NUCLEOPHILIC SUBSTITUTION IN A SERIES OF 4-NITRONICOTINIC ACID 1-OXIDE DERIVATIVES

Article abstract of DOI:10.1135/cccc19951170

Nucleophilic substitution of the nitro group in 4-nitro-3-pyridinecarboxanilide 1-oxide (IIa) afforded 4-hydroxy- (IIb), 4-chloro- (IIc), 4-methoxy- (IId), 4-ethoxy- (IIe), and 4-dimethylamino-3-pyridinecarboxanilide (IIf).The 1H and 13C NMR chemical shifts of the pyridine moiety were correlated with the Hammett constants of the substituent in position 4, with the exception of compound IIb.The reason of this phenomenon is discussed.

Full text of DOI:10.1135/cccc19951170

1170
Pohl, Prutianov, Smrckova-Voltrova:
NUCLEOPHILIC SUBSTITUTION IN A SERIES OF 4-NITRONICOTINIC
ACID 1-OXIDE DERIVATIVES
Radek POHL, Viktor PRUTIANOV and Svatava SMRCKOVA-VOLTROVA*
Department of Organic Chemistry,
Prague Institute of Chemical Technology, 166 28 Prague 6, Czech Republic
Received February 16, 1995
Accepted May 18, 1995
Dedicated to Professor Otakar Cervinka on the occasion of his 70th birthday.
Nucleophilic substitution of the nitro group in 4-nitro-3-pyridinecarboxanilide 1-oxide (IIa) afforded
4-hydroxy- (IIb), 4-chloro- (IIc), 4-methoxy- (IId), 4-ethoxy- (IIe), and 4-dimethylamino-3-pyridine-
1
carboxanilide (IIf). The H and 13C NMR chemical shifts of the pyridine moiety were correlated with
the Hammett constants of the substituent in position 4, with the exception of compound IIb. The
reason of this phenomenon is discussed.
In the course of preparation of 4-aminonicotinates from methyl 4-nitropyridine-3-
carboxylate 1-oxide1 we found a very simple substitution of the nitro group by the
methoxy group under conditions of acid-catalyzed esterification2. This brought us to a
more detailed study of nucleophilic aromatic substitution in the series of pyridine-1-
oxide derivatives.
Pyridine 1-oxide is an interesting molecule, with positions 2 and 4 activated for
either electrophilic or nucleophilic substitution3,4 (Scheme 1).
SCHEME 1
* The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Nucleophilic Substitution
1171
It is generally known that nucleophilic substitution at the aromatic ring is facilitated
by the presence of an electron-withdrawing group. In our case, a modified carboxyl
group is present in position 3. Using different C-, N-, O- and S-nucleophiles we found5
that the reaction of methyl 4-nitropyridine-3-carboxylate 1-oxide proceeds under very
mild conditions (low concentration, laboratory temperature) within very short reaction
periods (seconds) and with a 100% conversion of the reactant (determined by TLC).
The electron donor–electron acceptor complex6 formation was accompanied by an im-
mediate color change.
Nucleophilic substitution of the nitro group bonded to pyridine 1-oxide derivatives
was first described almost 50 years ago7. Since that time the preparation of 4-anilino8,
4-chloro9, 4-hydroxy9, 4-methoxy10 and 4-bromo derivative10 starting from the 4-nitro-
nicotinic acid 1-oxide has been reported. We extend now this kind of substitution to
other 4-nitronicotinic acid derivatives.
4-Nitronicotinic acid 1-oxide (I) was prepared by a three-step procedure from
3-methylpyridine, the first step being the oxidation by hydrogen peroxide to the corre-
sponding 1-oxide11. The 1-oxide was then nitrated with 100% nitric acid in concen-
trated sulfuric acid to 3-methyl-4-nitropyridine 1-oxide12. The oxidation of the methyl
group leading to compound I was done with sodium dichromate in sulfuric acid13.
4-Nitro-3-pyridinecarboxanilide 1-oxide (IIa) was obtained by the method14 described
for 4-nitronicotinamide 1-oxide via a mixed anhydride intermediate. The hydroxy deriva-
tive IIb was formed in two steps from acid I, the intermediate being the non-isolated
chloride of 4-chloronicotinic acid N-oxide. By the nucleophilic substitution of the nitro
group in IIa we obtained 4-chloro- (IIc), 4-methoxy- (IId), 4-ethoxy- (IIe) and 4-di-
methylamino-3-nitropyridinecarboxanilide 1-oxide (IIf) (Scheme 2).
1
We found the following interesting dependences in the H NMR spectra of com-
pounds II (Table I): While the proton signals of the benzene ring are not influenced by
the substituent in position 4 of the pyridine oxide ring, all the other protons are linearly
dependent on the Hammett substituent σp constants (see Fig. 1; the line slopes and
positions were calculated by linear regression); the range of chemical shifts of H-2
being 0.67 ppm, H-5 1.39 ppm, H-6 0.50 ppm and NH (the signal position is inde-
pendent of concentration) 0.47 ppm. One compound, however, behaves differently, viz.
the hydroxy derivative IIb (Table I, Fig. 1), whose signals H-2, H-5 and H-6 were not
included in the correlation analysis.
A similar dependence can be found in the analysis of 13C NMR spectral data (Table II).
The different nature of IIb is especially obvious from the C-4 chemical shift: while the
C-4 peaks of compounds IIa, IIc–IIf lie in the range of 134–153.5 ppm, the correspond-
ing signal of IIb occurs at 175 ppm, which indicates a strong deshielding effect.
The double-bond region of the IR spectrum of the hydroxy derivative IIb is slightly
different from the spectra of all other compounds II: There appeared a new band of
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1172
Pohl, Prutianov, Smrckova-Voltrova:
SCHEME 2
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Nucleophilic Substitution
1173
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1174
Pohl, Prutianov, Smrckova-Voltrova:
ν(C=C) at 1 640 cm–1 (see Table III), which can be assigned to the carbon–carbon
double bond conjugated to the oxo group of the pyridone tautomer.
From the results of all the mentioned analyses it is possible to conclude that the
hydroxy derivative IIb, formed by nucleophilic substitution of the nitro group, occurs
exclusively in the 1-hydroxy-4-pyridone form.
EXPERIMENTAL
The melting points were determined on a Boetius block and are uncorrected. The IR spectra were
1
recorded on a Bruker IFS 88 spectrometer in KBr pellets. The H NMR spectra (δ, ppm; J, Hz) were
measured on a Gemini-300HC instrument (300.075 MHz, digital resolution 0.3 Hz/point), the 13C NMR
TABLE II
13C NMR spectral data (δ, ppm) of compounds II
Compound C=O
C-2
C-3
C-4
C-5
C-6
i
o
m
p
IIa
IIb
IIc
IIda
IIeb
IIfc
159.48 140.56 130.72 139.52 122.37 139.19 138.26 128.39 119.72 124.39
161.48 141.20 117.15 175.30 119.60 139.66 138.42 129.00 119.64 123.67
160.20 140.36 126.44 134.93 127.55 138.49 138.28 128.87 119.69 124.35
160.17 140.60 124.27 153.52 110.51 138.39 138.47 128.78 119.76 124.09
160.07 140.72 124.02 152.94 111.22 138.61 138.43 128.85 119.62 124.08
163.56 138.72 121.04 145.94 111.85 137.66 138.80 128.75 119.78 123.96
a
c
b
Chemical shift of the methoxy group: 59.92 ppm. Ethoxy group: 65.47 (CH2), 14.14 (CH3).
Dimethylamino group: 41.41 ppm.
10
3
δ
2
1
8
6
4
2
0
FIG. 1
The pyridine moiety 1H NMR chemical shift de-
pendence on the Hammett substituent constants
for compounds II (1, H-2, the range of δ being
7.9–8.9 ppm; 2, H-5, 6.4–8.4 ppm; 3, H-6, 8.0–8.5
ppm). The hydroxy derivative IIb was not in-
cluded in the correlation analysis
NMe
OH OEt
OMe
Cl
NO
2
2
σ
p
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Nucleophilic Substitution
1175
spectra (δ, ppm) on a Bruker-400 instrument (100.614 MHz, digital resolution 1 Hz/point, APT tech-
nique, pulse sequence) in hexadeuteriodimethyl sulfoxide. For the concentration dependence study
solutions were measured at 0.07, 0.14 and 0.21 mol l–1. Flash column chromatography was performed
on Merck silica gel 40 in dichloromethane followed by acetone, TLC on Silufol plates (Kavalier,
Czech Republic) in a mixture of chloroform–methanol 4 : 1. Dimethylammonium N,N-dimethylcarba-
mate (dimcarb) was a gift from Professor W. Schroth, Martin-Luther University, Halle, Germany.
4-Nitro-3-pyridinecarboxanilide 1-Oxide (IIa)
A suspension of 4-nitronicotinic acid 1-oxide (I, 0.5 g, 2.7 mmol) in dry dioxane (6.8 ml) and dry
tetrahydrofuran (8.2 ml) was combined with freshly distilled triethylamine (0.76 ml, 5.4 mmol). The
resulting solution was then cooled to –15 °C and ethyl chloroformate (0.52 ml, 5.4 mmol) was added
dropwise at such a rate that the temperature of the reaction mixture did not exceed –12 °C. The re-
sulting suspension was then stirred at –15 °C for 3 h, aniline (1.0 ml, 11 mmol) was added in one
portion and the mixture was stirred at room temperature for 30 min. Water (5 ml) was then added,
the organic layer was evaporated to dryness, dissolved in dichloromethane (5 ml) and column-chro-
matographed. The amorphous red solid was recrystallized from water, and 90 mg (13%) of IIa was
obtained, m.p. 168–170 °C, RF 0.56. For C12H9N3O4 (259.2) calculated: 55.60% C, 3.50% H, 16.21% N;
found: 55.89% C, 3.68% H, 16.07% N. 1H NMR spectra are given in Table I, 13C NMR spectra in
Table II and IR spectra in Table III.
4-Hydroxy-3-pyridinecarboxanilide 1-Oxide (IIb)
A suspension of 4-nitronicotinic acid 1-oxide (I, 0.2 g, 1.1 mmol) in acetyl chloride (5.0 ml, 70 mmol)
was refluxed for 5 h. Acetyl chloride was then distilled off and aniline (5.0 ml, 55 mmol) was added
TABLE III
IR spectra of compounds II (s strong, br broad, w weak)
Compound
ν(NH)
Amide I
Amide II
ν(CH-arom.)
IIa
IIba
IIc
3 258(w)
3 111(w)
3 448(br)
3 252(br)
3 400(br)
3 240
1 679(s)
1 554(s)
1 551(s)
1 552(s)
756
689
759
692
692
1 683(s)
1 681 (br,s)
3 180
IId
IIe
3 447(br)
3 353(s)
1 677(s)
1 676(s)
1 559(s)
1 558(s)
763(s)
3 438(br)
3 344(s)
3 223(br)
3 117(s)
765
778(s)b
IIf
3 336(br)
1 676(s)
1 562(s)
764
695
a
b
ν(C=C) 1 640 cm–1, ν(C=O) 1 592 cm–1
.
Rocking vibration of the ethyl group.
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

1176
Pohl, Prutianov, Smrckova-Voltrova:
dropwise. After 1 h stirring at room temperature the precipitated solid was filtered, washed with to-
luene and, after dissolving in water, alkalified to pH 8. The remaining aniline was washed off with
ethyl acetate, the residue after evaporation of the water portion was dissolved in acetone (25 ml ) and
filtered. After evaporation of acetone 40 mg (15%) of IIb was obtained, m.p. 282–286 °C, RF 0.52.
For C12H10N2O3 (230.2) calculated: 62.61% C, 4.35% H, 12.17% N; found: 62.58% C, 4.40% H,
12.08% N. 1H NMR spectra are given in Table I, 13C NMR spectra in Table II and IR spectra in
Table III.
4-Chloro-3-pyridinecarboxanilide 1-Oxide (IIc)
4-Nitro-3-pyridinecarboxanilide 1-oxide (IIa, 50 mg, 0.2 mmol) was suspended in acetyl chloride (2 ml)
and refluxed for 4 h. Acetyl chloride was then distilled off and the solid residue was washed with
acetone, filtered and recrystallized from water. After drying a quantitative yield of IIc was obtained,
m.p. 172–175 °C, RF 0.52. For C12H9ClN2O2 . 1.5 H2O (275.7) calculated: 52.28% C, 4.38% H,
10.16% N; found: 52.32% C, 3.80% H, 9.70% N. 1H NMR spectra are given in Table I, 13C NMR
spectra in Table II and IR spectra in Table III.
4-Methoxy-3-pyridinecarboxanilide 1-Oxide (IId)
4-Nitro-3-pyridinecarboxanilide 1-oxide (IIa, 100 mg, 0.4 mmol) and 7% sodium methoxide in methanol
(3 ml, 2.6 mmol) were stirred at room temperature for 0.5 h. The mixture was diluted with acetone
and filtered through a silica gel layer. After evaporation of the filtrate compound IId was obtained
(60 mg, 55%), m.p. 160–162 °C, RF 0.37. For C13H12N2O3 . 1.5 H2O (271.3) calculated: 57.56% C,
1
5.57% H, 10.33% N; found: 57.52% C, 5.80% H, 10.33% N. H NMR spectra are given in Table I,
13C NMR spectra in Table II and IR spectra in Table III.
4-Ethoxy-3-pyridinecarboxanilide 1-Oxide (IIe)
4-Nitro-3-pyridinecarboxanilide 1-oxide (IIa, 100 mg, 0.4 mmol) and 7% sodium ethoxide in ethanol
(5 ml) were stirred at room temperature for 0.5 h. The solvent was then evaporated under reduced
pressure and the residue was triturated with water. The resulting crystalline compound was the pure
anilide IIe (35 mg, 30%), m.p. 153–154 °C, RF 0.41. For C14H14N2O3 . 2 H2O (294.3) calculated:
1
57.14% C, 6.16% H, 9.52% N; found: 57.51% C, 6.52% H, 9.67% N. H NMR spectra are given in
Table I, 13C NMR spectra in Table II and IR spectra in Table III.
4-Dimethylamino-3-pyridinecarboxanilide 1-Oxide (IIf)
4-Nitro-3-pyridinecarboxanilide 1-oxide (IIa, 100 mg, 0.4 mmol) and freshly distilled dimethylammonium
N,N-dimethylcarbamate (2 ml, 15 mmol) in water (2 ml) were stirred at room temperature for 5 h.
The solvent was then evaporated under reduced pressure and codistilled with toluene; the residue was
column chromatographed (eluent chloroform–methanol 9 : 1) to give the anilide IIf (80 mg, 68%),
m.p. 230–233 °C, RF 0.34. For C14H15N3O2 . 2 H2O (293.3) calculated: 57.33% C, 6.53% H, 14.33% N;
found: 57.56% C, 6.01% H, 14.26% N. 1H NMR spectra are given in Table I, 13C NMR spectra in
Table II and IR spectra in Table III.
The authors are indebted to Dr Antonin Holy from the Institute of Organic Chemistry and Bioche-
mistry, Academy of Sciences of the Czech Republic, for valuable advice and discussions. Their thanks
are also due to Mrs Zdenka Hladikova for excellent technical assistance. This work was supported by
Collect. Czech. Chem. Commun. (Vol. 60) (1995)

Nucleophilic Substitution
1177
the Grant Agency of the Czech Republic (Grant No. 93/203/0118) and the Ministry of Education of the
Czech Republic (Grant No. 93/0766).
REFERENCES
1. Smrckova S., Juricova K., Prutianov V.: Collect. Czech. Chem. Commun. 59, 2057 (1994).
2. Prutianov V., Pohl R., Smrckova S.: Presented at 4th Blue Danube Symposium on Heterocyclic
Chemistry, St. Poelten, Austria, June 22–26, 1994.
3. Ochiai E.: Aromatic Amine Oxides. Elsevier, Amsterdam 1967.
4. Abramovitch R. A., Smith E. M. in: Pyridine and Its Derivatives (R. A. Abramovitch, Ed.), Vol.
14 Suppl., Part 2, p. 1. Wiley, New York 1974.
5. Prutianov V.: Unpublished results.
6. Shein S. M.: Mekhanizmy geteroliticheskikh reaktsii, p. 51. Nauka, Moskva 1976.
7. Suzuki I.: J. Pharm. Soc. Jpn. 68, 126 (1948); Chem. Abstr. 47, 8074 (1953).
8. Herz W., Murty D. R. K.: J. Org. Chem. 26, 122 (1961).
9. Taylor E. C., Driscoll J. S.: J. Am. Chem. Soc. 82, 3141 (1960).
10. Lyle R. E., Bristol J. A., Kane M. J., Portlock D. E.: J. Org. Chem. 38, 3268 (1973).
11. Ochiai E.: J. Org. Chem. 18, 548 (1953).
12. Taylor E. C., Crovetti A. J.: J. Org. Chem. 19, 1633 (1954).
13. Taylor E. C., Crovetti A. J.: J. Am. Chem. Soc. 78, 214 (1956).
14. Wieland T., Biener H.: Chem. Ber. 96, 266 (1963).
Collect. Czech. Chem. Commun. (Vol. 60) (1995)