From 2,3-, 2,6-, 3,4- and 4,6-dichloroquinolines to isomeric chloroquinolinesulfonyl chlorides

Article abstract of DOI:10.3987/COM-09-11855

The action of sodium methanethiolate (in boiling DMF) on x,y-dichloroquinolines (1) (x=3 or 6, y=2 or 4) occured via chlorine ipso-substitution followed by methanethiolato-S-demethylation to yield x,y-quinolinedithiolates 2A which were: i) subjected to S-

Full text of DOI:10.3987/COM-09-11855

HETEROCYCLES, Vol. 81, No. 2, 2010
305
HETEROCYCLES, Vol. 81, No. 2, 2010, pp. 305 - 316. © The Japan Institute of Heterocyclic Chemistry
Received, 14th October, 2009, Accepted, 30th November, 2009, Published online, 1st December, 2009
DOI: 10.3987/COM-09-11855
FROM 2,3-, 2,6-, 3,4- AND 4,6-DICHLOROQUINOLINES TO ISOMERIC
CHLOROQUINOLINESULFONYL CHLORIDES #
Krzysztof Marciniec* and Andrzej Maślankiewicz
Department of Organic Chemistry,The Medical University of Silesia,
Jagiellońska 4, 41-200 Sosnowiec, Poland
E-mail: kmarciniec@sum.edu.pl; maslankiewicz@sum.edu.pl
Abstract – The action of sodium methanethiolate (in boiling DMF) on x,y-
dichloroquinolines (1) (x=3 or 6, y=2 or 4) occured via chlorine ipso-substitution
followed by methanethiolato-S-demethylation to yield x,y-quinolinedithiolates 2A
which were: i) subjected to S-methylation, ii) oxidatively chlorinated to y-chloro-
x-quinolinesulfonyl chlorides (5). Oxidative chlorination of y,y'-bis(x-chloro-
quinolinyl) disulfides (7) led to x-chloro-y-quinolinesulfonyl chlorides (8)
accompanied by x,y-dichloroquinolines (1). Both quinolinesulfonyl chlorides 5
and 8 were efficiently converted to the corresponding quinolinesulfonamides 6
and 9.
INTRODUCTION
2-Chloro- and 4-chloroquinoline moieties,1 as well as quinolinesulfonyl chloride units2,3,4,5 give broad
access to further functionalization of quinolines. Co-occurrence of both functional groups in one
quinoline molecule broaden the above potential, as was shown for 4-chloro-3-quinolinesulfonyl chloride
(5b)4,5 and 2-chloro-6-quinolinesulfonyl chloride (5c)6 in studies directed at the preparation of
biologically active compounds.1-6 The 3- or 7-chlorosulfonyl-4-chloroquinolines (5b,e),4,5,8 8-
chlorosulfonyl-4-chloroquinolines,7 4-chlorosulfonyl-7-chloroquinoline (8e),8 and 2-chloro-6-quinoline-
sulfonyl chloride (5c),6 are well known but only the 4,7-isomers 5e and 8e were prepared from the
respective dichloroquinoline (1e).8
Azinesulfonyl chlorides could be directly obtained by oxidative chlorination of thioazines – thiols8,9,10
disulfides,8,9 benzylsulfides5,11 with a thio substituents at non-aza-activated positions. On the other hand,
the results of the same treatment of thioazines with a thio substituent at aza-activated positions strongly
depends on the experimental conditions. Since the oxidative chlorination when performed in acetic acid
solution leads to the respective chloroazines,8,9,12-14 but the oxidative chlorination of - and -

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thiopyridines and thioquinolines performed in conc. hydrochloric acid permits unstable - and -
azinesulfonyl chlorides8,9,16,18,19 to be isolated. These underwent decomposition even below 0 ºC to
chloroazine and sulfur dioxide,8,9,16,18,19 but freshly prepared samples could be succesfully characterized
1
13
with the H and C NMR spectra8,9,19 and effective trapped (with yields up to 90%) in the form of the
respective sulfonamides.8,9,16,18,19 It is worth noting that structural modification may affect the stability of
- and -azinesulfonyl halides, as was exemplified for 5-acetylamino-2-pyridinesulfonyl chloride,15 for
tetrachloro-4-pyridinesulfonyl chloride,17 and even for 2-pyrimidinesulfonyl fluoride.19
The starting point for this paper was the previously elaborated methodology based on formation of a
quinolinethiolate function from chloroquinolines and an excess of sodium methanethiolate.20 The final
step of this approach was the transformation of the divalent-sulfur substituent to chlorosulfonyl group. To
extend the above study concerning 4,7-dichloroquinoline (1e),8 we turned our attention to other
dichloroquinolines (isomers 2,3-, 2,6-, 3,4- and 4,6-) containing one chloro substituent at aza- and another
one at non-aza-activated positions as a source of both isomeric chloroquinolinesulfonyl chlorides 5 and 8
with one substituent at aza- and the second one at non-aza-activated positions.
RESULTS AND DISCUSSION
Quinoline- and pyridinethiolates are easily available from the respective chloro- or bromo-derivatives in a
one-pot process performed with an excess of sodium methanethiolate.8,20 This process proceeds stepwise
by halogen ipso-substitution leading to the respective methylsulfanyl derivatives, which are then
S-dealkylated to the respective azinethiolates.8,20 They can be trapped by methylation to
methylsulfanylazines20,8 or by oxidation to disulfides8,9 or they can be oxidative chlorinated to
quinolinesulfonyl chlorides.8,9
Synthesis of quinoline derivatives 5a-d with chlorosulfonyl a substituent at non-aza-activated position
Synthesis of the y-chloro-x-chlorosulfonylquinolines (5) (x=3 or 6, y=2 or 4) was performed using the
previously elaborated methodology applied for the preparation of 4-chloro-7-chlorosulfonylquinoline (5e)
from 4,7-dichloroquinoline (1e).9 (see Scheme 1). It comprises three steps:
i) Formation of dithiolates (2A) in the reaction of dichloroderivatives (1) with sodium methanethiolate.
To confirm the structure of the expected x,y-quinolinedithiolates (2A), crude thiolate solution was
methylated to x,y-dimethylsulfanylquinolines (2a-d).
ii) Oxidative chlorination of quinolinedithiols 2T to di(chlorosulfonyl)quinolines 4. For this purpose
dithiolates 2A were acidified to non-isolated dithiols 2T, which were then oxidatively chlorinated with
sodium hypochlorite in conc. hydrochloric acid. This should lead to x,y-di(chlorosulfonyl)quinolines (4).

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N

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HETEROCYCLES, Vol. 81, No. 2, 2010
iii) The third step is decomposition of di(chlorosulfonyl)quinolines 4 to y-chloro-x-chlorosulfonyl-
quinolines 5a-d. It is well documented that - and -azinesulfonyl chlorides undergo decomposition even
at 0 oC to - and -chloroazines and sulfur dioxide.8,12-14,16,19 In the result the oxidative chlorination of 2T
via x,y-di(chlorosulfonyl)quinolines (4) led to y-chloro-x-chlorosulfonyl-quinolines 5a-d.
Table 1. Synthesis of dimethylsulfanylquinolines 2, chloroquinolinesulfonylchlorides 5 and
chloroquinolinesulfonamides 6 from dichloroquinolines 1 via quinolinedithiolates 2A.
Entry
Substrate
Products, yield (%), procedure
SMe
SMe
SO2Cl
SO2NH2
Cl
Cl
Cl
1
N
N
N
Cl
N
2a (91) B
5a (86) C
6a (86) D
1a
Cl
Cl
Cl
SMe
SO2NH2
Cl
SMe
SO2Cl
2
3
4
N
N
N
N
2b (82) B
5b (80) C
6b (81) D
1b
MeS
ClO2S
H2NO2S
Cl
N
Cl
N
Cl
N
SMe
6c (81) D
5c (79) C
N
Cl
2c (92) B
1c
Cl
Cl
SMe
Cl
Cl
MeS
ClO2S
H2NO2S
N
N
N
N
2d (80) B
5d (80) C
6d (78) D
1d
*procedure A,B,C,D, – see experimental
Synthesis of quinoline derivatives 8 with chlorosulfonyl substituent at aza-activated position
Synthesis of 7-chloro-4-chlorosulfonylquinoline (8e) from 4,7-dichloroquinoline (1e) was performed as
outlined in Scheme 1.8 This methodology was applied for the preparation of compounds 8 and 9. The
key-step was the chlorination of x,x'-bis (y-chloroquinolinyl) disulfides (7) (x=2 or 4, y=3 or 6) in conc.
hydrochloric acid at -8 C. Despite the instability of sulfonyl chlorides 8a,c,d, they were extracted with
1
cold (-5 C) CDCl3 immediately after the synthesis and fully characterized (at 0 C, up to 1 h) with H
and 13C NMR spectra. Moreover, both NMR spectra showed that the compounds 8a,c,d in CDCl3
solution are accompanied by the respective x,y-dichloroquinolines (Table 2). Due to the instability of the
sulfonyl chlorides 8a,c,d, they should be immediately consumed e.g. by amination to the respective
sulfonamides 9. Oxidative chlorination of disulfide 7b performed even at -20 C led directly to 3,4-
dichloroquinoline (1b).

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309
Table 2. Synthesis of chloroquinolinesulfonylchlorides 8 and chloroquinolinesulfonamides 9 from
disulfides 7.
Entry
Substrate
Products, yield (%), procedure
Cl
Cl
Cl
+ 1a (48)
+ 1a (3)
1
N
SO2NH2
N
SO2Cl
)
N
S
2
9a (50) E
7a
8a (97) E
Cl
N
)
S
N
2
Cl
Cl
2
3
4
1b (100 %)E
7b
Cl
Cl
Cl
+ 1c (59)
SO2NH2
+ 1c (30)
SO2Cl
N
N
N
S
)
2
9c (40) E
8c (70) E
7c
SO2Cl
SO2NH2
)
S
2
Cl
Cl
Cl
+ 1d (61)
N
N
N
8d (100) E
9d (28) E
7d
*procedure E – see experimental
CONCLUSIONS
A previously elaborated methodology based on formation of quinolinethiolate function from
chloroquinolines and an excess of sodium methanethiolate followed by oxidative chlorination of
quinolinethiolate or diquinolinyl disulfide to quinolinesulfonyl chlorides8,9 could be successfully extended
for the preparation of four pairs of isomeric chloroquinolinesulfonyl chlorides 5 and 8, with one
substituent at aza- and the second one at non-aza-activated positions, starting from x,y-dichloroquinolines
(1). Both types of sulfonyl chlorides were converted to the respective quinolinesulfonamides 6 and 9.
4
3
6
7
y-SNa
x-S_)2
x-Cl
x-NaS
y-Cl
y-Cl
2
N
2A
N
N
N
7
8
1 a, x,y=2,3; b, x,y=3, 4;
c, x,y=2,6; d, x,y=4,6;
e, x,y=4,7 ref.8
x-SO2Cl
y-Cl
y-Cl
x-ClO2S
N
5
x-SO2NH2
y-Cl
y-Cl
x-H2NO2S
N
N
9
6
(x=2 or 4; y=3,6,7)
(x=3,6,7; y=2 or 4)
Scheme 2

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HETEROCYCLES, Vol. 81, No. 2, 2010
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected. All NMR spectra were recorded on
1
13
a Bruker AVANCE 400 spectrometer operating at 400.22 MHz and 100.64 MHz for H and C nuclei,
respectively, in deuterochloroform (CDCl3) or in hexadeuterodimethyl sulfoxide (DMSO-d6) solutions
with tetramethylsilane ( 0.0 ppm) as internal standard. TLC analyses were performed employing
Merck’s silicagel 60 F254 plates and a solution of CHCl3-EtOH (19 : 1, v/v) as an eluent (system I) or a
mixture of CH2Cl2/EtOH, (19 : 1, v/v) (system II) and Merck’s aluminium oxide 60 F254 neutral (type E)
plates using mixture of CHCl3-EtOH (19 : 1, or 10 : 1, v/v) as an eluent (system III). Sodium
methanethiolate was prepared from methanethiol and sodium methoxide (1 mol. eqv.) in methanol
solution as reported previously.9 2,6- and 4,6-Dichloroquinolines (1c and 1d) were prepared from 6-
chloroquinoline N-oxide and phosphoryl chloride as reported by Bachman and Cooper21 – the same
experimental protocol was applied for the preparation of 2,3-dichloroquinoline (1a) from
3-chloroquinoline N-oxide. 3,4-Dichloroquinoline (1b) was prepared by pyrolysis of 4-chloro-
3-quinolinesulfonyl chloride (5b).5
Reaction of dichloroquinoline (1) with sodium methanethiolate leading to x,y-quinolinedithiolate (2A)
(Procedure A)
A mixture of dichloroquinoline (1) (0.794 g, 4 mmol), sodium methanethiolate (2.80 g, 40 mmol) and dry
DMF (24 mL) was boiled with stirring under argon atmosphere for 4 h (or 6h for 4,6-dichloroquinoline
1d). (The reaction must be carried out in hood as it proceeds with strong evolution of dimethyl sulfide).
This mixture was assigned as solution A. It was then cooled to 70 C and the volatile components were
evaporated under vacuum from water bath. The residue was cooled down in an ice-water bath, (under
argon atmosphere) carefully acidified with 20% hydrochloric acid (8 mL) and then kept at vacuum to
remove methanethiol. This residue - assigned as solution B - contains crude (non-isolated) x,y-
dimercaptoquinoline (2T) and could be used for the preparation of sulfonyl chlorides 5.
Methylation of x,y-quinolinedithiolate (2A)
(Procedure B)
Methyl iodide (0.37 mL, 5.9 mmol) was added dropwise on stirring to a solution composed of 8%
aqueous sodium hydroxide (15 mL) and solution A (3 mL, containing ca. 0.5 mmol of thiolate 2A -
prepared as described above in procedure A). The stirring was continued at rt for 1 h. The solid was
filtered off, washed with water and dried on air. It was recrystallized from aqueous EtOH or from hexane
to give x,y-dimethylsulfanylquinoline (2) (0.1 g, ca. 91%).

HETEROCYCLES, Vol. 81, No. 2, 2010
311
2,3-Dimethylsulfanylquinoline (2a)
1
mp 62-63 ºC (hexane). EI MS (70eV) (m/z): 221 (100, M+). H NMR (CDCl3), : 2.57 (s, 3H, SCH3),
2.72 (s, 3H, SCH3), 7.40 (ddd, 1H, J=7.8 Hz, J=7.6 Hz, J=1.2 Hz, H6), 7.59 (ddd, 1H, J=8.4 Hz, J=7.8
Hz, J=0.8 Hz, H7), 7.67 (dd, 1H, J=7.6 Hz, J=0.8 Hz, H5), 7.76 (s, 1H, H4), 7.93, (dd, 1H, J=8.4 Hz,
J=1.2 Hz, H8). Anal. Calcd for C11H11NS2 (221.33): C 59.69, H 5.01, N 6.33. Found: C 59.58, H 4.91, N
6.23.
3,4-Dimethylsulfanylquinoline (2b)
1
Mp 92-93 ºC (hexane), lit.,22 mp 93-94 ºC. H NMR spectrum (CDCl3) was identical with the sample
prepared previously.22
2,6-Dimethylsulfanylquinoline (2c)
1
mp 104-105 ºC (EtOH). EI MS (70eV) (m/z): 221 (100, M+). H NMR (CDCl3), : 2.57 (s, 3H, SCH3),
2.69 (s, 3H, SCH3), 7.21 (d, 1H, J=8.6 Hz, H3), 7.47 (d, 1H, J=2.1 Hz, H5), 7.54 (dd, 1H, J=8.8 Hz,
J=2.1 Hz, H7), 7.78 (d, 1H, J=8.6 Hz, H4), 7.84 (d, 1H, J=8.8 Hz, H8). Anal. Calcd for C11H11NS2
(221.33): C 59.69, H 5.01, N 6.33. Found: C 59.63, H 5.01, N 6.21.
4,6-Dimethylsulfanylquinoline (2d)
1
mp 51-52 ºC (hexane). EI MS (70eV) (m/z): 221 (100, M+). H NMR (CDCl3), : 2.62 (s, 3H, SCH3),
2.71 (s, 3H, SCH3), 7.17 (d, 1H, J=4.8 Hz, H3), 7.69 (dd, 1H, J=8.8 Hz, J=2.0 Hz, H7), 8.10 (d, 1H,
J=2.0 Hz, H5), 8.31 (d, 1H, J=8.8 Hz, H8), 8.62 (d, 1H, J=4.8 Hz, H2). Anal. Calcd for C11H11NS2
(221.33): C 59.69, H 5.01, N 6.33. Found: C 59.51, H 5.12, N 6.32.
Preparation of x,x'-bis(y-chloroquinolinyl) disulfides (7)
Starting y-chloro-x-mercaptoquinolines 7Y were prepared via thiouronium salts treating x,y-
dichloroquinoline (1) with 1.1 molar eqvs. of thiourea in ethanol (1 mL /1 mmol of 1) at rt for 1 day. The
mixture was then transferred on cold to 5% aqueous NaOH (1 mL /1 mmol of 1) and oxidized to disulfide
7 with 8% aqueous potassium ferricyanide (65 mL / 1 mmol of 1 ) as reported previously for 4,4'-bis(7-
chloroquinolinyl disulfide) (7e).24
2,2'-Bis(3-chloroquinolinyl) disulfide (7a)
1
mp 221-222 ºC (EtOH). Yield 83%. EI MS (70eV) (m/z): 388 (3, M+), 390 (1.9, M+ + 2), 195 (100). H
NMR (CDCl3), : 7.43 (ddd, 2H, J=8.0 Hz, J=7.6 Hz, J=1.6 Hz, H6 and H6'), 7.55 (ddd, 2H, J=8.4 Hz,
J=7.6 Hz, J=1.6 Hz, H7and H7'), 7.68 (dd, 2H, J=8.0 Hz, J=1.6 Hz, H5 and H5'), 7.83 (dd, 2H, J=8.4 Hz,
J=1.4 Hz, H8 and H8'), 8.07 (s, 2H, H4 and H4'). Anal. Calcd for C18H10Cl2N2S2 (389.31): C 55.53, H
2.59, N 7.20. Found: C 55.37, H 2.69, N 7.28.
4,4'-Bis(3-chloroquinolinyl) disulfide (7b)
mp 102-103 ºC (EtOH). Yield 86%. EI MS (70eV) (m/z): 388 (20, M+), 390 (16, M+ + 2), 195 (100). 1H

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HETEROCYCLES, Vol. 81, No. 2, 2010
NMR (CDCl3), : 7.49 (ddd, 2H, J=8.4 Hz, J=7.6 Hz, J=1.2 Hz, H6 and H6'), 7.74 (ddd, 2H, J=8.4 Hz,
J=7.6 Hz, J=1.2 Hz, H7 and H7'), 8.03 (dd, 2H, J=8.4 Hz, J=1.2 Hz, H5 and H5'), 8.12 (dd, 2H, J=8.4 Hz,
J=1.2 Hz, H8 and H8'), 8.80 (s, 2H, H2 and H2'). Anal. Calcd for C18H10Cl2N2S2 (389.31): C 55.53, H
2.59, N 7.20. Found: C 55.69, H 2.61, N 7.32.
2,2'-Bis(6-chloroquinolinyl) disulfide (7c)
mp 241-242 ºC (EtOH). Yield 90%. EI MS (70eV) (m/z): 388 (20, M+), 390 (15, M+ + 2), 195 (100). 1H
NMR (CDCl3), : 7.65 (dd, 2H, J=9.0 Hz, J=2.3 Hz, H7 and H7'), 7.75 (d, 2H, J=2.3 Hz, H5 and H5'),
7.81 (d, 2H, J=8.7 Hz, H3 and H3'), 7.93 (d, 2H, J=9.0 Hz, H8 and H8'), 7.98 (d, 2H, J=8.7 Hz, H4 and
H4'), Anal. Calcd for C18H10Cl2N2S2 (389.31: C 55.53, H 2.59, N 7.20. Found: C 55.37, H 2.55, N 7.33.
4,4'-Bis(6-chloroquinolinyl) disulfide (7d)
mp 169-170 ºC (EtOH), lit.,23 mp 169-170 ºC. Yield 89%.
Preparation of y-chloro-x-quinolinesulfonamides (6)
(Procedure C)
6% Aqueous solution of sodium hypochlorite (39.5 g, 38 mL, 26.6 mmol) was cooled down to 5 C and
then dropped within 30 min to a cold well-stirred mixture of hydrochloric acid solution of x,y-
dimercaptoquinoline (2T) (ca. 4 mmol) (prepared from x,y-dichloroquinoline according to procedure A),
conc. hydrochloric acid (12 mL) and CHCl3 (12 mL) at such a rate that temperature was maintained
below 10 C. The mixture was poured into 60 g of ice. The chloroform layer was separated, and aqueous
layer was extracted with CHCl3 (3 x 10 mL). The chloroform extracts were combined, washed with water
and dried over anhydrous sodium sulfate. CHCl3 was evaporated to leave solid residue. The residue was
recrystallized from CCl4 or from benzene to give y-chloro-x-quinolinesulfonyl chloride (5) (79-86%).
2-Chloro-3-chlorosulfonylquinoline (5a)
1
mp 180-181 ºC (CCl4). EI MS (70eV) (m/z): 261 (33, M+), 263 (21, M+ + 2), 162 (100). H NMR
(CDCl3), : 7.94 (ddd, 1H, J=8.2 Hz, J=7.6 Hz, J=0.9 Hz, H6), 8.13 (ddd, 1H, J=8.5 Hz, J=7.6 Hz, J=1.3
Hz, H7), 8.17 (dd, 1H, J=8.2 Hz, J=1.3 Hz, H5), 8.31 (dd, 1H, J=8.5 Hz, J=0.9 Hz, H8), 9.22 (s, 1H, H4).
Anal. Calcd for C9H5Cl2NO2S (262.11): C 41.24, H 1.92, N 5.34. Found: C 41.34, H 1.98, N 5.54.
4-Chloro-3-chlorosulfonylquinoline (5b)
mp 129-130 ºC (benzene), lit.,5 mp 129-130 ºC. 1H NMR spectrum (CDCl3) was identical with the sample
prepared previously.5
2-Chloro-6-chlorosulfonylquinoline (5c)
1
mp 138-140 ºC (CCl4). EI MS (70eV) (m/z): 261 (34, M+), 263 (23, M+ + 2), 162 (100). H NMR
(CDCl3), : 7.61 (d, 1H, J=8.8 Hz, H3), 8.24-8.32 (m, 3H, H4, H7 and H8), 8.60 (d, 1H, J=2.0 Hz, H5).

HETEROCYCLES, Vol. 81, No. 2, 2010
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Anal. Calcd for C9H5Cl2NO2S (262.11): C 41.24, H 1.92, N 5.34. Found: C 41.05, H 1.88, N 5.50.
Compound 5c was mentioned in references6a,b but no analytical data was given.
4-Chloro-6-chlorosulfonylquinoline (5d)
1
mp 101-102 ºC (CCl4). EI MS (70eV) (m/z): 261 (43, M+), 263 (30, M+ + 2), 162 (100). H NMR
(CDCl3), : 7.69 (d, 1H, J=4.8 Hz, H3), 8.26 (dd, 1H, J=8.8 Hz, J=2.0 Hz, H7), 8.37 (d, 1H, J=8.8 Hz,
H8), 8.93 (d, 1H, J=2.0 Hz, H5), 8.98 (d, 1H, J=4.8 Hz, H2). Anal. Calcd for C9H5Cl2NO2S (262.11): C
41.24, H 1.92, N 5.34. Found: C 41.24, H 2.09, N 5.53.
Preparation of y-chloro-x-quinolinesulfonamides (6)
(Procedure D)
Crude y-chloro-x-quinolinesulfonyl chloride (5) (0.65 g, 2.5 mmol) and conc. NH4OH (12.5 mL) was
stirred at 45 C for 0.5 h. An excess of ammonia was evaporated under vacuum. Then water was added up
to the volume of 10 mL. The solid was filtered off and washed with cold water. It was finally
recrystallized from 10% aqueous EtOH (78-86%).
2-Chloro-3-quinolinesulfonamide (6a)
mp 238-240 ºC (EtOH- water). EI MS (70eV) (m/z): 242 (100, M+), 244 (36, M+ + 2). 1H NMR (DMSO-
d6), : 7.39 (s, 2H, NH2), 7.96 (ddd, 1H, J=7.6 Hz, J=7.0 Hz, J=1.0 Hz, H6), 8.12 (ddd, 1H, J=7.9 Hz,
J=7.0 Hz, J=1.2 Hz, H7), 8.27 (dd, 1H, J=7.6 Hz, J=1.2 Hz, H5), 8.43 (dd, 1H, J=7.9 Hz, J=1.0 Hz, H8),
9.25 (s, 1H, H4). Anal. Calcd for C9H7ClN2O2S (242.67): C 44.54; H 2.91; N 11.54. Found: C 44.41, H
3.10, N 11.65.
4-Chloro-3-quinolinesulfonamide (6b)
mp 201-202 ºC (EtOH), lit.,5 mp 201-202 ºC.
2-Chloro-6-quinolinesulfonamide (6c)
mp 213-214 ºC (EtOH- water). EI MS (70eV) (m/z): 242 (100, M+). 1H NMR (DMSO-d6), : 7.58 (s, 2H,
NH2), 7.75 (d, 1H, J=8.6 Hz, H3), 8.13-8-19 (m, 2H, H7 and H8), 8.57 (d, 1H, J=1.8 Hz, H5), 8.70 (d, 1H,
J=8.6 Hz, H4). Anal. Calcd for C9H7ClN2O2S (242.67): C 44.54; H 2.91; N 11.54. Found: C 44.60, H
2.98, N 11.45.
4-Chloro-6-quinolinesulfonamide (6d)
mp 133-134 ºC (EtOH- water). EI MS (70eV) (m/z): 242 (100, M+), 244 (37, M+ + 2). 1H NMR (DMSO-
d6), : 7.69 (s, 2H, NH2), 7.93 (d, 1H, J=4.8 Hz, H3), 8.22 (dd, 1H, J=8.8 Hz, J=2.0 Hz, H7), 8.30 (d, 1H,
J=8.8 Hz, H8), 8.66 (d, 1H, J=2.0 Hz, H5), 8.99 (d, 1H, J=4.8 Hz, H2). Anal. Calcd for C9H7ClN2O2S
(242.67): C 44.54; H 2.91; N 11.54. Found: C 44.41, H 3.10, N 11.65.

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Synthesis of y-chloro-x-quinolinesulfochloride (8)
Procedure E
Solution of x,x'-bis(y-chloroquinolinyl disulfide (7) (0.39g, 1 mmol) in conc. hydrochloric acid (10 mL)
o
was cooled in an ice-salt bath down to - 10 C. Then, cold 6% aqueous solution of sodium hypochlorite
(8.2 g, 7.8 mL, 5.5 mmol) was added dropwise within 15 min to the above well-stirred mixture at such a
rate that temperature was maintained between -8 to -10 C. The mixture was poured into 60 g of ice and,
due to instability of y-chloro-x-quinolinesulfonyl chloride (8), the solution was treated with cold
ammonia as described previously for quinolinesulfonyl chlorides with chlorosulfonyl substituent in the
aza-activated position.9 Aqueous ammonia insoluble solid was filtered off and air-dried to give x,y-
dichloroquinoline (1) (0.18-28 g, 48-68%). Further work-up8,9 of the filtrate resulted in y-chloro-x-
quinolinesulfonamide (9) (0.135-275 g, 28-50%).
1
For purpose of H and 13C NMR analysis of 8, chlorination of disulfide 7 was performed in CDCl3
solution (5 mL). Organic layer was separated, washed with ice-cold water and dried over anhydrous
1
sodium sulfate. H and 13C NMR spectra showed that the content of compound 8 in CDCl3 solution
ranged from 70 to 100% and that 8 is accompanied by x,y-dichloroquinoline (1) 0-30%. Amination of
chloroform extract of 8 performed in above mentioned manner led to x,y-dichloroquinoline (1) and y-
chloro-x-quinolinesulfonamide (9) with close results to those of direct amination of 8.
3-Chloro-2-chlorosulfonylquinoline (8a)
1
Isolated in the form of CDCl3 solution. H NMR (CDCl3), : 7.61 (dd, 1H, J=7.4 Hz, J=7.2 Hz, H6),
7.74-7.79 (m, 2H, H5 and H7), 8.08 (d, 1H, J=8.8 Hz, H8), 8.27 (s, 1H, H4). 13C NMR (CDCl3), : 126.8,
127.4, 128.3, 130.2, 131.1, 133.8, 137.8.
6-Chloro-2-chlorosulfonylquinoline (8c)
1
13
Chlorination of 7c resulted in the mixture of 8c (ca. 70%) and 1c (ca. 30%). Both H and C NMR data
of 8 were extracted from the spectra (CDCl3 solution) of the 8c and 1c mixture, taking into account
spectral data of 1c.25 1H NMR (CDCl3), : 7.86 (dd, 1H, J=9.04 Hz, J=8.8 Hz, H7), 7.98 (d, 1H, J=9.08
13
Hz, H7), 8.15 (d, 1H, J=8.6 Hz, H3) 8.26 (d, 1H, J=9.0 Hz, H8), 8.44 (d, 1H, J=8.6 Hz, H4). C NMR
(CDCl3), : 118.0, 123.8, 126.7, 127.6, 133.3, 136.9, 139.1, 145.3, 158.1.
6-Chloro-4-chlorosulfonylquinoline (8d)
1
Isolated in the form of CDCl3 solution. H NMR (CDCl3), : 8.06 (d, 1H, J=8.8 Hz, H7), 8.11 (d, 1H,
J=5.6 Hz, H3), 8.42 (s, 1H, H5), 8.84 (d, 1H, J=8.8 Hz, H8), 9.20 (d, 1H, J=5.6 Hz, H2). 13C NMR
(CDCl3), : 123.3, 124.2, 124.5, 125.9, 128.2, 130.2, 132.2, 134.8, 136.8.
3-Chloro-2-quinolinesulfonamide (9a)
1
mp 234-235 ºC (EtOH-H2O). EI MS (70eV) (m/z): 242 (33, M+), 244 (12, M+ +2), 162 (100). H NMR

HETEROCYCLES, Vol. 81, No. 2, 2010
315
(DMSO-d6), : 7.80 (ddd, 1H, J=8.0 Hz, J=7.6 Hz, J=0.9 Hz, H6), 7.87 (s, 2H, NH2), 7.94 (ddd, 1H,
J=7.7 Hz, J=6.7 Hz, J=1.3 Hz, H7), 8.08-8.13 (m, 2H, H5 and H8), 8.84 (s, 1H, H4). Anal. Calcd for
C9H7ClN2O2S (242.67): C 44.54; H 2.91; N 11.54. Found: C 44.31, H 3.09, N 11.65.
6-Chloro-2-quinolinesulfonamide (9c)
mp 213-214 ºC (EtOH- water). EI MS (70eV) (m/z): 242 (40, M+), 244 (15, M+ +2), 162 (100). 1H NMR
(DMSO-d6), : 7.58 (s, 2H, NH2), 7.75 (d, 1H, J=8.8 Hz, H3), 8.13-8.19 (m, 2H, H7 and H8), 8.57 (d, 1H,
J=1.8 Hz, H5), 8.70 (d, 1H, J=8.8 Hz, H4). Anal. Calcd for C9H7ClN2O2S (242.67): C 44.54; H 2.91; Cl
14.61; N 11.54; S 13.21. Found: C 44.41, H 3.10, N 11.65.
6-Chloro-4-quinolinesulfonamide (9d)
mp 211-212 ºC (EtOH-water). EI MS (70eV) (m/z): 242 (34, M+), 244 (13, M+ +2), 162 (100). 1H NMR
(DMSO-d6), : 7.93 (dd, 1H, J=9.0 Hz, J=2.3 Hz, H7), 8.01 (d, 1H, J=4.4 Hz, H3), 8.11 (s, 2H, NH2),
8.20 (d, 1H, J=9.0 Hz, H8), 8.63 (d, 1H, J=2.3 Hz, H5), 9.13 (d, 1H, J=4.4 Hz, H2). Anal. Calcd for
C9H7ClN2O2S (242.67): C 44.54; H 2.91; N 11.54. Found: C 44.61, H 3.06, N 11.61.
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