Investigation of the regioselectivity of alkylation of 3-nitropyridin-2(1H)-ones

Article abstract of DOI:10.1023/A:1011361207658

Alkylation of 3-nitropyridin-2(1H)-ones in the presence of bases affords N-alkylated products and sometimes O-alkylated products. The yields and relative amounts of N- and O-alkylated products depend substantially on the size of the substituent at the C(6

Full text of DOI:10.1023/A:1011361207658

460
Russian Chemical Bulletin, International Edition, Vol. 50, No. 3, pp. 460—463, March, 2001
Investigation of the regioselectivity of alkylation
of 3-nitropyridin-2(1H)-ones
V. P. Kislyi« and V. V. Semenov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119992 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. E-mail: muskat@cacr.ioc.ac.ru
Alkylation of 3-nitropyridin-2(1H)-ones in the presence of bases affords N-alkylated
products and sometimes O-alkylated products. The yields and relative amounts of N- and
O-alkylated products depend substantially on the size of the substituent at the C(6) atom of
pyridone.
Key words: 3-nitropyridin-2(1H)-ones, alkylation, regioselectivity.
In the last few years, a number of derivatives of
We found that alkylation of 3-nitropyridin-2(1H)-
3-amino-2-oxopyridin-1-ylacetic acid were covered by
patents as inhibitors of thrombin1,2 and human elastase.3
An apparent procedure for the synthesis of these com-
pounds involves alkylation of 3-nitropyridin-2(1H)-ones
followed by hydrogenation of the nitro group to form the
amino group. However, alkylation of 3-nitropyridin-
2(1H)-ones, like alkylation of 3-cyanopyridin-2(1H)-
ones described previously,4—6 may afford both N- and
O-alkylation products. Since data on the regioselectivity
of alkylation of 3-nitropyridin-2(1H)-ones are lacking in
the literature, it was of interest to study this problem.
one (1a), which does not contain a substituent at posi-
tion 6, gave rise only to N-alkylation products (2a—d),
while O-alkylation products were not detected. Alkyla-
tion was performed in MeOH in the presence of MeONa.
The formation of O-alkylation products was also not
observed upon alkylation of 4,6-dimethyl-3-nitropyridin-
2(1H)-one (1b) with methyl iodide or benzyl bromide
performed under the same conditions. The melting points
Table 1. Yields and characteristics of the synthesized com-
pounds
Com- YieldM.p.
pound(%)
Molecular
formula
Found
Calculated
(%)
R1
/
°C
NO2
C
H
N
2a
2b
2c
2d
2e
2f
71.7 171—173 Ñ6H6N2O3
47.2
46.75
3.7
18.0
R2
3.92 18.18
4.1 12.0
4.38 12.17
3.8 10.9
3.90 10.85
3.1 14.0
3.05 14.14
5.4 15.0
5.53 15.38
5.2 10.3
5.46 10.85
4.7 9.9
4.93 9.78
5.7 10.9
5.55 11.02
4.9 12.2
4.45 12.38
4.6 12.1
4.37 12.17
4.9 9.7
4.93 9.78
5.6 10.5
5.55 11.02
4.5 12.3
4.38 12.16
N
O
53
86—88
C12H10N2O3 61.9
62.61
H
1a—c
40.8 135—137 Ñ13H10N2O4 60.5
60.47
R1 = R2 = H (1a); Me (1b);
R1 = H, R2 = Ph (1c)
68
205—207 Ñ7H6N2O5
42.4
42.43
R1
R1
70.3 163—165 Ñ8H10N2O3 52.9
52.74
46.0 116—118 Ñ14H14N2O3 64.8
65.11
NO2
NO2
OR3
+
2g
2h
2i
31
164—166 Ñ15H14N2O4 62.5
62.93
R2
R2
N
O
N
R3
52.1 115—116 Ñ11H14N2O5 51.5
51.97
2a—j
3a—c
25
275—278 Ñ9H10N2O5 47.2
(decomp.) 47.79
R1
R2
R3
2a
2b
2c
2d
2e
2f
H
H
Me
CH2Ph
CH2COPh
CH2COOH
Me
CH2Ph
CH2COPh
CH2COOEt
CH2COOH
Me
2j
17.3 157—158 Ñ12H10N2O3 62.0
62.60
H
H
H
H
H
3a
3b
3c
3.7
93—95
C15H14N2O4 62.8
62.93
H
Me
Me
Me
Me
Me
H
Me
Me
Me
Me
Me
Ph
2.9
34—36
Ñ11H14N2O5 51.6
51.97
2g, 3a
2h, 3b
2i
50.3 102—103 Ñ12H10N2O3 61.9
62.61
2j, 3c
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 441—444, March, 2001.
1066-5285/01/5003-460 $25.00 © 2001 Plenum Publishing Corporation

Alkylation of 3-nitropyridin-2-ones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
461
Table 2. 1H NMR and IR spectra of compounds 2a—j and 3a—c
–1
Com-
pound
IR (ν/cm
)
1H NMR,
δ (J/Hz)
2a
2b
2c
2d
1680 + 1592 (CON)
1540 (νas(NO2))
1376 (νs(NO2))
1672 + 1592 (CON)
1536 (νas(NO2))
1340 (νs(NO2))
1668 + 1592 (CON)
1536 (νas(NO2))
1348 (νs(NO2))
1728 (COO)
1688 + 1600 (CON)
1516 (νas(NO2))
1352 (νs(NO2))
1660 + 1595 (CON)
1535 (νas(NO2))
1380 (νs(NO2))
1665 + 1600 (CON)
1525 (νas(NO2))
1360 (νs(NO2))
1680 (CO)
3.60 (s, 3 H, NMe); 6.40 (t, 1 H, H(5), 3J = 7.0);
8.20 (dd, 1 H, H(4), 3J = 6.7, 4J = 1.5);
8.35 (dd, 1 H, H(6), 3J = 7.4, 4J = 1.5)
5.25 (s, 2 H, CH2); 6.45 (t, 1 H, H(5), 3J = 7.0);
7.30—7.40 (m, 5 H, Ph); 8.30 (dd, 1 H, H(4), 3J = 6.6, 4J = 1.5);
8.38 (dd, 1 H, H(6), 3J = 7.4, 4J = 1.5)
5.73 (s, 2 H, CH2CO); 6.50 (t, 1 H, H(5), 3J = 7.3);
7.60—8.05 (m, 5 H, Ph); 8.15 (d, 1 H, H(4), 3J = 6.7, 4J = 1.8);
8.45 (d, 1 H, H(6), 3J = 7.9, 4J = 1.8)
4.80 (s, 2 H, CH2COO); 6.45 (t, 1 H, H(5), 3J = 7.3);
8.20 (d, 1 H, H(4), 3J = 6.7, 4J = 1.8);
8.40 (d, 1 H, H(6), 3J = 8.0, 4J = 1.8)
2e
2f
2.18 (s, 3 H, 4-Me); 2.42 (s, 3 H, 6-Me);
3.50 (s, 3 H, NMe); 6.20 (s, 1 H, H(5))
2.23, 2.38 (both s, 6 H, Me + Me); 5.35 (s, 2 H, CH2);
6.20 (s, 1 H, H(5)); 7.10—7.40 (m, 5 H, Ph)
2g
2.25, 2.35 (both s, 6 H, Me + Me);
5.71 (s, 2 H, CH2CO); 6.30 (s, 1 H, H(5));
7.50—8.20 (m, 5 H, Ph)
1600 (CON)
1520 (νas(NO2))
1360 (νs(NO2))
1740 (COO)
1670 + 1600 (CON)
1530 (νas(NO2))
1375 (νs(NO2))
1736 (COO)
1660 + 1584 (CON)
1524 (νas(NO2))
1376 (νs(NO2))
1672 + 1600 (CON)
1504 (νas(NO2))
1336 (νs(NO2))
1700 (CO)
2h
2i
1.30 (t, 3 H, CH3CH2, J = 7.1);
2.23, 2.38 (both s, 6 H, Me + Me); 4.21 (q, 2 H, CH2, J = 7.1);
4.87 (s, 2 H, CH2COO); 6.27 (s, 1 H, H(5))
2.20 (s, 3 H, 4-Me); 2.35 (s, 3 H, 6-Me);
4.75 (s, 2 H, CH2COO); 6.25 (s, 1 H, H(5))
2j
3.40 (s, 3 H, NMe); 6.35 (d, 1 H, H(5), 3J = 7.9);
8.40 (d, 1 H, H(4), 3J = 7.9); 7.55 (m, 5 H, Ph)
3a
2.30 (s, 6 H, Me + Me); 5.79 (s, 2 H, OCH2CO);
6.90 (s, 1 H, H(5); 7.50—8.00 (m, 5 H, Ph)
1610 (CON)
1580 (νas(NO2))
1380 (νs(NO2))
1740 (COO)
3b
3c
1.30 (t, 3 H, CH3CH2, J = 7.2);
2.31, 2.41 (both s, 6 H, Me + Me);
4.20 (q, 2 H, CH2, J = 7.2); 4.95 (s, 2 H, CH2COO);
6.95 (s, 1 H, H(5))
4.15 (s, 3 H, OMe); 7.50—8.20 (m, 5 H, Ph);
7.75 (d, 1 H, H(5), 3J = 7.3);
8.50 (d, 1 H, H(4), 3J = 7.3)
1610 (CON)
1575 (νas(NO2))
1380 (νs(NO2))
1595 + 1576 (CON)
1508 (νas(NO2))
1344 (νs(NO2))
and the spectra of the resulting compounds are given in
Tables 1—3.
pyridin-2(1H)-one (1c) with methyl iodide was carried
out in DMF (due to the low solubility of the initial
nitropyridone in MeOH and EtOH). It was found that
the latter reaction gave rise to a mixture of products 2j
and 3c. Later on, it turned out that alkylation in DMF
was preparatively much more convenient in the case of
nitropyridones 1a,b as well.
However, alkylation of compound 1b with halogeno-
carbonyl compounds (bromoacetophenone, ethyl bromo-
acetate, or chloroacetic acid) afforded both N- and
O-alkylation products. In the reactions with bromoaceto-
phenone or ethyl bromoacetate, products of both series
were isolated (2g and 3a; or 2h and 3b, respectively),
whereas the O-alkylation product, which was formed in
the reaction with chloroacetic acid, decomposed in the
course of isolation and attempts to obtain the latter in
the pure form failed. Alkylation of 3-nitro-6-phenyl-
The ratios between the products of N- and O-alkyla-
tion of pyridones 1b and 1c, which were determined
from the integral intensities of the corresponding signals
1
in the H NMR spectra of the reaction mixtures, are
given in Table 4. From the data in Table 4 it follows that

462
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
Kislyi and Semenov
Table 3. UV spectra (EtOH) of the initial pyridones 1a—c and
alkylated products 2c, 2e, 2g, 2j, 3a, 3b, and 3c
pare the regioselectivity of alkylation of 3-cyano- and
3-nitropyridin-2(1H)-ones and there is a need to perform
special studies in which identically substituted pyridones
will be alkylated under strictly standard conditions.
The structures of the resulting compounds were es-
Com-
pound
UV,
max/nm (ε)
λ
1
tablished by H NMR and UV spectroscopy. Previ-
1a
2c
1b
2e
2g
3a
1c
2j
254
(1410)
245
360
(5760)
362
(7250)
359
(1350)
362
(3900)
359
ously,4,6 it was proposed to use the chemical shift of the
methylene group at the nitrogen or oxygen atom in the
case of 3-cyanopyridin-2(1H)-ones and it was stated that
the signal of the OCH2 group is shifted downfield with
respect to the signal of the NCH2 group by 0.6—1.0 ppm.
In the case under consideration, the difference between
the chemical shifts of the methyl groups at the nitrogen
and oxygen atoms in compounds 2j and 3c is actually
0.75 ppm. However, the differences between the chemi-
cal shifts of the OCH2 and NCH2 groups for the pair 2g
and 3a and for the pair 2h and 3b are small (less than
0.1 ppm). Hence, this method is in reality usable only if
two isomers are present. The chemical shift for the
proton at the C(5) atom proves to be much more
informative. In the N-alkylated isomer of pyridone, the
signal for this proton is insignificantly shifted downfield
(by 0.05—0.2 ppm) relative to the signal for the H(5)
proton in the initial pyridone, whereas the signal for this
proton in O-alkylated pyridine is substantially shifted (by
0.6—1.4 ppm) downfield compared to that of the initial
pyridone. The strong downfield shift is attributable to
the appearance of the "aromatic" ring current on going
from the pyridone to pyridine structure. Analogous dif-
ferences are observed in the UV spectra of N- and
O-alkylated pyridones (Table 3). The long-wavelength
band with λmax = 360—390 nm typical of nitropyridones
is retained in the spectrum of the N-alkylated pyridone
isomer and disappears in the spectra of O-alkylated
aromatic structures 3a and 3c. The difference in the UV
spectra is clearly seen in TLC plates using an indicator
with the absorption maximum at 254 nm. Thus, the
initial pyridone and the N-alkylated product were yel-
low, while the O-alkylated pyridine isomers were color-
less and were observed as dark-blue spots under UV
light.
(10150)
309
(3240)
313
(5400)
318
(1900)
282
(1400)
241
(10400)
244
(5080)
264.4
(2090)
258
(730)
390.6
(5690)
376
(3010)
257.7
(2380)
(8030)
3c
343.6
(8440)
the ratio between isomeric products 2 and 3 changes
insignificantly on going from MeOH to aqueous DMF,
but depends substantially on the nature of the substitu-
ents both in the starting pyridone and in the alkylating
agent.
Therefore, it can be concluded that the regioselectivity
of alkylation of 3-nitropyridin-2(1H)-ones depends on a
number of factors and primarily on the size of the
substituent at the C(6) atom of the initial substrate.
It should be noted that alkylation of 3-cyanopyridin-
2(1H)-ones described in the literature is characterized by
similar features. Thus, the reactions of 3-cyanopyridin-
2(1H)-ones containing the hydrogen atom or the alkyl
group at the C(6) atom performed in EtOH (or in
mixtures of EtOH and DMSO) afford predominantly
N-alkylation products, although the content of O-al-
kylated compounds increases as the size of the substitu-
ent becomes larger (simultaneously, the reaction time
increases and the total yield of the products decreases).4
Alkylation of 3-cyano-4,6-diphenylpyridin-2(1H)-one
with methyl iodide in DMF gave rise only to the
O-alkylation product.5 However, it should be noted that
the avaialble data are inadequate to quantitatively com-
Therefore, alkylation of 3-nitropyridin-2(1H)-ones
affords primarily N-alkylation products, whereas the rela-
tive amounts of O-alkylation products depend substan-
tially on the size of the substituent at the C(6) atom of
pyridone.
Table 4. Ratios between the N- and O-alkylation products of 3-nitropyridin-2(1H)-ones
Pyridone
Alkylating agent
Solvent
Base
Ratio between
N- and O-alkylation products
1b
1b
1c
BrCH2COPh
BrCH2COOEt
MeI
MeOH
DMF + H2O
MeOH
DMF + MeOH
DMF + H2O
MeONa
KOH
MeONa
MeONa
KOH
2g : 3a
2g : 3a
2h : 3b
2h : 3b
2j :: 3c
86.7 : 13.3
91.2 : 08.8
82.5 : 17.5
80.3 : 19.7
35.7 : 64.3

Alkylation of 3-nitropyridin-2-ones
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
463
Compound 2h was obtained in a yield of 3.95 g (52.1%). The
mother liquor was concentrated together with silica gel (1 g)
and the powder that formed was transferred on a Schott filter.
Chromatographic separation was performed according to a pro-
cedure reported previously7 to obtain compound 3b in a yield of
0.22 g (2.9%).
Experimental
The 1H NMR spectra were recorded on a Bruker WM-250
instrument (250.13 MHz) in DMSO-d6. The IR spectra were
measured on a Specord M80 instrument in KBr pellets. The UV
spectra were obtained on a Specord UV VIS instrument in
EtOH. The yields and the melting points are listed in Table 1.
The spectra are given in Tables 2 and 3.
The ratios between the N- and O-alkylation products were
determined based on the intensity ratios for the corresponding
signals in the H NMR spectra of the reaction mixtures (see
1-Methyl-3-nitro-6-phenylpyridin-2(1H)-one (2j) and
2-methoxy-3-nitro-6-phenylpyridine (3c). Pyridone 1c (200 mg,
0.92 mmol) was dissolved in DMF (10 mL). Then MeI (0.5 mL,
8 mmol) and a solution of KOH (70 mg, 1.25 mmol) in water
(1 mL) were added. After 24 h, DMF was evaporated on a
rotary evaporator (50—70 °C). Water (5 mL) and benzene
(20 mL) were added to the residue, the benzene layer was
separated and dried over MgSO4, and the solvent was evapo-
rated on a rotary evaporator in the presence of silica gel (1 g).
The powder that formed was transferred on a Schott filter.
Chromatographic separation was performed according to a pro-
cedure reported previously7 to obtain compounds 2j and 3c in
yields of 37.3 mg (17.3%) and 107.1 mg (50.3%), respectively.
Alkylation of nitropyridones with chloroacetic acid (general
procedure for compounds 2d and 2i). Water (30 mL) was added
to a mixture of pyridone 1b (10 mmol) and ClCH2CO2H
(20 mmol). Then NaHCO3 (4.2 g, 50 mmol) was added
portionwise with stirring. The reaction mixture was refluxed
(15 min for 2d and 4 h for 2i), cooled, and acidified to pH 7.
The unconsumed nitropyridone was filtered off and the reaction
mixture was acidified to pH 1 and kept at +4 °C for 12 h. The
crystals that formed were filtered off, washed with cold water,
and dried at 50—60 °C to obtain products 2d and 2i.
1
Table 2).
Synthesis of 1-R-3-nitropyridin-2(1H)-ones (general pro-
cedure for alkylation of compounds 2a—2c, 2e, and 2f).
Nitropyridone 1a,b (10 mmol) was dissolved in DMF
(5—10 mL). Then a 10% aqueous solution of KOH (15 mmol)
and haloalkane (20 mmol) were successively added to the
reaction mixture. After 1—2 days, the initial pyridone was not
detected in the mixture (TLC data). Then DMF was evaporated
to one-third of the initial volume on a rotary evaporator
(50—70 °C). Water (10 mL) and benzene (20—30 mL) were
added to the residue. The benzene layer was separated and dried
over MgSO4 and the solvent was evaporated. The resulting
products were recrystallized from a 1 : 1 benzene—hexane
mixture.
Alkylation of nitropyridinones 1a,b in methanol (general
procedure). Nitropyridone 1a,b (10 mmol) was suspended in
MeOH (200 mL) containing MeONa (14 mmol). Then the
corresponding halogenocarbonyl compound (15 mmol) was
added, the mixture was refluxed with stirring for 10 h, and the
methanol was evaporated. Water (10 mL) and benzene
(20—30 mL) were added to the residue, the benzene layer was
separated and dried over MgSO4, and the solvent was evapo-
rated. The resulting products were recrystallized from a 1 : 1
benzene—hexane mixture.
We thank I. B. Karmanova for supplying 3-nitro-6-
phenylpyridin-2(1H)-one.
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benzene solution was diluted threefold with hexane and the
pyridone (2g) was filtered off. The mother liquor was concen-
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Received July 20, 2000;
in revised form November 22, 2000