anhydrous DMF for a long time.
Under the specified conditions (20 °C, 75% aqueous DMF),
the reaction with S-nucleophiles such as 4-bromothiophenol
occurred more readily (Scheme 5). The product of selective
substitution for the nitro group precipitated from the reaction
mixture 1 to 2 min after mixing the reactant solutions.
The reaction of 1 with thiourea began with the formation
of an isothiuronium salt, which was rearranged into a mercapto
derivative in the presence of a base (triethylamine). The result-
ing thiophenoxide is reactive, and it attacked substrate 1 in
the presence of triethylamine to afford 4-(1-benzotriazolyl)-
5-[2-(1-benzotriazolyl)-4,5-dicyanophenylsulfanyl]phthalonitrile
6
‡,†† (Scheme 6).
N
N
Br
OH
N
NaNO2, K2CO3
75% aq. DMF
1
N
N
SH
N
S
K2CO3
1
7
N
75% aq. DMF
N
Scheme 7
N
N
Br
Compound 1 can react with alkali metal nitrites in the pres-
ence of potassium carbonate at elevated temperatures (Scheme 7).
Compound 7¶,†† was formed by the replacement of the nitro group
on an O-attack of the nitrite ion.11 In contrast to thiophenoxide,
the resulting compound is inactive in nucleophilic substitution
reactions, and it can be easily separated from the reaction mixture.
Thus, the above results are indicative of a higher reactivity of
4-(1-benzotriazolyl)-5-nitrophthalonitrile in nucleophilic substi-
tution reactions than that of 4-nitrophthalonitrile. It is believed
that the benzotriazole unit has a considerable activating effect
on the test reaction of selective substitution for the nitro group.
Both donor and acceptor substituents are simultaneously present
in the prepared compounds, and this fact is responsible for their
unique properties. On this basis, new promising materials with
special photophysical properties, for example, phthalocyanines12
and hexazocyclanes,13 can be synthesised.
5
Scheme 5
If benzotriazole was used as an N-nucleophile in the con-
sidered reaction with compound 1 under the specified conditions,
the substitution of the benzotriazole ring for the nitro group
primarily took place at the second nitrogen atom. In this case,
the yield of compound 2a was as high as 76%. According to
1H NMR data, compound 2a precipitated from the reaction
mixture exhibited a non-symmetrical structure identical to that
described previously.4 Compound 2b was not precipitated from
the reaction mixture, and it was detected in a mixture with 2a
in the analysis of the product obtained after diluting the filtrate
‡
4-(1-Benzotriazolyl)-5-phenoxyphthalonitrile 3a. Compound 1 (2.00 g,
0.07 mol), phenol (0.66 g, 0.07 mol) and K2CO3 (0.97 g, 0.07 mol) dis-
solved in 5 ml of water were added to 15 ml of DMF. The resulting
mixture was intensely stirred at room temperature for 0.5 h. The formed
precipitate was filtered off, washed with 20 ml of ethanol and then 100 ml
of water, and dried at 70 °C.
References
1 I. G. Abramov, V. V. Plachtinsky, G. S. Mironov and O. A. Yasinsky, Izv.
Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 1997, 2, 31 (in Russian).
2 I. G. Abramov, M. V. Dorogov, S. A. Ivanovskii, A. V. Smirnov and
M. B. Abramova, Mendeleev Commun., 2000, 78.
Compounds 3b–l, 5 and 6 were prepared in a similar manner with the
use of equimolar amounts of other phenols, 4-bromothiophenol and thio-
acetamide as reactants.
¶
4-(1-Benzotriazolyl)-5-hydroxyphthalonitrile 7. Compound 1 (2.00 g,
§
4-(1-Benzotriazolyl)-5-{4-[2-(1-benzotriazolyl)-4,5-dicyanophenoxy]-
0.07 mol), NaNO2 (0.69 g, 0.07 mol) and K2CO3 (0.97 g, 0.07 mol) dis-
solved in 5 ml of water were added to 15 ml of DMF. The resulting
mixture was heated to 70 °C and intensely stirred at this temperature for
0.5 h. After cooling to room temperature, HCl was added to the reaction
mixture to pH 1. The formed precipitate was filtered off, washed with
20 ml of ethanol and dried at 70 °C.
phenoxy}phthalonitrile 4. Compound 1 (2.00 g, 0.07 mol), a bisphenol
(0.04 mol) and K2CO3 (0.97 g, 0.07 mol) dissolved in 5 ml of water were
added to 15 ml of DMF. The resulting mixture was intensely stirred at
room temperature for 1 h. The formed precipitate was filtered off, washed
with 20 ml of ethanol and then 100 ml of water, and dried at 70 °C.
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Mendeleev Commun., 2002, 12(2), 72–74
3 I. G. Abramov, V. V. Plachtinsky, M. B. Abramova, A. V. Smirnov and
5
I. G. Abramov, S. A. Ivanovskii, A. V. Smirnov and M. V. Dorogov,
G. G. Krasovskaya, Khim. Geterotsikl. Soedin., 1999, 1537 [Chem.
Heterocycl. Compd. (Engl. Transl.), 1999, 35, 1342].
4 I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, M. B. Abramova and
V. V. Plachtinsky, Khim. Geterotsikl. Soedin., 2000, 1219 [Chem.
Heterocycl. Compd. (Engl. Transl.), 2000, 36, 1062].
Izv. Vyssh. Uchebn. Zaved., Khim. Khim. Tekhnol., 2000, 1, 120 (in
Russian).
I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, M. B. Abramova and
V. V. Plachtinsky, Heterocycles, 2001, 6, 1161.
A. R. Katritzky, T. Kurz, S. Zhang and M. Voronkov, Heterocycles,
2001, 9, 1703.
A. R. Katritzky, A. V. Ignatchenko and H. Lang, Heterocycles, 1995,
41, 131.
A. R. Katritzky and J. Wu, Synthesis, 1994, 597.
6
7
8
9
†† The 1H NMR spectra of 5% sample solutions in [2H6]DMSO were
measured on a Bruker DRX-500 instrument using TMS as an internal
standard.
3a: yield 89%, mp 188–191 °C. 1H NMR, d: 8.62 (s, 1H), 7.13 (d, 1H,
J 8.2 Hz), 7.80 (d, 1H, J 8.2 Hz), 7.75 (s, 1H), 7.64 (t, 1H), 7.50 (t, 1H),
7.42 (t, 2H), 7.27 (t, 1H), 7.18 (d, 2H, J 8.81 Hz). Found (%): C, 71.09;
H, 3.30; N, 20.80. Calc. for C20H11N5O (%): C, 71.21; H, 3.29; N, 20.76.
3b: yield 94%, mp 236–238 °C. 1H NMR, d: 8.62 (s, 1H), 8.14 (d, 1H,
J 8.1 Hz), 7.80 (d, 1H, J 8.1 Hz), 7.72 (s, 1H), 7.63 (t, 1H), 7.50 (t, 1H),
6.90 (s, 1H), 6.75 (s, 2H), 2.25 (s, 6H). Found (%): C, 72.15; H, 4.14; N,
19.25. Calc. for C22H15N5O (%): C, 72.32; H, 4.14; N, 18.17.
3c: yield 92%, mp 237–239 °C. 1H NMR, d: 8.62 (s, 1H), 8.15 (d, 1H,
J 8.2 Hz), 7.90 (s, 1H), 7.80 (d, 1H, J 8.0 Hz), 7.63 (t, 1H), 7.50 (t, 1H),
7.40 (d, 2H, J 8.4 Hz), 7.15 (d, 2H, J 8.1 Hz). Found (%): C, 64.51; H,
2.72; N, 18.90. Calc. for C20H10ClN5O (%): C, 64.61; H, 2.71; N, 18.84.
3d: yield 96%, mp 251–253 °C. 1H NMR, d: 8.65 (s, 1H), 8.14 (d, 1H,
J 8.2 Hz), 7.90 (s, 1H), 7.80 (d, 1H, J 8.1 Hz), 7.64 (t, 1H), 7.56 (d, 2H,
J 8.0 Hz), 7.50 (t, 1H), 7.15 (d, 2H, J 8.1 Hz). Found (%): C, 57.60; H,
2.43; N, 16.78. Calc. for C20H10BrN5O (%): C, 57.71; H, 2.42; N, 16.83.
3e: yield 84%, mp 215–217 °C. 1H NMR, d: 8.67 (s, 1H), 8.17 (d, 1H,
J 8.3 Hz), 7.87 (d, 1H, J 8.0 Hz), 7.83 (s, 1H), 7.67 (m, 3H), 7.50 (t,
3H), 7.25 (d, 4H, J 7.9 Hz), 2.33 (s, 3H). Found (%): C, 75.68; H, 4.01;
N, 16.45. Calc. for C27H17N5O (%): C, 75.86; H, 4.01; N, 16.38.
3f: yield 87%, mp 208–210 °C. 1H NMR, d: 8.66 (s, 1H), 8.16 (d, 1H,
J 8.3 Hz), 7.88 (s, 1H), 7.83 (d, 1H, J 8.0 Hz), 7.67 (m, 3H), 7.60 (d,
2H, J 7.9 Hz), 7.50 (t, 1H), 7.45 (t, 2H), 7.35 (t, 1H), 2.27 (d, 2H, J
8.1 Hz). Found (%): C, 75.38; H, 3.67; N, 17.01. Calc. for C26H15N5O
(%): C, 75.53; H, 3.66; N, 16.94.
10 F. Terrier, Nucleophilic Aromatic Displacement: The Influence of the
Nitro Group, VSH Publishers, New York, 1991.
11 T. J. Broxton, D. M. Muir and A. J. Parker, J. Org. Chem., 1975, 14,
2037.
12 O. V. Shishkina, V. E. Mayzlish and G. P. Shaposhnikov, Zh. Obshch.
Khim., 2001, 2, 271 (Russ. J. Gen. Chem., 2001, 2, 1712).
13 S. A. Siling, S. V. Shamshin, A. B. Grachev, O. Yu. Tsiganova, V. I.
Yuzhakov, I. G. Abramov, A. V. Smirnov, S. A. Ivanovskii, A. G.
Vitukhnovsky, A. S. Averjushkin and Bui Chi Lap, Oxidation
Commun., 2000, 4, 481.
3g: yield 82%, mp 204–206 °C. 1H NMR, d: 8.62 (s, 1H), 8.14 (d, 1H,
J 8.2 Hz), 7.80 (d, 2H, J 8.2 Hz), 7.70 (s, 1H), 7.65 (t, 1H), 7.50 (t, 1H),
7.25 (d, 2H, J 8.1 Hz), 7.10 (d, 2H, J 8.0 Hz), 2.55 (s, 1H), 1.80 (d, 4H,
J 7.8 Hz), 1.60 (d, 1H, J 8.5 Hz), 1.35 (m, 4H), 1.25 (m, 1H). Found (%):
C, 74.31; H, 5.05; N, 14.64. Calc. for C26H21N5O (%): C, 74.44; H, 5.05;
N, 16.70.
3h: yield 91%, mp 215–217 °C. 1H NMR, d: 8.70 (s, 1H), 8.12 (d, 1H,
J 8.3 Hz), 8.00 (s, 1H), 7.93 (d, 2H, J 8.3 Hz), 7.80 (d, 1H, J 8.0 Hz),
7.65 (t, 1H), 7.50 (t, 1H), 7.20 (d, 2H, J 8.2 Hz). Found (%): C, 69.52;
H, 3.46; N, 18.50. Calc. for C22H13N5O2 (%): C, 69.65; H, 3.45; N, 18.46.
3i: yield 83%, mp 209–211 °C. 1H NMR, d: 8.65 (s, 1H), 8.15 (d, 1H,
J 8.1 Hz), 7.84 (d, 1H, J 8.3 Hz), 7.78 (s, 1H), 7.65 (t, 1H), 7.50 (t, 1H),
7.25 (m, 4H). Found (%): C, 67.49; H, 2.85; N, 19.70. Calc. for
C20H10FN5O (%): C, 67.60; H, 2.84; N, 19.71.
3j: yield 96%, mp 225–227 °C. 1H NMR, d: 8.60 (s, 1H), 8.13 (d, 1H,
J 8.2 Hz), 7.87 (s, 1H), 7.80 (d, 1H, J 7.9 Hz), 7.65 (t, 1H), 7.50 (t, 1H),
7.00 (s, 2H), 2.30 (s, 6H). Found (%): C, 65.93; H, 3.53; N, 17.49. Calc.
for C22H14ClN5O (%): C, 66.09; H, 3.53; N, 17.43.
3k: yield 94%, mp 213–215 °C. 1H NMR, d: 8.60 (s, 1H), 7.12 (d, 1H,
J 8.0 Hz), 7.90 (s, 1H), 7.80 (d, 1H, J 8.3 Hz), 7.62 (t, 1H), 7.50 (t, 1H),
7.40 (d, 1H, J 8.0 Hz), 7.15 (s, 1H), 7.0 (d, 1H, J 7.9 Hz), 2.30 (s, 3H).
Found (%): C, 65.20; H, 3.14; N, 18.20. Calc. for C21H12ClN5O (%): C,
65.38; H, 3.14; N, 18.15.
3l: yield 89%, mp 186–188 °C. 1H NMR, d: 8.67 (s, 1H), 8.12 (d, 1H,
J 8.0 Hz), 7.90 (s, 1H), 7.83 (d, 2H, J 8.4 Hz), 7.70 (s, 1H), 7.65 (t, 1H),
7.56 (t, 1H), 7.50 (t, 1H), 7.45 (d, 1H, J 8.1 Hz). Found (%): C, 69.57; H,
3.46; N, 18.41. Calc. for C22H113N5O2 (%): C, 69.65; H, 3.45; N, 18.46.
4: yield 77%, mp > 300 °C. H NMR, d: 8.60 (s, 2H), 8.15 (d, 2H, J
8.2 Hz), 7.90 (s, 2H, J 8.1 Hz), 7.80 (d, 2H, J 7.9 Hz), 7.65 (t, 2H), 7.50
(t, 2H), 7.20 (s, 4H). Found (%): C, 68.33; H, 2.71; N, 23.54. Calc. for
C34H16N10O2 (%): C, 68.45; H, 2.70; N, 23.48.
5: yield 97%, mp 181–183 °C. 1H NMR, d: 8.40 (s, 1H), 7.15 (d, 1H,
J 8.2 Hz), 7.70 (d, 2H, J 8.5 Hz), 7.65 (t, 1H), 7.57 (d, 1H, J 7.9 Hz),
7.50 (t, 1H), 7.40 (d, 1H, J 8.0 Hz). Found (%): C, 55.45; H, 2.33; N,
16.25; S, 7.43. Calc. for C20H10BrN5S (%): C, 55.57; H, 2.33; N, 16.20;
S, 7.42.
6: yield 86%, mp 285–287 °C. 1H NMR, d: 8.45 (s, 2H), 8.35 (s, 2H),
8.13 (d, 2H, J 8.5 Hz), 7.60 (m, 4H), 7.50 (d, 2H, J 8.3 Hz). Found (%):
C, 64.47; H, 2.33; N, 27.01; S, 6.17. Calc. for C28H12N10S (%): C, 64.61;
H, 2.32; N, 26.91; S, 6.16.
1
7: yield 90%, mp > 300 °C. H NMR, d: 12.60 (s, 1H), 8.40 (s, 1H),
8.15 (d, 1H, J 8.0 Hz), 7.70 (s, 1H), 7.63 (t, 1H), 7.57 (t, 1H), 7.48
(d, 1H, J 8.1 Hz). Found (%): C, 64.20; H, 2.70; N, 26.70. Calc. for
C14H7N5O (%): C, 64.37; H, 2.70; N, 26.81.
Received: 6th December 2001; Com. 01/1864
– 74 –