Investigations on 2,3′-biquinolines. 18*. New convenient one-pot synthesis of 1′-alkyl-1′,4′-dihydro-2,3′- biquinolyl-4′-thiones and their conversion into 1′-alkyl-1′, 4′-dihydro-2,3′-biquinolyl-4′-ones

Article abstract of DOI:10.1007/s10593-006-0047-9

A method has been developed for the one pot synthesis of 1′-alkyl-1′,4′-dihydro-2.3′-biquinolyl-4′-thiones based on the reduction of 1-alkyl-3-(2-quinolyl)quinolinium halides with sodium borohydride and subsequent thiolation. 1′-Alkyl-1′,4′-dihydro- 2,3′-

Full text of DOI:10.1007/s10593-006-0047-9

Chemistry of Heterocyclic Compounds, Vol. 42, No. 1, 2006
INVESTIGATIONS ON 2,3'-BIQUINOLINES.
18*. NEW CONVENIENT ONE-POT SYNTHESIS
OF 1'-ALKYL-1',4'-DIHYDRO-2,3'-BIQUINOLYL-
4'-THIONES AND THEIR CONVERSION INTO
1'-ALKYL-1',4'-DIHYDRO-2,3'-BIQUINOLYL-4'-ONES
D. V. Moiseev1, N. V. Demidova1, V. I. Goncharov2, and A. V. Aksenov1
A method has been developed for the one pot synthesis of 1'-alkyl-1',4'-dihydro-2.3'-biquinolyl-4'-thiones
based on the reduction of 1-alkyl-3-(2-quinolyl)quinolinium halides with sodium borohydride and
subsequent thiolation. 1'-Alkyl-1',4'-dihydro-2,3'-biquinolyl-4'-ones were obtained in close to
quantitative yield by the oxidation of 1'-alkyl-1',4'-dihydro-2,3'-biquinolyl-4'-thiones.
Keywords:
1'-alkyl-1',4'-dihydro-2,3'-biquinolyl-4'-ones,
1'-alkyl-1',4'-dihydro-2,3'-biquinolyl-4'-
thiones, sodium borohydride, 1-alkyl-3-(2-quinolyl)-quinolinium halides, 1',4'-dihydro-2,3'-biquinolines,
sulfur, oxidation, thiolation.
The thiocarbonyl group offers broad possibilities for the synthetic chemist. As a result of its ready
polarizability it acts as an a0, a1, d0, and even a d1 synthon [2]. In addition many 4-quinolones possess high
biological activity. In view of this the development of methods of synthesizing thioaldehydes and thioketones,
and also 4-quinolones is an urgent problem.
S
S/KOH
+
DMF
N
N
N
N
R
N
R
N
+
–
4
I
3a–e
1a–e
S
3a
N
DMF
N
2a
Me
1, 3 a R = Me, b R = Et, c R = Bu, d R = CH2CH2CHMe2, e R = CH2Ph
_______
* For Part 17 see [1].
__________________________________________________________________________________________
1
2
Stavropol State University, Stavropol 355009, Russia; e-mail: biochem-org@stavsu.ru. Stavropol
State Medical Academy, Stavropol 355017, Russia; e-mail: sgma@stavropol.ru. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 1, pp. 67-70, January, 2006. Original article submitted May 3, 2004.
60
0009-3122/06/4201-0060©2006 Springer Science+Business Media, Inc.

Previously we developed two methods of synthesizing 1'-alkyl-1',4'-dihydro-2,3'-biquinolyl-4'-thiones
from quaternized 2,3'-biquinolines 1a-c [3] and from 1'-alkyl-1',4'-dihydro derivatives 2 [4]. In the first case the
synthetic value of the method is reduced due to the low yield of thiones 3 for salts 1a,b,e which is linked with
competing dealkylation (with the formation of biquinolyl 4) and thiolation. In the second, in spite of the close to
quantitative yield of thiones 1, limitations exist linked with the stability, and consequently the accessibility, of
dihydro derivatives 2.
We improved the method of thiolating of salts 1, using the following sequence of steps: protection of the
1'-alkyl group in salts 1 by reducing them with NaBH4 into dihydro derivatives 2 and then thiolation of the latter
with elementary sulfur as a one pot conversion.
1. NaBH4, EtOH
3a–e
1a–e
2. S/DMF
Such a method permitted thiones 3 to be obtained from salts 1 almost quantitatively (90-96% after
recrystallization), including some which were impossible to obtain by the direct thiolation of salts 1, such as
1'-benzyl-1',4'-dihydro-2,3'-biquinolyl-4'-thione (3e) [2].
In view of the biological activity of 4-quinolones we developed an efficient method of synthesizing the
poorly accessible quinolones 5a-e by the oxidation of thiones 3a-e. The acetates of lead and mercury or
elementary bromine were used as oxidizing agent. In all cases compounds 5a-e were formed in yields close to
quantitative.
O
[O]
3a–e
N
N
R
5a–e
5 а R = Me; b R = Et; c R = Bu; d R = CH2CH2CHMe2; e R = CH2Ph
Further, we succeeded in combining the process of oxidizing thiones 3 with bromine and the
bromination of quinolones 5. Treatment of compounds 3 with an excess of bromine in the presence of sodium
acetate in boiling glacial acetic acid led to the 6'-bromo derivative 6 in 65-74% yield.
O
Br2, AcONa
AcOH, ∆
Br
3a–c
N
N
R
6a–c
6 а R = Me; b R = Et, c R = Bu
EXPERIMENTAL
The NMR spectra were recorded on a Bruker WP 200 (200 MHz) instrument, internal standard was
TMS. The IR spectra were recorded in KBr disks on a Hitachi 215 spectrometer. A check on the progress of
reactions and the homogeneity of the compounds synthesized was effected on Silufol UV 254 plates in the
system ethyl acetate–hexane, 1:1.
61

1'-Alkyl-1',4'-dihydro-2,3'-biquinolyl-4'-thiones 3a-e (General Procedure). 1-Alkyl-3-(2-
quinolyl)quinolinium iodide [4] 1a-e (2 mmol) and NaBH4 (0.152 g, 4 mmol) in a mixture of ethanol (5 ml) and
DMF (10 ml) (reduction goes slowly in pure DMF) were boiled with an air condenser for 1 h (to remove ethanol
after reduction: thiolation proceeds in boiling DMF). Sulfur (6 mmol) was added to the reaction mixture, which
was then boiled for a further 3 h, and poured into 1% KOH solution (100 ml). The orange solid was filtered off,
dried, and recrystallized from alcohol.
1'-Methyl-1',4'-dihydro-2,3'-biquinolyl-4'-thione (3a). Yield 0.57 g (95%); mp 180-182°C (alcohol)
(Lit. mp 179-180°C [2]). The 1H NMR spectrum was identical with that described in [2].
1'-Ethyl-1',4'-dihydro-2,3'-biquinolyl-4'-thione (3b). Yield 0.58 g (91%); mp 118-119°C (alcohol)
(Lit. mp 115-116°C [2]). The 1H NMR spectrum was identical with that described in [2].
1'-Butyl-1',4'-dihydro-2,3'-biquinolyl-4'-thione (3c). Yield 0.66 g (96%); mp 122-124°C (alcohol)
(Lit. mp 122-123°C [2]. The 1H NMR spectrum was identical to that described in [2].
1'-Isopentyl-1',4'-dihydro-2,3'-biquinolyl-4'-thione (3d). Yield 0.68 g (95%); mp 131-134°C
(alcohol). 1H NMR spectrum (CD3CN), δ, ppm (J, Hz): 1.01 (6H, d, J = 7.4, Me2); 1.82 (2H, m, CH2CH2CHMe2,
CH2CH2CHMe2); 4.41 (2H, t, J = 7.1, CH2CH2CHMe2); 7.57 (1H, m, H-6'); 7.59 (1H, m, H-6); 7.74 (1H, dd, J67
= 7.1, J78 = 8.5, H-7); 7.83 (2H, m, H-7', 8'); 7.93 (1H, d, J56 = 7.7, H-5); 8.05 (1H, d, J78 = 8.5, H-8); 8.20 (1H,
d, J34 = 8.5, H-4); 8.27 (1H, s, H-2'); 8.32 (1H, d, J34 = 8.5, H-3); 9.15 (1H, d, J5'6' = 8.5, H-5'). Found, %: C
77.58; H 5.51; N 7.74. C23H22N2S. Calculated, %: C 77.09; H 5.59; N 7.82.
1'-Benzyl-1',4'-dihydro-2,3'-biquinolyl-4'-thione (3e). Yield 0.68 g (90%); mp 219-221°C (alcohol).
1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 5.84 (2H, s, CH2); 7.3-7.4 (5H, m, C6H5); 7.56 (1H, d d,
J5'6' = 8.0, J6'7' = 6.9, H-6'); 7.60 (1H, dd, J56 = 8.41, J67 = 7.0, H-6); 7.75 (2H, m, H-7, 7'); 7.86 (1H, d, J7'8' = 8.4,
H-8'); 7.99 (1H, d, J56 = 8.4, H-5); 8.05 (1H, d, J78 = 8.4, H-8); 8.28 (1H, d, J34 = 8.8, H-4); 8.30 (1H, d,
J34 = 8.8, H-3); 8.68 (1H, s, H-2'); 9.03 (1H, d, J5'6' = 8.0, H-5'). Found, %: C 79.87; H 4.69; N 7.33. C25H18N2S.
Calculated, %: C 79.37; H 4.76; N 7.41.
1'-R-1',4'-Dihydro-2,3'-biquinolyl-4'-ones 5a-e (General Procedure). A. A mixture of 1'-R-1',4'-
dihydro-2,3'-biquinolyl-4'-thione 3 (1 mmol) and Pb3O4 or HgO (2 mmol) was dissolved in glacial acetic acid
and stirred for 3 h at ~20°C. The reaction mixture was poured into water (50 ml), neutralized with KOH solution,
extracted with benzene (3 × 30 ml), and the extract evaporated.
B. A mixture of compound 3 (1 mmol) and bromine (0.32 g, 2 mmol) was dissolved in glacial acetic acid
(10 ml) and stirred for 10 min at ~20°C. The reaction mixture was poured into water (50 ml), neutralized with
25% ammonia solution, extracted with benzene (3 × 30 ml), and the extract evaporated.
1'-Methyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (5a). A, yield 0.17 g (58%). B, yield 0.27 g (94%);
mp 193-195°C (benzene). Lit. mp 193-194°C [6]. The 1H NMR spectrum was identical to that described in [6].
1'-Ethyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (5b). A, yield 0.21 g (71%). B, yield 0.26 g (88%);
mp 139-140°C (benzene). Lit. mp 139-140°C [6]. The 1H NMR spectrum was identical to that described in [6].
1'-Butyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (5c). A, yield 0.14 g (42%). B, yield 0.3 g (92%);
mp 124-126°C (benzene). Lit. mp 125-126°C [6]. The 1H NMR spectrum was identical to that described in [6].
1'-Isopentyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (5d). A, yield 0.16 g (46%). B, yield 0.31 g (91%);
mp 105-107°C (benzene). 1H NMR spectrum, (CDCl3), δ, ppm (J, Hz): 1.06 (6H, d, J = 6.7, CH3); 1.87 (3H, m,
1'-CH2CH2CHMe2, 1'-CH2CH2CHMe2); 4.39 (2H, t, J = 7.7, 1'-CH2CH2CH2CH3); 7.47 (1H, dd, J5'6' = 7.9,
J
J
6'7' = 7.3, H-6'); 7.53 (1H, dd, J56 = 7.5, J67 = 7.2, H-6); 7.56 (1H, d, J7'8' = 8.2, H-8'); 7.69 (1H, dd, J6'7' = 7.3,
7'8' = 8.2, H-7'); 7.71 (1H, dd, J67 = 7.2, J78 = 8.3, H-7); 7.84 (1H, d, J56 = 7.5, H-5); 8.10 (1H, dd, J78 = 8.3,
J48 = 0.6, H-8); 8.25 (1H, dd, J34 = 8.8, J48 = 0.6, H-4); 8.65 (1H, d, J5'6' = 7.9, H-5'); 8.94 (1H, d, J34 = 8.8, H-3);
9.09 (1H, s, H-2'). IR spectrum, ν, cm-1: 1619 (C=O). Found, %: C 80.75; H 6.41; N 8.13. C23H22N2O.
Calculated, %: C 80.67; H 6.48; N 8.18.
1'-Benzyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (5e). A, yield 0.24 g (67%). B, yield 0.34 g (93%);
mp 170-172°C (benzene). Lit. mp 171-172°C [6]. The 1H NMR spectrum was identical to that described in [6].
62

1'-Alkyl-6'-bromo-1',4'-dihydro-2,3'-biquinolyl-4'-ones 6a-c (General Procedure). A mixture of
compound 3a-c (1 mmol), anhydrous sodium acetate (0.2 g, 2.5 mmol), and bromine (0.8 g, 5 mmol) in glacial
acetic acid (15 ml) was boiled for 5 h. The reaction mixture was poured into water (50 ml), and neutralized with
25% ammonia solution to a weakly alkaline reaction. The mixture was then extracted with benzene (3 × 30 ml).
The organic layer was separated, dried over Na2SO4, and evaporated. Beige crystals were obtained.
6'-Bromo-1'-methyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (6a). Yield was 0.26
g
(71%);
mp 230-231°C (alcohol). Lit. 230-231°C [1]. The 1H NMR spectrum was identical to that described in [1].
6'-Bromo-1'-ethyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (6b). Yield 0.25 g (65%); mp 206-207°C
(alcohol). Lit. mp 206-207°C [1]. The 1H NMR spectrum was identical to that described in [1].
6'-Bromo-1'-butyl-1',4'-dihydro-2,3'-biquinolyl-4'-one (6c). Yield 0.3 g (74%); mp 186-188°C
(alcohol). Lit. mp 186-187°C [1]. The 1H NMR spectrum was identical to that described in [1].
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