Synthesis of some halogen- and nitro-substituted nicotinic acids and their fragmentation under electron impact

Article abstract of DOI:10.1023/B:COHC.0000028626.45566.67

Features of electrophilic and nucleophilic substitution under chlorination and nitration reactions conditions have been investigated for 6-hydroxy- and 6-methyl-substituted derivatives of 3-cyano-4-methyl-2(1H)-pyridones. The polychloro- and nitro-substituted 3-cyano-4-methylpyridines obtained were used as synthons in the synthesis of some polyhalo- and nitro-substituted nicotinic acids and their amides. The fragmentation pathways of the synthesized compounds under electron impact have been studied.

Full text of DOI:10.1023/B:COHC.0000028626.45566.67

Chemistry of Heterocyclic Compounds, Vol. 40, No. 3, 2004
SYNTHESIS OF SOME HALOGEN-
AND NITRO-SUBSTITUTED NICOTINIC
ACIDS AND THEIR FRAGMENTATION
UNDER ELECTRON IMPACT
1
1
1
2
L. V. Dyadyuchenko , V. D. Strelkov , S. N. Mikhailichenko , and V. N. Zaplishny
Features of electrophilic and nucleophilic substitution under chlorination and nitration reactions
conditions have been investigated for 6-hydroxy- and 6-methyl-substituted derivatives of 3-cyano-4-
methyl-2(1H)-pyridones. The polychloro- and nitro-substituted 3-cyano-4-methylpyridines obtained
were used as synthons in the synthesis of some polyhalo- and nitro-substituted nicotinic acids and their
amides. The fragmentation pathways of the synthesized compounds under electron impact have been
studied.
Keywords: halo and nitro derivatives, nicotinic acids, fragmentation under electron impact.
Substituted nicotinic acids and their functional derivatives attract the attention of investigators as
potential physiologically active substances belonging to a group in which compounds are known possessing a
broad spectrum of pharmacological [1-3], and also pesticidal [4, 5] activity. However there is no information in
the literature on nicotinic acids containing 3-4 identical or different substituents in the pyridine ring.
In the present work the synthesis is described of new polysubstituted derivatives of nicotinic acid
starting from 3-cyano-4-methyl-2(1H)-pyridones 1a,b, containing methyl or hydroxyl groups in position 6 of the
ring, by the conversions given in the scheme. Electrophilic substitution of the hydrogen atom in position 5 of the
ring of compounds 1a,b and also nucleophilic substitution of the 2-OH group and the 6-OH of the enolic form of
pyridones 1 by a chlorine atom and a nitro group depends on the substituent in position 6, and also on the type of
chlorinating or nitrating agent. Thus 6-methylpyridine 1a on chlorination with an excess of SO Cl in CCl
2
2
4
forms the product of electrophilic substitution, the 5-chloro derivative 2a, in 94% yield. Nitration with nitric acid
also proceeds selectively at the same position, leading to the 5-nitro derivative 2b. Treatment with an excess of
POCl at ~105°C leads to substitution of the 2-OH group of the enolic form of pyridone 1a by an atom of
3
chlorine, with aromatization of the ring and the formation of 2-chloro-3-cyano-4,6-dimethylpyridine (3a). The 5-
chloro and 5-nitro derivatives 2a,b react analogously with POCl and lead to the 2,5-dichloro- and 2-chloro-5-
3
nitro-substituted products 3c,d respectively (in the case of nitro compound 2b chlorination was conducted at
1
80°C). 2,6-Dichloro-3-cyanopyridine 3b is formed from 3-cyano-6-hydroxy-4-methyl-2(1H)-pyridone (1b)
with POCl (1b : POCl , 1:2) after 6 h at 120°C.
3
3
_
_________________________________________________________________________________________
1
2
All-Russian Research Institute for Biological Plant Protection, Krasnodar 350039, Russia. Kuban
State Agricultural University, Krasnodar 350044, Russia; e-mail: vlad_zpl@mail.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 3, pp. 381-388, March, 2004. Original article submitted March 23, 2001;
revision submitted January 10, 2002.
3
08
0009-3122/04/4003-0308©2004 Plenum Publishing Corporation

Me
Me
Me
R1
Cl
CN
Cl
Cl
Cl
CN
O
CN
O
+
O
O
O
N
H
5a
Me
N
H
N
H
5
b
2
a,b
(1b)
(1a)
Me
CN
O
Me
Me
N
R
N
H
R1
R2
Cl
CN
O
(1b)
(1a)
CN
Cl
1
a,b
HO
N
H
3
a–e
4
(
3b)
Me
Me
R1
R2
R1
R2
CONH2
Cl
COOH
Cl
N
N
7
a–f
6a–e
1
1
1
2
1
2
1
а R = CH
3
, b R = OH; 2 a R = Cl, b R = NO
2
; 3, 6, 7 a R = H, R = Me; b R = H, R = Cl;
1
2
1
2
1
2
1
2
3 2 2
c R = Cl, R = CH ; d R = NO , R = Me; e R = Cl, R = Cl; f R = NO , R = Cl
The behavior of pyridone 1b, in position 6 of which an OH group possessing a +M effect is found in
place of a methyl group possessing a marked +I effect, differs markedly in the reactions described above. Its
chlorination with sulfuryl chloride or the direct action of chlorine does not lead to the desired 5-chloro-6-
hydroxypyridone 4, but is completed by the formation of a mixture of isomeric dichlorides 5a and 5b (varying
the reaction conditions affects only the ratio of isomers), which is in agreement with the data of [6]. Reduction of
this mixture with zinc dust in a protic solvent proceeds smoothly with the formation only of 5-chloro-3-cyano-6-
hydroxy-4-methyl-2(1H)-pyridone (4). On treating the latter with an excess of POCl the trichloro-substituted
3
pyridine derivative 3e is formed.
Attempts to nitrate pyridone 1b, in spite of a wide variation of the conditions (HNO of various
3
concentrations, mixtures of it with AcOH, Ac O, and H SO , and also HNO and isoamyl nitrate [7]), were
2
2
4
2
unsuccessful. Even at reduced temperature (-9±1°C) the reaction was accompanied by resinification, destruction
of the 2-pyridone ring, and the formation of a complex mixture of colored resinous products, which it was not
possible to identify.
Acid hydrolysis of halogen-substituted cyanopyridines 3a-e with aqueous 80% sulfuric acid solution
leads smoothly and in maximum yield to the corresponding amides of nicotinic acid 6a-e. Subsequent
diazotization of these difficultly hydrolyzable amides 6a-e with nitrous acid by the known method of Bouveault
[8] led to the target substituted acids 7a-e. The halonitro-substituted acid 7f was successfully obtained only by
the nitration of nitrile 3b with a mixture of conc. HNO and H SO at ~100°C. It transpired that hydrolysis of the
3
2
4
cyano group to carboxyl occurs simultaneously with the introduction of the nitro group.
All the synthesized compounds were amorphous or white finely crystalline powders. The aromatic
nitriles 3a-e (mp 67-110°C) were readily soluble in the usual organic solvents. Amides 6a-e and acids 7a-e were
high-melting substances, soluble with difficulty or not at all in the usual organic solvents, soluble in some highly
polar solvents, except for of DMF and DMSO. The characteristics of the synthesized compounds are given in
Tables 1 and 2.
3
09

TABLE 1. Characteristics of Compounds 2a,b, 3a-e, 6a-e
Found, %
Calculated, %
Mass
spectrum, m/z
Com-
pound
Empirical
formula
——————
Yield,
%
mp, °C*
rel
(I )
C
H
Cl
N
+
2
2
3
3
3
3
a
b
a
b
c
C
C
C
C
C
C
8
8
8
7
8
8
H
H
H
H
H
H
7
7
7
4
6
6
ClN
2
O
52.84 3.69 19.53 15.40 260-261
2.61 3.87 19.41 15.34
[M] 182 (100);
54 (39); 119
(
94
54
95
98
76
61
5
1
29); 92 (8)
+
N
3
O
3
50.01 3.72
9.74 3.66
21.94 265-266
21.76
[M] 193 (68);
4
1
(
76 (100); 148
21); 119 (53); 92 (28)
+
ClN
2
57.94 4.32 21.58 17.01
7.66 4.24 21.28 16.82
95-96
[M] 166 (100);
5
1
1
30 (21); 131
04 (13); 132 77 (7)
+
Cl
2
2
N
2
44.78 2.04 37.72 14.75 107-108
4.95 2.16 37.91 14.98
[M] 186 (60);
4
1
(
51 (100); 125
41); 105 (32)
+
Cl
N
2
47.68 3.18 35.44 13.60
7.96 3.01 35.26 13.96
67-68
90-91
[M] 200 (100);
4
1
(
64 (15); 129
21); 102 (11)
+
d
ClN
3
O
2
45.12 2.77 16.61 19.50
5.40 2.86 16.75 19.86
[M] 21 (59);
4
1
(
1
94 (100); 165
32); 139 (69);
30 (45); 102 (23)
+
3
6
6
6
e
a
b
c
C
C
C
C
7
8
7
8
H
3
H
9
H
6
H
8
Cl
3
N
2
38.14 1.24 47.94 12.49 110-111
7.96 1.37 48.02 12.65
[M] 184 (89);
68 (100); 140
33); 104 (13); 78 (30)
69
89
93
91
3
1
(
+
ClN
2
O
51.95 5.04 19.28 15.01 154-155
2.04 4.92 19.20 15.18
[M] 184 (89);
40 (33); 104
13); 78 (30)
5
1
(
+
Cl
2
2
N
2
2
O
O
40.79 2.84 34.65 13.49 170-171
1.00 2.96 34.58 13.66
[M] 204 (74);
88 (100); 160
23); 124 (24); 99 (14)
4
1
(
+
Cl
N
43.61 3.64 32.51 12.87 146-147
3.86 3.69 32.36 12.79
[M] 218 (86);
02 (100); 183
12); 174 (38);
4
2
(
1
47 (26); 133 (9)
+
6
6
d
e
C
C
8
7
H
8
5
ClN
3
O
3
42.00 3.46 15.68 18.26 188-189
1.84 3.52 15.44 18.30
[M] 229 (29);
47
69
4
2
1
13 (21); 196 (16);
68 (24); 140 (100)
+
H
Cl
3
N
2
O
35.31 2.13 44.67 11.73 167-168
5.10 2.11 44.41 11.70
[M] 238 (41); 222
3
(100); 194 (14); 187
(18); 159 (28); 133 (9)
_
*
2
______
Solvents for crystallization: acetone (compound 2a), EtOH (compounds
b, 6a-e), cyclohexane (compounds 3a,b,d), hexane (compound 3c).
The dissociation constants pK
Table 2), which enables them to be assigned to the strong acids, exceeding the strength of nicotinic acid by two
orders of magnitude.
There were broadened absorption bands in the IR spectra of the synthesized acids for the carboxyl OH
a
of the substituted nicotinic acids 7a-f were within the range 2.55-2.79
(
-
1
group at 3200-3600 with maxima at 3430-3448 cm (see Table 2). Medium and strong sharp absorption bands
-
1
-1
for the C=C and C=N bonds of the conjugated pyridine ring were found at 1539-1603 cm . At 1715-1734 cm
there was an absorption band for the C=O group, which is characteristic of strong acids existing as dimers [9]. In
-
1
the spectra of the acids containing a nitro group there were also intense bands at 1540-1545 and 1339-1348 cm
which may be interpreted as being characteristic for NO .
2
1
It is not expedient to give and discuss the H NMR spectra of the synthesized compounds because they
were not very informative.
3
10

TABLE 2. Characteristics of the Synthesized Compounds 7a-f
Found, %
Calculated, %
Com-
pound
Empirical
formula
——————
mp, °C*
pKa
Yield, %
C
H
Cl
N
7
7
7
7
7
7
a
b
c
d
e
f
C
C
C
C
C
C
8
7
8
8
7
7
H
8
H
5
H
7
H
7
H
4
H
4
ClNO
2
51.55
4.50
4.34
2.31
2.45
2.43
2.31
3.21
3.06
1.52
1.68
1.52
1.61
19.2
19.1
34.3
34.4
32.4
32.5
15.3
15.4
44.3
44.2
28.2
28.3
7.42
7.54
6.83
6.79
6.35
6.42
12.28
2.15
5.73
5.82
11.25
11.16
139-140
119-120
159-160
170-171
150-151
168-169
2.79
2.64
2.72
2.57
2.64
2.55
60
88
96
76
75
60
5
1.77
Cl
2
2
NO
2
2
4
2
40.66
0.81
4
Cl
NO
47.21
7.07
4
ClN
2
O
41.79
1.67
4
Cl
3
2
NO
34.78
4.95
3
Cl
N
2
O
4
33.35
3.49
3
_
*
______
Solvents for crystallization: EtOAc (compounds 7a,b,e) and EtOH
(
compounds 7c,d,f).
Study of the behavior of the synthesized acids under the action of electron impact showed that their
+
molecular ions [M] were characterized by enhanced stability and relative intensity (54-100%), while the
directions of their primary fragmentation were fairly diverse. It is known [10] that as a result of the primary
+
fragmentation of M of nicotinic acid under electron impact there is loss of COOH, hydroxyl, or a H O
2
molecule. This turned out to be characteristic also for the substituted nicotinic acids 7a-e, in the mass spectra of
+
which peaks for [M-H O] ions were detected with a relative intensity (I ) of 10-46%. Elimination of the COOH
2
rel
+
group and the formation of highly stable [M-COOH] ions also takes place (I 18-100%). In addition ejection of
rel
a molecule of CO was observed in the mass spectra of acids 7a-e, as indicated by the presence of peaks for [M-
2
+
CO ] ions (I 21-31%).
2
rel
We note that the 5-nitro-substituted acid 7f loses an NO group in the initial stage of decomposition and
2
elimination of CO is a characteristic only for the secondary processes of fragmentation. The formation of
2
+
[
M-HCl] fragments (I 20-100%) is characteristic of the primary fragmentation processes of the molecular ions
rel
of all the halogen-substituted nicotinic acids with the exception of compounds 7d,f containing a 5-nitro group.
The latter probably split off a chlorine atom in the later stages of fragmentation.
In the fragment ions from electron impact of the majority of the 2-chloronicotinic acids being discussed,
it is probable that migration of the hydroxyl group occurs to the position where the positive charge is localized,
i.e. to carbon atom 2, which corresponds to the fragmentation pathway of o-nitrobenzoic acids [11], with
subsequent elimination of CO.
Me
O
Me
Me
+
+
C
C
O
OH
–
CO
+
N
Me
N
OH
N
OH
–
OH
– CO
Me
N
Me
N
H
3
11

TABLE 3. Spectral Characteristics of Compounds 7a-f
-
1
Mass spectrum: molecular
and characteristic ions,
m/z (Irel, % of maximal)
IR spectrum, νmax, cm
Com-
pound
Yield,
%
С=С,
С=N
ОН
С=О
NO2
+
+
+
7
7
7
7
7
а
b
c
[M] 185 (93); [M–OH] 168 (20); [M–H
2
O]
3600,
3300
(3443)
1725 1603
—
—
—
60
88
96
76
75
+
+
1
1
[
67 (10); [M–HCl] 149 (100); [168-CO]
+
40 (12); [149–CH
3
, –CH
2
] 120 (25);
+
149–CO] 105 (17)
+
+
+
[M] 205(100); [M–OH] 188 (68); [M–H
2
O]
3600,
3000
(3430)
1717 1570
1539
+
+
1
1
1
87 (44); [M–HCl] 168 (41); [M–CO ]
2
+
+
61 (31); [M–COOH] 160 (19); [169–CO]
41 (33)
+
+
[M] 219 (100); [M–HOH] 201 (32);
3600,
3300
(3431)
1734 1576
+
+
[
[
[
M–HCl] 183 (75); [M–COOH] 174 (18);
183–Cl] 148 (81); [183–COOH] 138 (15);
+
+
+
148–CO] 120 (22)
+
+
d
e
[M] 230(64); [M–OH] 213 (52);
3600,
3200
(3430)
1726 1589 1540
1348
+
+
[
M–OH,–H
84 (13); [213–Cl,–CN] 142 (27);
2
O] 195 (11); [M–NO ]
2
+
1
[
+
+
2
184–CO ] 140 (33); [140–Cl] 105 (44)
+
+
+
[M] 239 (100); [M–OH] 222 (28); [M–H
2
О]
3600
2200
(3448)
1718 1545
—
+
+
2
1
1
1
21 (35); [M–HСl] 203 (20); [M–CO ]
92 (10); [M–COOH] 194 (12); [203–Cl]
68 (55); [203–COOH] 158 (16); [168–CO
2
+
+
+
+
2
]
24 (19)
+
+
7
f
[M] 250 (54); [M–OH] 233 (49);
3600
3200
(3430)
1715 1576 1545
1389
60
+
+
[
1
[
[
M–OH,–H
69 (45); [M–CO
169–CO] 141 (28); [169–Cl] 134 (28);
141–OH] 124 (28)
O] 205 (100); [M–NO ,–Cl]
2 2
+
2
,–NO
2
] 160 (68);
+
+
+
In the later stages of fragmentation, elimination of a hydroxyl group or one further CO fragment is
possible with the formation of more stable five-membered heterocyclic ions with a relative intensity of 17-33%.
The features of the electrophilic and nucleophilic substitution in 6-oxo- and 6-methyl-substituted
3
-cyano-4-methyl-2(1H)-pyridones have been studied. Accessible routes have been developed for the synthesis
of polysubstituted nicotinic acids, which are potentially biologically active substances.
EXPERIMENTAL
The IR spectra were recorded on a Bruker IFS-45 spectrometer with an analyzing Aspekt-1000 computer
for compounds in KBr disks. The mass spectra were recorded on an LKB-2091 chromato-mass spectrometer
with direct insertion of samples into the ion source (energy of ionizing electrons 70 eV). The elemental analysis
of the synthesized compounds was carried out on a Carlo Erba model 1106 analyzer. The dissociation constants
of acids 7a-f were determined on a type I130.2M.1 ionomer. The homogeneity of the synthesized compounds
was confirmed by TLC on Silufol UV-vis plates, solvent was hexane–acetone, 1:1, visualizing with iodine
vapor.
The solvents used were purified and dried by known methods [14].
The initial 3-cyano-4,6-dimethyl-2(1H)-pyridone 1a and 3-cyano-6-hydroxy-4-methyl-2(1H)-pyridone
1
5
b were obtained and purified as described previously in [12, 13]. The synthesis of mixtures of isomeric nitriles
a and 5b and their reduction to 5-chloro-3-cyano-6-hydroxy-4-methyl-2(1H)-pyridone 4 was carried out
analogously to [6]. Their physicochemical characteristics are given in the cited work.
3
12

5
-Chloro-3-cyano-4,6-dimethyl-2(1H)-pyridone (2a). A mixture of cyanopyridone 1a (5 g,
3
3.7 mmol) and sulfuryl chloride (18.25 g, 135.2 mmol) in dry CCl (50 ml) was boiled under reflux for 6 h.
4
After cooling, the precipitated solid was filtered off, washed with CCl , and dried. Product 2a (5.8 g) was
4
obtained as a white, finely crystalline powder.
3
3
-Cyano-4,6-dimethyl-5-nitro-2(1H)-pyridone (2b). A solution of HNO (d = 1.51 g/cm , 2.1 ml) in
3
Ac O (1.8 ml) was added slowly with stirring to a suspension of cyanopyridone 1a (3.48 g, 18 mmol) in Ac O
2
2
(
12 ml) at 0±1°C. The reaction mixture was maintained at 5°C for 0.5 h, then at 20°C for 0.5 h, and poured onto
ice. The precipitated solid was filtered off, washed with ice water (3 × 50 ml), and dried in vacuum. Product 2b
2.5 g) was obtained as a white powder.
-Chloro-4,6-dimethylnicotinic Acid Nitrile (3a). A mixture of cyanopyridone 1a (5.0 g, 33.7 mmol)
(
2
and POCl (5.17 g, 33.7 mmol) was heated in a sealed ampule at 120°C for 5.5-6.0 h. The ampule was opened
3
and the contents were poured onto crushed ice (30 g). The resulting solid was filtered off, washed with ice water
(
3 × 50 ml), and dried under reduced pressure. Nitrile 3a (5.35 g) was obtained as a white, finely crystalline
powder.
Nitriles 3b-e were obtained analogously from compounds 1b, 2a,b, and 4 respectively.
,6-Dichloro-4-methylnicotinic Acid Amide (6b). A mixture of nitrile 3b (1 g, 5.35 mmol) and 80%
H SO (15 ml) was stirred at 98±2°C for 6 h. The cooled reaction mixture was poured onto crushed ice (30 g),
2
2
4
and aqueous ammonia solution added to pH ~5. The resulting solid was filtered off, washed thoroughly with
water, and dried in a vacuum desiccator. Amide 6b (1 g) was obtained as a white, finely crystalline powder.
Amides 6a,c-e were obtained analogously, but at a hydrolysis time of 10 h.
2
,6-Dichloro-4-methylnicotinic Acid (7b). A mixture of amide 6b (5 g, 24 mmol) and conc. H SO (d =
2 4
3
1
.84 g/cm , 21.4 ml) was heated slowly until complete solution of the amide. A solution of NaNO (3.9 g, 56.5
2
mmol) in water (20 ml) was slowly added dropwise to the cooled solution at ~0°C. The reaction mixture was
kept for 40-60 min at 20-25°C, then poured onto crushed ice (50 g). The solid which separated was filtered off,
and purified by reprecipitation from 10% NaOH solution by acidifying with 10% HCl solution. The solid was
washed with water, dried at 20°C, and the crystallohydrate of 7b (4.8 g) was obtained; mp 108-110°C. After
additional drying in vacuum at 80°C for 1.5 h, the anhydrous 7b acid (4.4 g) was obtained as a white powder.
Substituted nicotinic acids 7a,c-d were obtained analogously from amides 6a,c-d respectively.
2
,6-Dichloro-4-methyl-5-nitronicotinic Acid (7f). A solution of nitrile 3b (1 g, 5.35 mmol) in a
3
3
mixture of HNO (d = 1.51 g/cm , 7 ml) and H SO (d = 1.84 g/cm , 7 ml) was heated at ~100°C for 10 h. The
3
2
4
mixture was cooled to 0°C and added dropwise to ice (30 g) powdered and cooled to -40°C. The precipitated
solid was filtered off, washed with water, reprecipitated from saturated NaHCO solution, washed with water to
3
pH 7, and dried. Acid 7f (0.81 g, 60%) was obtained as a white, finely crystalline powder.
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1
2
3
.
.
.
A. I. Mikhalev, V. K. Kudryashova, and M. E. Konshin, Khim.-farm. Zh., No. 5, 7 (1973).
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5
6
7
.
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.
A. D. Gutman, US Patent 4251263; Ref. Zh. Khim., 17 O339P (1973).
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.
K. V. Vatsuro and G. L. Mishchenko, in: Named Reactions in Organic Chemistry [in Russian],
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3
13

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.
K. Nakanishi, in: Infrared Spectra and Structure of Organic Compounds [Russian translation], Mir,
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1
1
0.
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