Reactions and reactivity of thienopyridines: Facile synthesis of Some pyridothienooxazepine derivatives

Article abstract of DOI:10.1080/10426500600883122

Pyridothienooxazepines were synthesized by the interaction salt of the 3-aminothienopyridine-2-carboxylate with activated α-haloketones or α-halonitriles. Several derivatives of thienopyridine were prepared either by the replacement of an amino group or b

Full text of DOI:10.1080/10426500600883122

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Reactions and Reactivity
of Thienopyridines:
Facile Synthesis of Some
Pyridothienooxazepine
Derivatives
Y. A. El-Osaily a , A. A. O. Sarhan a & A. M. Kamal El-
Dean a
a Chemistry Department, Assiut University, Assiut,
Egypt
Version of record first published: 01 Feb 2007.
To cite this article: Y. A. El-Osaily, A. A. O. Sarhan & A. M. Kamal El-Dean
(2007): Reactions and Reactivity of Thienopyridines: Facile Synthesis of Some
Pyridothienooxazepine Derivatives, Phosphorus, Sulfur, and Silicon and the Related
Elements, 182:1, 121-132
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Phosphorus, Sulfur, and Silicon, 182:121–132, 2007
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500600883122
Reactions and Reactivity of Thienopyridines: Facile
Synthesis of Some Pyridothienooxazepine Derivatives
Y. A. El-Osaily
A. A. O. Sarhan
A. M. Kamal El-Dean
Chemistry Department, Assiut University, Assiut, Egypt
Pyridothienooxazepines were synthesized by the interaction salt of the 3-
aminothienopyridine-2-carboxylate with activated α-haloketones or α-halonitriles.
Several derivatives of thienopyridine were prepared either by the replacement of an
amino group or by using an amino group in 3-aminothienopyridine-2-carboxylate
to synthesize another derivative of thienopyridine.
Keywords Reactions; synthesis; thienopyridines; triazolylthienopyridine; thienopyri-
doxazepines
INTRODUCTION
Oxazepines have attracted widespread interest in view of their biolog-
ical and pharmacological activities.1 Oxazepines and benzoxazepines
have been the subject of the most extensive studies, and numerous
synthetic methods have been developed for them.2−5 Compared to the
heterocyclic system fused with oxazepines, the articles that describe the
synthesis of a heterocyclic system fused with oxazepines are limited,6−9
and there is no one article reported that describes the synthesis of
pyridothienoxazepines.
Many thienopyridines have been evaluated pharmacologically and
have been found to show activity against, for example, diabetes
mellitus,10−12 and as analgesics and antiinflammatories, sedatives,13
anticoagulants,14 antiartherosclerotics,15 and gonadotropin-releasing
hormone antagonists.16 In continuation of our program in the syn-
thesis of heterocycles compounds containing a thieno[2,3-b] pyridine
moiety,17−25 we report herein the synthesis of some new thienopyridine
derivatives with hope that they have potential biological activities.
Received May 15, 2006; accepted June 6, 2006.
Address correspondence to A. M. Kamal El-Dean, Assiut University, Chemistry
Department, Faculty of Science, Assiut, 71616 Egypt. E-mail: a.eldean@acc.aun.edu.eg
121

122
Y. A. El-Osaily et al.
RESULTS AND DISCUSSIONS
The potassium salt of 3-aminothieno[2,3-b]pyridine-2-carboxylate 2
was reacted with phenacyl bromide and/or chloroacetone to afford the
corresponding esters 3a,b. In an attempt to cyclize the produced com-
pound 3a with acetic anhydride, neither compounds 4 nor 5 were ob-
tained, but diacylation of an amino group occurred to give diacylated
amino derivative 6. The formation of compound 6 was established on
the basis of NMR and mass spectra of the produced compound. The
NMR spectrum revealed two signals at δ 2.2 and 2.3 corresponding to
the two acetyl groups. The mass spectrum gave a molecular ion beak at
424 corresponding to the molecular weight of 6.
The synthesis of compound 5 was accomplished according to the lit-
26,27
erature,
which used a phenacyl ester of anthranilic acid. Simi-
larly, when ester 3a was treated with polyphosphoric acid expecting
that the rearrangement accompanied with cyclization occurred to give
pyridinothienopyridone derivative 7, but in our case the dedydration
occurred to give oxazepine 5. The structure was established on the ba-
1
sis of H NMR, while its spectrum revealed signals at δ 6.95 for the
-CH- pyridine and at d 7.15 for the –CH- of oxzazepine.
On the other hand, when salt
2 was allowed to react
with α-halogenated nitrile, namely chloroacetonitrile and α-
bromcyanoacetamide, the corresponding ester was formed as an
intermediate, which spontaneously cyclized under the reaction condi-
tion to give the oxazepine 8a,b (Scheme 1). The structure of oxazepine
1
was confirmed using IR, H NMR, and mass spectra, while the IR did
not reveal any absorption band for the CN group and at the same time
gave a band at 3350 and 3250 characteristic for the amino group. Also
the mass spectrum gave a peak at 260 as a molecular ion peak. The
1H NMR of compound 8 in (CDCl3) gave a characteristic signal at δ
4.85 characteristic for -CH2- and at δ −6.3 for NH2; the latter signal
disappeared when treated with D2O.
The amino group in ethyl 3-aminothienopyridine-2-carboxylate 1
was converted into the corresponding diazonium chloride upon treat-
ment with sodium nitrite in the presence of HCl. The produced diazo-
nium chloride underwent a Sandmeyer reaction, which was replaced
with the azido group when treated with sodium azide in situ to give the
corresponding azido derivative 9. The azido group underwent cycload-
dition reaction with malononitrile to afford the triazolyl derivative 10
(Scheme 2).
When 3-amino-4,6-dimethylthieno[2,3-b]pyridine 11a and 3-amino-
2,4,6-trimethylthieno[2,3-b] pyridine 11b were allowed to react with
chloroacetyl chloride in dioxane followed by treating with sod, carbonate

Reactions and Reactivity of Thienopyridines
123
SCHEME 1
SCHEME 2

124
Y. A. El-Osaily et al.
afforded the corresponding chloroacetylamino derivative 12a,b, but
when they were allowed to react with acetic anhydride on a steam bath
at 60◦C, they afforded N-acyl derivatives 13a,b.
Chloroacetyl compounds 21a,b were reacted with 4,6-dimethyl-
2-mercapto-pyridine-3-carbonitrile in ethanol and in the presence
of sodium acetate to afford pyridylmercaptoacetaminothienopyri-
dine derivatives 14a,b, which, upon treatment with sod, ethoxide
in ethanol, were cyclized into thienopyridinoylaminothienopyridines
15a,b. Also, the chloroacetyl derivatives 12a,b were condensed with
secondary amines to afforded compounds 16a,b. The reaction of
chloroacetyl derivative 12 with malononitrile in ethanol in the pres-
ence of sodium ethoxide afford the pyrrolyl derivative 17. Bromi-
nation of acyl compound 13b using bromine/acetic at r.t. afforded
2-bromomethylthienopyridine derivative 18. The condensation of
amino compounds 11b with aromatic aldehyde gave the correspond-
ing Schiff’s base 19 (Scheme 3).
EXPERIMENTAL
All melting points were uncorrected and were determined on a Kofler
melting-point apparatus. IR spectra were recorded on a Pye-Unicam
SCHEME 3

Reactions and Reactivity of Thienopyridines
125
1
spectrometer using the KBr Wafer technique. H NMR spectra were
recorded on a Varian 390 90 MHz and JEOL 400 MHz NMR spectrome-
ters using TMS as an internal standard. Chemical shifts were expressed
as δ, units ppm. Mass spectra were recorded in on JEOL JMS 600 spec-
trometer. Elemental analyses were performed on a Perkin-Elmer 240 C.
The Synthesis of 3a,b and 8ab:General Procedure
To a stirred suspension of potassium salt 1 (1.3 g, 5 mmol) in DMF (30
mL), α-halocompound (0.005 mol), namely phenacyl bromide, chloroace-
tone, chloroacetonitrile or α-bromocyanoacetamide, was added. The re-
action mixture was stirred at r.t. (30◦C) for 2 h and then poured to an
ice/water mixture (200 g). The solid product was collected and recrys-
tallized from ethanol.
Benzoylmethyl 3-aminothieno[2,3-b]pyridine-
2-carboxylate (3a)
Produced as white crystals, 1.5 g (88%), m.p. 210◦C. IR: ν = 3410,
3310 cm−1 (NH2), 1680 cm−1 (C O). 1H NMR(CDCl3): 2.5, 2.8 (2s, 6H,
3CH3), 5.5 (s, 2H, CH2), 6.4 (s, 2H, NH2), 6.85 (s, 1H, CH-pyridine) and
7.2–8.0 (m,5H, Ar-H).
Anal. calcd. for C18H16N2O3S(340.40): C, 63.51; H, 4.74; N, 8.23; S,
9.42%. Found: C, 63.69; H, 4.53; N, 8.00; S, 9.18%.
Acetylmethyl 3-aminothieno [2,3-b]pyridine-
2-carboxylate (3b)
Produced as white crystals, 1.14 g (82%) yield, m.p. 160◦C. IR: ν = 3400,
1
3300 cm−1 (NH2), 1680 cm−1 (C O). H NMR (CDCl3): 2.2, 2.4, 2.6
(3s, 9H, 3CH3), 4.7 (s, 2H, CH2), 6.15, (s, 2H, NH2) and 6.85 (s, 1H,
CH-pyridine).
Anal. calcd. for C13H14N2O3S (278.33): C, 56.10; H, 5.07; N, 10.06; S,
11.52%. Found: C, 55.92; H, 5.34; N, 10.17; S, 11.29%.
2-Amino-8,10-dimethyl-3[H]-pyrido[2ꢀ,3ꢀ:2,3]thieno[4,5-e]
[1,4] Oxazepin-5-one (8a)
Produced as white crystals, 1.07 g (85%), m.p. 238◦C. IR: ν =
3350, 3250 cm−1 (NH2), 1695 cm−1 (C O). 1H NMR(CDCl3): 2.6, 2.75(2s.
6H, 2CH3), 4.85(s, 2H, CH2), 6.3(s, 2H, NH2) and at 6.9(s, 1H, CH-
pyridine). MS: M+(260) as a molecular ion peak and base peak (203,
175, 148, 131, 103, 76, 39).

126
Y. A. El-Osaily et al.
Anal. calcd. for C12H11N3O2S (261.30): C, 55.16; H, 4.24; N, 16.08; S,
12.27%. Found: C, 54.92; H, 4.08; N, 15.90; S, 12.52%.
2-Amino-8,10-dimethyl-3[H]-5-oxo-pyrido[2ꢀ,3ꢀ:2,3]thieno[4,5-
e][1,4]oxazepin-3-carboxamide (8b)
Produced as yellow crystals 1.34 g (68%), m.p. 285◦C. IR: ν = 3350,
1
3250 cm−1 (NH2), 1695 cm−1 (C O). H NMR(CDCl3): 2.6, 2.85 (2s,
6H, 2CH3), 5.2(s, 1H, CH), 6.3 (s, 2H, NH2), 6.9 (s, 1H, CH-pyridine)
and 7.8 (s, 2H, CONH2).
Anal. calcd. for C13H12N4O3S (304.33): C, 51.31; H, 3.97; N, 18.41; S,
10.54%. Found: C, 51.52; H, 4.17; N, 18.63; S, 10.52%.
Benzoylmethyl 3-diacetylaminothieno[2,3-b]pyridine-
2-carboxylate 6
A sample of compound 3a (1.7 g, 5 mmol) in acetic anhydride (10 mL)
was heated under reflux for 4 h, allowed to cool, and poured into cold
water (500 mL). The solid product was collected and recrystallized from
ethanol as white crystals, 1.74 g (82%), m.p. 187–188◦C. IR: ν = 173,
1720, 1700 cm−1 (3CO). 1H NMR(CDCl3): δ = 2.2, 2.3, 2.7, 2.9 (4s, 12H,
4CH3), 5.6 (s, 2H, CH2), 6.9 (s, 1H, CH-pyridine), 7.1–7.7 (m, 5H, Ar-H).
MS: M+(424) as a molecular ion peak.
Anal. calcd. for C22H20N2O5S (424.48): C, 62.25; H, 4.75; N, 6.60; S,
7.55%. Found: C, 62.08; H, 4.94; N, 6.84; S, 7.29%.
8,10-Dimethyl-2-phenyl-1[H]-pyrido[2’,3’:2,3]thieno[4,5-
e][1,4]oxazepin-5-one (5)
A sample of compound 3a (1.7 g, 5 mmol) in polyphosphoric acid (10
mL) was heated at 60–70◦C on a steam bath for 4 h, poured into cold
water, and neutralized with ammonia solution. The solid product was
collected and recrystallized from dioxan as white crystals 0.97 g (60%).
IR: ν = 3270 cm−1 (NH), 1690 cm−1 (CO). 1H NMR(DMSO-d6): 2.7, 3.0
(2s, 6H, 2CH3), 6.95 (s, 1H, CH-pyridine), 7.15 (s, 1H, CH-oxzaepine),
7.2–8.3 (m, 5H, Ar-H), 8.9 (s, 1H, NH).
Anal. calcd. for C18H14N2O2S (322.39): C, 67.06; H, 4.38; N, 8.69; S,
9.95%. Found: C, 66.86; H, 4.568; N, 8.47; S, 10.21%.
Ethyl 3-Azido-4,6-dimethylthieno[2,3-b]pyridine-
2-carboxylate (9)
To a stirred cooled solution at 0–5◦C of compound 1 (2.5 g, 10 mmol) in
an HCl/water mixture (2 mL conc. HCl, 5 mL, H2O), sod. nitrite solution

Reactions and Reactivity of Thienopyridines
127
(0.7 g in 3 mL H2O) was added dropwise. After the addition was finished,
stirring of the solution was continued for 30 min and then allowed to
stand for 1 h. A solution of sodium azide (10 mmol in 2 mL H2O) was
added dropwise. The azido compound was collected by filtration, 1.77g
(64%), m.p. 80◦C decomposed and used without further purification. IR:
ν = 2200 cm−1 (N3), 1700 cm−1 (CO). 1H NMR (CDCl3): 1.3 (t, 3H, CH3
ester), 2.6, 2.9 (2s, 6H, 2CH3 pyridine), 4.0 (q, 2H, CH2 ester) and 6.95
(s, 1H, CH-pyridine).
Anal. calcd. for C12H12N4O2S (276.32): C, 52.16; H, 4.38; N, 20.28; S,
11.60%. Found: C, 52.03; H, 4.14; N, 20.51; S, 11.84%.
Ethyl 4,5-dimethyl-[4,amino-5-cyano-2(H)(1,2,3)triazol-1-
yl)]thieno[2,3-b]pyridine-2-carboxylate (10)
A mixture of Azide compound 9 (1.38 g, 0.005 mol) and malononitrile
(0.33 g, 5 mmol) in absolute ethanol (20 mL) containing sod. ethoxide
(0.001 mol) was stirred at r.t. for 1 h, refluxed on a steam bath for an
additional h, and then allowed to cool. The solid product was collected
and recrystallized from ethanol as yellow crystals 1.1 g (64%) yield,
m.p. 218◦C. IR: ν = 3440, 3340, 3210 cm−1(NH2, NH), 2950 cm−1(CH
aliphatic), 2220 cm−1(CN) and at 1710 cm−1 (CO). 1H NMR(DMSO-d6):
1.3 (t, 3H, CH3 ester), 2.6, 2.9 (2s, 6H, 2CH3 pyridine), 3.9(q, 2H, CH2
ester), 6.4(s, 2H, NH2) and 6.95 (s, 1H, CH-pyridine), 10.5 (NH).
Anal. calcd. for C15H16N6O2S(344.40): C, 52.31; H, 4.68; N, 24.40; S,
9.31%. Found: C, 52.14; H, 4.44; N, 24.63; S, 9.54%.
3-Amino-4,6-dimethylthieno[2,3-b]pyridine (11a)
This was prepared according to the literature.28
3-Amino-2,4,6-trimethylthieno[2,3-b]pyridine (11b)
This was prepared according to the literature.17
3-Chloroacetylamino-2-(H) or (CH3)-4,6-trimethylthieno
[2,3-b]pyridine(12a,b)
To a solution of compound 11a and/or 11b (0.01 mol) in dioxan (50 mL),
chloroacetyl chloride (0.01 mol) was added dropwise with stirring and
then heated on a steam bath at 50◦C for 1h. The reaction micture was
poured into cold water (400 mL) and neutralized with sod. carbonate
solution 10%. The solid product was collected and dried.

128
Y. A. El-Osaily et al.
12a; R = H; recrystallized from toluene as yellowish white crystals
1.99 g (78%), m.p. 180◦C.
1
IR: ν = 3250 cm−1(NH), 1690 (C O). H NMR (CDCl3): δ = 2.6, 2.8
(2s. 6H, 2CH3), 4.25 (s, 2H, CH2), 6.90(s, 1H, CH-thiophene), 7.1 (s, 1H,
CH-pyridine), 8.95 (s, 1H, NH).
Anal. calcd. for C11H11ClN2OS (254.74): C, 51.86; H, 4.35; Cl, 13.92;
N, 11.00; S, 12.59%. Found: C, 52.08; H, 4.12; Cl, 14.15; N, 10.82; S,
12.37%.
12b; R = CH3; recrystallized from toluene as yellowish white crystals
1.99 g (74%), m.p. 217–218◦C.
1
IR: ν = 3250 cm−1(NH), 1690 (C O). H NMR (CDCl3): δ = 2.4, 2.7,
2.9 (3s. 9H, 3CH3), 4.25 (s, 2H, CH2), 6.9 (s, 1H, CH-pyridine), 9.95 (s,
1H, NH).
Anal. calcd. for C12H13ClN2OS (268.76): C, 53.63; H, 4.88; Cl, 13.19;
N, 10.42; S, 11.93%. Found: C, 53.41; H, 5.06; Cl, 13.36; N, 10.63; S,
12.18%.
3-Aceylamino-4,6-dimethylthieno[2,3-b]pyridine or
3-Aceylamino-2,4,6-trimethylthieno[2,3-b] pyridine(13a,b)
A sample of compound 11 (0.005 mol) in acetic anhydride (20 mL) was
heated at 60◦C on a steam bath for 1 h, allowed to cool, poured into an
ice/water mixture (200 g), and then neutralized with aq. ammonia until
it became alkaline to litmus paper. The solid product was collected and
recrystallized from ethanol as white crystals.
13a, the product is 1.43 g (65%), m.p. 205◦C Lit.28 m.p. 205◦C.
13b, the product is 0.84 g (72%), m.p. 200◦C.
Anal. calcd. for C12H14N2OS (234.32): C, 61.51; H, 6.02; N, 11.96; S,
13.68%. Found: C, 61.72; H, 5.79; N, 12.20; S, 13.81%.
IR: ν = 3250 cm−1 (NH) and 1680 cm−1 (C O). 1H NMR (CDCl3): 2.4,
2.7, 2.9 (3s, 9H, 3CH3), 7.0 (s, 1H, CH-pyridine) and 10.5 (s, 1H, NH).
Pyridylmercaptoacetylaminothienopyridine 14a,b
A mixture of compound 12 (0.005 mol), 2-mercaptopyridine-3-
carbonitrile (0.01 mol), and sodium acetate (0.02 mol) in ethanol
(50 mL) was heated under reflux for 3 h, allowed to cool, filtered off,
washed well with water, and dried.
14a; R = H; the product was recrystallized from ethanol as white
crystals 1.3 g (68%), m.p. 203◦C.
1
IR: ν = 3260 cm−1 (NH), 2220 cm−1 (CN), and 1690 cm−1 (CO). H
NMR (CDCl3): δ = 2.6, 2.8 (4s. 12H, 4CH3), 4.25 (s, 2H, CH2), 6.9(s, 1H,
CH-thiophene), 7.05 (s, 2H, 2CH-pyridine), 8.95 (s, 1H, NH).

Reactions and Reactivity of Thienopyridines
129
Anal. calcd. for C19H18N4OS2 (382.51): C, 59.66; H, 4.74; N, 14.65; S,
16.77%. Found: C, 59.85; H, 4.98; N, 14.39; S, 17.00%.
14b; R = Me; the product was recrystallized from ethanol as yellow-
ish white crystals 1.29 g (65%), m.p. 237–239◦C.
1
IR: ν = 3310 cm−1 (NH), 2220 cm−1 (CN), and 1690 cm−1 (CO). H
NMR (CDCl3): δ = 2.3, 2.6, 2.8 (5s, 15H, 5CH3), 4.25 (s, 2H, CH2), 6.9
(s, 2H, 2CH-pyridine), 8.95 (s, 1H, NH).
Anal. calcd. for C20H20N4OS2 (396.54): C, 60.58; H, 5.08; N, 14.13; S,
16.17%. Found: C, 60.78; H, 4.88; N, 14.00; S, 16.38%.
3-Amino-4,6-dimethyl-2-N-[4,6-dimethylthieno[2,3-b]pyridine-
3-yl]thieno[2,3-b]pyridinecarbo-xamide (15a) and
3-Amino-4,6-dimethyl-2-N-[2,4,6-trimethylthieno[2,3-
b]pyridine-3-yl]-thieno[2,3-b]pyridine-carboxamide 15b
A sample of compound 14 (0.005 mol) in absolute ethanol (20 mL) con-
taining [0.005 mol] sod. ethoxide was refluxed for 1 h, and then allowed
to cool. The solid product was collected, washed with water, and recrys-
tallized from dioxin.
15a, produced as white crystals 1.37 g (72), m.p. > 300◦C.
1
IR: ν = 3450, 3350, 3180 cm−1 (NH2, NH) and 1670 cm−1 (CO). H
NMR (DMSO-d6):δ = 2.6, 2.8 (4s, 12H, 4CH3), 6.25 (s, 2H, NH2), 6.75 (s,
1H, CH-thiophene), 6.9 (s, 2H, 2CH-pyridine), 8.95 (s, 1H, NH).
Anal. calcd. for C19H18N4OS2 (382.51): C, 59.66; H, 4.74; N, 14.65; S,
16.77%. Found: C, 59.42; H, 4.52; N, 14.90; S, 16.61%.
15b, produced as white crystals 1.27 g (64%), m.p. > 300◦C.
IR: ν = 3400, 3300, 3220 cm−1 (NH2, NH) and 1670 cm−1 (CO). H
1
NMR (DMSO-d6):δ = 2.3, 2.6, 2.8 (5s, 15H, 5CH3), 6.3 (s, 2H, NH2), 6.9
(s, 2H, 2CH-pyridine), 8.95 (s, 1H, NH).
Anal. calcd. for C20H20N4OS2 (396.54): C, 60.58; H, 5.08; N, 14.13; S,
16.17%. Found: C, 60.33; H, 5.30; N, 13.89; S, 15.95%.
3-Alkyl(aryl)aminoacetylamino-4,6-dimethylthieno[2,3-
b]pyridine and 3-Alkyl(aryl)amino-2,4,6-trimethylthieno[2,3-b]
pyridine(16a–c)
A mixture of compound 12 (0.005 mol) and alkyl amine or aryl amine
(2 mol) was heated above their melting point for 30 min and then
ethanol (30 mL) was added, and the reflux was continued for an ad-
ditional hour. The solvent was evaporated under vacuum, and the
residue was washed with sodium carbonate solution (50 mL, 10%).
The solid product was collected and recrystallized from the proper
solvent.

130
Y. A. El-Osaily et al.
16a, R = H, R1, R2 = -(CH2)5-; produced 1.9 g (72), m.p. 195◦C.
IR: ν = 3330 cm−1 (NH), 1700 cm−1 (C O). 1H NMR(CDCl3): δ = 1.6
(m, 9H, 3CH2), 1.8 (m, 4h, 2CH2), 2.6, 2.8 (2s, 6H, 2CH3), 3.95(s, 2H,
CH2), 6.9 (s, 1H, CH-pyridine), 8.0(s, 1H, CH-thiophene), 9.95 (s, 1H,
NH).
Anal. calcd. for C16H21N3OS(303.42): C, 63.33; H, 6.98; N, 13.85; S,
10.57%. Found: C, 63.17; H, 6.78; N, 14.08; S, 10.37%.
16b, R = CH3, R1, R2 = -(CH2)5-; produced 1.1 g (70%), m.p. 133–
135◦C.
1
IR: ν = 3270 cm−1 (NH), 1680 cm−1 (C O). H NMR(CDCl3: δ = 1.5
(m, 9H, 3CH2), 2.3 (m, 4H, 2CH2), 2.2 (s, 3H, CH3), 2.6, 2.9 (2s,
6H, 2CH3), 3.6(s, 2H, CH2), 6.9 (s, 1H, CH-pyridine), 9.95 (s, 1H,
NH).
Anal. calcd. for C17H23N3OS(317.45): C, 64.32; H, 7.30; N, 13.24; S,
10.10%. Found: C, 64.08; H, 7.11; N, 13.43; S, 9.88%.
16c, , R = H, R1, R2 = -(CH2)4O-; produced 1.16 g (76), m.p. 193–
195◦C.
Anal. calcd. for C15H19N3O2S(305.40): C, 58.99; H, 6.27; N, 13.76; S,
10.50%. Found: C, 59.22; H, 6.03; N, 14.00; S, 10.37%.
IR: ν = 3250 cm−1 (NH), 1690 cm−1 (C O). 1H NMR(CDCl3): δ = 2.7
(m, 4H, 2CH2), 3.1 (m, 4H, 2CH2), 2.6, 2.9 (2s, 6H, 2CH3), 3.99(s, 2H,
CH2), 6.85(s, 1H, CH-thiophene), 6.95 (s, 1H, CH-pyridine), 9.95 (s, 1H,
NH).
4,6-Dimethy-3-[2-amino-3-cyano-5-oxopyrrolidin-1-yl]thieno
[2,3-b]pyridine(17a) and 2,4,6-Trimethyl-3-[2-amino-3-cyano-5-
oxopyrrolidin-1-yl]thieno[2,3-b]pyridine(17b)
A mixture of compound 12 (0.005 mol) and malononitrile (0.33 g,
5 mmol) in ethanol (20 mL) containing sod. ethoxide (0.005 mol) was
heated under reflux for 4 h, allowed to cool, and poured into water
(100 mL). The solid product was collected and recrystallized from
ethanol.
17a; produced 0.94 g (66%), m.p. 175◦C.
1
IR: ν = 3360, 3260 cm−1(NH2), 2220 cm−1 (CN), 1670 cm−1(CO). H
NMR(DMSO-d6): δ = 2.6, 2.9 (2s, 6H, 2CH3), 3.8 (s, 2H, CH2), 6.4 (s, 2H,
NH2), 6.9 (s, 1H, CH-thiophene), 7.0 (s, 1H, CH-pyridine).
Anal. calcd. for C14H12N4OS(284.34): C, 59.14; H, 4.25; N, 19.70; S,
11.28%. Found: C, 58.90; H, 4.01; N, 19.93; S, 11.51%.
17b; produced 0.92 g (62%), m.p. > 300◦C.
IR: ν = 3390, 3290 cm−1 (NH2), 2220 cm−1 (CN), 1670 cm−1 (CO). 1H
NMR(DMSO-d6): δ = 2.4, 2.6, 2.9 (3s, 9H, 3CH3), 3.8 (s, 2H, CH2), 6.4
(s, 2H, NH2), 6.9 (s, 1H, CH-pyridine).

Reactions and Reactivity of Thienopyridines
131
Anal. calcd. for C15H14N4OS(298.37): C, 60.38; H, 4.73; N, 18.78; S,
10.75%. Found: C, 60.53; H, 4.50; N, 18.61; S, 11.00%.
3-Aceylamino-2-bromomethyl-4,6-dimethylthieno
[2,3-b]pyridine (18)
To a solution of compound 13b (1.17 g, 0.005 mol) in acetic acid
(30 mL), bromine (0.8 g, 5 mmol) in acetic acid (10 mL) was added
dropwise during 10 min. The stirring was continued for 1 h. The solid
product was collected, dissolved in water (100 mL), and neutralized
with sodium carbonate solution (10%). The solid product was filtered
off and recrystallized from pet. ether 60–80◦C as white crystals 1.0 g
(65%), m.p. 72◦C.
1
IR: ν = 3260 cm−1 (NH), 1670 cm−1 (CO). H NMR (CDCl3): δ = 2.3,
2.6, 2.9 (2s, 6H, 2CH3), 4.3 (s, 2H, CH2Br), 6.9 (s, 1H, CH-pyridine),
9.95 (s, 1H, NH).
Anal. calcd. for C12H13BrN2OS (313.21): C, 46.02; H, 4.18; Br, 25.51;
N, 8.94; S, 10.24%. Found: C, 45.79; H, 4.33; Br, 25.28; N, 9.18; S, 10.00%.
3-Aryledineamino-2,4,6-trimethylthieno[2,3-b]pyridine (19)
A mixture of compound 11b (0.96 g, 5 mmol) and aromatic aldehyde
(0.005 mol) in ethanol (20 mL) was refluxed for 5 h and then allowed to
cool. The solid product was collected and recrystallized from ethanol.
19a; produced 1.17 g (72%), m.p. 172–174◦C.
IR: ν = 3050 cm−1 (CH aromatic), 2950 cm−1 (CH aliphatic), 1630
cm−1 (C N). 1H NMR (CDCl3): 2.4, 2.7, 3.0 (3s, 9H, 3CH3), 7.05 (s, 1H,
CH-pyridine), 7.7, 7.9 (2d, 4H, CH-aromatic) and 8.6 (s, 1H, -CH N).
Anal. calcd. for C17H15N3O2S(325.39): C, 62.75; H, 4.65; N, 12.91; S,
9.85%. Found: C, 62.58; H, 4.87; N, 13.14; S, 10.08%.
19b; produced 1.11 g (69%), 220◦C.
IR: ν = 3050 cm−1 (CH aromatic), 2950 cm−1 (CH aliphatic),
1
1630 cm−1 (C N). H NMR(CDCl3): 2.4, 2.6, 2.9 (3s, 9H, 3CH3), 3.0
(s, 6H, 2CH3), 6.95 (s, 1H, CH-pyridine), 7.3, 7.5 (2d, 4H, CH-aromatic)
and 8.4 (s, 1H, -CH N).
Anal. calcd. for C19H21N3S(323.46): C, 70.55; H, 6.54; N, 12.99; S,
9.91%. Found: C, 70.33; H, 6.87; N, 13.20; S, 10.12%
19c; produced 1.16 g (74%), m.p.
IR: ν = 3050 cm−1 (CH aromatic), 2950 cm−1 (CH aliphatic), 1630
cm−1 (C N). 1H NMR(CDCl3): 2.35, 2.6, 2.9 (3s, 9H, 3CH3), 6.95 (s, 1H,
CH-pyridine), 7.3, 7.5 (2d, 4H, CH-aromatic) and 8.4 (s, 1H, -CH N).
Anal. calcd. for C17H15ClN2SS(314.84): C, 64.86; H, 4.80; Cl, 11.26; N,
8.90; S, 10.18%. Found: C, 65.08; H, 5.03; Cl, 11.03; N, 9.12; S, 10.00%.

132
Y. A. El-Osaily et al.
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