Acid cyclization of amino-substituted heterocycles. Synthesis of 1,3-dioxo- pyrrolo[3,4-c]- and thieno[3,4-c]isoquino- lines and cinnolines

Article abstract of DOI:10.1007/s10593-009-0262-2

The reaction of 3-amino-4-(3,4-dimethoxyphenyl)maleimide and the methyl esters of 3-amino-4-(3,4-dimethoxyphenyl)-5-R-thiophene-2-carboxylic acids with carbonyl compounds and nitrous acid has been investigated. Dioxopyrrolo[3,4-c]- and thieno[3,4-c]isoqui

Full text of DOI:10.1007/s10593-009-0262-2

Chemistry of Heterocyclic Compounds, Vol. 45, No. 3, 2009
ACID CYCLIZATION OF AMINO-SUBSTITUTED
HETEROCYCLES. SYNTHESIS OF 1,3-DIOXO-
PYRROLO[3,4-c]- AND THIENO[3,4-c]ISOQUINO-
LINES AND CINNOLINES
S. Yu. Zinchenko1, R. A. Efimenko1, S. Yu. Suikov1,
K. I. Kobrakov1, and S. L. Bogza1*
The reaction of 3-amino-4-(3,4-dimethoxyphenyl)maleimide and the methyl esters of 3-amino-4-(3,4-
dimethoxyphenyl)-5-R-thiophene-2-carboxylic acids with carbonyl compounds and nitrous acid has
been investigated. Dioxopyrrolo[3,4-c]- and thieno[3,4-c]isoquinolines and cinnolines were obtained.
Keywords: aminomaleimide, 3-aminothiophene, carbonyl compounds, cyclization.
We have shown in previous studies that 5-amino-4-arylpyrazoles may readily be converted into
pyrazolo[3,4-c]isoquinolines on interaction with benzaldehydes and certain other carbonyl compounds under acid
catalysis conditions [1, 2]. Possibilities have been investigated in the present study for obtaining polyannelated
heterocycles from 4-aryl-substituted 3-aminomaleimides and 3-aminothiophenes.
The formation of imides of isoquinoline-3,4-dicarboxylic acids on acylation of 3-amino-4-(3,4-
dimethoxyphenyl)maleimide (1) with acyl perchlorates is known [3]. Investigation of the reactions of compound 1
with carbonyl compounds showed that on interaction with benzaldehydes in strong organic acids 5-aryl-
7,8-dimethoxy-1,3(2H)-dioxopyrrolo[3,4-c]isoquinolines (2) may be obtained in 40-60% yield.
O
O
H
N
H
O
H
N
N
O
MeO
MeO
MeO
MeO
O
O
MeO
MeO
ArCHO / H+
+
NH2
N
OH
Ar
2a–d
1
3
2 a Ar = 3,4-(MeO)2C6H3, b Ar = 2-MeOC6H4, c Ar = 3-ClC6H4; d Ar = 2-Br-4,5-(MeO)2C6H2
_______
* To whom correspondence should be addressed, e-mail: serge-bogza@yandex.ru.
1L. M. Litvinenko Institute of Physical-Organic Chemistry and Coal Chemistry, National Academy of Sciences
of Ukraine, Donetsk 83114, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 3, pp. 449-454, March, 2009. Original
article submitted December 14, 2007.
0009-3122/09/4503-0365©2009 Springer Science+Business Media, Inc.
365

The lower yields of final products in comparison with pyrazoloisoquinolines, are caused by the partial
hydrolysis of the initial compound to the corresponding hydroxymaleimide 3 (5-10% yield) with the participation of
water eliminated in the course of the reaction [3]. On using aliphatic aldehydes and ketones only the starting
materials were isolated from the reaction.
Among heterocyclic structures containing an annelated thiophene ring only single examples of obtaining
thieno[c]isoquinolines have been reported in the literature. The strategy of their synthesis comprizes interaction of
2-formylaryl borates with 3-amino-2-halothiophenes in the presence of palladium catalysts [4]. The low availability
of reactants for assembling the thienoisoquinoline system and the low yields of reaction products did not make this
method preparative. We investigated the possibility of obtaining polyannelated heterocycles from derivatives of
3-amino-4-arylthiophene. Methyl esters of 3-amino-4-(3,4-dimethoxyphenyl)-5-R-thiophene-2-carboxylic acids 4a,b
were used as starting materials. These were obtained from tosylates of β-keto nitriles analogous to the procedure of
[5].
R
R
OTs
S
O
1. MeONa
2. HSCH2CO2Me
MeO
MeO
MeO
MeO
OMe
N
NH2
4a,b
4 a R = H, b R = Me
Reactions of aminothiophenes 4 with acyl perchlorates (mixtures of carboxylic acid anhydrides with
perchloric acid) and various carbonyl compounds have been studied.
It was established that only acylation of the amino group without cyclization of acylamide 5 occurred on the
action of acetyl perchlorate on aminothiophenes 4 in the temperature range 20-100oC. On the other hand heating
compounds 4a,b with various benzaldehydes in trifluoroacetic acid leads to the methyl esters of 1-R-5-aryl-
7,8-dimethoxythieno[3,4-c]isoquinoline-3-carboxylic acids 6 in 50-75% yield.
R
Me
S
O
S
O
O
MeO
MeO
MeO
MeO
OMe
O
N
OMe
NH
N
H
Ar
O
Ar–CHO
6a–e
N
R = Me
(CH2O)n
H
4
8
Ac2O/HClO4
R = H
R = Me
Me
S
S
O
O
MeO
MeO
MeO
MeO
OMe
OMe
NH
Me
N
O
5
7
6 a R = H, Ar = 4-ClC6H4; b R = H, Ar = 3-MeO-4-OH-C6H3; c R = Me, Ar = 4-ClC6H4;
d R = Me, Ar = 3-EtO-4-OH-C6H3; e R = Me, Ar = 4-MeOC6H4
366

Like aminopyrazoles [1], aminothiophenes 4 did not react with acetophenones, aldehydes, and ketones of the
aliphatic series with the exception of paraformaldehyde and isatin. In the reaction of compound 4b with
paraformaldehyde the methyl ester of 1-methyl-7,8-dimethoxythieno[3,4-c]isoquinoline-3-carboxylic acid (7) was
obtained, and on interaction with isatin – 3-methoxycarbonyl-7,8-dimethoxy-1-methyl-4,5-dihydrothieno-
[3,4-c]isoquinoline-5-spiro-3'-(2-oxoindoline) (8).
Recently we reported that aryl-substituted 5-aminopyrazoles and isoxazoles are successfully cyclized into
derivatives of pyrazolo- and isoxazolo[3,4-c]cinnoline by the action of sodium nitrite in glacial acetic acid [6]. Under
the same conditions 7,8-dimethoxy-1,3(2H)-dioxopyrrolo[3,4-c]cinnoline (9) was obtained in high yield from
aminomaleimide 1. Diazotization of aminothiophenes 4a,b enabled us to obtain derivatives of a new heterocyclic
system, thieno[3,4-c]cinnoline 10.
O
R
H
N
S
O
O
MeO
MeO
MeO
MeO
NaNO2/AcOH
NaNO2/AcOH
OMe
4a,b
1
N
N
N
N
9
10a,b
10 a R = H, b R = Me
TABLE 1. Physicochemical Characteristics of the Obtained Compounds
Found, %
——————
Calculated, %
Com-
pound
Empirical
formula
mp, °C
Yield, %
С
H
N
2a
2b
2c
2d
4a
4b
5
C21H18N2O6
63.89
63.96
65.87
65.93
61.82
61.88
53.25
53.29
57.29
57.32
58.57
58.62
56.65
57.30
60.89
60.94
62.05
62.11
61.70
61.75
63.45
63.56
65.15
65.23
60.48
60.55
63.18
63.29
55.51
55.60
55.20
55.26
4.42
4.60
4.32
4.43
3.40
3.55
3.35
3.62
4.90
5.15
5.20
5.57
4.80
5.11
3.78
3.90
4.30
4.50
4.00
4.24
4.90
5.11
4.85
5.00
4.55
4.76
4.52
4.62
3.38
3.50
3.75
3.97
7.05
7.10
7.60
7.69
7.62
7.66
5.87
5.92
4.70
4.77
4.49
4.56
4.12
4.18
3.19
3.38
3.25
3.29
3.12
3.27
3.00
3.09
3.28
3.31
4.35
4.41
6.38
6.42
16.14
16.21
9.12
9.21
293-295
287-289
294-296
288-290
141-143
151-153
180-182
264-266
260-262
250-252
257-260
237-239
241-243
262-264
381-383
240-242
239-241
68
64
66
65
63
68
50
52
63
51
68
75
90
71
66
96
94
C20H16N2O5
C19H13ClN2O4
C21H17BrN2O6
C14H17NO4S
C15H19NO4S
C16H17NO5S
C21H16ClNO4S
C22H19NO6S
C22H18ClNO4S
C24H23NO6S
C23H21NO5S
C16H15NO4S
C23H20N2O5S
C12H9N3O4
6a
6b
6c
6d
6e
7
8
9
10a
10b
C14H12N2O4S
C15H14N2O4S
56.61
56.59
4.20
4.43
8.74
8.80
367

The investigated directions of cyclization of derivatives of aminomaleimide and of 3-aminothiophene may
be a basis of preparative methods for obtaining polyannelated heterocycles, including new heterocyclic systems with
fragments of isoquinoline and cinnoline.
TABLE 2. Spectral Characteristics of Compounds
IR spectrum,
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
ν, cm-1
2а
3200, 1760, 1725,
1685
3.81 (3Н, s, СН3О); 3.83 (3Н, s, СН3О); 4.02 (3Н, s, СН3О);
4.05 (3Н, s, СН3О); 7.10 (1Н, s, Н arom.);
7.14-7.47 (4Н, m, Н arom.); 7.91 (1Н, s, Н arom.);
11.25 (1Н, s, NН)
2b
2c
2d
3210, 1760, 1720,
1690
3.70 (3Н, s, СН3О); 3.72 (3Н, s, СН3О); 4.02 (3Н, s, СН3О);
6.95 (1Н, s, Н arom.); 7.10-7.65 (4Н, m, Н arom.);
7.98 (1Н, s, Н arom.); 11.36 (1Н, s, NН)
3200, 1760, 1725,
1685
3.85 (3Н, s, СН3О); 4.04 (3Н, s, СН3О); 7.37 (1Н, s, Н arom.);
7.60-7.75 (4Н, m, Н arom.); 8.01 (1Н, s, Н arom.);
11.35 (1Н, s, NН)
3205, 1765, 1720,
1695
3.77 (3Н, s, СН3О); 3.80 (3Н, s, СН3О); 3.90 (3Н, s, СН3О);
4.05 (3Н, s, СН3О); 6.95 (1Н, s, Н arom.); 7 .98 (1Н, s, Н arom.);
7.15 (1Н, s, Н arom.); 7.35 (1Н, s, Н arom.); 11.42 (1Н, s, NН)
4а
4b
5
3460, 3350, 1660
3450, 3350, 1660
3360, 1750, 1630
3.75 (3Н, s, СН3О); 3.78 (3Н, s, СН3О); 3.79 (3Н, s, СН3О);
6.30 (2Н, s, NH2); 6.95-7.06 (3Н, m, Н arom.); 7.61 (1Н, s, Н arom.)
2.23 (3Н, s, СН3); 3.72 (3Н, s, СН3О); 3.76 (3Н, s, СН3О);
3.82 (3Н, s, СН3О); 6.04 (2Н, s, NH2); 6.75-7.10 (3Н, m, Н arom.)
1.94 (3Н, s, СН3); 3.75 (3Н, s, ОСН3); 3.76 (3Н, s, ОСН3);
3.77 (3Н, s, ОСН3); 6.98 (1Н, s, NH); 7.00 (2H, d, J = 8, Н arom.);
7.86 (1Н, s, Н arom.); 9.61 (1Н, s, Н arom.)
6а
1700, 1610, 1230
3.74 (3Н, s, СН3О); 3.84 (3Н, s, СН3О); 4.03 (3Н, s, СН3О);
7.22 (1Н, s, Н arom.); 8.06 (1Н, s, Н arom.);
7.64 (2H, d, J = 8, Н arom.); 7.77 (2Н, d, J = 8, Н arom.);
9.04 (1Н, s, Н arom.)
6b
3200, 1700, 1610,
1240
3.78 (3Н, s, СН3О); 3.85 (3Н, s, СН3О); 3.86 (3Н, s, СН3О);
4.04 (3Н, s, СН3О); 6.98 (1Н, d, J = 8, Н arom.);
7.18 (1Н, d, J = 8, Н arom.); 7.35 (1Н, s, Н arom.);
7.46 (1Н, s, Н arom.); 8.03 (1Н, s, Н arom.); 9.00 (1Н, s, Н arom.);
9.48 (1Н, s, ОН)
6c
6d
6e
1720, 1610, 1220
3.10 (3Н, s, СН3); 3.75 (3Н, s, СН3О); 3.82 (3Н, s, СН3О);
4.08 (3Н, s, СН3О); 7.30 (1H, s, H arom.);
7.62 (2Н, d, J = 8.5, Н arom.); 7.78 (2Н, d, J = 8.2, Н arom.);
7.90 (1Н, s, Н arom.)
3350, 1700, 1610,
1220
1.37 (3H, t, J = 9, CH3); 2.98 (3Н, s, СН3); 3.70 (3Н, s, СН3О);
3.81 (3Н, s, СН3О); 4.00 (3Н, s, СН3О); 4.10 (2H, q, J = 9, CH2);
6.95 (1H, d, J = 9, H arom.); 7.15 (1H, d, J = 8, H arom.);
7.30 (1H, s, Н arom.); 7.43 (1H, s, Н arom.); 7.75 (1H, s, Н arom.)
1700, 1610, 1220
1700, 1620, 1210
3.05 (3Н, s, СН3); 3.71 (3Н, s, СН3О); 3.77 (3Н, s, СН3О);
3.85 (3Н, s, СН3О); 7.10 (2Н, d, J = 8.8, Н arom.);
7.40 (1Н, s, Н arom.); 7.72 (2Н, d, J = 8.5, Н arom.);
8.83 (1Н, s, Н arom.)
7
8
3.10 (3Н, s, СН3); 3.85 (3Н, s, СН3О); 3.94 (3Н, s, СН3О);
4.04 (3Н, s, СН3О); 7.68 (1Н, s, Н arom.);
7.80 (1Н, s, Н arom.); 9.05 (1Н, s, Н arom.)
3350, 1730, 1620,
1230
2.75 (3Н, s, СН3); 3.45 (3Н, s, СН3О); 3.68 (3Н, s, СН3О);
3.86 (3Н, s, СН3О); 6.00 (1Н, s, NH);
6.93-7.20 (4Н, m, Н arom.); 7.05 (1Н, s, Н arom.);
7.34 (1Н, s, Н arom.); 10.40 (1Н, s, NН)
9
3200, 1760, 1730
1695, 1620, 1240
4.10 (3Н, s, ОСН3); 4.17 (3Н, s, ОСН3); 7.67 (1Н, s, H arom.);
8.05 (1Н, s, H arom.); 11.25 (1H, s, NH)
10а
3.99 (3Н, s, СН3О); 4.03 (3Н, s, СН3О); 4.05 (3Н, s, СН3О);
7.95 (1Н, s, Н arom.); 7.98 (1Н, s, Н arom.);
9.07 (1Н, s, Н arom.)
10b
1690, 1620, 1230
2.42 (3H, s, H arom.); 3.97 (3Н, s, СН3О); 4.01 (3Н, s, СН3О);
4.03 (3Н, s, СН3О); 7.90 (1Н, s, Н arom.); 7.95 (1Н, s, Н arom.)
368

EXPERIMENTAL
1
The H NMR spectra were recorded on a Varian Geminy (200 MHz) spectrometer in DMSO-d6, internal
standard was TMS. Melting points were determined on a Boetius apparatus and are not corrected. The IR spectra
were recorded on a Perkin-Elmer 881 spectrometer in nujol. Aminomaleimide 1 was obtained by the method
described by us previously in [3]. Analytical characteristics, melting points, and spectral data of the synthesized
compounds are given in Tables 1 and 2.
5-Aryl-7,8-dimethoxy-1,3(2H)-dioxopyrrolo[3,4-c]isoquinolines 2 and Methyl Esters of 1-R-5-aryl-
7,8-dimethoxythieno[3,4-c]isoquinoline-3-carboxylic Acids 6 (General Method). An equimolar amount of
aldehyde was added with cooling to a solution of maleimide 1 (5 mmol) or aminothiophene 4a,b (5 mmol) in
trifluoroacetic acid (50 ml) and the mixture heated for 7-10 h. The solvent was evaporated in vacuum, and the residue
triturated with 5% aqueous ammonia solution. The solid was filtered off, washed with water, dried, and crystallized
from ethanol or acetonitrile.
7,8-Dimethoxy-1-methylthieno[3,4-c]isoquinoline-3-carboxylic Acid Methyl Ester (7). Paraform-
aldehyde (0.6 g, 10 mmol) was added with cooling to a solution of aminothiophene 4b (5 mmol) in trifluoroacetic
acid (50 ml) and the mixture heated for 10 h. The solvent was evaporated in vacuum, and the residue neutralized with
5% aqueous ammonia solution. The solid was filtered off, washed with water, dried, and crystallized from
acetonitrile.
3-Acetylamino-4-(3,4-dimethoxyphenyl)-5-R-thiophene-2-carboxylic Acid Methyl Ester (5).
Aminothiophene 4a (1 g, 3.4 mmol) was added to a mixture of acetic anhydride (4 ml, 40 mmol) and 70% perchloric
acid (0.68 ml, 6.8 mmol). The reaction mixture was heated for 2 h at 90-100oC, then evaporated in vacuum at a
temperature not exceeding 50oC. The residue was treated with 5% aqueous ammonia solution, the solid filtered off,
washed with water, and crystallized from ethanol.
7,8-Dimethoxy-1,3(2H)-dioxopyrrolo[3,4-c]cinnoline (9) and 1-R-7,8-dimethoxythieno[3,4-c]cinno-
line-3-carboxylic Acid Methyl Ester (10). Sodium nitrite (0.4 g, 6 mmol) was added with stirring to a suspension of
aminomaleimide 1 (3 mmol) or aminothiophene 4a,b (3 mmol) in acetic acid (10 ml). Stirring was continued until
precipitation began, and the mixture was left for 2-3 h to complete the reaction. Water (50 ml) was poured onto the
reaction mass, the precipitated solid was filtered off, washed with water, and dried.
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369