3-(2-methylthiopyridin-3-yl)-3-oxopropionic esters

Article abstract of DOI:10.1007/s11172-011-0082-2

A reaction of alkyl bromoacetates with substituted 3-cyano-2- methylthiopyridines in the presence of zinc dust furnishes 3-amino-3-(2- methylthiopyridin-3-yl)propenoic esters. Their hydrolysis under mild conditions leads to 3-(2-methylthiopyridin-3-yl)-3-

Full text of DOI:10.1007/s11172-011-0082-2

Russian Chemical Bulletin, International Edition, Vol. 60, No. 3, pp. 526—532, March, 2011
526
3ꢀ(2ꢀMethylthiopyridinꢀ3ꢀyl)ꢀ3ꢀoxopropionic esters
A. A. Zubarev, V. K. Zav´yalova, and A. M. Shestopalov
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (499) 135 5328. Eꢀmail: zvk@ioc.ac.ru
A reaction of alkyl bromoacetates with substituted 3ꢀcyanoꢀ2ꢀmethylthiopyridines in the
presence of zinc dust furnishes 3ꢀaminoꢀ3ꢀ(2ꢀmethylthiopyridinꢀ3ꢀyl)propenoic esters. Their
hydrolysis under mild conditions leads to 3ꢀ(2ꢀmethylthiopyridinꢀ3ꢀyl)ꢀ3ꢀoxopropionic esters.
The latter were used in the synthesis of pyridineꢀsubstituted pyrazolones.
Key words: 3ꢀcyanoꢀ2ꢀmethylthiopyridines, methyl bromoacetate, ethyl bromoacetate, zinc
dust, 3ꢀ(2ꢀmethylthiopyridinꢀ3ꢀyl)ꢀ3ꢀoxopropionic acids, hydrazine, dinitrophenylhydrazine,
pyridylpyrazolones, the Blaise reaction.
Substituted compounds of pyridine series are key buildꢀ
in the synthesis of βꢀamino acids and some heterocyclic
compounds.
ing blocks frequently used in the synthesis of biologically
active compounds and for preparation of new fused heteroꢀ
cyclic systems. Earlier, working on the methods for funcꢀ
tionalization of a nitrile group in substituted 3ꢀcyanopyriꢀ
dineꢀ2(1H)ꢀthiones and their alkylthio derivatives, we
studied their reaction with alkyllithium compounds.1—3
The carbonyl compounds obtained, as well as the prodꢀ
ucts of their bromination were found to be convenient
reagents for the synthesis of fused heterocyclic systems
and 3ꢀhetarylꢀsubstituted 2ꢀalkylthiopyridines.1,3 In contiꢀ
nuation of these studies, it seems promising to develop
methods for the synthesis of more complex pyridineꢀ
2(1H)ꢀthions substituted at position 3 and their alkylthio
derivatives containing several reactive groups. Substituted
3ꢀpyridoylacetic esters are of interest from this point of view.
Such compounds are widely used in the preparation of
annulated heterocyclic systems and 3ꢀhetarylꢀsubstituted
pyridines displaying biological activities of various kinds.4,5
Separate examples of synthesis of 2ꢀalkylthioꢀ3ꢀpyridoꢀ
ylacetic esters are based on the transformation of correꢀ
sponding nicotinic acids using organolithium compounds
or metallic sodium.6,7
At the same time, another method for the synthesis of
βꢀketo esters from nitriles by the Blaise reaction which
uses zinc and bromoacetic ester found wide application in
the synthetic practice.8 The use of this method in the
present work seems promising, since it allows us to use
easily available 3ꢀcyanoꢀ2ꢀmethylthiopyridines for the
synthesis of the target compounds. It should be especially
noted that the intermediately obtained 3ꢀaminoꢀ3ꢀ(pyriꢀ
dinꢀ3ꢀyl)propenoic esters are not virtually described in the
literature (there are only several publications9—11 on these
compounds unsubstituted at the pyridine ring), though
they can also be of certain interest as starting compounds
Results and Discussion
The reaction of 3ꢀcyanoꢀ2ꢀmethylthiopyridines 1a—e
with ethylꢀ or methyl bromoacetate in the presence of
activated zinc dust upon reflux in THF leads to enamino
esters 2a—f in good yields (Scheme 1). We found that
optimum yield of compounds 2a,d—f obtained from pyꢀ
ridines 1a,d,e is reached at the ratio of the starting reꢀ
agents 1 : 4 : 6. In the case of pyridines 1b,c, such a ratio of
reagents leaves up to 25% of the starting compound in the
reaction products (the 1H NMR data). Apparently, this is
due to the steric effect of the substituent at position 4 of
the pyridine ring. The ratio of reagents 1 : 6 : 10 is the
optimum for pyridines 1b,c, but even in this case the conꢀ
tent of the starting pyridine in 2b is no less than 15%. In
this connection, enamino ester 2b was characterized in
the form of oxalate.
Enamino esters 2a—f are white or light yellow crystalꢀ
line powders, whose structures were confirmed by IR and
1H NMR spectroscopy and mass spectrometry. The IR
spectra of compounds 2a—f exhibit two absorption bands
of the amino group in the region 3300—3450 cm–1 and
an absorption band of the conjugated ester group at
1660—1668 cm–1. The 1H NMR spectra are characterized
by the presence of signals for the protons of the alkyl group
of the ester fragment, as well as a signal for the proton of
the fragment C=CH as a singlet with the intensity of one
proton at δ 4.6—4.8 (Table 1).
Enamino esters 2a,d—f are easily and in high yields
hydrolyzed in THF in the presence of dilute HCl at 20 °C to
the corresponding βꢀketo esters 3a,d—f. At the same time,
compounds 2b,c do not hydrolyze under these conditions.
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 514—519, March, 2011.
1066ꢀ5285/11/6003ꢀ526 © 2011 Springer Science+Business Media, Inc.

Alkyl 3ꢀoxoꢀ3ꢀ(2ꢀmethylthiopyridinꢀ3ꢀyl)propionates Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
527
Scheme 1
1, 2
a
b
c
d
R1
Me
Me
Ph
R2
H
H
H
Me
H
R3
H
Me
Ph
H
R4
Et
Et
Et
Et
3
a
d
e
f
R1
Me
R2
H
Me
H
R3
H
H
H
H
R4
Et
Et
Et
Me
Et
3,4ꢀ(OCH2O)C6H3
Me
Et
3,4ꢀ(OCH2O)C6H3
Me
H
e
f
H
H
Et
Me
H
Table 1. Spectroscopic characteristics of compounds 1d,e, 2a—f, 3a,d—f, 4a,d,e, 5a,d,e, and 6a,d
Comꢀ
pound
IR,
ν/cm–1
MS,
m/z (I (%))
1H NMR, δ (J/Hz)
1da
1ea
2ab
2212 (CN)
192 [M]+ (100), 177 (21.7),
159 (88.1), 146 (67.1), 132
(19.9), 116 (33.4), 102 (13.3),
96 (6.3)
270 [M]+ (100), 255 (19.0),
225 (20.6), 179 (29.9), 165
(24.5), 140 (17.8), 131 (64.3),
105 (36.0), 77 (52.4)
252 [M]+ (43.4), 237 (57.3),
207 (17.5), 205 (42.6), 191
(29.4), 179 (37.1), 165 (100),
146 (31.5), 119 (28.7), 105
(41.3)
1.24 (t, 3 H, CH2CH3, J = 7.1); 2.23 (s, 3 H, Me(5));
2.60 (s, 3 H, SMe); 2.79 (q, 2 H, CH2CH3, J = 7.1);
7.90 (s, 1 H, H(4))
2220 (CN)
2.68 (s, 3 H, SMe); 6.11 (s, 2 H, OCH2O); 7.04 (d,
1 H, C6H3 (H(5)), J = 8.2); 7.70—7.80 (m, 3 H, H(4) +
+ C6H3 (H(2) + H(6))); 8.12 (d, 1 H, H(5), J = 8.1)
3408, 3304 (NH2);
1660 (C=CH, CO2Et )
1.29 (t, 3 H, CH2CH3, J = 7.1); 2.53 (s, 3 H, SMe);
2.55 (s, 3 H, Me(6)); 4.18 (q, 2 H, CH2CH3, J = 7.1);
4.76 (s, 1 H, CH); 6.86 (d, 1 H, H(5), J = 7.7); 7.40
(d, 1 H, H(4), J = 7.7)
2bb
2cb
3440, 3324 (NH2);
1668 (C=CH, CO2Et)
266 [M]+ (49.7), 251 (100),
221 (39.5), 219 (49.8), 205
(34.9), 193 (74.8), 179 (87.3),
164 (30.4), 151 (30.7), 145
(40.6), 132 (33.3), 107 (26.6)
390 [М]+ (5.2), 375 (100),
345 (8.4), 317 (21.0), 302
(31.1), 160 (31.8), 98 (33.4)
1.29 (t, 3 H, CH2CH3, J = 7.1); 2.25 (s, 3 H, Me(4));
2.47 (s, 3 H, SMe); 2.51 (s, 3 H, Me(6)); 4.17
(q, 2 H, CH2CH3, J = 7.1); 4.62 (s, 1 H, CH); 6.72
(s, 1 H, H(5))
3444, 3324 (NH2);
1664 (C=CH, CO2Et)
1.27 (t, 3 H, CH2CH3, J = 7.1); 2.68 (s, 3 H, SMe);
4.13 (q, 2 H, CH2CH3, J = 7.1); 4.77 (s, 1 H, CH);
7.40—7.55 (m, 9 H, 4ꢀPh (H(2)—H(6)) + 6ꢀPh
(H(3)—H(5)) + H(5)); 8.12 (d, 2 H, 6ꢀPh (H(2),
H(6)), J = 7.8)
2db
2eb
3448, 3328 (NH2);
1668 (C=CH, CO2Et)
280 [М]+ (6.3), 265 (21.8),
233 (69.7), 219 (14.0), 205
(28.7), 193 (100), 178 (11.3),
146 (10.3), 102 (20.3)
358 [М]+ (26.6), 343 (100),
311 (21.7), 285 (32.2), 270
(88.1), 101 (58.7)
1.28 (m, 6 H, CO2CH2CH3 + CH2CH3); 2.22 (s, 3 H,
Me(5)); 2.53 (s, 3 H, SMe); 2.77 (q, 2 H, CH2CH3,
J = 7.1); 4.15 (q, 2 H, CO2CH2CH3, J = 7.1); 4.74
(s, 1 H, CH); 7.24 (s, 1 H, H(4))
3412, 3296 (NH2);
1668 (C=CH, CO2Et)
1.31 (t, 3 H, CH2CH3, J = 7.1); 2.65 (s, 3 H, SMe);
4.19 (q, 2 H, CH2CH3, J = 7.1); 4.83 (s, 1 H, CH);
6.04 (s, 2 H, OCH2O); 6.91 (d, 1 H, C6H3 H(5),
J = 8.2); 7.38 (d, 1 H, H(4), J = 7.9); 7.54—7.62
(m, 3 H, H(5) + C6H3 (H(2) + H(6)))
2fb
3424, 3312 (NH2);
1668 (C=CH, CO2Me)
238 [М]+ (24.5), 223 (71.3),
191 (66.4), 179 (34.3), 164
(100), 136 (12.6), 118 (21.0),
2.52 (s, 3 H, SMe); 2.53 (s, 3 H, Me(6)); 3.70 (s, 3 H,
CO2Me); 4.76 (s, 1 H, CH); 6.86 (d, 1 H, H(5),
J = 7.7); 7.39 (d, 1 H, H(4), J = 7.7)
(to be continued)

528
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Zubarev et al.
Table 1 (continued)
Comꢀ
pound
IR,
ν/cm–1
MS,
m/z (I (%))
1H NMR, δ (J/Hz)
3ab
1740 (CO2Et);
1672 (C=O)
253 [М]+ (16.8), 238 (11.2),
219 (23.1), 207 (14), 179
(37.8), 165 (100), 135 (47.9),
91 (54.5)
1.25 (t, 3 H, CH2CH3, J = 7.1); 2.52 (s, 3 H, SMe);
2.57 (s, 3 H, Me(6)); 3.94 (s, 2 H, COCH2); 4.20
(q, 2 H, CH2CH3, J = 7.1); 6.92 (d, 1 H, H(5), J = 8.0);
7.92 (d, 1 H, H(4), J = 8.0)
3db
1716 (CO2Et);
1672 (C=O)
281 [М]+ (12.6), 266 (11.9),
249 (34.3), 236 (11.7), 208
(26.6), 193 (100), 177 (13.8),
164 (16.3), 160 (29.0), 146
(16.2), 121 (13.8), 91 (18.9)
1.23—1.35 (m, 6 H, CO2CH2CH3 + CH2CH3); 2.29
(s, 3 H, Me(5)); 2.53 (s, 3 H, SMe); 2.82 (q, 2 H,
CH2CH3, J = 7.1); 3.94 (s, 2 H, COCH2); 4.19
(q, 2 H, CO2CH2CH3, J = 7.1); 7.73 (s, 1 H, H(4))
3eb
1724 (CO2Et);
1672 (C=O)
359 [М]+ (23.9), 344 (18.6),
327 (43.4), 313 (37.1), 285
(44.8), 272 (100), 254 (43.3),
229 (21.0), 170 (22.4), 140
(21.4), 127 (23.9), 113 (22.2)
1.27 (t, 3 H, CH2CH3, J = 7.1); 2.62 (s, 3 H, SMe);
3.97 (s, 2 H, COCH2); 4.22 (q, 2 H, CH2CH3, J = 7.1);
6.04 (s, 2 H, OCH2O); 6.92 (d, 1 H, C6H3 (H(5)), J = 8.8);
7.42 (d, 1 H, H(4), J = 8.3); 7.64—7.67 (m, 2 H, C6H3
(H(2) + H(6))); 8.06 (d, 1 H, H(5), J = 8.3)
3fb
1740 (CO2Me);
1668 (C=O)
239 [М]+ (14.7), 224 (9.8),
207 (37.1), 206 (39.9), 192
(19.2), 180 (54.9), 166 (100),
150 (25.2), 136 (48.3), 123
(14.9), 106 (14.6), 92 (44.1)
2.51 (s, 3 H, SMe); 2.56 (s, 3 H, Me(6)); 3.73 (s, 3 H,
CO2Me); 3.96 (s, 2 H, COCH2); 6.92 (d, 1 H, H(5),
J = 8.0); 7.92 (d, 1 H, H(4), J = 8.0)
4aa
4da
4ea
5aa
1616 (CO)
1620 (CO)
1616 (CO)
221 [М]+ (100), 206 (10.8),
188 (58.0), 177 (48.3), 163
(26.4), 150 (55.9), 145 (39.8),
118 (20.8), 101 (9.2)
249 [М]+ (12.7), 216 (8.7),
203 (11.1), 188 (15.4), 178
(100), 158 (20.3), 146 (22.5),
131 (14.8), 125 (12.7)
327 [М]+ (100), 294 (26.6),
270 (13.3), 251 (23.8), 238
(12.0), 224 (14.7), 133 (13.3),
121 (41.3), 101 (21.3)
433 [М]+ (25.2), 418 (12.8),
237 (37.8), 205 (18.2), 177
(17.8), 164 (100), 118 (60.1),
101 (71.3)
2.47 (s, 3 H, SMe); 2.48 (s, 3 H, Me(6)); 5.86 (s, 1 H,
H(4´)); 7.03 (d, 1 H, H(5), J = 7.7); 7.63 (d, 1 H, H(4),
J = 7.7); 9.90 (br.s, 1 H, N(2)H); 11.90 (br.s, 1 H,
N(1)H)
1.25 (t, 3 H, CH2CH3, J = 7.2); 2.23 (s, 3 H, Me(5));
2.48 (s, 3 H, SMe); 2.74 (q, 2 H, CH2CH3, J = 7.2);
5.86 (s, 1 H, H(4´)); 7.52 (s, 1 H, H(4)); 10.90 (br.s,
2 H, 2 NH)
2.59 (s, 3 H, SMe); 5.95 (s, 1 H, H(4´)); 6.09 (s, 2 H,
OCH2O); 7.03 (d, 1 H, C6H3 (H(5)), J = 8.4); 7.65—7.85
(m, 4 H, C6H3 (H(2) + H(6)), H(5), H(4)); 10.15 (br.s,
1 H, N(2)H); 11.88 (br.s, 1 H, N(1)H)
3292 (NH);
1736 (CO2Et);
1516 (NO2);
1332 (NO2)
1.31 (t, 3 H, CH2CH3, J = 7.1); 2.58 (s, 3 H, SMe);
2.60 (s, 3 H, Me(6)); 3.90 (s, 2 H, CH2); 4.29 (q, 2 H,
CH2CH3, J = 7.1); 6.97 (d, 1 H, H(5), J = 8.0); 7.71
(d, 1 H, H(4), J = 8.0); 8.39 (m, 2 H, C6H3 (H(5) + H(6)));
9.16 (d, 1 H, C6H3 (H(3)), J = 2.4); 11.83 (s, 1 H, NH)
5da
3288 (NH);
1732 (CO2Et);
1516 (NO2);
1328 (NO2)
461 [М]+ (16.8), 282 (32.2),
264 (37.2), 249 (45.9), 209
(49.7), 194 (100), 177 (46.2),
164 (44.4), 118 (24.6), 104
(29.2)
1.20 (t, 3 H, CH2CH3, J = 7.1); 1.28 (t, 3 H,
CO2CH2CH3, J = 7.1); 2.29 (s, 3 H, Me(5)); 2.51
(s, 3 H, SMe); 2.80 (q, 2 H, CH2CH3, J = 7.1); 4.13
(s, 2 H, CH2); 4.17 (q, 2 H, CO2CH2CH3, J = 7.1); 7.73
(s, 1 H, H(4)); 8.23 (d, 1 H, C6H3 (H(6)), J = 9.6); 8.48
(dd, 1 H, C6H3 (H(6)), J3 = 9.6, J4 = 2.7); 8.89 (d, 1 H,
C6H3 (H(3)), J = 2.7); 11.37 (s, 1 H, NH)
5ea
3292 (NH);
1732 (CO2Et);
1500 (NO2);
1336 (NO2)
539 [М]+ (5.1), 270 (100),
165 (9.1), 149 (8.7), 101
(25.9)
1.21 (t, 3 H, CO2CH2CH3, J = 7.1); 2.63 (s, 3 H, SMe);
4.16 (m, 4 H, CH2 + CO2CH2CH3); 6.10 (s, 2 H,
OCH2O); 7.05 (d, 1 H, C6H3 (H(5)), J = 7.8); 7.72—7.87
(m, 3 H, C6H3 (H(2) + H(6)), H(4)); 8.02 (d, 1 H, H(5),
J = 8.3); 8.28 (d, 1 H, 2,4ꢀ(NO3)2C6H3 (H(6)), J = 9.5);
8.50 (dd, 1 H, 2,4ꢀ(NO3)2C6H3 (H(5)), J3 = 9.5,
J4 = 2.6); 8.91 (d, 1 H, 2,4ꢀ(NO3)2C6H3 (H(3)), J = 2.7);
11.40 (s, 1 H, NH)
6aa
1748 (CO);
1540 (NO2);
1340 (NO2)
387 [М]+ (48.9), 358 (10.8),
341 (9.9), 277 (20.3), 178
(97.2), 164 (100), 148 (55.7),
118 (74.1), 92 (65.4)
2.48 (s, 3 H, SMe); 2.54 (s, 3 H, Me(6)); 6.04 (s, 1 H,
CH); 7.07 (d, 1 H, H(5), J = 7.8); 7.81 (d, 1 H, H(4),
J = 7.8); 8.11 (d, 1 H, C6H3 (H(6)), J = 8.9); 8.65
(dd, 1 H, C6H3 (H(5)), J3 = 8.9, J4 = 2.5); 8.79 (d, 1 H,
C6H3 (H(3)), J = 2.5)
(to be continued)

Alkyl 3ꢀoxoꢀ3ꢀ(2ꢀmethylthiopyridinꢀ3ꢀyl)propionates Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Table 1 (continued)
529
Comꢀ
pound
IR,
ν/cm–1
MS,
m/z (I (%))
1H NMR, δ (J/Hz)
6da
1748 (CO);
1532 (NO2);
1340 (NO2)
415 [М]+ (100), 206 (17.5),
191 (9.4), 173 (8.4), 146
(4.9), 104 (5.0)
1.27 (t, 3 H, CH2CH3, J = 7.2); 2.26 (s, 3 H, Me(5));
2.51 (s, 3 H, SMe); 2.77 (q, 2 H, CH2CH3, J = 7.2);
6.04 (s, 1 H, CH); 7.69 (s, 1 H, H(4)); 8.09 (d, 1 H,
C6H3 (H(6)), J = 8.9); 8.64 (d, 1 H, C6H3 (H(5)),
J = 8.9); 8.78 (s, 1 H, C6H3 (H(3)))
a 1H NMR spectra were obtained for solutions in DMSOꢀd6.
b 1H NMR spectra were recorded for solutions in CDCl3.
βꢀKeto esters 3a,d—f are light yellow lowꢀmelting crysꢀ
in ethanol in the presence of an acidic catalyst. In the case
of hydrazine hydrate, pyrazolones 4a,d,e were obtained in
good yields (Scheme 2). The reaction with dinitrophenylꢀ
hydrazine under similar conditions stops at the step of
formation of hydrazones 5a,d,e. Pyrazolones 6a,d were
synthesized by heating compounds 5a,d with concentratꢀ
ed sulfuric acid (see Scheme 2).
talline compounds, their structures were confirmed by IR
1
and H NMR spectroscopy and mass spectrometry. The
IR spectra of compounds 3a,d—f exhibit an absorption
band of the ester group at 1715—1740 cm–1 and an abꢀ
sorption band of the carbonyl group at 1668—1672 cm–1
.
The 1H NMR spectra are characterized by the presence of
the signals for the protons of the methylene group of the
βꢀketo ester fragment as a singlet with the intensity of two
protons at δ 3.94—3.97 (see Table 1).
Pyrazoles 4a,d,e are colorless crystals, whereas comꢀ
pounds 5a,d,e and 6a,d are red and dark yellow crystalline
powders, respectively. Their structures were confirmed by
1
Compounds 3a,d,e as typical βꢀketo esters react with
hydrazine and its 2,4ꢀdinitrophenyl derivative on heating
IR and H NMR spectroscopy and mass spectrometry.
The IR spectra of compounds 5a,d,e exhibit absorption
Scheme 2
3—6
R1
Me
Et
R2
H
Me
H
R3
H
H
R4
Et
Et
Et
a
d
e
3,4ꢀ(OCH2O)C6H3
H
DNPH is 2,4ꢀdinitrophenylhydrazine

530
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Zubarev et al.
bands of the NH group at 3288—3292 cm–1, the ester
group at 1732—1736 cm–1, and characteristic absorption
azolꢀ5ꢀones, and this is confirmed by the 1H NMR spectꢀ
roscopic data. Like in the case of pyrazoles 4a,d,e, a signal
for the proton at position 4 of the pyrazole ring is present
as a singlet with the intensity of one proton at δ 6.04.
In conclusion, we synthesized 3ꢀaminoꢀ3ꢀ(2ꢀmethylꢀ
thiopyridinꢀ3ꢀyl)propenoic esters by the Blaise reaction.8
The compounds obtained easily hydrolyze to the corꢀ
responding βꢀketo carboxylic esters, which are of interest
as building blocks in the synthesis of substituted pyꢀ
ridylpyrazoles.
bands of the nitro group in the regions 1500 and 1330 cm–1
.
The 1H NMR spectra are characterized by the presence of
the signal for the NH group as a singlet with the intensity
of one proton at δ 11.4—11.8 It is known that pyrazolꢀ5ꢀ
ones can exist as different tautomeric forms,12 however,
compounds unsubstituted at the nitrogen atom exist as
1,2ꢀdihydropyrazolꢀ5ꢀones, which was confirmed by Xꢀray
diffraction analysis.13 The spectral characteristics of obꢀ
tained by us pyrazoles 4a,d,e are analogous to those pubꢀ
lished earlier,14 that allows us to assign to them the strucꢀ
ture of 1,2ꢀdihydropyrazolꢀ5ꢀones. The IR spectra of pyrꢀ
azoles 4a,d,e exhibit an absorption band of the conjugated
Experimental
Melting points were determined on a Kofler heating stage.
IR spectra were recorded on a Specord Mꢀ82 spectrophotometer
in KBr pellets, 1H NMR spectra were recorded on a Bruker
AMꢀ300 spectrometer (300.13 MHz) in DMSOꢀd6 and CDCl3. The
1
carbonyl group at 1616—1620 cm–1. The H NMR specꢀ
tra of pyrazoles 4a,d,e are characterized by the presence of
the signal for the proton at position 4 of the pyrazole ring
as a singlet with the intensity of one proton in the region
δ 5.86—6.09, as well as the signals for the protons of two
NH groups as broad singlets with the intensity of one
proton each or as a very broad singlet with the intensity of
two protons in the region δ 9.90—11.90.
Unlike for pyrazoles 4a,d,e, a strong absorption band
of the endocyclic amide group at 1748 cm–1 is observed in
the IR spectra of pyrazoles 6a,d, that indicates that these
compounds in the solid phase exist as 1,4ꢀdihydropyrazolꢀ
5ꢀones, which also agrees with the literature data.15 Howꢀ
ever, in DMSO these compounds exist as 1,2ꢀdihydropyrꢀ
solvent signals were used as references (δ = 2.5 and 7.27, reꢀ
H
spectively). Mass spectra were obtained on a Finnigan MAT
INCOSꢀ50 instrument (70 eV). Compounds 1a—e were syntheꢀ
sized similarly to the method described3 for the preparation of
compound 1a. Physicochemical and spectroscopic characterisꢀ
tics of compounds 1a—c are identical to those reported earliꢀ
er,3,16,17 such characteristics of compounds 1d,e are given in
Tables 1 and 2.
Synthesis of alkyl 3ꢀaminoꢀ3ꢀ(pyridinꢀ3ꢀyl)propꢀ2ꢀenoates
2a—f (general procedure). Ethyl or methyl bromoacetate (5 drops
out of 12 mmol) was added to a boiling suspension of activated5
zinc dust (1.2 g, 18 mmol) in THF (10 mL), followed by reflux
until the mixture turned light green (~10 min). In the case of
Table 2. Physicochemical characteristics of compounds 1d,e, 2a—f, 3a,d—f, 4a,d,e, 5a,d,e, and 6a,d
Comꢀ
pound
Mol.
weight
Yield
(%)
M.p./°C
(solvent)
Found
Calculated
Molecular formula
(%)
C
H
N
S
1d
1e
2a
2b*
2c
2d
2e
2f
192
270
252
266
390
280
358
238
253
91
84
103—104
(hexane)
62.22
62.46
6.32
6.29
14.43
14.57
16.44
16.68
C10H12N2S
C14H10N2O2S
C12H16N2O2S
C13H18N2O2S
C23H22N2O2S
C14H20N2O2S
C18H18N2O4S
C11H14N2O2S
C12H15NO3S
202—204
(AcOEt)
61.94
62.21
3.76
3.73
10.27
10.36
11.59
11.86
92
98—100
(hexane—AcOEt)
56.24
57.12
6.33
6.39
10.84
11.10
12.62
12.71
81
95—98
(Et2O)
45.04
45.74
4.97
4.97
6.34
6.27
6.48
7.18
95
152—154
(AcOEt)
70.41
70.74
5.75
5.68
6.98
7.17
8.04
8.21
94
52—56
(hexane)
59.82
59.97
7.24
7.19
9.91
9.99
11.19
11.43
85.5
90
150.5—152.5
(hexane—AcOEt)
59.68
60.32
5.16
5.06
7.57
7.82
8.72
8.95
123.5—124.5
(hexane—AcOEt)
55.27
55.44
6.14
5.92
11.45
11.76
13.37
13.45
3a
100
32—34
(hexane)
57.01
56.90
5.93
5.97
5.65
5.53
12.43
12.66
(to be continued)

Alkyl 3ꢀoxoꢀ3ꢀ(2ꢀmethylthiopyridinꢀ3ꢀyl)propionates Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Table 2 (continued)
531
Comꢀ
pound
Mol.
weight
Yield
(%)
M.p./°C
(solvent)
Found
Calculated
Molecular formula
(%)
C
H
N
S
3d
3e
3f
281
359
239
221
249
327
433
461
539
387
415
91.5
82
44—46
(hexane)
59.62
59.76
6.77
6.81
5.11
4.98
11.23
11.39
C14H19NO3S
C18H17NO5S
C11H13NO3S
C10H11N3OS
C12H15N3OS
C16H13N3O3S
C18H19N5O6S
C20H23N5O6S
C24H21N5O8S
C16H13N5O5S
C18H17N5O6S
112—114
(AcOEt)
60.28
60.16
4.72
4.77
3.86
3.90
8.74
8.92
100
68
56—58
(hexane)
55.30
55.21
5.60
5.48
5.72
5.85
13.20
13.40
4a
4d
4e
5a
5d
5e
6a
6d
244.5—245.5
54.04
54.28
5.06
5.01
18.90
18.99
14.34
14.49
58
216—217
57.23
57.81
6.28
6.06
16.69
16.85
12.09
12.86
66
245—248
58.49
58.71
4.12
4.00
12.68
12.84
9.51
9.79
62.5
77
175—178
(AcOEt)
50.12
49.88
4.36
4.42
16.24
16.16
7.24
7.40
177.5—179
192—195
214—217
217—220
51.81
52.05
5.08
5.02
15.08
15.18
6.79
6.95
65
53.06
53.43
4.04
3.92
12.74
12.98
5.65
5.94
62
49.34
49.61
3.45
3.38
17.87
18.08
8.14
8.28
80
51.78
52.04
4.19
4.12
16.96
16.86
7.57
7.72
* Was isolated as a complex with oxalic acid, melts with decomposition.
synthesis of compounds 2b,c, 1.95 g (30 mmol) of zinc dust and
18 mmol of the corresponding bromo ester were used. Nitrile
1a—e (3 mmol) was added to the reaction mixture, then, while
refluxing, the rest of bromo ester was added dropwise over 1.5 h.
The mixture was refluxed for another 10 min, cooled, diluted
with THF (20 mL) and 50% aqueous K2CO3 (5 mL), and stirred
for 30 min. The organic layer was separated, the residue was
washed with THF. A combined organic phase was dried with
MgSO4, the solvent was evaporated in vacuo. The product was
recrystallized from hexane—AcOEt (5 : 1) to obtain esters 2a—f as
colorless or light yellow crystals in 80—95% yields (see Table 2).
Synthesis of alkyl 3ꢀpyridoylacetates 3a,d—f (general proceꢀ
dure). A 10% aq. HCl (3 mL) was added to a solution of
compound 2a,d—f (2.5 mmol) in THF (20 mL), the mixture
obtained was vigorously stirred for 50 min at ~20 °C, then
made basic with aq. K2CO3, the organic layer was separated,
washed with water, and dried with MgSO4. The solvent was
evaporated in vacuo to obtain esters 3a,d—f as clear light yellow
oils, which crystallized on standing, the yields were 80—100%
(see Table 2).
Synthesis of alkyl 3ꢀpyridoylacetate 2,4ꢀdinitrophenylhydraꢀ
zones 5a,d,e (general procedure). A solution of 2,4ꢀdinitropheꢀ
nylhydrazine (0.3 g) in ethanol (5 mL) containing sulfuric acid
(3 drops) was added to a solution of keto ester 3a,d,e (1.5 mmol)
in ethanol (5 mL), the mixture was refluxed for 1 h. The solution
obtained was cooled, a precipitate formed was filtered off. The
product was washed with water and recrystallized from AcOEt to
obtain hydrazones 5a,d,e as red crystalline powders in 60—80%
yields (see Table 2).
Synthesis of 1ꢀ(2,4ꢀdinitrophenyl)ꢀ3ꢀ(pyridinꢀ3ꢀyl)ꢀ1,4ꢀdihyꢀ
dropyrazolꢀ5ꢀones 6a,d (general procedure). A solution of phenylꢀ
hydrazone 5a,d (0.4 mmol) in concentrated sulfuric acid (3 mL)
was heated with stirring at 60 °C for 1 h. The solution obtained
was cooled, poured into water (10 mL) and neutralized with
sodium hydrogen carbonate. Precipitates formed were filtered
off, washed with water, and recrystallized from aq. alcohol to
obtain compounds 6a,d in 60—80% yields (see Table 2).
This work was partially financially supported by the
Russian Foundation for Basic Research (Project No. 09ꢀ
03ꢀ00349a).
Synthesis of 3ꢀ(pyridinꢀ3ꢀyl)ꢀ1,2ꢀdihydropyrazolꢀ5ꢀones 4a,d,e
(general procedure). Acetic acid (2 drops) and 64% aq. hydrazine
hydrate (0.1 mL, 2 mmol) were added to a solution of keto ester
3a,d,e (2 mmol) in methanol (5 mL). The solution was refluxed
for 3 h and cooled. A precipitate formed was filtered off and
washed with hot methanol to obtain pyrazolones 4a,d,e as colorꢀ
less crystals in 60—70% yields (see Table 2).
References
1. V. K. Zav´yalova, A. A. Zubarev, V. P. Litvinov, Izv. Akad.
Nauk, Ser. Khim., 2008, 1504 [Russ. Chem. Bull., Int. Ed.,
2008, 57, 1534].

532
Russ.Chem.Bull., Int.Ed., Vol. 60, No. 3, March, 2011
Zubarev et al.
2. V. K. Zav´yalova, A. A. Zubarev, A. M. Shestopalov, Izv.
Akad. Nauk, Ser. Khim., 2008, 2303 [Russ. Chem. Bull., Int.
Ed., 2008, 57, 2349].
11. N. L. Racheva, Z. G. Aliev, M. A. Belova, I. V. Mashevskaya,
A. N. Maslivets, Zh. Org. Khim., 2008, 44, 710 [Russ. J. Org.
Chem. (Engl. Transl.), 2008, 44, 701].
3. V. K. Zav´yalova, A. A. Zubarev, A. M. Shestopalov, Izv.
Akad. Nauk, Ser. Khim., 2009, 1878 [Russ. Chem. Bull., Int.
Ed., 2009, 58, 1939].
12. V. I. Ivanskii, Khimiya Geterotsiklicheskikh Soedinenii [Chemꢀ
istry of Heterocyclic Compounds], Vysshaya Shkola, Moscow,
1978, p. 171 (in Russian).
4. M. Fray, D. Bull, K. Cooper, M. Parry, M. Stefaniak, J. Med.
Chem., 1995, 38, 3524.
5. K. Tomita, Y. Tsuzuki, K. Shibamori, M. Tashima, F. Kajiꢀ
kawa, Y. Sato, S. Kashimoto, K. Chiba, K. Hino, J. Med.
Chem., 2002, 45, 5564.
6. S. McCombie, S. Lin, J. Tagat, Heterocycles, 1993, 35, 93.
7. P. I. Abramenko, V. G. Zhiryakov, Khim. Geterotsikl. Soeꢀ
din., 1972, 1539 [Chem. Heterocycl. Compd. (Engl. Transl.),
1972].
13. W. De Camp, J. Stewart, Acta Crystallogr., 1971, 27, 1227.
14. B. Burja, M. Kocevar, S. Polanc, Tetrahedron, 2009,
65, 8690.
15. Y. Huang, H. Lin, K. Cheng, W. Su, K. Sung, T. Lin,
J. Huang, S. Lin, F. Wong, Tetrahedron, 2009, 65, 9592.
16. L. S. Liebeskind, J. Srogi, Org. Lett., 2002, 4, 979.
17. A. A. Krauze, Yu. E. Pelcher, Z. A. Kalme, G. Ya. Dubur,
Khim. Geterotsikl. Soedin., 1984, 1140 [Chem. Heterocycl.
Compd. (Engl. Transl.), 1984, 20, 935].
8. S. Hannick, Y. Kishi, J. Org. Chem., 1983, 48, 3833.
9. T. Hiyama, K. Kobayashi, Tetrahedron Lett., 1982, 23, 1597.
10. Y. Hsiao, N. Rivera, T. Rosner, S. Krska, E. Njolito,
F. Wang, Y. Sun, J. Armstrong, E. Grabowski, R. Tillyer,
F. Spindler, C. Malan, J. Am. Chem. Soc., 2004, 126, 9918.
Received November 8, 2010