Alkyl heterocycles in heterocyclic synthesis (II): Novel synthesis of isoquinoline, thiazolopyridine, and thieno[2,3-b]pyridine derivatives

Article abstract of DOI:10.1002/jhet.5570410614

Treating 5-(4-phenylcarboxamido)-3-cyano-4-methylpyridin-2(1H)thione (3) with elemental sulfur yielded thienopyridine 4. Compound 4 reacts with acrylonitrile to give isoquinoline 7. Compound 7 was also, prepared from 3 and methylenemalononitrile. Reaction of 3 with dimethylacetylene dicarboxylate (DMAD) gave the pyridothiazole 9. Also, 3 reacted with N,N- dimethylchloroacetamide (10) to afford compound 11 which further reacted with the reagents 12, 13 and 14 providing the thieno[2,3-b]pyridine derivatives 15, 16 and 17 respectively.

Full text of DOI:10.1002/jhet.5570410614

Nov-Dec 2004
947
Alkyl Heterocycles in Heterocyclic Synthesis (II): Novel Synthesis of
Isoquinoline, Thiazolopyridine, and Thieno[2,3-b]pyridine Derivatives
*
Tarek M. Abu Elmaati
Department of Textile Printing & Dyeing, Faculty of Applied Arts, Damietta, Mansoura University, Egypt
Email.tasaid@hotmail.com
Received February 28, 2004
Treating 5-(4-phenylcarboxamido)-3-cyano-4-methylpyridin-2(1H)thione (3) with elemental sulfur
yielded thienopyridine 4. Compound 4 reacts with acrylonitrile to give isoquinoline 7. Compound 7 was
also, prepared from 3 and methylenemalononitrile. Reaction of 3 with dimethylacetylene dicarboxylate
(DMAD) gave the pyridothiazole 9. Also, 3 reacted with N,N-dimethylchloroacetamide (10) to afford com-
pound 11 which further reacted with the reagents 12, 13 and 14 providing the thieno[2,3-b]pyridine deriva-
tives 15, 16 and 17 respectively.
J. Heterocyclic Chem., 41, 947 (2004).
Alkylheterocycles are versatile reagents and can be uti-
Compound 3 reacted with elemental sulfur in ethanolic
triethylamine solution to yield the thienopyridine 4
(61%). Compound 4 was found to be highly reactive
toward activated double bond systems. Thus, the product
of addition and hydrogen sulfide elimination was
obtained upon reacting 4 with acrylonitrile in dioxane
under reflux conditions with acetic acid catalyst.
Structure 7 (65%) was assigned as a reaction product
based on correct elemental composition and spectral data.
Compound 7 was also synthesized via reacting 3 with
methylenemalononitrile in ethanol containing a catalytic
amount of piperidine (cf. Scheme 2).
Reaction of 2(1H)-pyridinethiones with dimethyl-
acetylene dicarboxylate (DMAD) is known to give thia-
zolo[3,2-a]pyridinium salts. At the same time, the reac-
tion of 2(1H)-pyridinethiones with methyl propynoate
results in acyclic condensation products [10,11]. By anal-
ogy with the reaction of malonothioamide and with the
chemistry of the 5-mercaptoazoles [12], one can expect
the formation of both pyridothiazine 8 and pyridothiazole
of type 9 from the reaction of compound 3 with DMAD.
It has been found that the reaction of pyridinethione 3
with DMAD in chloroform in the presence of triethyl
amine selectively affords thiazolo[3,2-a]pyridine 9 in
good yield. The structure assignment of the compound
lized in synthesis of polyfunctionally substituted benzo[c]-
coumarine, benzo[c]pyrano[3,2-c]quinoline and pyridopy-
ridazine derivatives [1-7]. These heterocycles are interest-
ing as potential biodegradable agrochemicals [1-4,6],
pharmaceuticals and intermediates for the preparation of
dyes [6]. In the past decade, our research group was
involved in a program to develop new synthetic routes to
polyfunctionally substituted heteroarenes using methyl-
azinylcarbonitriles as starting compounds [8,9].
In continuation to this interest, we report here the util-
ity of 3-cyano-4-methylpyridin-2(1H)one derivative 3 as
starting material to prepare polyfunctional substituted
isoquinoline, pyridothiazole and thieno[2,3-b]pyridine
derivatives. Thus, it has been found that 1-(N-p-
chlorophenyl)-2-(N-dimethylaminomethino)-3-oxobu-
tanamide [8] (1) was condensed with cyanothioacetamide
in ethanol/sodium ethoxide to yield 3 (68%). The pyri-
dine structure 3 is supported from its elemental composi-
tion and spectral data.
1
prepared follows from its NMR spectrum. The H NMR
spectrum of 9 shows a signal at 6.68 ppm. This is in
accordance with the presence of an exocyclic double
bond in the structure.
Thieno[2,3-b]pyridines are known for their anti-allergic
activity in the passive coetaneous anaphylaxis [13,14] and
as starting materials for tricyclic heterocycles. Thus, com-
pound 3 was reacted with N,N-chloroacetamide (10) to
give the target compound 11 in a one pot reaction via a car-
boxamidomethylthio derivative as intermediate (cf.
Scheme 4).

948
T. M. Abu Elmaati
Vol. 41
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded in
1
KBr disks using a Shimadzu IR-740 spectrophotomter. H and
13
C NMR spectra were recorded on a Bruker AC-300 spectrome-
2
ter with [ H ] DMSO as solvent and TMS as internal standard;
6
chemical shifts are reported in ppm (δ). Mass spectra were mea-
sured on GC/MS INCOS XL Finnigan MAT. Microanalysis were
performed on LECOCHNS-932
Reaction of 1 with Cyanothioacetamide: Formation of 5-(4-
Phenylcarboxamido)-3-cyano-4-methylpyridin-2(1H)thione (3).
A mixture of compound 1 (2.32 g, 0.01 mol) and cyanothioac-
etamide (1.0 g, 0.01 mol) in ethanolic sodium ethoxide (30 mL)
was refluxed for 30 min. The reaction mixture was poured into
water and acidified with dil. HCl. The precipitate formed was
collected by filtration and crystallized from ethanol to give com-
pound 3. Compound 3 was obtained as yellow crystals; mp 235
1
°C; yield 68 %; IR: ν
3322, 3200 (NH); 2220 (CN); H-NMR
max
2
([ H ] DMSO): δ 1.71 (s, 3 H, CH ); 7.00-7.64 (m, 5 H, arom-
H); 8.2 (s, 1 H, CH); 9.2 (s, 1 H, NH); 14.2 (br s, 1H, NH); C-
NMR([ H ] DMSO): δ 185.8 (thioamide), 163.8 (CO-amide);
6
H
3
13
2
6
C
135.2, 128.7, 128.7, 124.1, 120.4, 120.4 (aromatic-carbons);
167.5, 143.1, 116.6, 107.8 (vinyl-carbons); 117.2 (CN); 12.00
Other ways for the synthesis of the title compounds
were the aminolysis of compound 11 with morphline-4-
caboxaldehyde (12) and dimethylformamide (13) as well
as the reaction of compound 11 with 2,5-dimethoxyte-
trahydrofuran (14) to give the thieno[2,3-b]derivatives 15,
16 and 17 respectively (cf. Scheme 4).
(CH ); MS (m/z) 269.
3
Anal. Calcd. For C H N OS (269.32): C, 62.43; H, 4.12; N,
14 11
3
15.60. Found: C, 62.80; H, 4.16; N, 15.65.
3-Amino-4-(4-phenylcarboxamido)thienopyridine-2(1H)thione
(4).
A solution of compound 3 (2.69 g, 0.01 mol) in DMF (10 mL)
was treated with elemental sulfur (0.32 g, 0.01 mol) and piperi-
dine (0.2 mL). The reaction mixture was refluxed for 4 h, then
poured into water, the solid product, so formed, was collected by
filtration and crystallized from ethanol-DMF. Compound 4 was
In conclusion, this paper describes a novel one pot syn-
thesis of isoquinoline, thiazolopyridine and thieno[2,3-
b]pyridine derivatives using inexpensive and readily
obtainable starting materials.

Nov-Dec 2004
Alkyl Heterocycles in Heterocyclic Synthesis (II)
949
obtained as brown crystals; mp 275 °C; yield 61%; IR: ν
cool to rt, poured into ice-cold water, and neutralized with HCl
(10 %). The solid product was collected by filtration and crystal-
lized from ethanol. Compound 7 was obtained as brown crystals;
max
1
2
3400, 3280 (NH and NH); 1680 (CO); H-NMR ([ H ] DMSO):
2
6
δ
6.4 (s, 1 H, thiophene-H); 7.00-8.3 (7 H, arom-H and NH );
H
2
13
8.18 (s, 1 H, CH); 9.24 (s, 1 H, NH); 12.4 (br s, 1 H, NH). C-
NMR ([ H ] DMSO): δ 195.1 (thioamide), 163.8 (CO); 138.2,
mp 300 °C; yield 65 %; IR: ν
3448, 3290 (NH and NH);
max
2
2
1
2
2221 (CN) and 1660 (CO); H-NMR ([ H ] DMSO): δ 6.16 (s,
6
C
6
H
120.4, 128.7, 124.1, 128.7, 120.4 (aromatic-carbons); 122.1,
133.3, 142.0, 138.2 (thiophene-carbons); 117.5 (vinyl-carbon);
MS (m/z) 301.
1 H, CH); 6.8-7.1 (m, 6 H, arom-H and NH ), 7.33(d, 1H, CH),
2
7.46(d, 1H, CH), 8.34 (s, 1 H, CH); 9.40 (br s, 1 H, NH); 12.21
13
2
(br s, 1H, NH); C-NMR ([ H ] DMSO): δ 195.5 (thioamide),
6
C
Anal. Calcd. for C H N OS (301.39): C, 55.79; H, 3.68; N,
164.2(CO-amide), 148.9, 136.3, 136.2, 135.1, 129.4, 129.1,
129.1, 121.8, 121.8, 118.5, 117.0, 98.4 (aromatic-carbons),
126.1, 117.4 (vinyl-carbons), 116.2 (nitrile-carbon); MS (m/z)
320.37.
14 10
3
2
13.94. Found: C, 55.40; H, 4.10; N, 13.82.
Preparation of 3-Amino-7-(phenylcarboxamido)-4-cyanoiso-
quinoline-2(1H)thione (7).
Anal. Calcd. for C H N OS (320.37): C, 63.73; H, 3.78; N,
17 12
4
Method A.
17.49 %. Found: C, 63.70; H, 3.42; N, 17.42
A mixture of compound 4 (3.01 g, 0.01 mol) and (0.65 g, 0.01
mol) of acrylonitrile in dioxane (30 mL) was heated under reflux
for 6 hours. The reaction mixture was cooled and the solvent
evaporated in vacuo to give a solid product that was collected by
filtration and recrystallized from ethanol/DMF.
Reaction of Compound 3 with DMAD: Formation of Methyl (8-
Cyano-7-methyl-3-oxo-6-phenylcarbamoyl-8aH-thiazolo[3,2-a]-
pyridine-2-ylidine)acetate (9).
The acetylenecarboxylic ester (0.0015 mol) was added to a sus-
pension of compound 3 (2.69 g, 0.001 mol) in chloroform with tri-
ethylamine (0.001 mol). The reaction mixture was stirred at room
temperature for 1-3 h until, according to TLC, all the starting
material had disappeared. On cooling, a precipitate was formed,
which was collected by filtration and crystallized from methanol
Method B.
In a 100 ml flask, a solution of compound 3 (2.69g, 0.01 mol)
in pyridine (30 mL) was treated with methylenemalononitrile
(0.01 mol). The reaction mixture was refluxed for 4-6 h, left to

950
T. M. Abu Elmaati
Vol. 41
to afford compound 9 as yellow crystals, mp> 300 °C; yield 50 %;
Compound 16 was obtained as brown crystals from dioxan, mp
IR: ν
3448 (NH); 2221 (CN), 1710 (CO-ester) and 1660 (CO-
275 °C; yield 63 %; IR: ν
3548 (NH); 1700, 1685 (CO-
max
max
1
2
1
2
amide); H-NMR ([ H ] DMSO): δ 2.30 (s, 3 H, CH ); 3.81 (s, 3
amide); H-NMR ([ H ] DMSO): δ 2.22 (s, 3 H, CH ); 3.41 (s,
6
H
3
6 H 3
H, OCH ), 4.76 (s, 1H, CH), 6.68 (s, 1H, C H), 7.25-7.60 (m, 5
6 H, 2 NCH ), 7.00-7.50 (m, 5 H, arom. H), 8.20 (s, 1H, CH),
9.32 (br s, 1 H, NH); (m/z) 411.
3
(5)
3
13
H, arom. H), 8.2 (s, 1H, CH), 9.40 (br s, 1 H, NH); C-NMR
2
([ H ] DMSO): δ 166.2(CO), 138.2, 128.7, 128.7, 124.1, 120.4,
Anal. Calcd. for C H N O S (411.52); C, 61.29; H, 6.12; N,
6
C
21 25
5 2
120.4 (aromatic-carbons), 143.1, 113.7 (vinyl-carbons), 52.3
(OCH ), 11.6 (CH ), 119.2 (CN); MS (m/z) 381.
17.02 %. Found: C, 61.23; H, 6.00; N, 17.12.
3
3
4-Methyl-3-pyrrol-1-yl-4,7-dihydrothieno[2,3-b]pyridine-2,5-
dicarboxylicacid-2-dimethylamide-5-phenylamide (17).
Anal. Calcd. For C H N O S (381.41): C, 59.83; H, 3.96; N,
19 15
3 4
11.02 %. Found: C, 60.00; H, 3.91; N, 11.12.
Compound 17 was obtained as yellow crystals from
Reaction of Compound 3 with N,N-Dimethylchloroacetamide:
Formation of Compound 11.
EtOH/DMF, mp > 300 °C; yield 60 %; IR: ν
3548 (NH);
max:
1
2
1700, 1685 (CO-amide); H-NMR ([ H ] DMSO): δ 2.22 (s, 3
6
H
To a solution of compound 3 (2.65 g, 0.01 mol) in methanol
(30 ml) containing sodium methoxide was added 0.01 mol of
compound 10. The mixture was heated under reflux for 1 h. After
cooling, the reaction mixture was poured into ice-cold water. The
solid product deposited was collected by filtration and crystal-
lized from ethanol to afford compound 11 as yellow crystals, mp
H, CH ); 3.41 (s, 6 H, 2 N-CH ), 7.00-7.50 (m, 5 H, arom. H),
8.20 (s, 1H, CH), 9.32 (br s, 1 H, NH); MS (m/z) 406.
3
3
Anal. Calcd. for C H N O S (406.50): C, 65.00; H, 5.46; N,
22 22
4 2
13.78 %. Found: C, 65.13; H, 5.33; N, 13.72.
REFERENCES AND NOTES
220 °C; yield 60 %; IR: ν
(CO-amide); H-NMR ([ H ] DMSO): δ 2.30 (s, 3 H, CH );
3448, 3330 (NH , NH); 1700, 1680
max
2
1
2
6
H
3
[1] E. A. Hafez, M. H. Elnagdi, A. A. Elagamey and F. M. A.
El-Taweel, Heterocycles, 26, 903 (1987).
[2] F. A. Abu- Shanab, B. Wakfield, F. Al-Omran, M. M.
Abdel Khalek and M. H. Elnagdi, J. Chem. Res., (S) 488, (M) 2924
(1995).
3.51 (s, 6 H, 2 N-CH ), 7.00-7.50 (m, 5 H, arom. H), 8.19 (s, 1H,
3
CH), 9.30 (br s, 1 H, NH); MS (m/z) 356.44.
Anal. Calcd. for C H N O S (356.44): C, 60.65; H, 5.66; N,
18 20
4 2
15.72 %. Found: C, 60.50; H, 5.61; N, 15.62.
General Procedure for the Reaction of Compound 11 with
Compounds 12, 13 and 14: Formation of Compounds 15, 16 and
17.
[3] H. Al-Awadhi, F. Al-Omran, M. H. Elnagdi, L. C. Infants,
C. Foces-Foces, N. Jagerovic and J. Elguero. Tetrahedron, 51, 12745
(1995).
[4] A. H. H. Elghandour, A. M. Hussein, M. H. Elnagdi, A. A.
Harb and S. A. Metwally J. Prakt. Chem., 334, 723 (1992).
[5] M. H. Mohamed, M. M. Abdel-Khalik and M. H. Elnagdi,
J. Heterocyclic Chem., 38, 685 (2001).
[6] S. Z. A. Swellim, F. M.A. El-Taweel and A. A. Elagamey,
Bull. Soc. Chim. Fr., 133, 229 (1996).
[7] A. M. Hussein, A. A. Atalla, A. M. Kamal El-Dean,
Pharmazie, 50, 788 (1995).
[8] T. M. Abu Elmaati and S. B. Said, N. S. Abu Elenein, M.
A. Sofan and M. N. Khodeir, Polish J. Chem., 76, 945 (2002).
[9] T. M. Abu Elmaati and F. M. A. El-Taweel, J. Chin. Chem.
Soc., 49, 1045 (2002).
To a solution of compound 11 (3.56 g, 0.01 mol) in POCl (15
3
ml) was added 0.01 mol of, as appropriate, reagents 12, 13 and 14.
The reaction mixture was heated under reflux for 2 h. After cool-
ing, the reaction mixture was poured into ice-cold water and then
neutralized with ammonia solution. The precipitate formed was
collected by filtration and crystallized from the proper solvent.
4-Methyl-3-[morphlino-4-ylmethylene)-amino]-4,7-dihydroth-
ieno[2,3-b]pyridine-2,5-dicarboxylic acid 2-dimethylamide-5-
phenylamide (15).
Compound 15 was obtained as yellow crystals from
[10] J. Becher and C. C. Stiden, Sulfur Reports, 8, 105 (1988).
[11] R. Lie and K. Undheim, Acta Chem. Scand., 27, 1756
(1973).
EtOH/DMF, mp 280 °C; yield 65 %; IR: ν
3548 (NH); 1700,
max:
1
2
1685 (CO-amide); H-NMR ([ H ] DMSO): δ 2.22 (s, 3 H,
6
H
CH ); 3.41 (s, 6 H, 2 NCH ), 7.00-7.50 (m, 5 H, arom. H), 8.20
3
3
[12] V. A.
Bakulev, V. S. Berseneva, N. P. Belskaia, Y. Y.
(s, 1H, CH), 9.32 (br s, 1 H, NH); MS (m/z) 453.
Anal. Calcd. For C H N O S (453.56): C, 60.91; H, 6.00;
Morzherin, A. Zaitsev, W. Dehaen, I Luyten and S. Tuppet, Org
Biomol. Chem., 1, 134 (2003).
[13] G. Wagner, H. Vieweg, S. Leistner, N. Bohm, U. Krasselt,
V. Hanfeld, J. Prantz and R. Grupe, Die Pharmazie, 45, 102 (1990).
[14] G. Wagner, H. Vieweg and S. Leistner, Die Pharmazie, 48,
464 (1993).
23 27
5 3
N, 15.44 %. Found: C, 60.83; H, 5.98; N, 15.42.
3-(Dimethylaminomethyleneamino)-4-methyl-4,7-dihydro-
thieno[2,3-b]pyridine-2,5-dicarboxy-2-dimethylamide-5-phenyl-
amide (16).