Novel heterocyclic systems based on 8-R-4,5-dihydro-4,4-dimethyl-[1,2] dithiolo[3,4-c]quinoline-1-thiones

Article abstract of DOI:10.1007/s10593-006-0122-2

Based on the reaction of 8-R-4,5-dihydro-4,4-dimethyl[1,2]dithiolo[3,4-c] quinoline-1-thiones with oxalyl chloride followed by the reactions of 1,3-dipolar cycloaddition and diene synthesis with participation of acetylenedicarboxylic acid dimethyl ester,

Full text of DOI:10.1007/s10593-006-0122-2

Chemistry of Heterocyclic Compounds, Vol. 42, No. 4, 2006
NOVEL HETEROCYCLIC SYSTEMS
BASED ON 8-R-4,5-DIHYDRO-4,4-DIMETHYL-
[1,2]DITHIOLO[3,4-c]QUINOLINE-1-THIONES
S. M. Medvedeva, E. V. Leshcheva, Kh. S. Shikhaliev, and A. S. Solov'ev
Based on the reaction of 8-R-4,5-dihydro-4,4-dimethyl[1,2]dithiolo[3,4-c]quinoline-1-thiones with
oxalyl chloride followed by the reactions of 1,3-dipolar cycloaddition and diene synthesis with
participation of acetylenedicarboxylic acid dimethyl ester, we have developed approaches to synthesis of
novel polycondensed heterocyclic systems: [1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-4,5-dione, 6-
(1,3-dithiol-2-ylidene)-1,2-dioxo-5-thioxo-7H-pyrrolo[3,2,1-ij]quinoline and 4,5-dioxospiro(pyrrolo)-
[3,2,1-ij]thiopyrano[2,3-c]quinoline-11,2'-[1,3]dithiole.
Keywords: acetylenedicarboxylic acid dimethyl ester, 4,5-dioxospiro(pyrrolo)[3,2,1-ij]thiopyrano-
[2,3-c]quinoline-11,2'-[1,3]dithiole, 6-(1,3-dithiol-2-ylidene)-1,2-dioxo-5-thioxo-7H-pyrrolo[3,2,1-ij]-
quinoline,
[1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-4,5-dione,
[1,2]dithiolo[3,4-c]quinoline-1-
thione, oxalyl chloride.
Many substances with a broad spectrum of biological action have been observed among substituted
4,4-dimethyl[1,2]dithiolo[3,4-c]quinoline-1-thiones, and these compounds furthermore exhibit antioxidant
activity and also are radical polymerization regulators [1, 2]. With the aim of obtaining novel polycondensed
heterocyclic systems, we have continued work on further modification of these compounds.
We reported earlier [3] that acylation of 8-R-4,4-dimethyl-4,5-dihydro[1,2]dithiolo[3,4-c]quinoline-1-
thiones 1a-c by oxalyl chloride, as in the case of simple acyl chlorides [4], occurs exclusively at the nitrogen
atom of the dihydroquinoline ring and is accompanied by spontaneous cyclization according to a Stolle reaction
[5]. The best solvent in this case is absolute toluene, in which the process goes to completion within 1.5-2 h. The
reaction does not require the use of Lewis acids, which are typically used as catalysts. This is possibly connected
with the fact that the limiting step of the two-step Stolle reaction in the case of 8-R-4,4-dimethyl-4,5-
dihydro[1,2]dithiolo[3,4-c]quinoline-1-thiones 1a-f is the first acylation reaction, with formation of the
corresponding intermediate chlorooxalyl amides 2a-f.
As a result, derivatives of a novel condensed heterocyclic system were synthesized in good yields
(60-80%): 2-R1-3-R2-7,7-dimethyl-10-thioxo-4,5,7,10-tetrahydro[1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-
4,5-diones 3a-f (Scheme 1).
Their structure is supported by the combination of IR, 1H NMR, and mass spectral data. In the IR spectra
of compounds 3a-f (Table 1), the frequencies of the stretching vibrations of the thioketone group are observed in
the 1230-1240 cm-1 region, and the vibrations of the two carbonyl groups of the isatin moiety are observed at
1740-1750 cm-1 and 1760-1770 cm-1.
__________________________________________________________________________________________
Voronezh State University, Voronezh 394006, Russia; e-mail: shikh@online.ru. Translated from
Khimiya Geterotsiklicheskikh Soedinenii, No. 4, pp. 610-615, April, 2006. Original article submitted April 29,
2003; revision submitted February 6, 2006.
534
0009-3122/06/4204-0534©2006 Springer Science+Business Media, Inc.

Scheme 1
S
S
S
S
R1
R2
R1
S
S
+
H
(COCl)2
– HCl
R2
PhMe, ∆
N
N
H
Cl
O
1a–g
O
2a–g
S
S
R1
S
R2
N
O
O
3a–g
1-3 а-d, g R2 = H, a R1 = H, b R1 = Me, c R1 = OМe, d R1 = OЕt, e R1 = Н, R2 = Ме,
f R1 = R2 = Ме; g R1 = PhCOO
1
In the H NMR spectra of dithiolopyrroloquinolines 3a-f (Table 1), compared with the starting
dithiolquinolines 1a-f the signal from the N–H proton in the 5.5-6.2 ppm region is missing, while in the
aromatic region we observe the characteristic set of signals reduced by 1 proton. The chemical shift of the
C(1)–H proton, which experiences the anisotropic effect of the adjacent thioketone group, is shifted further
downfield, all the way down to values of 9.50 ppm.
The yields and characteristics of the synthesized compounds 3d-g are given in Table 2.
TABLE 1. IR and 1H NMR Spectra of Compounds 3a-g
IR spectrum, ν, cm-1
Com-
pound
1Н NMR spectrum, δ, ppm (J, Hz)
C=S
C(1)=O
C(2)=O
3a
1235
1740
1770
2.13 (6H, s, С(CH3)2); 6.97 (1Н, d, J = 7.1, 3-СН);
7.13 (1Н, t, J = 7.1, 2-СН);
9.41 (1Н, d, J = 7.1, 1-СН)
3b
3c
3d
1230
1225
1230
1745
1748
1740
1763
1770
1765
2.00 (6H, s, С(CH3)2); 2.39 (3Н, s, 2-CH3);
7.19 (1Н, s, 3-СН); 9.43 (1Н, s, 1-СН)
2.12 (6H, s, С(CH3)2); 3.82 (3Н, s, 2-CH3О);
7.05 (1Н, s, 3-СН); 9.45 (1Н, s, 1-СН)
1.25 (3Н, t, J = 7.0, ОСН2СН3); 2.02 (6H, s, С(CH3)2);
4.25 (2Н, q, J = 7.0, ОСН2СН3); 7.01 (1Н, s, 3-СН);
9.40 (1Н, s, 1-СН)
3e
1228
1745
1770
2.00 (6H, s, С(CH3)2); 2.32 (3Н, s, 3-CH3);
7.11 (1Н, d, J = 7.2, 2-СН);
9.43 (1Н, d, J = 7.2, 1-СН)
3f
1230
1225
1748
1740
1760
1765
2.09 (6H, s, С(CH3)2); 2.28, 2.43 (6Н, 2s, 2,3-(CH3)2);
9.45 (1Н, s, 1-СН)
3g
2.15 (6H, s, С(CH3)2); 7.55-8.30 (6Н, m, arom.);
9.70 (1Н, s, 1-СН)
535

TABLE 2. Characteristics and Yields of Compounds 3a-g
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
mp, °С
Yield, %
С, %
Н, %
N, %
М*
3a
3b
3c
3d
3e
3f
C14H9NO2S3
C15H11NO2S3
C15H11NO3S3
C16H13NO3S3
C15H11NO2S3
C16H13NO2S3
C21H13NO4S3
52.74
52.64
54.17
54.03
51.47
51.65
52.95
52.87
54.11
54.03
55.46
55.31
57.31
57.39
2.92
2.84
3.45
3.33
3.09
3.17
3.56
3.61
3.27
3.33
3.89
3.77
3.06
2.98
4.43
4.38
4.30
4.20
4.17
4.01
3.72
3.85
4.29
4.20
4.12
4.03
3.23
3.19
319
295-300
254-256
278-279
270-272
305-307
233-235
268-270
65
74
68
62
58
70
74
319.43
333
333.46
349
349.46
363
363.49
333
333.46
347
347.49
439
439.52
3g
_______
* Mass spectrometrically.
The presence of a 1,2-dithiolethione ring in the structure of the tetracyclic compounds 3a-g obtained
makes it possible to modify them further, in particular using the 1,3-dipolar cycloaddition reaction.
We have established that compounds 3a-f, like the starting [1,2]dithiolo[3,4-c]quinoline-1-thiones 1a-f
[6], even at room temperature readily undergo a 1,3-dipolar cycloaddition reaction with acetylenedicarboxylic
acid dimethyl ester (ADM). Due to the poor solubility of compounds 3a-f and in order to accordingly avoid
secondary reactions, the reaction was carried out in DMF.
As a result, we isolated derivatives of a novel heterocyclic system in moderate yields (40-50%):
dimethyl 2-(8-R1-9-R2-4,4-dimethyl-1,2-dioxo-5-thioxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolin-6-
ylidene)-1,3-dithiole-4,5-dicarboxylates 4a-f.
Carrying out the reaction at higher temperatures, as expected, leads to the appearance of one more
competing product in addition to compounds 4a-f. This product may be just the expected adduct from
cycloaddition of one more ADM molecule to the diene system of products 4a-f.
We have established that compounds 4a-f react with the ADM molecule in a Diels–Alder reaction when
the reagents are boiled in toluene. We can unambiguously assign the structure of a novel condensed heterocyclic
system to the adducts formed in this case: dimethyl (2-R1,3-R2-4',5'-dimethoxycarbonyl-7,7-dimethyl-4,5-dioxo-
4,5,7,11-tetrahydrospiro(pyrrolo)[3,2,1-ij]thiopyrano[2,3-c]quinoline-11,2'-[1,3]dithiole)-9,10-dicarboxylates
5a-f. The latter are also obtained in one step by reaction of pyrrolo[3,2,1-ij]quinoline-4,5-diones 3a-f with a two-
fold excess of ADM in boiling toluene. In this case, the yields of the target products 5a-f are practically the same
in the first and second variants, and are rather high (60-80%) (Scheme 1).
In the 1H NMR spectra of ylidenes 4a-f (Table 3), compared with the spectra of starting
10-thioxoquinoline-4,5-diones 3a-f, the chemical shifts of the aromatic protons return to the "normal" region, in
the range from 7.0 ppm to 7.8 ppm, and in the 3.8-3.9 ppm region the chemical shifts of the methoxycarbonyl
groups appear as two singlets.
In the 1H NMR spectra of the bisadducts 5a-f in the 3.8-3.9 ppm region, we already observe a multiplet
of chemical shifts for the four methoxycarbonyl groups. Their magnetic nonequivalence is obviously explained
by inversion of both the spiro-1,3-dithiole and the dihydrothiopyran rings. Table 4 gives the characteristics and
yields of the synthesized compounds 4a-f and 5a-f.
536

Scheme 1
COOMe
MeOOC
S
S
S
S
R1
R2
S
R1
R2
S
ADM
ADM
PhMe, ∆
DMF, 20 оС
N
N
O
O
O
O
4a–f
3a–f
MeOOC
COOMe
MeOOC
S
COOMe
S
2ADM, PhMe, ∆
R1
S
N
R2
O
O
5a–f
4, 5 а-d R2 = H; а R1 = H, b R1 = Me, c R1 = OМe, d R1 = OЕt, e R1 = Н, R2 = Ме, f R1 = R2 = Ме
TABLE 3. 1H NMR Spectra of Compounds 4a-f, 5a-f
Com-
pound
Chemical shifts, δ, ppm (J, Hz)
4a
4b
4c
4d
4e
4f
2.10 (6H, s, С(CH3)2); 3.81, 3.88 (6Н, 2s, ОCH3); 6.99 (1Н, d, J = 7.1, 3-СН);
7.15 (1Н, t, J = 7.1, 2-СН); 7.71 (1Н, d, J = 7.1, 1-СН)
2.05 (6H, s, С(CH3)2); 2.33 (3Н, s, 2-CH3); 3.83, 3.90 (6Н, 2s, ОCH3);
7.19 (1Н, s, 3-СН); 7.63 (1Н, s, 1-СН)
2.12 (6H, s, С(CH3)2); 3.80, 3.82, 3.88 (9Н, 3s, CH3О); 7.05 (1Н, s, 3-СН);
7.73 (1Н, s, 1-СН)
1.22 (3Н, t, J = 7.0, ОСН2CН3); 2.02 (6H, s, С(CH3)2); 3.81, 3.88 (6Н, 2s, ОCH3);
4.28 (2Н, q, J = 7.0, ОСН2CН3); 7.01 (1Н, s, 3-СН); 7.70 (1Н, s, 1-СН)
2.00 (6H, s, С(CH3)2); 2.35 (3Н, s, 3-CH3); 3.80, 3.86 (6Н, 2s, ОCH3);
7.11 (1Н, d, J = 7.2, 2-СН); 7.43 (1Н, d, J = 7.2, 1-СН)
2.09 (6H, s, С(CH3)2); 2.23, 2.40 (6Н, 2s, 2,3-(CH3)2); 3.84, 3.90 (6Н, 2s, ОCH3);
9.45 (1Н, s, 1-СН)
5a
5b
2.13 (6H, s, С(CH3)2); 3.8-3.9 (12Н, m, ОCH3); 6.97 (1Н, d, J = 7.0, 3-СН);
7.13 (1Н, t, J = 7.0, 2-СН); 7.51 (1Н, d, J = 7.0, 1-СН)
2.05 (6H, s, С(CH3)2); 2.33 (3Н, s, 2-CH3); 3.8-3.9 (12Н, m, ОCH3);
7.19 (1Н, s, 3-СН); 7.43 (1Н, s, 1-СН)
5c
2.15 (6H, s, С(CH3)2); 3.82-3.95 (15Н, m, ОCH3); 7.05 (1Н, s, 3-СН); 7.51 (1Н, s, 1-СН)
5d
1.22 (3Н, t, J = 7.0, ОСН2CН3); 2.09 (6H, s, С(CH3)2); 3.8-3.9 (12Н, m, ОCH3);
4.20 (2Н, m, ОСН2CН3); 7.01 (1Н, s, 3-СН); 7.50 (1Н, s, 1-СН)
5e
5f
2.00 (6H, s, С(CH3)2); 2.30 (3Н, s, 3-CH3); 3.8-3.9 (12Н, m, ОCH3);
7.11 (1Н, d, J = 7.2, 2-СН); 7.47 (1Н, d, J = 7.2, 1-СН)
2.09 (6H, s, С(CH3)2); 2.26, 2.49 (6Н, 2s, 2,3-(CH3)2); 3.8-3.9 (12Н, m, ОCH3);
9.45 (1Н, s, 1-СН)
537

TABLE 4. Characteristics and Yields of Synthesized Compounds 4a-f and
Adducts 5a-f
Found, %
Calculated, %
——————
Com-
pound
Empirical
formul
mp, °С
Yield, %
С, %
Н, %
N, %
М*
4a
4b
4c
4d
4e
4f
C20H15NO6S3
C21H17NO6S3
C21H17NO7S3
C22H19NO7S3
C21H17NO6S3
C22H19NO6S3
C26H21NO10S3
C27H23NO10S3
C27H23NO11S3
C28H25NO11S3
C27H23NO10S3
C28H25NO10S3
52.18
52.05
53.18
53.04
51.40
51.31
52.37
52.26
53.13
53.04
54.10
53.97
51.87
51.73
52.61
52.50
51.24
51.18
52.03
51.92
52.63
52.50
53.37
53.24
3.34
3.28
3.72
3.60
3.54
3.49
3.87
3.79
3.74
3.60
4.03
3.91
3.64
3.51
3.81
3.75
3.73
3.66
3.77
3.89
3.80
3.75
3.89
3.96
3.12
3.03
2.87
2.95
2.78
2.85
2.84
2.77
2.83
2.95
2.91
2.86
2.48
2.32
2.34
2.27
2.31
2.27
2.24
2.16
2.39
2.27
2.36
2.22
461
172-173
184-186
179-181
173-174
187-188
182-183
184-185
228-230
199-201
210-211
225-226
289-290
42
53
45
50
47
40
70
65
68
62
60
72
461.54
475
475.57
491
491.57
505
505.60
475
475.57
489
489.60
603
603.65
617
617.68
633
633.68
5a
5b
5c
5d
5e
5f
647
647.71
617
617.68
631
631.71
_______
* Mass spectrometrically.
EXPERIMENTAL
The course of the reaction and the purity of the substances obtained were monitored by TLC on Silufol
UV-254 plates, with chloroform or ethyl acetate as the eluent. The IR spectra were taken on a Specord M-80 in
1
nujol. The H NMR spectra were taken on a Bruker AC-300 (300 MHz) in DMSO-d6, internal standard TMS.
The mass spectra were taken on an LKB-9000, ionizing electron energy 70 eV.
The starting [1,2]dithiolo[3,4-c]quinoline-1-thiones 1a-g were obtained as described in [1].
2-R1-R2-7,7-Dimethyl-10-thioxo-4,5,7,10-tetrahydro[1,2]dithiolo[3,4-c]pyrrolo[3,2,1-ij]quinoline-
4,5-diones 3a-g. A mixture of the corresponding [1,2]dithiolo[3,4-c]quinoline-1-thione 1a-f (0.01 mol) and
oxalyl chloride (0.011 mol) in absolute toluene (30 ml) was boiled for 1.5-2 h and then cooled down; the
precipitate was filtered out and recrystallized from DMF.
Dimethyl 2-(8-R1-9-R2-4,4-Dimethyl-1,2-dioxo-5-thioxo-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]-
quinolin-6-ylidene)-1,3-dithiole-4,5-dicarboxylates 4a-f. A mixture of the corresponding compound 3a-f
(0.01 mol) was dissolved in DMF (50 ml), ADM (0.01 mol) was added dropwise at room temperature, and the
reaction mixture was allowed to stand overnight. When the reaction was complete (monitored by TLC), the
reaction mixture was poured into water (200 ml), the precipitate was filtered out, dried, and recrystallized from
dioxane.
Dimethyl
(2-R1-3-R2-4',5'-Dimethoxycarbonyl-7,7-dimethyl-)-4,5-dioxo-4,5,7,11-tetrahydro-
spiro(pyrrolo)[3,2,1-ij]thiopyrano[2,3-c]quinoline-11,2'-[1,3]dithiole)-9,10-dicarboxylates 5a-f. A. A
mixture of the diene 4a-f (0.01 mol) and ADM (0.01 mol) in toluene (30 ml) was boiled for 4-5 h, the toluene
was distilled off under reduced pressure, and the residue was crystallized from dioxane.
538

B. A mixture of [1,2]dithiolo[3,4-c]quinoline-1-thione 3a-f (0.01 mol) and ADM (0.02 mol) in toluene
(30 ml) was boiled for 4-5 h, the toluene was distilled off under reduced pressure, and the residue was
crystallized from dioxane.
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2.
J. P. Brown, J. Chem. Soc. (C), 1074 (1968).
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Nauk SSSR, Ser. Khim., 782 (1991).
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6.
Kh. S. Shikhaliev, E. V. Leshcheva, and S. M. Medvedeva, Khim. Geterotsikl. Soedin., 852 (2002).
Kh. S. Shikhaliev, Zh. V. Shmyreva, and L. P. Zalukaev, Zh. Org. Khim., 24, 232 (1988).
R. Stolle, Ber., 46, 3915 (1913).
Kh. S. Shikhaliev, S. M. Medvedeva, G. I. Ermolova, and G. V. Shatalov, Khim. Geterotsikl. Soedin.,
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539