Synthesis of 2-thioxohydropyridine-3-carbonitrile, 2-alkylthiopyridine, thienopyridine, pyrazolopyridine derivatives and their theoretical calculations

Article abstract of DOI:10.1002/jccs.200200087

Cyanothioacetamide (1) reacted with but-2-enal (2) to give the corresponding 4-methyl-2-sulfanyl-pyridine-3-carbonitrile (7) which was used as a good starting material for the synthesis of 1-(3-amino-4-methylthieno[2,3-b] pyridin-2-yl)ethan-1-one (10), 3-amino-4-methylthieno[2,3-b]pyridine-2- carboxamide (15), 3-amino-4-methylthieno[2,3-b]pyridine-2-carboxylate (18) and 3-amino-4-methylthieno[2,3-b]pyridin-2-ylarylketone 25a-c through its reactions with each of (1-chloroacetone (8), 3-chloropentane-2,4-dione (11) or ethyl 2-chloro-3-oxo-butanoate (19)), 2-chloroacetamide (13), ethyl 2-chloroacetate (16) and 2-bromo-1-arylethan-1-one 23a-c, respectively. Considering the data of elemental analyses, IR, ¹H NMR, mass spectra and theoretical calculations, structures of the newly synthesized heterocyclic compounds were elucidated.

Full text of DOI:10.1002/jccs.200200087

Journal of the Chinese Chemical Society, 2002, 49, 561-569
561
Synthesis of 2-Thioxohydropyridine-3-carbonitrile, 2-Alkylthiopyridine,
Thienopyridine, Pyrazolopyridine Derivatives and Their Theoretical
Calculations
Fawzy A. Attaby*, Ahmed H. H. Elghandour, Hussein M. Mustafa and Yasser M. Ibrahem
Chemistry Department, Faculty of Science, Cairo University, Giza, Egypt
Cyanothioacetamide (1) reacted with but-2-enal (2) to give the corresponding 4-methyl-2-sulfanyl-
pyridine-3-carbonitrile (7) which was used as a good starting material for the synthesis of 1-(3-amino-4-
methylthieno[2,3-b]pyridin-2-yl)ethan-1-one (10), 3-amino-4-methylthieno[2,3-b]pyridine-2-carboxamide
(15), 3-amino-4-methylthieno[2,3-b]pyridine-2-carboxylate (18) and 3-amino-4-methylthieno[2,3-b]pyri-
din-2-ylarylketone 25a-c through its reactions with each of (1-chloroacetone (8), 3-chloropentane-2,4-dione
(11) or ethyl -chloro-3-oxo-butanoate (19)), 2-chloroacetamide (13), ethyl 2-chloroacetate (16) and 2-
bromo-1-arylethan-1-one 23a-c, respectively. Considering the data of elemental analyses, IR, 1H NMR, mass
spectra and theoretical calculations, structures of the newly synthesized heterocyclic compounds were eluci-
dated.
INTRODUCTION
In conjunction with our previous work1-8 cyanothio-
which corresponded to the molecular weight of the molecular
formula C7H8N2S of the assigned structure (cf. Chart 1). By
considering the above-mentioned data in addition to that of
the elemental analyses, such reaction product could be for-
mulated as 4-methyl-2-thioxo-1,3,4-trihydropyridine-3-car-
bonitrile (6) (cf. Chart 1). On refluxing such a reaction prod-
acetamide (1) was used as a good synthon for the synthesis of
2-thioxohydropyridine-3-carbonitrile derivatives, which
were used for building up several newly synthesized pyra-
zolopyridine and thienopyridine derivatives. The reported bi-
ological activities of pyridines9-11 and thienopyridines12-14
stimulated our interest for the synthesis of several new deriv-
atives of these ring systems which are required for the medic-
inal chemistry program.
Chart 1
H3C
CHO
CN-CH2-CSNH2 + CH3-CH=CH-CHO
NH2
1
2
NC
S
3
RESULTS AND DISCUSSION
It has been found that Shelyakin et al.15 reported that
cyanothioacetamide (1) reacted with but-2-enal (2) in eth-
anolic sodium ethoxide to afford the corresponding 4-meth-
yl-2-thioxopyridine-3-carbonitrile (7a) but on carrying out
such reaction in our laboratory we found that such reaction
was proceeded via very low yield and an impure product.
This induced our attention to change the reaction condition,
and thus 1 reacted with 2 in absolute ethanol containing a cat-
alytic amount of triethylamine to afford the reaction product
via the non-isolated products 3-5. The IR (cm-1) spectrum of
such reaction product showed the bands corresponding to
H3C
NC
H3C
NC
OH
N
NH2
S
S
4
5
H3C
NC
H3C
NC
H3C
NC
NH
NH
N
S
1
NH, CN, C=S and C=C groups while its H NMR spectrum
S
SH
6
revealed the signals of CH3, pyridine H-3, H-4, H-5, H-6 and
7a
7
NH protons. Moreover, its mass spectrum gave m/z = 152
* Corresponding author. E-mail: Fattaby@hotmail.com or Fawzy@chem-sci.cairo.eun.eg

562 J. Chin. Chem. Soc., Vol. 49, No. 4, 2002
Attaby et al.
1
uct in absolute ethanol containing a catalytic amount of tri-
ethylamine for three hours it gave 4-methyl-2-sulfanylpyri-
dine-3-carbonitrile (7) rather than 4-methyl-2-thioxohydro-
pyridine-3-carbonitrile (7a). Considering the data of IR, H
NMR and elemental analyses the structure 7 was elucidated
(cf. Tables 1 and 2). Moreover, its mass spectrum gave m/z =
Table 1. Characterization and Analytical Data of the Newly Synthesized Compounds
Comp.
Colour
Yield
M.P.
( C)
Molecular
formula
Chemical Analysis (Calcd./Found)
(
)
C
H
N
S
Cl
6
Yellowish-
white
55.23 5.30
55.0 5.5
55.98 4.03
55.7 4.1
58.23 4.89
56.4 5.0
52.16 4.38
52.3 4.5
52.16 4.38
52.0 4.4
55.91 5.12
56.1 5.3
58.51 4.91
58.3 5.1
56.75 5.44
56.8 5.3
69.97 5.03
70.1 5.1
70.83 5.55
70.9 5.4
61.20 4.04
61.4 4.2
18.40
18.2
18.65
18.7
13.58
13.3
20.27
20.0
20.27
20.4
11.86
11.7
17.06
16.9
37.81
37.7
21.07
20.9
21.35
21.5
15.55
15.7
15.47
15.2
15.47
15.6
13.57
13.7
19.53
19.4
----
----
13.34
13.5
12.61
12.8
11.67
11.7
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
----
12.90
13.1
72
155-7
C7H8N2S
7
Yellow
87
69
70
76
68
62
66
68
72
77
186-8
197-9
154
C7H6N2S
C10H10N2OS
C9H9N3OS
C9H9N3OS
C11H12N2O2S
C8H8N2S
10
14
15
18
20
22
25a
25b
25c
Brown
Yellowish-
white
Brown
Yellow
Yellow
220-2
287-9
85
Pale-
brown
238-9
297-9
267-8
311-3
C7H8N4
11.06
11.2
11.01
10.9
10.20
10.3
Yellow
Brown
Yellow
C14H12N2S
C15H14N2S
C14H11ClN2S
Table 2. IR and 1H NMR Spectral Data
Comp.
IR (cm-1)
1H NMR ( ppm)
6
3157 (NH); 3089 (olefinic CH); 2946, 2833 (sat. CH);
2222 (CN) and 1600 (C=C).
3143 (NH); 3081 (olefinic CH); 2934, 2852 (sat. CH);
2218 (CN) and 1605 (C=C).
1.0 (s, 3H, CH3); 3.1 (d, 2H, pyridine H-3, H-4); 4.1 (s, br., 1H,
NH) and 6.5-6.9 (dd, 2H, pyridine H-5, H-6).
1.2 (s, 3H, CH3); 7.2-6.7 (dd, 2H, pyridine H-5, H-6) and 12.3
(s, br., 1H, SH).
7
10
14
15
18
20
22
25a
3460, 3291 (NH2); 2978 (CH sat.) and 1712 (CO-acetyl). 0.9 (s, 3H, CH3); 2.4 (s, 3H, COCH3); 5.2 (s, br., 2H, NH2); 6.8-7.3
(dd, 2H, pyridine H-5, H-6).
3410, 3289 (NH2); 2985 (sat. CH); 2219 (CN); 1683 (CO 1.2 (s, 3H, CH3); 3.1 (s, 2H, -SCH2-); 5.1 (s, br., 2H, NH2) and 6.7-
amidic) and 1602 (C=C).
7.0 (dd, 2H, pyridine H-4, H-5).
3459, 3325, 3254 (NH2); 2982 (sat. CH); 1672 (CO
amidic) and 1600 (C=C).
1.1 (s, 3H, CH3); 5.21 (s, br., 4H, two NH2) and 6.8-7.1 (dd, 2H,
pyridine H-5, H-6).
3460, 3289 (NH2); 2986 (CH sat.); 1718 (CO-ester)
and 1601 (C=C).
2980 (sat. CH); 2214 (CN) and 1604 (C=C).
0.9 (s, 3H, CH3); 1.4 (t, 3H, CH3CH2); 4.3 (q, 2H, CH3CH2); 5.4
(s, br., 2H, NH2) and 6.8-7.3 (dd, 2h, pyridine H-5, H-6).
1.2 (s, 3H, CH3); 3.1 (s, 3H, SCH3) and 6.7-7.1 (dd, 2H, pyridine H-
5, H-6).
3462, 3334, 3248, 3197 (NH2 and NH); 2982 (sat. CH)
and 1600 (C=C).
1.3 (s, 3H, CH3); 5.1 (s, br., 3H, NH, NH2) and 6.8-7.3 (dd, 2H,
pyridine H-5, H-6).
3422, 3387 (NH2); 3051 (aromatic CH); 2987 (sat. CH)
and 1712 (CO ketonic) and 1603 (C=C).
1.5 (s, 3H, CH3); 5.5 (s, br., 2H, NH2) and 6.2-7.8 (m, 7H, aromatic
and pyridine H-5, H-6 protons).
25b 3431, 3385 (NH2); 3043 (aromatic CH); 2982 (sat. CH)
1.3 (s, 6H, two CH3); 5.7 (s, br., 2H, NH2) and 6.5-7.6 (m, 6H,
aromatic and pyridine H-5, H-6 protons).
and 1715 (CO ketonic) and 1600 (C=C).
25c
3420, 3379 (NH2); 3063 (aromatic CH); 2988 (sat.
CH) and 1717 (CO ketonic) and 1602 (C=C).
1.5 (s, 3H, CH3); 5.3 (s, br., 2H, NH2) and 6.5-7.6 (m, 6H,
aromatic and pyridine H-5, H-6 protons).

Novel Synthesis and Theoretical Studies of Some Pyridine Derivatives
Table 3.
J. Chin. Chem. Soc., Vol. 49, No. 4, 2002 563
Comp.
No.
Total
energy
(eV)
Binding
energy
(Kcal)
Isolated
A.E.
(Kcal)
Electronic
energy
(Kcal)
Nuclear-
Nuclear
repulsion
(Kcal)
Heat of
formation
(Kcal)
EHOMO
(IP)
(eV)
ELUMO
(EA)
(eV)
Energy Dipole
gap
moment
(D)
(eV)
6
7
7a
9
-1614.16
-1586.90
-1586.42
-2346.68
-2347.52
-2950.53
-2412.14
-2413.13
-2823.55
-2824.36
-1742.73
-1742.91
-1833.28
-1833.17
-3013.86
-3014.95
-3170.89
-3375.22
-1844.10
-1741.19
-1730.16
-2554.90
-2574.40
-3086.20
-2444.90
-2467.80
-2945.60
-2964.10
-2021.46
-1998.50
-1980.80
-1978.30
-3477.16
-3502.17
-3785.04
-3486.05
-35362.40
-34836.77
-34836.77
-51535.90
-51535.90
-64923.40
-53154.80
-53154.70
-62137.30
-62137.30
-38148.52
-38148.50
-40276.30
-40276.30
-65992.30
-65992.30
-69304.02
-74312.73
-180052.80
-165919.25
-166595.00
-287231.00
-297619.60
-408398.70
-289779.30
-300195.20
-358739.30
-376688.30
-195383.40
-198834.80
-202592.30
-208316.10
-427441.20
-440008.70
-477952.77
-479989.47
142846.30
129341.30
130028.06
233140.10
243509.20
340389.00
234179.50
244572.60
293656.40
311586.90
155213.40
158687.70
160335.20
166061.50
357971.80
370514.30
404863.69
402190.68
61.38
60.05
71.078
26.92
7.47
1.14
26.89
4.04
29.08
47.60
54.90
77.80
84.26
86.80
63.36
38.35
30.57
31.36
-8.8942
-8.9711
-8.7699
-8.8478
-8.1767
-9.0348
-8.9472
-8.2543
-8.7920
-8.2252
-8.6081
-8.5723
-8.9876
-8.6083
-8.6546
-8.1182
-8.1114
-8.2214
-0.8599
-0.7531
-1.1231
-0.8703
-0.8134
-1.0391
-0.9283
-0.7371
-0.8018
-0.8467
-0.6363
-1.0835
-0.6240
-0.2645
-0.8189
-0.8783
-0.8640
-1.0021
8.0343
8.2180
7.6468
7.9775
7.3633
7.9957
8.0189
7.5172
7.9902
7.3785
7.9718
7.4888
8.3636
8.3438
7.8327
7.2399
7.2474
7.2139
6.061
3.475
7.720
4.125
6.277
6.178
4.644
5.544
2.976
5.424
3.153
7.781
2.674
2.939
3.728
2.177
1.793
3.443
10
12
14
15
17
18
20
20a
21
22
24a
25a
25b
25c
150 which corresponded to the dehydrogenated product of 6.
Furthermore, by considering the theoretical calculations (cf.
Table 3) structure 7 was elucidated.
Theoretical Consideration
Table 3 presents the ground state electronic structural
data of both 6 and 7. Fig. 1 shows the prospective drawing of
6 and 7 drawn to their optimised geometry computed at the
AM1 level. Compound 7 is theoretically more stable than 6 as
revealed by the corresponding Hf values and is much less
polar. That is, the high polarity of the reaction medium shifts
the reaction towards 7. Furthermore, 7 is a stronger elec-
tron-acceptor and a weaker electron-donor than 6. The possi-
bility of thione-thiol tautomerism is investigated; in the case
of 7 the thiol form is shown in Fig. 1 and its corresponding
ground state properties are given in Table 3. 7 also, is energet-
ically more favourable than 7a, yet much less polar. In high
polar medium, 7a would thus predominate.
Compound 7 was used as a good starting material for
the present study owing to the presence of more than one ac-
tive site in its structure. Thus, it has been found that pyri-
dine-3-carbonitrile derivative 7 reacted with 1-chloroacetone
(8) in sodium ethoxide to give a reaction product formed via
the loss of hydrogen chloride. Mass spectrum of such reac-
tion product gave m/z = 206, which corresponded to the mo-
lecular weight of the molecular formula C10H10N2SO of the
assigned structure (cf. Chart 2). Considering the above-
Fig. 1. Prospective drawing of compounds drawn at its
AM1 geometry.

564 J. Chin. Chem. Soc., Vol. 49, No. 4, 2002
Attaby et al.
Chart 2
Equation 1
CH3
CH3
CH3
ClCH(COCH3)2
ClCH2CONH2
NH
H
CN
8
11
13
N
CN
SCH2COCH3
N
N
S
COCH3
SH
7
I
9
CH3
CN
CH3
CH3
ClCH2COCH3
CN
S
8
N
N
CN
10
N
H
SCH(COCH3)2
CH3
SCH2CONH2
7
12
H2O/-AcOH
N
14
CN
CH3
CH3
SCH2COCH3
CN
NH
9
11
COCH3
COCH3
SCH(COCH3
)
N
2
N
S
CH3
12
CH3
II
NH2
NH2
bles 1, 2). The mass spectra of 14 gave m/z = 207 which corre-
sponded to the exact molecular weight of a molecular for-
mula C9H9N3OS of an assigned structure (cf. Chart 2). More
evidence for the structure 14 was given through their cycliza-
tion in an ethanolic potassium hydroxide solution. The IR
spectrum of this cyclization product showed no bands for the
CN group while bands of the newly born NH2 were detected.
COCH3
N
S
N
S
CONH2
10
15
1
mentioned data in addition to IR, H NMR and elemental
analyses data, this reaction product was formulated as a
1-(3-amino-4-methylthieno[2,3-b]pyridin-2-yl)ethan-1-one
(10). The formation of such a thienopyridine derivative was
proposed to proceed through the non-isolated intermediate 9.
In a similar way compound 7 reacted with 3-chloro-
pentane-2,4-dione (11) to give the previously isolated com-
1
Its H NMR spectrum had no signals of the S-CH2 protons
and this proved that both the CN group and S-CH2 protons
were involved in the cyclization step. Considering all the
above-mentioned data, this cyclization product was formu-
lated as 3-amino-4-methylthieno[2,3-b]pyridine-2-carbox-
amide (15) (cf. Tables 1, 2, Equation 2 and Chart 2).
1
pound 10 with the same aspects (m.p, Mixed m.p., IR, H
NMR and mass spectra) of that obtained from the reaction of
7 with 8. The structure of 10 was further confirmed by con-
sidering the data of elemental analyses, IR and 1H NMR spec-
tra (cf. Tables 1, 2). The IR spectra of 10 showed the absence
of CN group and instead the band of the newly born NH2
Equation 2
CH3
CH3
NH
CN
13
7
1
H
15
group was detected. Its H NMR spectrum revealed no sig-
SCH2CONH2
N
N
S
CONH2
nals of -CH2CO- protons while the NH2 protons were de-
tected. Based on both IR and 1H-NMR spectral data it could
be concluded that both the -CH2CO- protons and the CN
group were involved in the cyclization step to give the
non-isolable intermediate (I) in case of reaction with 1-
chloroacetone while the addition of the anions from the
-CH(COCH3)2 to the CN groups afforded the non-isolable
3-iminothienopyridine intermediate (II) in case of the reac-
tion with 3-chloropentane-2,4-dione. These intermediates, in
turn, added water molecules to give 10 (cf. Equation 1).
Work was also extended to shed more light on the
chemical reactivity of 7. Thus, 7 reacted with 2-chloro-
acetamide (13) to afford 2-(3-cyano-4-methyl-2-pyridyl-
thio)acetamide (14) via the loss of hydrogen chloride (cf.
Chart 2). The structure of 14 was established based on the ele-
mental analyses, IR and 1H NMR spectra (cf. Chart 2 and Ta-
14
The synthetic potentiality of 7 was further demon-
strated via its reaction with ethyl 2-chloroacetate (16) in so-
dium methoxide to give a reaction product formed via de-
hydrochlorination. The IR spectrum of this reaction product
showed the bands corresponded to the NH2 group and ester
CO. Its 1H-NMR spectrum revealed the signals corresponded
to NH2, CH3 at pyridine, pyridine H-5, H-6 and CH3CH2-pro-
tons (cf. Table 2). Moreover, its mass spectrum gave m/z =
236 which corresponded to the exact molecular weight of a
molecular formula C11H12N2SO2 of the assigned structure.
Considering all the above data, this reaction product was for-
mulated as ethyl 3-amino-4-methylthieno[2,3-b]pyridine-2-
carboxylate (18) through the non-isolable intermediate 17
(cf. Chart 3).

Novel Synthesis and Theoretical Studies of Some Pyridine Derivatives
J. Chin. Chem. Soc., Vol. 49, No. 4, 2002 565
Chart 3
Equation 3
COOCH2CH3
CH3
CH3
CH3
Cl-CH-COCH3
CN
S
CH3I
NH
19
Hydrolysis
-CO2
7
19
N
COCH3
COOEt
CN
N
CH-COCH3
COOEt
N
S
SH
7
20
CH3
10
CH3
ClCH2COOCH2CH3
16
CH3
CH3
N
N
NH
H
CN
CH3
CN
CN
S
S-CH-COCH3
COOCH2CH3
SCH3
18
CH2-COOEt
16
N
N
S
COOEt
CN
SCH2COOCH2CH3
17
N
21
20
17
CH3
N
CN
Tables 1, 2 and Chart 3). A further confirmation of structure
20 was given through its reaction with hydrazine hydrate to
give the sulfur-free reaction product 22. Compound 22 was
most probably formed via the substitution of the S-CH3 group
to give the non-isolable 2-hydrazino pyridine 21. The hy-
drazino group was then added to the CN group to afford the
corresponding 4-methylpyrazolo[3,4-b]pyridine-3-ylamine
22. The structure of 22 was established based on elemental
analyses, IR and 1H NMR data (cf. Tables 1, 2 and Chart 4).
H3C
CH3
S
CH3
NH2
20a
NH2
COCH3
N
S
COOCH2CH3
N
S
10
18
Theoretical Consideration
The reaction of 7 with 13, would theoretically give the
open structure 14 or the cyclic one 15. Table 3 summarizes
the ground state electronic properties of 14 and 15, whereas
Fig. 2 presents the two compounds drawn to their optimized
geometries. While 15 seems to be energetically more stable
than 14, the energy difference is appreciable 23 Kcal/mol.
Furthermore, 15 is more polar and hence would be stabilized
by the reaction medium to a much higher extent. Further-
more, the energy gap E (defined as the difference of energy
between the HOMO and LUMO) indicates that 14 is less re-
active. The reaction of 7 with 8 or 11 to finally give 10 pro-
ceeds via two routes and intermediates 9 and 12. The ground
state electronic properties of all these structures are presented
in Table 3. Inspection of the data given in this table we can
conclude that 10 is much more stable than 9 and also more po-
lar.
9
10
12
14
In a similar manner, compound 7 reacted with ethyl
-chloro-3-oxo-butanoate (19) to give the corresponding
thienopyridine derivative 10. The reaction product 10 was
most probably formed via the addition of the anions from
-CH(COOEt)COCH3 to the CN group to give the non-iso-
lable 3-iminothienopyridine intermediate. This intermediate
then added water to liberate acetic acid and gave the final
isolable 10 (cf. Equation 3).
15
Synthon 7 reacted also with methyl iodide in sodium
methoxide to give the corresponding 4-methyl-2-methyl-
thiopyridine-3-carbonitrile 20 whose structure was eluci-
dated based on elemental analyses, IR and 1H NMR data (cf.
Fig. 2. Prospective drawing of compounds drawn at its
AM1 geometry.

566 J. Chin. Chem. Soc., Vol. 49, No. 4, 2002
Attaby et al.
responding 3-amino-4-methylthieno[2,3-b]pyridin-2-yl-
(phenyl, 4-methylphenyl or 4-chlorophenyl)ketone 25a-c via
the non-isolable products 24a-c. The structures of 25a-c were
elucidated by considering the data of elemental analyses, IR
and 1H NMR spectra (cf. Tables 1, 2 and Chart 4).
Chart 4
CH3
NH2NH2
ArCOCH2Br
23a-c
N
CN
SH
7
CH3
CH3
CH3I
Theoretical Consideration
N
N
CN
SCH2COAr
CN
The final products of Chart 4, namely both 22 and 25,
are formed via intermediates 21 and 24, respectively. The
ground state electronic properties of all components investi-
gated in Chart 4 are presented in Table 3. The corresponding
geometrical features are shown in Fig. 4. It is interesting to
note that all ground state properties of 21 and 22 are almost
the same with small differences that favour 21 slightly; 22 is
formed through the cyclization which occurs spontaneously.
25 is more stable than 24 by about 25 Kcal./mol. However, 24
is much more reactive as indicated by Egap. Fig. 5 presents
free-energy relationships involving Hg, Et, and energy gap
CH3
NHNH2
24a-c
N
21
CN
SCH3
20
CH3
CH3
N
NH2
NH2NH2
N
S
NH2
COAr
N
N
H
a, Ar=C H
25
b, Ar=C66H45-p-CH3
c, Ar=C6H4-p-Cl
22
Moreover, the mass spectrum of 22, gave m/z = 148, which
corresponded to the exact molecular weight of a molecular
formula C7H8N4 of the assigned structure. Good evidence of
structure 22 was given through its synthesis via another
route. Thus, compound 7 reacted with hydrazine hydrate to
give a reaction product which was found to be identical in all
aspects with the 22 obtained from the reaction of 20 with
hydrazine hydrate (cf. Chart 4 and Equation 4).
against the Hammet constant
for the substituents a-c for
p
compound 25.
Equation 4
CH3
17
18
CN
CH3I
CH3
N2H4
7
22
SCH3
N
N
NHNH2
20
N2H4
Theoretical Consideration
Methylation of 7 may take place to afford the –SCH3
(20) or the –N-CH3 (20a) derivatives. Both structures are
drawn to their optimized geometries and are presented in Fig.
3, whereas the corresponding ground state properties are
given in Table 3. The CH3N- derivative seems to be energeti-
cally and thermodynamically more stable. Thus, methylation
seems to occur on the HN- and then rearranged to the –SCH3
form. The formation of 18 from 17 is energetically and ther-
modynamically favorable especially in polar solvents (cf. Ta-
ble 3).
20
20a
21
Chemical reactivity of 7 was further investigated
through its reaction with 2-bromo-1-(phenyl or 4-methyl-
phenyl, 4-chlorophenyl)ethan-1-one (23a-c) to give the cor-
Fig. 3. Prospective drawing of compounds drawn at its
AM1 geometry.

Novel Synthesis and Theoretical Studies of Some Pyridine Derivatives
J. Chin. Chem. Soc., Vol. 49, No. 4, 2002 567
EXPERIMENTAL
All melting points were uncorrected. IR spectra (KBr
amine or piperidine (0.5 mL) was heated under reflux for 1-2
hours. The mixture was cooled and the product so formed was
collected by filtration and then crystallized from ethanol to
give 6 (cf. Tables 1 and 2).
discs) were recorded on Brucker Vector 22 and Perkin-Elmer
FT-IR type 4 spectrophotometers. 1H NMR spectra were re-
corded on Varian EM 390 MHz. Gemnai-200 MHz. and
Brucker WP-80 spectrometers using TMS as an internal stan-
dard and CDCl3, DMSO-d6 and (CD3)2CO as solvents and
chemical shifts are expressed as ppm units. Mass spectra
were recorded on Hewlett-Packard GC-MS type 2988 using
inlet type at 70 eV. Microanalyses were performed by the
Microanalytical Center of Cairo University. Molecular or-
bital calculations were performed by considering the
Schordinger equation,16 variational methods and Hartree-
Fock theory,17 Semi-empirical methods,18 Modifiedneglect
of the Diatomic Overlap (MNDO)19 and Austin mode 1
(AM1).20-22
Synthesis of 7
Method (A)
A solution of 1 with buten-2-al (2) (0.01 mole of each)
in ethanol (50 mL) containing a catalytic amount of triethyl-
amine or piperidine (0.5 mL) was heated under reflux for 5-7
hours. The reaction mixture was cooled and the product so
formed was collected by filtration and washed with cold etha-
nol then crystallized from ethanol to give 7 (cf. Tables 1 and
2).
Method (B)
A solution of 6 in ethanol (50 mL) containing a cata-
lytic amount of triethylamine (0.5 mL) was heated under re-
flux for 3-5 hours. The reaction mixture was cooled and the
product so formed was collected by filtration and then crys-
tallized from ethanol to give 7 (cf. Tables 1 and 2).
Synthesis of 6
A solution of 1 and buten-2-al (2) (0.01 mole of each) in
ethanol (50 mL) containing a catalytic amount of triethyl-
Synthesis of 14
A mixture of 7 and chloroacetamide (13), 0.01 mole of
each, in methanol containing sodium methoxide (prepared by
0.01 atom Na in methanol) was refluxed for 3 hours. The re-
action mixture was then evaporated till dryness and then
cooled. The product so formed was collected by filtration,
washed with cold ethanol and then crystallized from ethanol
to give 14 (cf. Tables 1 and 2).
22
24a
Synthesis of 15
A solution of 14 (0.01 mole) in ethanol containing
KOH 10% (10 mL) was refluxed for 3 hours. The reaction
mixture was then poured onto water and acidified with hydro-
chloric acid. The product so formed was collected by filtra-
tion, washed with cold water and then crystallized from etha-
nol to give 15 (cf. Tables 1 and 2).
Synthesis 10, 18 and 25a-c: (General method)
25b
25a
A solution of 7 with each of (8, 11 or 19), 16 and 23a-c
(0.01 mole of each) in ethanol (50 mL) containing the cata-
lytic amounts of triethyl amine or piperidine (0.5 mL) was
refluxed for 3-5 hours. The reaction mixture was then cooled
and the products so formed were collected by filtration,
washed with cold ethanol and then crystallized from ethanol
to give 10, 18 and 25a-c, respectively (cf. Tables 1 and 2).
25c
Fig. 4. Prospective drawing of compounds drawn at its
AM1 geometry.
Synthesis of 20
A solution of 7 and methyl iodide (0.01 mole of each) in

568 J. Chin. Chem. Soc., Vol. 49, No. 4, 2002
Attaby et al.
Fig. 5. Free energy relationships for ET, Hf, energy gab and against Hammet constant of compound 25a-c.
methanolic sodium methoxide (prepared by 0.01 atom of Na
in 20 mL methanol) was heated under reflux for 2 hours. The
reaction mixture was cooled and poured onto ice-cold water
and then acidified with hydrochloric acid. The products so
formed were collected by filtration, washed with water and
crystallized from ethanol to give 20 (cf. Tables 1 and 2).
Key Words
Thieno[2,3-b]pyridin-2-yl)ethan-1-one;
Thieno[2,3-b]pyridine-2-carboxylate;
Thieno[2,3-b]pyridin-2-ylarylketone;
2-Methylthiopyridine-3-carbonitrile and
pyrazolo[3,4-b]pyridine-3-ylamine.
Synthesis of 22
A mixture of 7 or 20 (0.01 mole of each) and hydrazine
hydrate (15 mL) was heated under reflux for 6 hours. The re-
action mixture was then heated till dryness and then acidified
with acetic acid. The product so formed after cooling, was fil-
trated and washed with cold ethanol then crystallized from
ethanol to give 22 (cf. Tables 1 and 2).
REFERENCES
1. Attaby, F. A.; Abdel-Fattah, A. M. Phosphours, Sulfur and
Silicon 1996, 119, 257.
2. Attaby, F. A. Phosphours, Sulfur and Silicon 1997, 126, 27.
3. Attaby, F. A. Phosphours; Sulfur and Silicon 1998, 139, 1.
4. Attaby, F. A.; Eldin, S. M.; Elneairy, M. A. A. Heteroatom
Chem. 1998, 9, 571.
5. Attaby, F. A.; Eldin, S. M.; Elneairy, M. A. A. J. Chem. Res.
(M). 1998, 10, 2754; (S) 10, 632.
Received October 18, 2001.
6. Attaby, F. A.; El-neairy, M. A. A.; Elsayed, M. S.

Novel Synthesis and Theoretical Studies of Some Pyridine Derivatives
J. Chin. Chem. Soc., Vol. 49, No. 4, 2002 569
Phosphours, Sulfur and Silicon 1999, 149, 49.
7. Attaby, F. A.; Abdel-Fattah, A. M. Phosphorus, Sulfur and
Silicon 1999, 155, 253.
14. achet, M.; Ohlmann, P.; Hechler, B.; Lecchi, A.; Chevalier,
J.; Cassel, D.; Mannucci, P. M.; Cazenave, J. P. Br. J.
Haematol. 1995, 91, 434.
8. Attaby, F. A.; Elneairy, M. A. A.; Eldin, S. M.; El-Louh, A.
K. K. J. Chin. Chem. Soc. 2001, 48, 5.
9. Lohaus, G.; Dittmar, W. S.; Afric Patent, 1968, 6, 906, 036;
C. A., 1970, 73, 120308.
10. Youngdale, G. A., U. S. Patent, 1980, 4, 288, 440; C. A.,
1982, 96, 6596c.
11. Todd, H., Br. Patent, 1970, 1,203, 149; C. A., 73, 1970,
120508b.
12. Umemura, K.; Kawai, H.; Ishihara, H.; Nakkashima, M. Jpn.
J. Pharmcol. 1995, 67, 253.
13. Yao, S. K.; Ober, J. C.; Maffrand, J. J.; Anderson, H. V.;
Buja, L. M.; Willerson, J. T. Am. J. Physiol. 1994, 267, 488.
15. Shelyakin, V.; Dyachenko, V. D.; Sharanin, Yu. A. Khim.
Geterotsikl Soedin 1995, 2, 269; C. A., 1995, 123, 256481v.
16. Schrodinger, E. Ann. Pgysik 1926, 79, 361.
17. Levine, I. N. Quantum Chemistry; 3rd Ed.; Allyn and Bacon,
Boston, 1983.
18. Pople, J. A.; Beveridge, D. L.; Ostiund, N. S. J. Quantum
Chem. 1967, 1, 293.
19. Dewar, M. J. S.; Theil, W. J. Am. Chem. Soc. 1977, 99, 4899.
20. Ruedenberg, K. Rev. Mod. Phys. 1962, 34, 326.
21. Burstein, K. Y.; Isaev, A. N. Theor. Chem. Acta 1984, 64,
397.
22. Prllman, A.; Port, G. N. J. Theor. Chem. Acta 1973, 32, 77.