STUDY OF AMINO-IMINO TAUTOMERISM IN DERIVATIVES OF 2-, 4- AND 6-AMINONICOTINIC ACID

Article abstract of DOI:10.1135/cccc19942057

13C NMR spectra of p-nitrobenzoyl 2-, 4-, and 6-aminopyridine-3-carboxylates, their hydrochlorides, trifluoroacetates and 1-benzyl derivatives were studied.As found from the chemical shifts of pyridine carbon atoms C-2, C-4 and C-6, the free bases exist i

Full text of DOI:10.1135/cccc19942057

Aminonicotinic Acids
2057
STUDY OF AMINO–IMINO TAUTOMERISM IN DERIVATIVES
OF 2-, 4- AND 6-AMINONICOTINIC ACID
Svatava SMRCKOVA*, Kristina JURICOVA and Viktor PRUTIANOV
Department of Organic Chemistry,
Prague Institute of Chemical Technology, 166 28 Prague 6, The Czech Republic
Received February 28, 1994
Accepted April 14, 1994
13C NMR spectra of p-nitrobenzoyl 2-, 4-, and 6-aminopyridine-3-carboxylates, their hydrochlorides,
trifluoroacetates and 1-benzyl derivatives were studied. As found from the chemical shifts of pyridine
carbon atoms C-2, C-4 and C-6, the free bases exist in the amino form whereas hydrochlorides and
1-substituted pyridinium derivatives in the imino form. Trifluoroacetates of the 2- and 6-amino deri-
vatives have structure similar to that of amidiniumcarboxylates (parallel hydrogen bonds and partially
ionic character) whereas trifluoroacetate of the 4-amino derivative is structurally close to the corre-
sponding hydrochloride. The found structures were confirmed by 1H NMR and IR spectroscopy.
Most of antivirals are based on nucleoside analogs. Structure–activity studies of cytos-
tatic and antiviral effect of nucleosides led to modification of the base by replacement
of the =N− by the =CH− group as realized in the synthesis of deazapurine or deazapyri-
midine (pyridine) derivatives1. Since in natural nucleosides the heterocyclic nucleus
bears an amino group as well as a nitrogen-bound sugar component, the preparation of
aminopyridine derivatives substituted in position 1 was of interest. Unlike the purine
and pyrimidine nucleosides, the mentioned compounds contain a quaternary nitrogen
atom whose presence markedly influences the properties of the molecule. It affects e.g.
the transport of the molecule through biological membranes or, due to interaction with
enzymes, influences also other parameters that determine behaviour of the molecule in
biological systems. It is appropriate to compensate the positive charge of the nucleus by
a carboxy group or a similar functionality. Interestingly, 1-substituted 4-aminonicotinic
acid exists in nature as a part of the CNS-active alkaloid clitidin2.
In contrast to 3-amino derivatives of pyridine, the 2- and 4-amino derivatives can
exist in two tautomeric forms: in the amino and in the imino form. In free bases the
amino form prevails; this fact is explained by loss of aromatic resonance energy in the
imino form3,4. However, already protonation of 2- and 4-aminopyridines, which takes
* The author to whom correspondence should be addressed.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2058
Smrckova, Juricova, Prutianov:
place exclusively at the ring nitrogen, disturbs the aromatic character of the molecule
and the compound exists in the imino form: the salt formed is thus not an aminopyridi-
nium but a 1,2-dihydropyridin-2-iminium or 1, 4-dihydropyridin-4-iminium salt5. If the
2-aminopyridine in question forms a complex with acetic acid, its structure can be
depicted by the limiting formulae (A) and (B) in Scheme 1 (refs6,7). According to quan-
tum chemical calculations, the structure (C) in the ground state is unstable and its ex-
istence is improbable.
The structure of quaternary 2- and 4-aminopyridinium salts remained unsolved be-
cause no suitable method of study has been found so far. Alkylation of 2-aminopyridine
with methyl iodide afforded the 1-methyl derivative which upon mild treatment with
alkali was converted into 2-imino-1-methyl-1,2-dihydropyridine8; this fact is regarded
as the only proof of preference of imino form in 1-substituted 2-aminopyridinium salts.
In our present paper we investigate the structure of quaternary salts derived from
2- , 4- and 6-aminopyridines bearing an ester functionality in the position 3. We have
found a suitable method utilizing 13C NMR spectroscopy for the proof of structure and
character of an amino group, not only in these compounds but also in other aminoa-
zaheterocycles. The method is based on the fact that chemical shifts of the correspond-
ing atoms of the pyridine nucleus in free bases, their salts and 1-substituted compounds
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Aminonicotinic Acids
2059
vary in the range of 7 ppm in a defined way, according to the character of the amino
+
group (limiting cases are “pure” amino form, −NH2, and “pure” iminium form, =NH2 ).
For the study of character of the amino group we have chosen p-nitrobenzyl esters of
6- (Ia), 2- (IIa) and 4-aminonicotinic acid (IIIa), their trifluoroacetates Ib – IIIb, hydro-
chlorides Ic – IIIc and 1-benzyl derivatives Id – IIId. For comparison, we studied the
corresponding deaza derivatives, i.e. p-nitrobenzyl esters of 4- (IVa) and 2-aminoben-
zoic acid (Va) and their hydrochlorides IVb and Vb, as well as the corresponding
deamino derivatives, i.e. p-nitrobenzyl ester of nicotinic acid (VIa), its hydrochloride
VIb and 1-benzyl derivative VIc.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2060
Smrckova, Juricova, Prutianov:
Esters Ia, IIa, IVa – VIa were synthesized9 by reaction of cesium salt of the appropri-
ate carboxylic acid with p-nitrobenzyl bromide. Ester IIIa was prepared by reesterifica-
tion of methyl 4-aminonicotinate with p-nitrobenzyl alcohol. Methyl 4-aminonicotinate
was synthesized by the following reaction sequence. 3-Methylpyridine 1-oxide10 was
nitrated to give the nitro derivative which was oxidized to 4-nitronicotinic acid
1-oxide11. Its silver salt was methylated with methyl iodide12 and the obtained methyl
ester was catalytically hydrogenated. Esters Ia – VIa served as starting compounds for
the preparation of trifluoroacetates Ib – IIIb by treatment with trifluoroacetic acid in
acetone; analogously, on reaction with hydrochloric acid we obtained hydro-
chlorides Ic – IIIc and IVb. Compounds Vb and VIb were prepared only in the NMR
tube and were not isolated. Benzyl derivatives Id and IId were obtained by reaction of
the corresponding p-nitrobenzyl esters Ia and IIa with benzyl bromide in dimethylform-
amide at elevated temperature. Since under these conditions the compound VIa under-
went transesterification, the quaternization leading to compounds IIId and VIc was
performed in dioxane at room temperature.
The free bases (esters Ia – IIIa) were unequivocally assigned the amino structure on
the basis of literature data (vide supra) as well as our spectroscopic studies (vide infra).
On the other hand, hydrochlorides Ic – IIIc invariably exist in the iminium form.
The best method for determining the structure of quaternary salts proved to be the
13C NMR spectroscopy. The signals of the individual carbon atoms were assigned on
the basis of experimental distinction of tertiary and quaternary carbon atoms by the
APT (Attached Proton Test) method. The observed chemical shifts of carbon atoms in
compounds I – VI are given in Table I.
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Aminonicotinic Acids
2061
As follows from Table I, the 13C NMR spectra of bases Ia – IIIa and their hydro-
chlorides Ic – IIIc are considerably different, particularly as concerns the carbon atoms
C-2, C-4 and C-6 or atoms in the immediate vicinity of the amino group. The dif-
ferences between the corresponding signals are in the range 3 – 11 ppm. Worth notice
is the fact that in the case of 6- and 2-amino derivatives I and II (compounds of the
amidine type) the chemical shifts change evenly in the order base – trifluoroacetate –
hydrochloride – benzyl derivative whereas the spectra of compounds IIIb – IIId are
similar to each other but different from that of the base IIIa. To assess the magnitude of
the effect of the ring nitrogen atom on the chemical shifts, we synthesized esters of
4-aminobenzoic acid IVa and Va and their respective hydrochlorides IVb and Vb. As
TABLE I
13C NMR spectra (δ, ppm) of compoundsa I – VI
Compound
C-2
C-3
C-4
C-5
C-6
C=O
Ia
151.2
145.5
146.4
144.3
159.7
156.1
153.9
152.8
152.6
141.1
140.3
141.0
131.7
131.5
151.9
144.6
153.7
153.6
153.0
113.2
114.0
114.3
116.0
104.4
107.6
110.0
112.6
106.1
108.1
106.7
107.1
115.6
120.4
108.4
117.3
125.1
127.7
130.6
138.3
140.6
141.9
141.3
140.0
143.7
143.5
145.8
155.4
158.0
158.4
157.2
131.7
131.5
130.8
131.8
136.8
136.0
136.2
108.0
111.2
113.2
116.1
112.3
111.9
111.9
112.5
111.0
112.0
112.4
113.4
113.1
117.2
116.8
123.3
123.8
126.8
128.9
162.7
159.1
156.8
155.9
154.5
148.0
146.4
146.5
152.0
145.4
144.8
147.4
154.2
148.1
134.6
135.2
149.9
144.1
146.2
165.0
163.8
163.2
162.8
166.2
164.4
163.4
163.6
166.4
163.8
163.9
163.2
165.8
165.5
167.0
166.1
164.2
162.1
162.0
Ib
Ic
Id
IIa
IIb
IIc
IId
IIIa
IIIb
IIIc
IIId
IVab
IVbb
Vab
Vbb
VIa
VIb
VIc
a
p-Nitrobenzyl group (compounds I – VI): 65.0 (CH2), 123.9 (C-3 and C-5), 128.7 (C-2 and C-6),
144.7 (C-1), 147.5 (C-4). Benzyl group (Id – IIId): 56.3 (CH2), 128.0 (C-2 and C-6), 129.0 (C-4),
129.5 (C-3 and C-5), 134.2 (C-1). Benzyl group (VIc) 63.9 (CH2), 129.0 (C-2 and C-6), 129.3 (C-4),
129.5 (C-3 and C-5). b The data are given in the order C-2, C-1, C-6, C-5, C-4 and C=O.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2062
Smrckova, Juricova, Prutianov:
shown in Table I, the formation of salts affects considerably not only the shift of the
carbon atom bearing the amino group but also the signals of C-3 and C-5 in the hetero-
cycle (4 – 9 ppm). To study the effect of the amino group on the spectral changes due
to protonation or quaternization, we prepared model compounds VI. Upon protonation
(compound VIb) or quaternization (compound VIc), the spectrum of the nicotinic ester
VIa also shows changes of only the C-3 and C-5 signals (5 ppm). The C-2 signal is not
affected and the C-6 shift relative to the base is greater for the hydrochloride (5 ppm)
than for the benzyl derivative (3 ppm). For compound VIc, the benzyl methylene signal
is shifted 7.6 ppm downfield which indicates a greater positive charge on nitrogen than
in the amino derivatives Id – IIId.
Of interest are the spectra of trifluoroacetates Ib and IIb whose chemical shifts are
located between those of the base and the hydrochloride (Table I). This fact can be
explained by the amidinium structure of the studied compounds: they are capable of
forming two strong hydrogen bonds between the amidine group and the carboxyl group
of trifluoroacetic acid. The aromatic character of the nucleus is thus disturbed only
partially because the positive charge is delocalized between the atoms of the amidinium
group. Both bonds N−C−N are then almost equivalent (as far as allowed by the asym-
metric substitution) and the structure of trifluoroacetates Ib and IIb can be well de-
scribed by formulae with delocalized π-electrons. The mentioned facts are in accord
with the conclusions of our earlier studies on amidinium carboxylates (see e.g.
refs13,14). In compound IIIb the mentioned parallel hydrogen bonds cannot exist and
therefore its spectrum is very similar to that of hydrochloride IIIc.
If the base is quaternized, its 13C NMR signals (in compounds I – III) are invariably
located outside the interval given by signals of the base or the hydrochloride (Table I).
Since no such shifts were observed on benzylation of a compound without an amino
group, this proved unequivocally that 1-substituted derivatives of 2-, 4- or 6-aminoni-
cotinic acid exist in the form of iminium salts.
1
Table II shows H NMR spectra of the compounds synthesized. The proton shifts
exhibit relationships similar to those found in the 13C NMR spectra discussed above.
Worth notice is the signal of the =NH+2 protons in compound IIIb and particularly IIIc
where the nonequivalence of the iminium protons due to hydrogen bond to the carbonyl
oxygen is indicated by the presence of two sharp singlets (∆δ = 0.81 ppm).
The structure of the studied compounds determined by NMR data has been con-
firmed also by their IR spectra. The spectra of bases Ia – Va exhibit bands charac-
teristic of an amino group: two or three vibration bands in the region 3 200 – 3 500
cm−1 and a deformation band at about 1 635 cm−1 (Table III). In addition to the defor-
mation band, compounds Ia – IIIa and VIa display a strong band at 1 600 – 1 605 cm−1
due to skeletal vibrations of the pyridine nucleus15,16. This band is also present in the
spectra of 1-benzylpyridine derivatives containing an amino group (Id – IIId) and salts
(Ib – IIIb, Ic – IIIc). Although in these compounds the band is somewhat weaker and is
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Aminonicotinic Acids
2063
shifted to higher wavenumbers (1 605 – 1 612 cm−1), this shift is not so large as to
correspond to protonation or quaternization of the pyridine nucleus (ref.15 reports a
hypsochromic shift to 1 631 – 1 647 cm−1; for compound VIc we have found 1 630 cm−1,
see Table III). This fact, together with appearance of amidinium bands (1 600 – 1 700 cm−1),
shows a delocalization of the positive charge, not only in the amidine structures (com-
pounds I and II) but also in the amidine vinylogs (compounds III).
Of diagnostic importance is the stretching vibration band ν(C=O) in the pyridine
trifluoroacetates17,18, since the formation of hydrogen bond reduces the difference be-
TABLE II
1H NMR spectra (δ, ppm; J, Hz) of compoundsa I – VI
Chemical shifts
H-5
J(H,H)
Compound
H-2
H-4
H-6
NH2
4,5
5,4
5,6
6,5
Ia
8.59
8.62
8.63
8.92
–
7.91
8.12
8.23
8.31
8.15
8.32
8.40
8.69
–
6.50
6.83
7.06
7.27
6.64
6.87
6.98
7.14
6.70
7.04
7.12
7.10
6.59
6.99
6.54
7.11
7.61
8.10
8.32
–
7.01
8.20
8.7
8.5
8.6
9.4
7.8
5.5
5.5
5.0
–
8.8
8.7
9.3
8.2
7.7
5.2
5.0
4.8
–
–
–
–
Ib
–
–
Ic
–
8.65
c
–
–
Id
–
–
–
IIa
8.23
8.45
8.68
9.10
8.09
8.21
8.23
8.66
–
7.20
8.20
7.3
8.0
6.4
4.9
6.1
7.5
7.1
7.4
–
7.5
7.9
7.1
5.5
–
IIb
–
IIc
–
8.40
c
IId
–
IIIa
IIIb
IIIc
IIId
IVab
IVbb
Vab
Vbb
VIa
VIb
VIc
8.78
8.91
8.87
9.18
7.68
7.87
–
7.30
8.50d
8.56e
c
–
–
–
8.7
8.0
–
–
–
–
–
–
–
7.68
7.87
7.79
7.91
8.36
8.91
9.04
6.06
8.62
8.0
6.9
8.0
8.1
8.2
8.1
8.1
8.6
7.0
8.5
7.9
7.7
7.9
6.4
–
–
–
–
7.27
7.52
8.85
9.08
9.44
6.67
c
6.1
7.0
5.9
6.2
6.1
6.0
7.0
5.1
5.1
6.1
–
9.17
9.32
9.81
–
–
–
a p-Nitrobenzyl group (compounds I – VI): 5.45 s, 2 H (CH2); 7.80 d, 2 H, J = 8.5 (H-2 and H-6); 8.25 d,
2 H, J = 8.4 (H-3 and H-5); benzyl group (Id – IIId, VIc): 5.55 s, 2 H (CH2); 7.20 – 7.45 m, 5 H
b
(H-arom.). The data are given in the order H-2, H-6, H-5, H-4, NH2, J(6,5), J(5,6), J(5,4),
J(4,5). c Not observed. d Another NH2 signal at 9.0 ppm.e Another NH2 signal at 9.37 ppm.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2064
Smrckova, Juricova, Prutianov:
tween the carbonyl and carboxyl absorption bands. In our case (compounds Ib – IIIb),
however, the situation is more complicated because of the presence of the amino and
the ester carbonyl groups. Nevertheless, from the position of the C=O band in the spec-
trum of trifluoroacetate (1 703 – 1 717 cm−1; thus between ν(COO−) and ν(C=O); Table III)
we can conclude that in the complex aminopyridine–trifluoroacetic acid both electros-
tatic interaction between the ions and parallel hydrogen bonds participate.
EXPERIMENTAL
The melting points were determined on a Boetius block and are uncorrected. The NMR spectra (δ,
ppm; J, Hz) were measured on a Gemini-300HC instrument in hexadeuteriodimethyl sulfoxide. Ex-
perimental parameters: for 1H NMR 300.075 MHz, digital resolution 0.3 Hz/point; for 13C NMR
75.462 MHz, digital resolution 0.6 Hz/point; APT technique. The IR spectra were recorded on a
Bruker IFS 88 spectrometer in KBr pellets.
TABLE III
Infrared spectra of compounds I – VI
Compound
ν(NH2)
δ(NH2)
ν(C=N)
ν(C=O)
Ia
3 409, 3 315
1 652
1 635
1 624
1 640
1 618
–
1 600
1 606
1 605
–
1 603
IIa
IIIa
IVa
Va
VIa
Ib
3 449, 3 274, 3 216
1 698
3 481, 3 444, 3 371
1 699
3 468, 3 354, 3 232
1 682
3 475, 3 370
–
1 688
–
1 605
1 607
1 607
1 605
1 610
1 612
1 605
–
1 724
3 322a
3 361
3 396
3 404
3 383a
3 393
3 419
3 416
3 320a
3 379a
–
–
1 706
IIb
IIIb
Ic
–
1 713, 1 681
1 717, 1 685
1 720
1 671a
1 687a
1 643
1 655
1 632
1 666
1 650
1 671
–
IIc
IIIc
IVb
Id
1 709
1 714
1 723
1 601
1 601
1 605
1 630
1 720
IId
IIId
VIc
1 704
1 723
1 729
a Broad band.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Aminonicotinic Acids
2065
2-Aminonicotinic and trifluoroacetic acids were purchased from Fluka, 6-aminonico-
tinic acid from Aldrich. Methyl 4-nitronicotinate 1-oxide was obtained from 3-methyl-
pyridine 1-oxide according to a published procedure10–12
.
Methyl 4-Aminopyridine-3-carboxylate
Methyl 4-nitronicotinate 1-oxide (5.7 g, 29 mmol) was hydrogenated in methanol (120 ml) over 10%
Pd/C (2.7 g) at atmospheric pressure and 40 °C for 3 h (consumption 2 910 ml, 130 mmol H2). The
catalyst was filtered through a layer of microcrystalline cellulose and washed with methanol (2 × 50 ml).
After evaporation of the solvent, the crystalline residue was sublimed at 120 °C/2 kPa to give 1.75 g
(40%) of methyl 4-aminopyridine-3-carboxylate, m.p. 174.5 – 175.5 °C. For C7H8N2O2 (152.2) cal-
1
culated: 55.25% C, 5.29% H, 18.41% N; found: 55.17% C, 5.31% H, 18.01% N. H NMR spectrum:
3.82 s, 3 H (OCH3); 7.15 d, 1 H, J(5,6) = 7.4 (H-5); 7.45 bs, 2 H (NH2); 8.11 d, 1 H, J(6,5) = 7.1
(H-6); 8.30 s, 1 H (H-2).
p-Nitrobenzyl Esters Ia, IIa, IVa – VIa. General Procedure7
A mixture of the appropriate carboxylic acid (1 mmol), water (10 ml) and cesium carbonate (163 mg,
0.5 mmol) was stirred at room temperature to dissolution (about 2 h). After evaporation of the sol-
vent under diminished pressure and codistillation of the residue with dimethylformamide (3 × 5 ml),
the colourless crystalline material was dissolved in anhydrous dimethylformamide (15 ml). p-Nitro-
benzyl bromide (216 mg, 1 mmol) was added to this solution under vigorous stirring. The reaction
mixture was stirred at room temperature overnight, and the dimethylformamide was evaporated under
diminished pressure. The residue was codistilled with toluene (6 × 20 ml), mixed with hot acetone,
the suspension was filtered and the filtrate was evaporated under diminished pressure. The yellow
crystalline residue was crystallized from acetone–ethanol (9 : 1). For yields, elemental analyses and
melting points see Table IV.
p-Nitrobenzyl 4-Aminopyridine-3-carboxylate (IIIa)
A mixture of methyl 4-aminopyridine-3-carboxylate (110 mg, 0.72 mmol), p-nitrobenzyl alcohol (137 mg,
0.89 mmol) and Amberlite GC-120 (H+ form, 20 mg) was heated at 95 °C and 5 kPa for 17 h. The
reaction mixture was filtered and codistilled with toluene (5 × 5 ml). The residue was washed with
acetone (−30 °C) and crystallized from acetone–ethanol (9 : 1). For yield, elemental analysis and
melting point see Table IV.
Trifluoroacetates Ib – IIIb. General Procedure
p-Nitrobenzyl ester Ia – IIIa (82 mg, 0.3 mmol) was dissolved in warm mixture of acetone (2 ml)
and ethanol (1 ml). Trifluoroacetic acid (23 µl, 34 mg, 0.3 mmol) was then added to the solution and
the reaction mixture was stirred at 40 °C for 30 min. Upon cooling, the colourless crystalline product
was collected. For yields, melting points and elemental analyses see Table IV.
Hydrochlorides Ic – IIIc and IVb. General Procedure
p-Nitrobenzyl ester Ia – IVa (0.39 mmol) was dissolved in a warm mixture of acetone (2 ml) and
methanol (0.5 ml). Hydrochloric acid (0.1 ml) was added to the solution and the colourless crystal-
line hydrochloride deposited immediately. For physical characteristics and yields see Table IV.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2066
Smrckova, Juricova, Prutianov:
Calculated/Found
TABLE IV
Characteristic data of compounds I – VI
Formula
Compound
M.p., °C
Yield, %
(M.w.)
% C
% H
4.06
% N
Ia
C13H11N3O4
(273.2)68
226 – 227
56.99
57.13
15.38
4.10
3.15
4.15
4.32
4.10
3.22
4.13
3.89
4.51
2.95
3.99
15.52
10.53
12.23
Ib
C15H12F3N3O6
(387.2)85
167 – 168
46.32
46.50
45.16
51.96
57.13
46.50
50.48
54.17
55.27
46.50
46.37
3.12
4.66
4.36
4.06
3.12
3.91
4.09
4.25
3.12
4.45
10.85
12.15
Ic
C13H12ClN3O4 . 2 H2O
(345.7)78
180 – 182
44.94
Id
C20H18BrN3O4 . H2O
(462.3)67
224 – 225
51.74
9.08
9.34
IIa
IIb
IIc
IId
IIIa
IIIb
IIIc
IIId
IVa
IVb
Va
VIa
VIc
C13H11N3O4
(273.2)60
199 – 200
57.23
15.38
10.85
13.59
14.92
10.50
13.59
C15H12F3N4O6
(387.2)50
156 – 159
46.55
C13H12ClN3O4
(309.7)43
174 – 177
50.47
C20H18BrN3O4
(444.3)56
206 – 209
54.09
9.48
9.81
C13H11N3O4 . 0.5 H2O
(282.2)50
171 – 172
54.92
14.88
10.85
12.48
14.41
10.40
12.31
C15H12F3N3O6
(387.2)74
155 – 158
46.44
C13H12ClN3O4 . 1.5 H2O
(336.7)85
215 – 216
46.78
C20H18BrN3O4
(444.3)
226 – 228
54.17
53.89
4.09
3.94
9.48
9.10
a
C14H12N2O4 . 0.5 H2O
(281.3)55
124 – 125
61.42
61.75
54.54
61.75
60.47
55.96
4.44
4.25
4.44
3.90
3.91
10.29
9.94
4.76
4.41
4.83
3.62
3.90
C14H13ClN2O4
(308.8)82
150 – 152
54.78
9.09
8.86
C14H12N2O4
(272.3)64
127 – 129
61.51
10.29
10.15
10.57
C13H10N2O4
(258.2)62
137 – 138
60.26
10.85
C20H17N2O4
(429.3)47
180 – 182
55.58
6.53
6.12
a Quantitative yield.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

Aminonicotinic Acids
2067
1-Benzyl-5- (Id) and 1-Benzyl-3-(p-nitrobenzyloxycarbonyl)-1,2-dihydropyridin-2-iminium
Bromide (IId)
Benzyl bromide (73 mg, 0.43 mmol) was added in portions to a solution of compound Ia or IIa
(73 mg, 0.27 mmol) in anhydrous dimethylformamide (2 ml) and the mixture was heated at 70 °C for
6 h. The solvent was evaporated under diminished pressure and the residue was codistilled with
toluene (6 × 5 ml). The solid residue was washed with ether and dried. For physical characteristics
and yields see Table IV.
1-Benzyl-3-(p-nitrobenzyloxycarbonyl)-1,4-dihydropyridin-4-iminium Bromide (IIId) and
1-Benzyl-3-(p-nitrobenzyloxycarbonyl)pyridinium Bromide (VIc)
Benzyl bromide (85 mg, 0.5 mmol) was added to a solution of compound IIIa or VIa (0.27 mmol) in
dry dioxane (3 ml) and the reaction mixture was set aside at ambient temperature for 10 days. The
deposited colourless crystals were collected and dried. For melting points and elemental analyses of
the products see Table IV.
1-Benzyl-3-benzyloxycarbonylpyridinium Bromide
Benzyl bromide (143 mg, 0.84 mmol) was added dropwise to a solution of compound VIa (100 mg,
0.39 mmol) in anhydrous dimethylformamide (10 ml) and the reaction mixture was heated at 70 °C
for 14 h. The solvent was evaporated under diminished pressure and the residue was codistilled with
toluene (6 × 5 ml). The solid residue was dissolved in acetone (5 ml), filtered and tert-butyl methyl
ether (15 ml) was added. The deposited crystalline product was collected on filter and dried; yield 78 mg
1
(52%) of the title compound, m.p. 182.5 – 184 °C. H NMR spectrum: 5.48 s, 2 H (OCH2); 6.06 s,
2 H (N+−CH2); 7.34 – 7.66 m, 10 H (H-arom.); 8.32 dd, 1 H, J(5,4) = 6.4, J(5,6) = 6.1 (H-5); 9.05 d,
1 H, J(4,5) = 8.1 (H-4); 9.44 d, 1 H, J(6,5) = 6.0 (H-6); 9.81 s, 1 H (H-2). 13C NMR spectrum: 63.9
(N+−CH2), 68.4 (OCH2), 128.7 (2 C) + 129.0 (2 C) + 129.3 (1 C) + 129.5 (2 C) + 129.7 (2 C) + 129.9
(1 C) (C-arom.); 130.3 (C-5), 130.6 (C-3), 134.4 + 135.5 (C′-1 and C″-1), 136.2 (C-4), 146.2 (C-6),
152.0 (C-2), 161.9 (C=O).
The authors are indebted to Dr A. Holÿ of Institute of Organic Chemistry and Biochemistry, Academy
of Sciences of the Czech Republic, for valuable advice and discussions. Their thanks are also due to Mrs
Z. Hladikova for excellent technical assistance and to Mr J. Havlicek for the help in measurements of
ATP spectra. This study was subsidized by the Grant Agency of the Czech Republic (Grant No.
203/93/0118) and the Ministry of Education of the Czech Republic (Grant No. 93/0766).
REFERENCES
1. Dvorakova H., Holy A., Alexander P.: Collect. Czech. Chem. Commun. 58, 1403 (1993); and
references therein.
2. Konno K., Hayano K., Shirahama H., Saito H., Matsumoto T.: Tetrahedron 38, 3281 (1982).
3. Angyal S. J., Angyal C. L.: J. Chem. Soc. 1952, 1461.
4. Forlani L.: J. Heterocycl. Chem. 29, 1461 (1992).
5. Giam C. S. in: Pyridine and its Derivatives (R. A. Abramovitch, Ed.), Vol. 14, Suppl. 3, p. 62.
Wiley, New York 1974.
6. Inuzuka K., Fujimoto A.: Bull. Chem. Soc. Jpn. 63, 971 (1990).
7. Inuzuka K., Fujimoto A.: Bull. Chem. Soc. Jpn. 65, 1007 (1992).
Collect. Czech. Chem. Commun. (Vol. 59) (1994)

2068
Smrckova, Juricova, Prutianov:
8. Chichibabin A. E., Konowalowa R. A., Konowalowa A. A.: Ber. Dtsch. Chem. Ges. 54, 814
(1921).
9. Wang S. S., Gisin B. F., Winter D. P., Makofske R., Kuleska I. R., Tsougraki C., Meienhofer J.:
J. Org. Chem. 42, 1286 (1977).
10. Ross W. C. J.: J. Chem. Soc., C 1966, 1816.
11. Taylor E. C., Crovetti A. J.: J. Am. Chem. Soc. 78, 214 (1956).
12. Herz W., Murty D. R. K.: J. Org. Chem. 26, 122 (1961).
13. Krechl J., Bohm S., Smrckova S., Kuthan J.: Collect. Czech. Chem. Commun. 54, 673 (1989).
14. Kratochvil B., Novotny J., Smrckova S., Krechl J.: Collect. Czech. Chem. Commun. 55, 479
(1990).
15. Witkop B.: Experientia 10, 420 (1954); and references therein.
16. Spinner E.: J. Chem. Soc. 1962, 3119.
17. Dega-Szafran Z., Dulewicz E.: J. Chem. Soc., Perkin Trans. 2 1983, 345.
18. Dega-Szafran Z., Grundwald-Wyspianska M., Szafran M.: Spectrochim. Acta, A 47, 543 (1991).
Translated by M. Tichy.
Collect. Czech. Chem. Commun. (Vol. 59) (1994)