From haloquinolines and halopyridines to quinoline- and pyridinesulfonyl chlorides and sulfonamides

Article abstract of DOI:10.3987/COM-07-11088

The action of sodium methanethiolate (in boiling DMF) towards haloazines (i.e. chloro- or bromo-pyridines and quinolines) (1) (with halogen substituent in non-aza-activated position) causes sequentially halogen ipso-substitution to methylthioazines (2) and then S-demethylation to azinethiolates (3A), which were: i) subjected to S-methylation, ii) oxidized to diazinyl disulfides (4) and iii) oxidatively chlorinated to azinesulfonyl chlorides (5). α- and γ-pyridine- and quinolinesulfonyl chlorides (5a, 5c, 5d and 5f) were prepared by oxidative chlorination of respective disulfides (4) performed in conc. hydrochloric acid and characterized by ¹H and ¹³C NMR spectra. All azinesulfonyl chlorides (5) were effectively converted to corresponding azinesulfonamides (6).

Full text of DOI:10.3987/COM-07-11088

HETEROCYCLES, Vol. 71, No. 9, 2007
1975
HETEROCYCLES, Vol. 71, No. 9, 2007, pp. 1975 - 1990. © The Japan Institute of Heterocyclic Chemistry
Received, 23rd April, 2007, Accepted, 14th June, 2007, Published online, 15th June, 2007. COM-07-11088
FROM HALOQUINOLINES AND HALOPYRIDINES TO
QUINOLINE- AND PYRIDINESULFONYL CHLORIDES AND
SULFONAMIDES #
Andrzej Maślankiewicz,a) * Krzysztof Marciniec,a) Maciej Pawłowski,b)
and Paweł Zajdelb)
a) Department of Organic Chemistry, The Medical University of Silesia
Jagiellońska 4, 41-200 Sosnowiec, Poland
b) Department of Medicinal Chemistry, Jagiellonian University Medical
College, 9 Medyczna Street, 30-688 Kraków,Poland
E-mail: maslankiewicz@slam.katowice.pl
Abstract– The action of sodium methanethiolate (in boiling DMF) towards
haloazines (i.e. chloro- or bromo-pyridines and quinolines) (1) (with
halogen substituent in non-aza-activated position) causes sequentially
halogen ipso-substitution to methylthioazines (2) and then S-demethylation
to azinethiolates (3A), which were: i) subjected to S-methylation, ii)
oxidized to diazinyl disulfides (4) and iii) oxidatively chlorinated to
azinesulfonyl chlorides (5). α- and γ-pyridine- and quinolinesulfonyl
chlorides (5a, 5c, 5d and 5f) were prepared by oxidative chlorination of
respective disulfides (4) performed in conc. hydrochloric acid and
1
13
characterized by H and C NMR spectra. All azinesulfonyl chlorides (5)
were effectively converted to corresponding azinesulfonamides (6).
INTRODUCTION
Compounds containing an azinesulfamoyl moiety are of considerable interest since they exhibit diverse
biological activities with numerous therapeutic applications.1 They have been shown to inhibit several
enzymes as well as to modulate the activity of many receptors. Several pyridinesulfonamides showed
antitumor activity,2 while 4-amino-3-pyridinesulfonylurea derivatives, including drug e.g. torasemide,
were potent diuretic agents.3 Some quinolinesulfamoyl derivatives exerted anti-HIV-1 activity,4,5 other
displayed neuroprotective, antistroke, anticancer or antiviral properties.1 They also inhibited carbonic
anhydrase and thus acted as very potent antidiabetics, diuretics or topically acting antiglaucoma agents.6
Furthermore, quinolinesulfonamides showed antiinflammatory and immunomodulating properties7 as

1976
HETEROCYCLES, Vol. 71, No. 9, 2007
well being classified as potent and selective β3 receptor agonists with therapeutic potential for the
treatment of diabetes type II and obesity.8,9 Next, the quinolinesulfonamide moiety has been recently
found in compounds acting through the CNS receptor9 and compounds targeting pathomechanisms
involved in Alzheimer’s disease.10
Azinesulfonic acids (sometimes in the form of their sodium salt) with the sulfonic substituent in the aza-
activated position can be obtained in reactions of haloazines with sodium sulfite,11,12 or by careful
oxidation of respective thioazines.11-15
Azinesulfonic acid with the sulfonic substituent in non-aza-activated position can be prepared by direct
sulfonation,16,17,18 by oxidation of respective thioazines11,15 or by work-consuming cyclisation.17,19,20 To
the best of our knowledge, there exists no general preparative method for isomeric azinesulfonic acids.
As the azinesulfamoyl moiety is more and more frequently incorporated in molecules of biologically
active compounds,1-10 we considered elaboration of a more universal method of preparation of
azinesulfonyl chlorides as a source of building blocks for the generation of azinesulfonic acid derivatives
libraries.
RESULTS AND DISCUSSION
We chose haloazines (pyridines and quinolines) (1) as common substrates since they are easily available
derivatives of azines21,22 and because sulfido-de-halogenation in haloazines was mentioned several times
in the literature.23-27 The key-inspiration for the present study comes from the paper of Testaferri, Tiecco,
Tingoli et al.,27 who stated that treatment of haloarenes and some haloheteroarenes with an excess of
sodium alkanethiolate could be arranged as a one-pot process, leading directly and effectively to sodium
arene- or azinethiolates. Whereas the authors mentioned above trapped thiolates by methylation,27 we
decided to trap azinethiolates (3A) by oxidation, first to diazinyl disulfides (4) and then to azinesulfonyl
chlorides (5).
In the case of azinesulfonyl chlorides (5b, e, g, h, i, j and k) with the sulfonyl group in the non-aza-
activated position, the experimental protocol was composed of three main stages discussed in details
below: i) preparation of methylthioazines (2) or azinethiolates (3A) from haloazines (1) and sodium
methanethiolate, ii) oxidation of crude azinethiols (3) or azinethiolates (3A) to diazinyl disulfides (4) or to
azinesulfonyl chlorides (5), iii) amination of 5 to azinesulfonamides (6). In the first stage, sodium
methanethiolate (ca.1.5 mol. eqv.) in boiling DMF (within 1 h) appeared to be sufficiently reactive for the
purpose of methylthio-de-halogenation of bromo- and chloroazines (1) to methylthioazines (2) (yield up
to 60 %) accompanied by azinethiolates (3A) (ca. 21-25 %) (Table, entries 7.1, 8.1). Furthermore,
methylthioazines (2) treated within the same reaction system underwent complete methylthio-
S-demethylation to azinethiolates (3A). To remove the excess of methanethiol derivatives, the mixture

HETEROCYCLES, Vol. 71, No. 9, 2007
1977
was evaporated to dryness, diluted with cold water, acidified with conc. hydrochloric acid and the volatile
compounds were evaporated under vacuum. The resulting mixture of azinethiol (3) and inorganic salts
was either oxidized to diazinyl disulfides (4) with potassium ferricyanide28 or subjected to oxidative-
chlorination (‘wet’-chlorination)29 to azinesulfonyl chlorides (5). Both sub-stages with the use of sodium
methanethiolate could be combined and arranged after oxidation as a process leading directly from
haloazine (1) to disulfides (4) or to azinesulfonyl chlorides (5). Due to the low basicity of azinesulfonyl
chlorides (5), they were precipitated from acetic acid or conc. hydrochloric acid solutions by dilution with
water.
S c h e m e
MeSNa
an excess
+
H
-
- NaX
azinyl-SH
azinyl-S
azinyl-SMe
azinyl-X + MeSNa
- Me2S
3
3A
1
2
(non-isolated)
X= Cl, Br
Cl2 / H2O
[O][c]
[a] or [b]
NH3
Cl2 / H2O,
[a] or [b]
(azinyl-S-)2
azinyl-SO2Cl
azinyl-SO2NH2
H2O
4
6
5
[a] 80 % AcOH, 10 oC, [b] conc. HCl aq, 0 oC, [c] aq. K3Fe(CN)6 / OH-
Azinesulfonyl chlorides (5b, e, g, h, i, j) were stable when stored at room temperature except
4-isoquinolinesulfonyl chloride (5k), which underwent partial decomposition with evolution of sulfur
dioxide even at 5 ºC. All azinesulfonyl chlorides (5) were successfully converted to the respective
azinesulfonamides (6).
Introduction of thio-substituent by replacement of halogen in azine aza-activated positions is much easier
than in other isomers. High reactivity of halogen substituent at α- and γ-positions of azines toward the
action of S-nucleophiles was observed in reactions with sodium sulfide,23a,b, 24 potasssium hydrogen
sulfide,25,26 sodium alkane and arenethiolates,27,30 sodium thiosulfate,31 thiourea,32,33 and even in reactions
with sodium sulfite.11,12
Divalent sulfur derivatives of azines (thiones vs thiols, disulfides) could be oxidized to the respective
azinesulfonic acids by careful oxidation of respective thioazines.11-15 However, none of azinesulfonic
acids or of their sodium salts (with sulfonic substituent in the aza-activated position) could be converted
to azinesulfonyl chloride after treatment with phosphorus chlorides (PCl5 or POCl3)34,13 or with thionyl
11
chloride
as well as with benzylidyne chloride.34 Nevertheless, oxidative-chlorination performed in

1978
HETEROCYCLES, Vol. 71, No. 9, 2007
80 % aqueous acetic acid (gaseous chlorine, 0-20 ºC) also causes final splitting of C(α- or γ-azinyl)-
S-bond and leads to chloroazine and sulfate anion.29
Table
Substrate or
Sulphonamide 6, 7)
Entry
1.
Product, yield [%], procedure
substrate system
(yield ) [%]
SO2NH2
N
Cl
SO2Cl
6), 8), 9)
N
N
S
N
2
5)
9)
5a
4a
1a (82)
6a (62)
S
SO2Cl
Br
SO2NH2
2
+
MeSNa
2.
3.
N
N
1b
N
N
1)
4)
5)
6b (86)
4b (82)
5b (81)
SO2Cl
SO2NH2
S
2
N
N
5c
N
4c
10)
6), 8)
6c (32)
Cl
N
1c (92)
SO2NH2
N
6d (78)
4.
5.
SO2Cl
6), 8), 11)
N
N
S
5)
2
7)
4d
5d
Br
SO2Cl
+
MeSNa
N
N
5), 6)
1)
5e (88)
SO2NH2
1d
SMe
S
S
SO2Cl
6)
N
2
+ MeSNa
6e (91)
5.1.
N
N
N
4)
3)
4e (82)
2d
5e (88)
SO2Cl
SO2NH2
2
6.
7.
N
6), 8)
N
N
4f
6f (67)
5f
Br
SO2NH2
S
SO2Cl
2
+ MeSNa
+ MeSNa
N
1)
N
N
N
7)
4)
5)
6g (92)
4g (75)
1e
5g (86)
-
Br
SMe
S
+
7.1.
8.
-
N
N
N
2)
2)
13)
N
1e
2a (56)
(24)
X
H2NO2S
S
ClO2S
2
+ MeSNa(K)
1), 12)
N
N
N
4)
5), 6)
6h (87)
4h (88)
5h (89)
1f (X=Cl), 1g (X=Br)

HETEROCYCLES, Vol. 71, No. 9, 2007
1979
Br
MeS
-
S
+ MeSNa
+
8.1
-
N
N
N
2)
1g
2)
13)
2b
(58)
(26)
+ MeSNa(K)
1), 12)
9.
X
N
ClO2S
N
S
N
H2NO2S
N
2
4)
5), 6)
6i (90)
4i (85)
5i (84)
1h (X=Cl), 1i (X=Br)
+ MeSNa
N
N
10.
N
SO2NH2
SO2Cl
5j (89)
1)
Br
5)
1j
6j (91)
Br
S
SO2Cl
SO2NH2
2
+ MeSNa
11.
N
1)
N
N
N
4)
5)
6k (87)
4k (86)
1k
5k (81)
1)
2)
3)
4)
5)
6)
7)
8)
Procedure A; Procedure B; Procedure C; Procedure D; Procedure E; Procedure F; Procedure G.
Non-isolated in the pure form, characterized by 1H and 13C NMR spectra as well as by amination. 9) Could be also
10)
11)
prepared from 2(1H)-pyridinethione, ref.,5, 26, 34, 40
.
Prepared also from 4(1H)-pyridinethione, ref.,34. Prepared
12)
also from 2(1H)-quinolinethione, ref.,35.
Potassium thiomethanolate was used for the reaction with
chloroquinolines (1f) and (1h). 13) Characterized by methylation in the form of methylthioquinoline (2).
The same treatment of 2(1H)-quinolinethione or 2,2’-diquinolinyl disulfide (4d), performed in the course
of this work, also led to 2-chloroquinoline in 92 % yield. Fortunately, Talik and Płażek34 discovered that
careful treatment of conc. hydrochloric acid solution of 2(1H)-pyridinethione and even 4(1H)-pyridine
thione with gaseous chlorine at -10 ºC – 0 ºC may be a preparative source of 2- and 4-pyridinesulfonyl
chlorides (5a and 5c). Although both isomers are very unstable compounds, the 2-isomer 5a could be
isolated in pure form (at – 70 ºC) and characterized by elemental analysis. However, due to the instability
of the 4-isomer 5c, its solutions should be immediately consumed in further processes, e.g. amination.34
Talik and Płażek’s procedure34 was confirmed later for 2-pyridinesulfonyl chloride (5a)5,40 and was
applied to the preparation of 3- and 4-quinolinesulfonyl chlorides (5e and 5f),26 however both isomers
were not obtained in the pure form, moreover, the mp’s of compound 5f (109-111 ºC)26 is according to
our experience not possible to reach. The preparation of 2-quinolinesulfonyl chloride (5d) by chlorination
of 2(1H)-quinolinethione in water and in the presence of ferric chloride was also mentioned in a French
patent.35
The chlorination of hydrochloric acid solution of all thioazines (3 and 4) was successfully applied to the
preparation of all quinoline- and pyridinesulfonyl chlorides (5) described in this paper. (see Table)
Stability of (5d and 5f) was the same as that of the corresponding pyridine derivatives (5a and 5c).
Azinesulfonyl chlorides 5a, 5c, 5d and 5f were too unstable to be isolated and stored in the pure state, as

1980
HETEROCYCLES, Vol. 71, No. 9, 2007
they underwent decomposition to sulfur dioxide and the respective chloroazines. However, immediately
after the synthesis, compounds 5a, 5c, 5d and 5f could be extracted with cold (0 °C) deuterochloroform,
1
13
and fully characterized (at 10 °C, up to 1 h) with H and C NMR spectra, which exhibited substituent
effects (∆δ) typical for chlorosulfonyl group observed for other isomers of chlorosulfonylazines (5).
Additionally, both NMR spectra showed that content of compounds 5a, 5c, 5d and 5f in CDCl3 solution
ranged from 90 up to 95 % (or 99 % for 5a) contaminated with the respective chloropyridine or
chloroquinoline (1). Azinesulfonyl chlorides (5a, c, d and f) were successfully converted to the respective
azinesulfonamides (6a, c, d and f).
The structure of all thioazine derivatives (2, 4, 5 and 6) were proved by 1H NMR spectral data and mp’s
of our products fit well the literature data of all known compounds except 7-quinolinesulfonic acid
derivatives (5i and 6i) mentioned in the old papers of Claus.36
CONCLUSIONS
Our results (collected in Table) supplemented by corresponding literature data (mentioned as sub-scripts
to the Table) prove that both types of azinesulfonyl chlorides (5) with chlorosulfonyl group in non-aza-
activated position 5(b, e, g, h, i, j, k) and aza-activated position 5(a, c, d, f) are available as isolable
compounds by oxidative chlorination of the respective thioazines (3) or (4), which allows to omit the
stage of isolation of azinethiol (3) and azinesulfonic acid for non-aza-activated isomers. This approach is
advantageous over the method of the Barrett’s group,37 for formation of azinesulfonyl chloride in the
reaction of azinemetallic derivatives with sulfuryl chloride, which makes even the isolation of crude
azinesulfonyl chloride very difficult or impossible and, moreover, may reduce the application of these
azinesulfonyl chlorides to couple with the molecules of biologically active compounds.
Close approach concerning mainly α-pyrimidine- and α-pyridinesulfonyl chlorides and fluorides based
on the oxidation of azinethiols with hypochlorite systems has been recently reported.44
Key-entry to the synthesis of non-aza-activated thioazines isomers (3) and (4) comes from the reaction of
haloazines (1) with an excess of sodium methanethiolate as a source of azinethiolates (3A), diazinyl
disulfides (4) or methylthioazines (2).
EXPERIMENTAL
Melting points were taken in open capillary tubes and are uncorrected. All NMR spectra were recorded on
1
a Bruker AVANCE 400 spectrometer operating at 400.22 and 100.64 MHz for H and 13C nuclei,
respectively, in deuterochloroform or in hexadeuterodimethylsulfoxide solutions with tetramethylsilane
(δ 0.0 ppm) as internal standard. The COSY experiments were performed using standard Bruker program.
TLC analyses were performed employing Merck's aluminium oxide 60 F254 neutral (type E) plates and

HETEROCYCLES, Vol. 71, No. 9, 2007
1981
using a mixture of CHCl3 / EtOH, 10 :1 , v/v as an eluent.
Chloro- and bromoquinolines (1e), (1f), (1g), (1h), (1i), (1j) were obtained by Skraup synthesis.19
3-Bromoquinoline (1d) and 4-bromoisoquinoline (1k) were prepared as described by Kress and
Costantino.38 3-Bromopyridine (1b), 2,2'- bispyridinyl disulfide (4a) and 4,4'-bispyridinyl disulfide (4c)
were commercial products. 2,2'-Bisquinolinyl disulfide (4d) and 4,4'-bisquinolinyl disulfide (4f) were
prepared by oxidation of the respective quinolinethiones with aqueous potassium ferricyanide.28 Sodium
methanethiolate was prepared by dissolving methanethiol (1 mol. eqv.) in cold (-5 ºC) 5 % solution of
sodium methoxide (1 mol. eqv.) in methanol under argon atmosphere. The volatile compounds were then
evaporated to dryness under vacuum. Potassium methanethiolate was prepared in the same manner.
Reactions of haloazines (1) with sodium (or potassium) methanethiolate:
• General procedure A, leading to azinethiolate (3A) or crude (non-isolated) azinethiol (3).
A mixture of haloazine (1) (4 mmol), sodium methanethiolate (1.4 g, 20 mmol) and dry DMF (12 mL)
was boiled with stirring under argon atmosphere for 4 h. (The reaction must be carried out in hood as it
proceeded with strong evolution of dimethyl sulfide). It was then cooled to 50 °C and the volatile
components were evaporated under vacuum from water bath (ca. 70 °C). The residue was dissolved in 5
mL of water and this solution was cooled down in an ice-water bath and then (under argon atmosphere)
carefully acidified with 8 mL of 20 % hydrochloric acid. The mixture was again concentrated under
vacuum up to 1/3 volume. This residue contains crude (non-isolated) azinethiol and could be used for the
preparation of disulfides or azinesulfonyl chlorides as described below.
• Procedure B, leading to methylthioazines (2) (Table, entries 7.1 and 8.1)
A mixture of haloazine (1) (4 mmol), sodium methanethiolate (0.42 g, 6 mmol) and dry DMF (12 mL)
was boiled with stirring under argon atmosphere for 1.5 h and then treated as in procedure A. The residue
(after concentration of hydrochloric acid solution) was poured into cold (5 °C) solution of 8.5 % aqueous
NaOH (22 mL). The neutral products were extracted with CH2Cl2 (3 x 10 mL). The extracts were
combined , washed with cold water (2 x 5 mL) and dried with anhydrous sodium sulfate. The solvent was
next distilled off and the residue was subjected to TLC analysis which reveals complete consumption of
the starting haloazine (1). Methylthioazine (2) was separated by column chromatography (silicagel 60 /
CHCl3).
The aqueous layer contains some amounts of azinethiolate (3A) and could either be methylated with
methyl iodide (0.12 mL, 2 mmole) to the second portion of methylthioazine (2) (isolated by extraction
with CH2Cl2 as above) or oxidized to disulfide (4) as described below.
• Procedure C, demethylation of methylthioazine (2) with sodium methanethiolate (Table, entry 5.1)
A mixture of methylthioazine (2) (4 mmol), sodium methanethiolate (0.84 g, 12 mmol) and dry DMF

1982
HETEROCYCLES, Vol. 71, No. 9, 2007
(12 mL) was boiled with stirring under argon atmosphere until the evolution of dimethyl sulfide ceased
(ca. 1.5 h) and then treated as in procedure A. Azinethiolate (3A) was trapped and characterized by
methylation (as described above) or by oxidation as presented below.
Procedure D, preparation of diazinyl disulfides (4)
A solution of crude azinethiol (3) prepared from haloazine (1) (general procedure A) or by
S-demethylation of methylthioazine (2) (procedure C) in 8.5 % aqueous NaOH (52 mL) was dropped on
stirring at rt during 15 min into 8 % aqueous K3Fe(CN)6 (260 mL) and then stirred for 15 min. The
precipitate of solid disulfides (4) was filtered off and finally recrystallized from 50 % aqueous EtOH.
3,3’-Dipyridinyl disulfide (4b) was isolated by extraction with CHCl3 (3 x 20 mL), the extracts were
dried with anhydrous Na2SO4 and then subjected to typical work-up to give oily compound (4b) (82 %).
Preparation of azinesulfonyl chloride (5) from crude azinethiol (3A) (obtained according to procedure A)
or from diazinyl disulfide (4) (prepared according to procedure D.
Procedure E, chlorination in 80 % AcOH, for isomers with thio-substituent in non-aza-activated position:
• for diazinyl disulfide (4). Gaseous chlorine was passed through a well stirred mixture of diazinyl
disulfide (1.8 mmol), 6 mL of CHCl3 and 6 mL of 80 % AcOH cooled at 5 °C at such a rate that
temperature was maintained between 15-17 °C. After 15 min. no more heat seemed to be produced. The
passage of chlorine was discontinued after 30 min. The mixture was poured into 30 g of ice. The CHCl3
layer was separated, and aqueous layer was extracted with CHCl3 (3 x 5 mL). The CHCl3 extracts were
combined, washed with water and dried over. anh. Na2SO4. CHCl3 was evaporated to leave semi-solid
residue. Crude sulfonyl chlorides (5) were used for the preparation of azinesulfonamides (6). For
analytical purpose azinesulfonyl chlorides (5) were recrystallized from light petroleum (or hexane).
• for crude azinethiol (3). AcOH (15 mL) was added on cooling to the residue containing crude azinethiol
(3) (ca. 4 mmol) prepared according to procedure A. The mixture was then chlorinated as for diazinyl
disulfides (4) described above.
Procedure F: chlorination in concentrated hydrochloric acid, applied for all isomers of diazinyl disulfides
(4) or crude azinethiols (3)
• for diazinyl disulfide (4). Gaseous chlorine was passed through a well stirred solution of azinyl disulfide
(1.8 mmol), conc. hydrochloric acid (6.6 mL) and ice (1.5 g) at -10 °C at such a rate that temperature was
maintained between –8 to –10 °C. The passage of chlorine was discontinued after 30 min. The mixture
was poured onto ice (17 g) and NaHCO3 (2 g) was added in small portions. The product (solid or oil) was
extracted with CHCl3 (or CH2Cl2) (3 x 3 mL). Organic layer was washed with ice-cold water (2 x 3 mL)

HETEROCYCLES, Vol. 71, No. 9, 2007
1983
and dried with anhydrous Na2SO4. The solvent was distilled off under vacuum. Crude sulfonyl chlorides
(5) were used for the preparation of azinesulfonamides (6).
• for crude azinethiol (3): Conc. hydrochloric acid (10 mL) was added on cooling to the residue
containing crude azinethiol (ca. 4 mmol) prepared according to procedure A. The mixture was then
chlorinated as described above for diazinyl disulfides.
Characterization of α- and γ-azinesulfonyl chlorides (5a), (5c), (5d) and (5f)
Compounds 5a, 5c, 5d and 5f were too unstable to be isolated and stored in the pure state, as they
underwent decomposition to sulfur dioxide and the respective chloroazine. However, immediately after
the synthesis, they could be extracted with cold (0 °C) CDCl3, and fully characterized (at 10 °C, up to 1 h)
with 1H and 13C NMR spectra.
The NMR spectra of compounds 5a, 5c, 5d and 5f exhibited substitent effects typical for chlorosulfonyl
group observed for other isomers of chlorosulfonylazines (5). Additionally, both NMR spectra showed,
that content of compounds 5a, 5c, 5d and 5f in CDCl3 solution ranged from 90 up to 99 % contaminated
with 5-10 % of the respective chloropyridine or chloroquinoline (1).
Synthesis of azinesulfonamides (6)
Crude azinesulfonyl chloride (5) (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. The best results in the preparation of azinesulfonamides (6a, c, d and f) were obtained when a
hydrochloric acid solution of azinesulfonyl chlorides (5a, c, d and f) (resulted from chlorination-
procedure F) was treated with two volumes of conc. NH4OH at 0 ºC, and then worked-up as above.
However, to remove residual chlorine, before amination, the hydrochloric acid solution was kept at water
pump vacuum at 0 ºC for 10 min.
5-Methylsulfanylquinoline (2a)
pale-yellow oil, lit.,17 oil. 1H NMR (CDCl3), δ: 2.58 (s, 3H, SCH3), 7.42-7.45 (m, 2H, H-3 and H-6), 7.63-
7.67 (dd, J = 8.8, 7.2 Hz, 1H, H-7), 7.91-7.93 (dd, J = 8.4, 1.4 Hz, 1H, H-8), 8.60-8.62 (dd, J = 8.4, 1.6
Hz, 1H, H-4), 8.91-8.93 (dd, J = 4.0 Hz, J = 1.6 Hz, 1H, H-2).
6-Methylsulfanylquinoline (2b)
o
o
1
mp 43-45 C (hexane), lit.,17 mp 44-46 C. H NMR (CDCl3): δ= 2.60 (s, 3H, SCH3), 7.42-7.46 (dd, J =
8.4, 4.4 Hz, 1H, H-3), 7.79-7.81 (dd, J = 8.8, 1.6 Hz, 1 H, H-7), 7.99-8.00 (m, 2 H, H-5 and H-8), 8.07-
8.10 (dd, J = 8.4, 1.6 Hz, 1 H, H-4), 8.93-8.95 (dd, J = 4.4, 1.6 Hz, 1H, H-2).

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HETEROCYCLES, Vol. 71, No. 9, 2007
3,3'-Bispyridinyl disulfide (4b)
pale-yellow oil, b.temp. 180-183 oC/ 4 mm Hg, lit.,39 b.temp. 155 oC/ 1 mm Hg.
3,3'-Bisquinolinyl disulfide (4e)
mp 150-151 oC (EtOH-water), lit.,17 mp 150-151.5 oC.
5,5'-Bisquinolinyl disulfide (4g)
mp 108-109 oC (benzene/hexane), lit.,17 mp 109 oC.
6,6'-Bisquinolinyl disulfide (4h)
mp 118-119 °C (EtOH-water), lit.,20 119 oC.
7,7'-Bisquinolinyl disulfide (4i)
mp 141-142 °C (EtOH-water). 1H NMR (CDCl3), δ: 7.28-7.39 (dd, J = 8.2 Hz, 4.2 Hz, 2H, H-3 and H-3'),
7.69-7.72 (dd, J =8.4 Hz, 2.0 Hz, 2H, H-6 and H-6'), 7.78-7.80 (d, J = 8.4 Hz, 2H, H-5 and H-5'), 8.11-
8.14 (dd, J = 8.2 Hz, 1.8 Hz, 2H, H-4 and H-4'), 8.28-8.29 (d, J = 2.0 Hz, 2H, H-8 and H-8'), 8.87-8.89
(dd, J = 4.2, 1.8 Hz, 2H, H-2 and H-2'). Anal. Calcd for C18H12N2S2 (320.42): C 67.47; H 3.77; N 8.74; S
20.01. Found C 67.30; H 3.69; N 8.61; S 19.77.
4,4'-Bisisoquinolinyl disulfide (4k)
1
mp 135-136 °C (EtOH-water). H NMR (CDCl3), δ: 7.62-7.71 (m, 4H, H-6, H-6', H-7 and H-7'), 7.98-
8.01 (dd, J = 8.2 Hz, 1.2 Hz, 2H, H-5 and H-5'), 8.15-8.17 (dd, J = 8.4 Hz, 1.0 Hz, 2H, H-8 and H-8'),
8.44 (s 2H, H-3 and H-3'), 9.20 (s, 2H, H-1 and H-1'). Anal. Calcd for C18H12N2S2 (320.42): C 67.47; H
3.77; N 8.74; S 20.01. Found C 67.27; H 3.70; N 8.84; S 19.79.
2-Pyridinesulfonyl chloride (5a)
1
solid at rt, unstable at rt. H NMR (CDCl3), δ: 7.60-7.64 (ddd, J = 8.0, 4.8 Hz, 1.2 Hz, 1H, H-5), 7.96-
8.01 (ddd, J = 8.0, 7.6, 2.0 Hz, 1H, H-4), 8.05-8.07 (dd, J = 8.0, 1.2 Hz, 1H, H-3), 8.76-8.77 (dd, J = 4.8,
13
2.0 Hz, 1H, H-6). C NMR (CDCl3), δ: 159.2 (C2), 159.0 (C6), 139.4 (C4), 129.5 (C3) 122.2 (C5).
Described in the references.5, 26, 34, 40
3-Pyridinesulfonyl chloride (5b)
colourless oil, lit.,40 oil. 1H NMR (CDCl3), δ: 7.70-7.74 (dd, J = 7.6, 4.8 Hz, 1H, H-5), 8.43-8.45 (dd, J =
7.6, 2.0 Hz, 1H, H-4), 9.03-9.05 (dd, J = 4.8, 2.0 Hz, 1H, H-6), 9.31-9.32 (d, J = 2.0 Hz, 1H, H-2). Bruice
and co-workers43 reported mp and 1H NMR spectrum of hydrochloride of 3-pyridinesulfochloride instead
of the respective data of parent compound (5b).
4-Pyridinesulfonyl chloride (5c)
Isolated only in the form of methylene chloride or chloroform solutions, unstable at 10 oC, decomposition
1
observed within 1 h. H NMR (CDCl3), δ: 7.86-7.88 (ddd, J = 4.5, 1.6, 0.3 Hz, 2H, H-3 and H-5), 8.99-
9.01 (ddd, J = 4.5, 1.6, 0.3 Hz, 2H, H-2 and H-6). 13C NMR (CDCl3), δ: 119.6 (C3 and C5), 151.6 (C4),

HETEROCYCLES, Vol. 71, No. 9, 2007
1985
152.2 (C2 and C6). Described in the reference.34
2-Quinolinesulfonyl chloride (5d)
1
Solid at rt, unstable at rt. H NMR (CDCl3), δ: 7.79-7.83 (ddd, J = 8.8, 7.0, 0.9 Hz, 1H, H-6), 7.92-7.96
(ddd, J = 8.8, 7.0, 1.2 Hz, 1H, H-7), 7.99-8.01 (d, J = 8.4 Hz, 1H, H-3), 8.14-8.16 (dd, J = 8.8, 0.9 Hz, 1H,
H-5), 8.32-8.34 (dd, J = 8.8, 1.2 Hz, 1 H, H-8), 8.52-8.54 (d, J = 8.4 Hz, 1H, H-4). 13C NMR (CDCl3), δ:
117.0 (IIIo), 128.2 (IIIo), 130.1 (C4a), 130.8 (2 x IIIo), 132.5 (IIIo), 140.2 (IIIo), 139.0 (C4), 147.3 (C8a),
158.1 (C2). Described in the reference.5
3-Quinolinesulfonyl chloride (5e)
o
mp 96-97 oC (hexane), lit.,26 mp 85-87 C, mentioned as a part of sample collection.4 1H NMR (CDCl3),
δ: 7.81-7.85 (ddd, J = 8.0, 7.2, 1.4 Hz, 1H, H-6), 8.03-8.06 (ddd, J = 8.4, 7.2, 1.6 Hz, 1H, H-7), 8.07-8.10
(dd, J = 8.0, 1.6 Hz, 1 H, H-5), 8.34-8.36 (dd, J = 8.4, 1.4 Hz, 1H, H-8), 8.94-8.95 (d, J = 2.0 Hz, 1H,
H-4), 9.44-9.45 (d, J = 2.0 Hz, 1H, H-2).
4-Quinolinesulfonyl chloride (5f)
Isolated only in the form of methylene chloride or chloroform solutions, unstable at 10 oC, within 1 h. 1H
NMR (CDCl3), δ: 8.00-8.04 (dd, J = 8.8, 7.6 Hz, 1H, H-6), 8.08-8.09 (d, J=6.0 Hz, 1H, H-3), 8.14-8.18
(dd, J = 8.4, 7.6 Hz, 1H, H-7), 8.47-8.49 (d, J = 8.4 Hz, 1H, H-8), 8.91-8.93 (d, J = 8.8 Hz, 1H, H-5),
9.15-9.16 (d, J = 6.0 Hz, 1H, H-2). 13C NMR (CDCl3), δ: 122.3 (C3), 122.9 (C6), 125.5 (C5), 127.5 (C4a),
131.6 (C7),136.0 (C8), 139.0 (C4), 143.13 (C8a), 153.5 (C2). Mentioned in the reference26 as a
compound with mp 109-111 ºC, which temperature is not possible to be reached without compound
decomposition according to our studies.
5-Quinolinesulfonyl chloride (5g)
o
o
1
mp 91-92 C (hexane), lit.,17 mp 91-95 C. H NMR (CDCl3), δ: 8.16-8.22 (m, 2H, H-3 and H-7), 8.69-
8.70 (dd, J = 7.2, 1.4 Hz, 1H, H-6), 9.25-9.29 (m, 2H, H-4 and H-8), 9.69-9.71 (dd, J =4.4, 1.2 Hz, 1H,
H-2).
6-Quinolinesulfonyl chloride (5h)
o
o
1
mp 89-90 C (hexane), lit.,20 mp 91 C. H NMR (CDCl3), δ: 7.62-7.66 (dd, J = 8.3, 4.2 Hz, 1H, H-3),
8.23-8.26 (dd, J = 9.0, 2.2 Hz, 1H, H-7), 8.33-8.35 (d, J = 9.0 Hz, 1H, H-8), 8.37-8.39 (dd, J=8.3, 1.6 Hz,
1H, H-4), 8.61-8.62 (d, J = 2.2 Hz, 1H, H-5), 9.14-9.15 (dd, J = 4.2, 1.6 Hz, 1H, H-2).
7-Quinolinesulfonyl chloride (5i)
mp 115-116 oC (hexane). 1H NMR (CDCl3), δ: 7.68-7.71 (dd, J = 8.4, 4.4 Hz, 1H, H-3), 8.10-8.16 (m, 2H,
H-5 and H-6), 8.35-8.37 (dd, J = 8.4, 1.6 Hz, 1H, H-4), 8.92-8.93 (d, J = 1.6 Hz, 1H, H-8), 9.14-9.15 (dd,
J = 4.4, 1.6 Hz, 1H, H-2). Anal. Calcd for C9H6ClNO2S (227.66): C 47.48; H 2.66; N 6.15; S 14.08.
Found C 47.28; H 2.46; N 6.01; S 13.78.

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HETEROCYCLES, Vol. 71, No. 9, 2007
8-Quinolinesulfonyl chloride (5j)
o
o
1
mp 130-131 C (hexane), lit.,17 mp 131 C. H NMR (CDCl3), δ: 7.63-7.66 (dd, J = 7.6, 4.4 Hz, 1H,
H-3), 7.68-7.72 (dd, J = 8.4, 8.0 Hz, 1H, H-6) 8.22-8.24 (dd, J = 8.0, 1.6 Hz, 1H, H-5), 8.31-8.33 (dd, J =
8.4, 1.6 Hz, 1H, H-7), 8.53-8.56 (dd, J = 7.6, 1.6 Hz, 1H, H-4), 9.23-9.25 (dd, J = 4.4, 1.6 Hz, 1H, H-2).
4-Isoquinolinesulfonyl chloride (5k)
o
1
mp 112-113 C (hexane). H NMR (CDCl3), δ: (ddd, J = 8.0, 7.2, 1.4 Hz, 1H, H-6), 7.98-8.03 (ddd, J =
8.4, 7.2, 1.6 Hz, 1H, H-7), 8.30-8.32 (dd, J = 8.0, 1.6 Hz, 1H, H-5), 8.75-8.77 (dd, J = 8.4, 1.4 Hz, 1H,
H-8), 9.25 (s, 1H, H-3), 9.69 (s, 1H, H-1). Anal. Calcd for C9H6ClNO2S (227.66): C 47.48; H 2.66;
N 6.15; S 14.08. Found C 47.23; H 2.60; N 5.95; S 13.81.
2-Pyridinesulfonamide (6a)
o
o
1
mp 140-141 C (EtOH-water), lit.34 mp 133 C. H NMR (DMSO-d6), δ: 7.46 (s, 2H, NH2), 7.62-7.65
(ddd, J = 7.6, 4.8, 1.6 Hz, 1H, H-5), 7.92-7.95 (dd, J = 8.0, 1.6 Hz, 1H, H-3), 8.05-8.09 (ddd, J = 8.0, 7.6,
1.6 Hz, 1H, H-4), 8.71-8.72 (dd, J = 4.8, 1.6 Hz, 1H, H-6).
3-Pyridinesulfonamide (6b)
mp 109-110 oC (hexane-acetone), lit.,41 mp 110-111 oC. 1H NMR (DMSO-d6), δ: 7.61 (s, 2H, NH2), 7.62-
7.65 (dd, J = 8.0, 4.8 Hz, 1H, H-5), 8.18-8.20 (dd, J = 8.0, 1.6 Hz, 1H, H-4), 8.78-8.80 (dd, J = 4.8, 1.6
Hz, 1H, H-6), 8.98-8.99 (d, J = 1.6 Hz, 1H, H-2).
4-Pyridinesulfonamide (6c)
mp 168-169 °C (water), lit.,34 mp 168-169 °C. 1H NMR (DMSO-d6), δ: 7.70 (s, 2H, NH2), 7.74-7.75 (dd,
J = 4.4, 1.6 Hz, 2H, H-3 and H-5), 8.82-8.84 (dd, J = 4.4, 1.6 Hz, 2H, H-2 and H-6).
2-Quinolinesulfonamide (6d)
o
1
mp 164-165 C (EtOH-water). H NMR (DMSO-d6), δ: 7.64 (s, 2 H, NH2), 7.76-7.80 (ddd, J = 8.2, 7.0,
1.2 Hz, 1H, H-6), 7.90-7.94 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, H-7), 8.02-8.04 (d, J = 8.8 Hz, 1H, H-3), 8.12-
8.14 (m, 2H, H-5 and H-8), 8.66-8.68 (d, J = 8.8 Hz, 1H, H-4). Anal. Calcd for C9H8N2O2S (208.33):
C 51.91; H 3.87; N 13.45; S 15.40. Found C 51.86; H 3.89 N 13.11; S 15.27.
3-Quinolinesulfonamide (6e)
mp 204-205 oC (EtOH-water). 1H NMR (DMSO-d6), δ: 7.67 (s, 2H, NH2), 7.72-7.76 (ddd, J = 8.0, 7.0,
1.2 Hz, 1H, H-6), 7.90-7.94 (ddd, J = 8.4, 7.0, 1.4 Hz, 1H, H-7), 8.11-8.13 (dd, J = 8.0, 1.4 Hz, 1H, H-5),
8.20-8.22 (dd, J = 8.4, 1.2 Hz, 1H, H-8), 8.83-8.84 (d, J = 2.4 Hz, 1H, H-4), 9.22-9.23 (d, J = 2.4 Hz, 1H,
H-2). Anal. Calcd.for C9H8N2O2S (208.33): C 51.91; H 3.87; N 13.45; S 15.40. Found C 51.80; H 3.86; N
13.29; S 15.2.
4-Quinolinesulfonamide (6f)
o
1
mp 184-185 C (EtOH-water). H NMR (DMSO-d6), δ: 7.77-7.81 (ddd, J = 8.0, 7.0, 1.2 Hz, 1H, H-6),

HETEROCYCLES, Vol. 71, No. 9, 2007
1987
7.88-7.92 (ddd, J = 8.4, 7.0, 1.2 Hz, 1H, H-7), 7.96-7.97 (d, J = 4.4 Hz, 1H, H-3), 8.00 (s, 2H, NH2),
8.17-8.19 (dd, J = 8.0, 1.2 Hz, 1H, H-5), 8.61-8.63 (dd, J = 8.4, 1.2 Hz, 1H, H-8), 9.11-9.12 (d, J = 4.8 Hz,
1H, H-2). Anal. Calcd. for C9H8N2O2S (208.33): C 51.91; H 3.87; N 13.45; S 15.40. Found C 51.90; H
3.86 N; 13.09; S 15.23.
5-Quinolinesulfonamide (6g)
mp 177-178 oC (EtOH-water). 1H NMR (DMSO-d6), δ: 7.71-7.75 (dd, J = 8.4, 4.4 Hz, 1H, H-3), 7.79 (s,
2H, NH2), 7.88-7.92 (dd, J = 8.4, 7.2 Hz, 1H, H-7), 8.19-8.22 (dd, J = 7.2, 1.2 Hz, 1H, H-6), 8.26-8.28
(dd, J = 8.4, 1.2 Hz, 1H, H-8), 9.01-9.03 (dd, J = 8.4, 1.2 Hz, 1H, H-4), 9.04-9.05 (dd, J = 4.4, 1.2 Hz, 1H,
H-2). Anal. Calcd. for C9H8N2O2S (208.33): C 51.91; H 3.87; N 13.45; S 15.40. Found C 51.79; H 3.83
N; 13.29; S 15.27.
6-Quinolinesulfonamide (6h)
mp 191-192 oC (EtOH-water), lit.,20 mp 192 oC. 1H NMR (DMSO-d6), δ: 7.56 (s, 2H, NH2), 7.65-7.69 (dd,
J = 8.4, 4.4 Hz, 1H, H-3), 8.01-8.14 (dd, J = 8.8, 2.0 Hz, 1H, H-7), 8.19-8.20 (d, J = 8.8 Hz, 1H,
H-8), 8.48-8.49 (d, J = 2.0 Hz, 1H, H-5), 8.59-8.60 (dd, J = 8.4, 1.6 Hz, 1H, H-4), 9.02-9.04 (dd, J = 4.4,
1.6 Hz, 1H, H-2).
7-Quinolinesulfonamide (6i)
mp 192-193 °C (EtOH-water). 1H NMR (DMSO-d6), δ: 7.60 (s, 2H, NH2), 7.68-7.71 (dd, J = 8.4, 4.0 Hz,
1H, H-3), 7.96-7.99 (dd, J = 8.6, 1.8 Hz, 1H, H-6), 8.19-8.21 (d, J = 8.6 Hz, 1H, H-5), 8.44-8.45 (d,
J = 1.8 Hz, 1H, H-8), 8.48-8.50 (dd, J = 8.4, 1.6 Hz, 1H, H-4), 9.04-9.05 (dd, J = 4.0, 1.6 Hz, 1H, H-2).
C9H8N2O2S (208.23): calcd. C 51.91; H 3.87; N 13.45; S 15.40; found C 51.90; H 3.86 N 13.18; S 15.18.
8-Quinolinesulfonamide (6j)
mp 183-184 oC (EtOH-water), lit.,42 mp 179 oC. 1H NMR (DMSO-d6), δ: 7.36 (s, 2H, NH2), 7.69-7.77 (m,
2H, H-3 and H-6), 8.25-8.28 (dd, J = 8.4, 1.4 Hz, 1H, H-5), 8.29-8.30 (dd, J = 7.2, 1.4 Hz, 1H, H-7),
8.53-8.55 (dd, J = 8.4, 1.6 Hz, 1H, H-4), 9.06-9.08 (dd, J = 4.4, 1.6 Hz, 1H, H-2).
4-Isoquinolinesulfonamide (6k)
o
1
mp 248-249 C (EtOH-water). H NMR (DMSO-d6), 7.84-7.87 (m, 3H, H-6 and NH2), 7.98-8.03 (ddd,
J = 8.4, 7.2, 1.6 Hz, 1H, H-7), 8.31-8.33 (dd, J = 8.4, 1.6 Hz, 1H, H-5), 8.59-8.61 (dd, J = 8.4, 1.4 Hz, 1H,
H-8), 8.98 (s, 1H, H-3), 9.55 (s, 1H, 1-H). Anal. Calcd for C9H8N2O2S (208.23): C 51.91; H 3.87;
N 13.45; S 15.40. Found C 51.66; H 3.93; N 13.36; S 15.21.
ACKNOWLEDGMENTS
This paper is dedicated to Professor Marian Mikołajczyk from the Centre of Molecular and
Macromolecular Studies of the Polish Academy of Sciences, Łódź, Poland, for His encouragement to
study organic chemistry of sulfur.

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HETEROCYCLES, Vol. 71, No. 9, 2007
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