Studies with polyfunctionally substituted heterocycles: Syntheses of polyfunctionally substituted isoquinolines

Article abstract of DOI:10.1023/A:1022126409122

The three-component reaction of acetaldehyde, cyanothioacetamide, and malononitrile results in 6-amino-3,5-dicyano-4-methylpyridine-2(1H)-thione. The latter reacts with different chemical reagents to afford new substituted isoquinolines and their fused derivatives, which show high fungicidal and bactericidal activities.

Full text of DOI:10.1023/A:1022126409122

Chemistry of Heterocyclic Compounds, Vol. 38, No. 11, 2002
STUDIES WITH POLYFUNCTIONALLY
SUBSTITUTED HETEROCYCLES:
SYNTHESES OF POLYFUNCTIONALLY
SUBSTITUTED ISOQUINOLINES
Yehya M. Elkholy
The three-component reaction of acetaldehyde, cyanothioacetamide, and malononitrile results in
6-amino-3,5-dicyano-4-methylpyridine-2(1H)-thione. The latter reacts with different chemical reagents
to afford new substituted isoquinolines and their fused derivatives, which show high fungicidal and
bactericidal activities.
Keywords: electrophilic reagents, isoquinoline, pyridinethiones, thieno[3,4-c]pyridine.
Alkylazinylcarbonitriles are important building blocks in synthetic heterocyclic chemistry, and their
utility for the preparation of condensed azines has been reported recently [1-10]. In continuation of our research
in this area, we report here results that enabled us to develop several new efficient syntheses for differently
substituted isoquinolines and thieno[3,4-c]pyridines.
RESULTS AND DISCUSSION
Pyridinethione 1 was prepared via the three-component reaction of acetaldehyde, malononitrile, and
cyanothioacetamide. The structure of the reaction product could be established via inspection of its mass, IR,
and 1H NMR spectra (see Experimental).
Me
CN
CH2
CN
CH2
CN
S
NC
MeCHO
+
+
C
NC
H2N
CN
CSNH2
Me
Me
NC
H2N
CN
S
NC
–H2
CN
S
N
H
1
H2N
N
H
__________________________________________________________________________________________
Department of chemistry, Faculty of Science, Helwan University, AinHewan, Cairo-Egypt; e-mail:
y_elkholy@yahoo.com. Published in Khimiya Geterotsiklicheskikh Soedinenii, No. 11, pp. 1525-1530,
November, 2002. Original article submitted February 8, 2001.
1342
0009-3122/02/3811-1342$27.00©2002 Plenum Publishing Corporation

The methyl group in the pyridinethione 1 is highly active towards electrophilic reagents. Thus,
compound 1 reacted readily with benzylidenemalononitrile to yield a 1:1 adduct which may be formulated as 2,
1
3, or 4. The "acyclic" structure 2 was ruled out based on the H NMR spectrum since the latter revealed the
absence of any multiplet for protons linked to sp3 carbon atoms which might be expected for such adducts. The
two isomeric forms 3 and 4 are expected to have almost the same 1H NMR spectra. Structure 4 was established
for the reaction product based on the chemical evidence: the substance reacted with phenacylbromide to yield
the thienoisoquinoline derivative 5 which was also obtained via reacting the thienopyridine derivative 6 with
benzylidenemalononitrile (Scheme 1).
Scheme 1
Ph
CN
CN
NC
NH
Ph
H2N
N
H
S
CN
CN
Ph
CN
CN
3
NC
1
CN
–HCN
PhCOCH2Br
H2N
N
H
S
Ph
NC
Me
2
NH2
NC
CN
S
HN
H2N
S
COPh
H2N
N
6
N
H
Ph
4
NC
CN
CN
Ph
NH2
COPh
PhCOCH2Br
HN
H2N
S
N
5
Although in 1 the cyano group at C(3) is expected to be more reactive than the one at C(5), cyclization
took place at the latter CN perhaps as hydrogen bonding between NH and NH2 in structure 4 is more efficient in
stabilizing the system than the hydrogen bonding that is expected to happen between the C=NH and C=S group
in structure 3.
The pyridinethione 1 reacted with sulfur to yield a product that may be formulated as 7 or isomeric 8.
Structure 8 was considered for the reaction product as its reaction with phenacylbromide gave compound 9
which has been obtained via treatment of thieno[2,3-b]pyridine 6 with sulfur. Spectral data are in agreement
with the proposed structure 8.
S
S
S
NH2
NC
H2N
H2N
NH2
CN
S
H2N
N
H
S
S
COPh
H2N
N
8
H2N
N
7
9
1343

Thieno[3,4-c]pyridine 8 reacted with acrylonitrile to yield a product of addition and H2S elimination.
This reaction product may be formulated as 10 or regioisomeric 11 which is assumed to be formed via adduct
12. Structure 11 has been confirmed as the correct one by its synthesis via reaction of pyridinethione 1 with
paraformaldehyde and malononitrile in the presence of a base. We assumed that ethylidenemalononitrile is first
formed and then adds to 1 to form an intermediate Michael adduct 13 that is spontaneously cyclized to
intermediate 14 which undergoes aromatization with elimination of hydrogen cyanide to yield the isoquinoline
11 (Scheme 2). The structure of 11 is supported by its spectral data.
Scheme 2
NC
S
paraformaldehyde
CH2(CN)2
CN
N=C
CN
S
1
8
B
H2N
N
H
CN
S
13
CN
B
CN
SH
H2N
H2N
CN
SH
NC
H2N
H2N
N
N
10
12
– H2S
CN
SH
H
H
NC
NC
NC
+
H
H2N
H2N
CN
SH
HN
– HCN
N
H2N
N
11
14
Acylation of thieno[3,4-c]pyridine 8 with acetic anhydride afforded the diacetyl derivative 15. The latter
reacted with maleic anhydride to yield 16 via Diels-Alder addition to the thiophene fragment as diene and
subsequent H2S elimination.
O
1
2
O
S
O
CN
MeCOHN
CN
MeCOHN
N
SH
MeCOHN
MeCOHN
N
SH
15
16
1344

TABLE 1. In Vitro Batericidal and Fungicidal Activity of Some of the
Newly Synthesized Compounds
Com-
pound
Staph.
B. Cerceus
E. Coli
P. Aeruginosa
A. Niger
C. Albicans
Aureus
+
+++
+++
++
+++
—
++
++
—
+
++
+++
++
—
++
++
++
++
—
++
+
—
++
—
+
+++
+++
+++
+++
++
+++
++
+++
++
+++
+++
+++
1
4
++
—
—
—
++
—
—
++
—
—
—
—
—
—
++
—
5
6
8
9
11
15
16
+
_______
Slight effect = +, moderate effect = ++, severe effect = +++, complete effect
= ++++. Rating percent control: no effect = 0; slight effect = 10, 20, 30;
moderate effect = 40, 50, 60; severe effect = 70, 80, 90; complete
effect = 100.
BIOLOGICAL ACTIVITY
The diverse biological activities of isoquinoline and its fused derivatives prompted us to test and study
the biological activities of some of the newly synthesized products. The bactericidal and fungicidal activities
were studied. The bactericidal effect was determined using the Gütter technique, while the antifungal effect was
determined turbidimetrically [11, 12]. Table 1 shows that most of the tested compounds had high activity.
EXPERIMENTAL
All melting points are uncorrected. IR spectra were recorded (KBr) with a Perkin-Elmer 1430
spectrophotometer.1H NMR spectra were obtained on a Varian EM-390 MHz (390 MHz) spectrometer in
DMSO-d6 using Me4Si as internal standard, and chemical shifts are expressed as δ ppm. Analytical data were
obtained from the analytical data unit at Cairo University.
Compound 1 was prepared following literature procedure [13].
6-Amino-4-methyl-2-thioxo-1,2-dihydropyridine-3,5-dicarbonitrile
(1).
A
solution
of
cyanothioacetamide (3 g, 0.03 mmol), malononitrile (1.9 g, 0.03 mmol), and acetaldehyde (1.4 g, 0.03 mmol) in
ethanol (20 ml) with a few drops of piperidine was refluxed for 30 min. The mixture was diluted with water, and
the solid product formed was collected by filtration and crystallized from ethanol as orange crystals (yield 1 g,
52%); mp 280°C. IR spectrum, ν, cm-1: 3450-3330 (NH2 and NH), 2222, 2220 (2CN). H NMR spectrum,
1
δ, ppm: 2.41 (s, 3H, CH3); 3.50 (br, 2H, NH2); 12.79 (s, 1H, NH). MS, m/z: 190 (M+). Found, %: C 50.41;
H 3.01; N 29.39; S 16.75. C8H6N4S. Calculated, %: C 50.51; H 3.17; N 29.45; S 16.85.
1-Amino-8-imino-2,3,7,8-tetrahydro-3-thioxoisoquinolino-4,7,7-tricarbonitrile (4). To a solution of
thione 1 (1.9 g, 0.01 mmol) in ethanol (30 ml), benzylidenemalononitrile (1.5 g, 0.01 mmol) and a catalytic
amount of piperidine were added. The reaction mixture was refluxed for 3 h. The precipitate formed on dilution
with water was collected by filtration and crystallized from dioxane as yellow crystals (yield 1 g, 32%);
mp >300°C. IR spectrum, ν, cm-1: 3400-3300 and 3220 (NH2 and NH); 2220 (CN). 1H NMR, spectrum, δ, ppm:
1345

3.51 (br, 2H, NH2); 7.15-7.67 (m, 7H, aromatic protons); 8.72 (s, 1H, NH); 10.10 (s, 1H, NH). MS, m/z 317
(M+). Found, %: C 64.59; H 3.20; N 22.32; S 9.81. C17H11N5S. Calculated, %: C 64.34; H 3.49; N 22.06;
S 10.10.
c
1,5-Diamino-2-benzoyl-6-imino-5-phenyl-6,7-dihydrothieno[2,3- ]isoquinoline-7-carbonitrile (5).
To a solution of 4 (3.42 g, 0.01 mmol) in dioxane (20 ml), phenacylbromide (1.89 g, 0.01 mmol) and a catalytic
amount of triethylamine were added. The reaction mixture was refluxed for 3 h and poured into ice water. The
solid product was crystallized from ethanol as yellow crystals (yield 2.9 g, 62%); mp 215°C. IR spectrum,
ν, cm-1: 3400-3300 (NH2 and NH), 2220 (CN). Found, %: C 68.71; H 3.45; N 16.19; S 6.85. C25H17N5OS.
Calculated, %: C 68.95; H 3.94; N 16.09; S 7.35.
b
A solution of
3,6-Diamino-2-benzoyl-4-methylthieno[2,3- ]pyridine-5-carbonitrile (6).
1
(1.9 g,
0.01 mmol) in dioxane (20 ml) containing phenacyl bromide (1.8 g, 0.01 mmol) and several drops of
triethylamine was refluxed for 3 h and poured into ice water. The solid product was collected by filtration and
crystallized from ethanol as yellow crystals (yield 1.2 g, 63%); mp >300°C. IR spectrum, ν, cm-1: 3400-3300
(NH2 and NH); 2220 (CN); 1720 (CO). Found, %: C 62.22; H 3.82; N 18.10; S 10.30. C16H12N4OS.
Calculated, %: C 62.32; H 3.93; N 18.18; S 10.38.
c
3,4-Diamino-6-mercaptothieno[3,4- ]pyridine-7-carbonitrile (8).
1
To a solution of thione (1.9 g,
0.01 mmol) in dioxane (30 ml), elemental sulfur (0.3 g, 0.01 mmol) and a catalytic amount of triethylamine were
added. The reaction mixture was refluxed for 3 h. The solid product formed on dilution with water was collected
by filtration and crystallized from dioxane–ethanol as brown crystals (yield 1.6 g, 72%); mp >300°C.
IR spectrum, ν, cm-1: 3480-3330 (NH2), 2221 (CN). 1H NMR spectrum, δ, ppm: 3.8 (br, 4H, 2NH2); 6.25 (s, 1H,
thiophene H); 8.21 (s, 1H, pyridinethione H). Found, %: C 43.20; H 2.62; N 25.19; S 28.79. C8H6N4S2.
Calculated, %: C 43.24; H 2.72; N 25.23; S 28.80.
b
d
To a solution of nitrile
2-Benzoyldithieno[2,3- :3,4- ]pyridine-1,5,6-triamine (9).
8
(2.2 g,
0.01 mmol) in ethanol (30 ml), phenacyl bromide (1.9 g, 0.01 mmol) and several drops of triethylamine were
added. The mixture was refluxed for 3 h and poured into ice water. The solid product was crystallized from
ethanol as brown crystals (1.9 g, 55%); mp >300°C. IR spectrum, ν, cm-1: 3400-3330 (NH2), 1720 (CO).
Found, %: C 56.33; H 3.41; N 16.32; S 18.71. C16H12N4OS2. Calculated, %: C 56.46; H 3.56; N 16.47; S 18.80.
1,8-Diamino-3-mercaptoisoquinoline-4,7-dicarbonitrile (11). A. To a solution of 8 (2.2 g,
0.01 mmol) in dioxane (20 ml) acrylonitrile (2 ml) and a few drops of acetic acid were added. The reaction
mixture was refluxed for 3 h, then left to cool at room temperature. The solid product was filtered off and
crystallized from ethanol.
B. To a solution of thione 1 (1.9 g, 0.01 mmol) in dioxane (10 ml), malononitrile (0.66 g, 0.01 mmol)
and (1 g) of paraformaldehyde were added together with a catalytic amount of piperidine. The reaction mixture
was refluxed for 3 h then poured into water (30 ml). The solid product was filtered off and crystallized from
ethanol (yield 1.5 g, 78%); mp >300°C. IR spectrum, ν, cm-1: 3400, 3300 (NH2); 2220 (CN). 1H NMR spectrum,
δ, ppm: 3.01 (br, 2H, NH2); 3.51 (br, 2H, NH2); 6.30 (s, 1H, SH); 7.98-8.21 (m, 2H, aromatic protons).
Found, %: C 54.61; H 2.81; N 29.01; S 13.21. C11H7N5S. Calculated, %: C 54.76; H 2.93; N 29.05; S 13.26.
c
. A solution of
3,4-Diacetylamino-6-mercaptothieno[3,4- ]pyridine-7-carbonitrile (15)
8
(2.2 g,
0.01 mmol) in acetic anhydride (10 ml) was refluxed for 1 h. The solid product was collected by filtration and
crystallized from acetic acid as brown crystals (yield 2 g, 67%); mp >300°C. IR spectrum, ν, cm-1: 3200 (NH);
2221 (CN); 1710 (CO). Found, %: C 47.01; H 3.20; N 18.21; S 20.82. C12H10N4O2S2. Calculated, %: C 47.06;
H 3.29; N 18.30; S 20.90.
f
4,5-Diacetylamino-7-mercapto-1,3-dioxo-1,3-dihydrofuro[3,4- ]isoquinoline-8-carbonitrile
(16).
An equimolar amount (0.01 mmol) of 15 and maleic anhydride was heated at 160°C (oil bath) for 20 min. The
resulting cold product was washed several times with water and crystallized from dioxane (yield 2g, 65%);
mp >300°C. IR spectrum, ν, cm-1: 3270 (NH); 2220 (CN); 1810 (CO). Found, %: C 51.88; H 2.52; N 15.10;
S 8.50. C16H10N4O5S. Calculated, %: C 51.89; H 2.72; N 15.14; S 8.64.
1346

ACKNOWLEDGEMENT
The author thanks Dr. Afaf Amin for recording the biological activities of the synthesized products.
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