Preparation of substituted quinolinyl and isoquinolinyl sulfonyl chlorides for the synthesis of novel sulfonamides

Article abstract of DOI:10.1081/SCC-120024002

Novel sulfonyl chlorides of quinolines and isoquinolines have successfully been prepared. This enabled the preparation of the corresponding sulfonamides via reaction with an amine using the "resin-capture and release" methodology.

Full text of DOI:10.1081/SCC-120024002

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Preparation of Substituted Quinolinyl and Isoquinolinyl
Sulfonyl Chlorides for the Synthesis of Novel
Sulfonamides
a
a
a
Justine Y. Q. Lai , Yvonne Ferguson & Mark Jones
a
Oncology Discovery Chemistry, Millennium Pharmaceuticals Limited, Granta Park, Great
Abington, Cambridgeshire, UK
Version of record first published: 15 Aug 2006.
To cite this article: Justine Y. Q. Lai , Yvonne Ferguson & Mark Jones (2003): Preparation of Substituted Quinolinyl and
Isoquinolinyl Sulfonyl Chlorides for the Synthesis of Novel Sulfonamides, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 33:19, 3427-3433
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Õ
SYNTHETIC COMMUNICATIONS
Vol. 33, No. 19, pp. 3427–3433, 2003
Preparation of Substituted Quinolinyl and
Isoquinolinyl Sulfonyl Chlorides for the Synthesis
of Novel Sulfonamides
Justine Y. Q. Lai,* Yvonne Ferguson, and Mark Jones
Oncology Discovery Chemistry, Millennium
Pharmaceuticals Limited, Granta Park, Great
Abington, Cambridgeshire, UK
ABSTRACT
Novel sulfonyl chlorides of quinolines and isoquinolines have
successfully been prepared. This enabled the preparation of the
corresponding sulfonamides via reaction with an amine using the
‘‘resin-capture and release’’ methodology.
Key Words: Quinoline; Isoquinoline; Sulfonylation; Sulfonation;
Sulfonamide.
*
Correspondence: Justine Y. Q. Lai, Scientist 1, Oncology Discovery Chemistry,
Millennium Pharmaceuticals Limited, Granta Park, Great Abington,
Cambridgeshire CB1 6ET, UK; Fax: þ44 1223-722401; E-mail: justine.lai@
mpi.com.
3
427
DOI: 10.1081/SCC-120024002
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
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428
Lai, Ferguson, and Jones
Within our laboratories, novel quinoline and isoquinoline sulfon-
amides, as exemplified by core template I, were sought. It was envisaged
that arrays of these compounds would be prepared from the respective
sulfonyl chloride and amine. Hence novel quinoline and isoquinoline
sulfonyl chlorides would provide useful building blocks for enhancing
novelty as well as structural diversity. Herein we report the successful
preparation of a series of novel quinoline and isoquinoline sulfonyl
chlorides (Entries 1–6).
O
O
S NR R
1 2
R
N
I
Chlorosulfonylation of the starting quinoline/isoquinoline was
effected by chlorosulfonic acid. Isolation of the sulfonyl chloride was
achieved either in a one-step procedure (Method B) or in two-steps via
initial isolation of the sulfonic acid (Method A). The isolation of the
sulfonic acid was identified by the characteristic stretch in the infrared
ꢀ
1
(
chloride in a subsequent step using thionyl chloride (Method A). The
ꢀmax 2800–2000 cm ). These were then converted to the sulfonyl
[
1]
results of our studies, including representative spectroscopic data, are
summarized in Table 1.
It was observed that sulfonation of the highly electron-rich quino-
lines occurred at ambient temperature within 2 h. Less electron-rich
quinolines required heating. For 1, the 5-position of the chlorosulfonyla-
tion was verified by COSY NMR of the corresponding sulfonic acid 1a.
The doublet at 10.39 ppm showed a coupling relationship with the
doublets at 8.09 ppm. These were assigned to the protons on the same
ring as the nitrogen. Unexpectedly, it was observed that there was a set of
doublets at 8.35 ppm and 8.19 ppm, which are coupled to each other.
With the methoxy substitution at the 6-position, this set of doublet was
therefore indicative that sulfonation had occurred on the 5-position.
Prolonged heating under these conditions lead to de-methylation of the
methoxy group. Hence the 6-hydroxy-quinoline-5-sulfonic acid 2a was
isolated when 6-methoxy-quinoline (Entry 2) was treated using condi-
tions outlined in Method B. In its COSY NMR, the double doublet
at 8.09 ppm showed a coupling relationship with the doublets at 9.58 ppm
and 9.11 ppm. These were assigned to the protons on the same ring as

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Quinolinyl and Isoquinolinyl Sulfonyl Chlorides
3429
the nitrogen. Again unexpectedly, it was observed that there was a set of
doublets at 7.49 ppm and 8.13 ppm, which are coupled to each other.
With the hydroxy-substitution at the 6-position, this set of doublet was
therefore also indicative that sulfonation had occurred on the 5-position,
as observed with 1. The recovery of unreacted starting material for the
electron-deficient analogues (Entries 7–9) was not unexpected.
O
O
O
S
OH
OH
O
S
OH
OMe
N
N
2
a
1
a
[
DMAP on polystyrene has been used for trapping sulfonyl chlo-
2]
[
3]
rides, which then react with amines to the corresponding sulfonamide.
We envisaged that this ‘‘resin-capture and release’’ method could be
applied in a combinatorial manner for the synthesis of small molecule
libraries for lead generation and drug discovery. Thus using this method-
ology, the corresponding novel sulfonamides, as exemplified by 10 and
11, were prepared.
O
S
O
S
O
NHBn
OMe
O
NHBn
N
N
1
0
11
In conclusion, we have synthesised novel sulfonyl chlorides of
isoquinoline/quinoline analogues in one or two steps using chlorosulfonic
acid followed by thionyl chloride. Reaction with an amine using the
‘‘resin-capture and release’’ methodology yielded the corresponding
novel sulfonamides in good yield and purity.
EXPERIMENTAL
NMR spectra were recorded on either Bruker DRX 400 or
AVANCE 400 spectrometers using residual solvent as internal reference.

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430
Lai, Ferguson, and Jones

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Quinolinyl and Isoquinolinyl Sulfonyl Chlorides
3431

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Lai, Ferguson, and Jones
Infrared spectra were recorded either on Perkin-Elmer Spectrum One or
Spectrum 1000 spectrophotometers. Mass spectra were determined by
LC-MS using Waters Symmetry [C8, 50 ꢂ 4.6 mm, 3.5 uM] eluting with
acetonitrile/water/0.1% formic acid (5–95% acetonitrile) for 5 min with a
flow rate of 1.5 mL/min. Elemental analyses were performed in the
Butterworth Analytical laboratory. Melting points were measured in
open capillary tubes on Electrothermal 9100 melting point apparatus
or by Differential Scanning Calorimetry (DSC). DSC data was collected
on TA (Thermal Analysis) instrument Q1000 equipped with a 50 position
autosampler. The energy and temperature calibration standard was
ꢁ
indium. Samples were heated at a rate of 10 C/min between 10 and
ꢁ
230 C. Between 1 and 3 mg of sample was used and all samples crimped
in a hermetically sealed aluminium pan.
Representative preparation procedure of sulfonyl chlorides/sulfonic acid
from the correspondingquinoline/isoquinoline. To a flask containing
ꢁ
chlorosulfonic acid (5 equiv.) at ꢀ10 C was added portion-wise the
quinoline/isoquinoline (10 g). The resultant mixture was stirred at the
specified time and temperature. The reaction was quenched by cautious
addition of ice until no fuming occurred. H O (80 mL) was added and the
2
reaction mixture was allowed to stir for 2–24 h to induce precipitation of
the HCl salt of the desired product. Where precipitation did not occur,
the mixture was neutralised with aq NaOH (5 M) until pH5 and extracted
with EtOAc (3 ꢂ 100 mL). The combined organic washings were dried
over MgSO and concentrated under vacuo to yield the desired product
4
as the free base.
ꢁ
6-Methoxy-2-methyl-quinoline-5-sulfonic acid 1a. M.p. 282–284 C; ꢁ
H
(
9
d6 DMSO) 10.39 (1H, d, J 9.2 Hz), 8.35 (1H, d, J 9.4 Hz), 8.19 (1H, d, J
.4 Hz), 8.09 (2H, d, J 9.2 Hz), 4.18 (3H, s, OCH ), 3.09 (3H, s, CH ).
3
3
ꢁ
6-Hydroxy-quinoline-5-sulfonic acid 2a. M.p. 367–370 C; ꢁH (d6
DMSO) 12.20 (1H, s, OH), 9.58 (1H, d, J 8.8 Hz), 9.11 (1H, dd, J 4.4,
1
9
.1 Hz), 8.13 (1H, d, J 9.6 Hz), 8.09 (1H, dd, J 8.8, 5.5 Hz), 7.49 (1H, d,
.6 Hz), 3.75 (3H, s).
Representative preparation procedure of sulfonyl chloride from the
correspondingsulfonic acid. To a flask containing the sulfonic acid
15 g) was added SOCl (30 equiv.) and DMF (0.1 equiv.). The resultant
(
2
mixture was allowed to reflux for 2 h and allowed to cool to rt.
Concentration under vacuo yielded the desired product.
Representative preparation procedure of sulfonamide from the corre-
spondingsulfonyl chloride.
3
shaken for 5 min and then drained. A solution of the sulfonyl chloride
DMAP on polystyrene resin (100 mg,
.75 ꢂ 10ꢀ mmol, 5 equiv.) was suspended in CH Cl (1 mL) and
2
2
2
(
10 equiv.) was added to the resin and shaken for 45 min. The excess

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Quinolinyl and Isoquinolinyl Sulfonyl Chlorides
3433
reagents were drained, and each well washed with CH Cl (3 times).
2
2
A solution of the amine (1 equiv.), DiPEA (10 equiv.) in CH Cl was
2
2
added. The resultant mixture was allowed to shake at rt for 20 h. The
reaction was then drained and washed with CH Cl (2 ꢂ 1 mL). The
2
2
filtrate was concentrated under vacuo to yield the desired sulfonamide.
6-Methoxy-quinoline-5-sulfonic acid benzylamide 10. Pale yellow solid
89%); m.p. 194–195 C; ꢁH (400 MHz; d DMSO) 9.82 (1H, dd, J 4.2,
ꢁ
(
6
1.6 Hz), 9.39 (1H, d, J 9.0 Hz), 8.18 (1H, d, J 9.5 Hz), 8.07 (1H, br t, J
6.4 Hz, NH), 7.67 (1H, d, J 9.5 Hz), 7.60 (1H, dd, J 9.0, 4.2 Hz), 7.10 (5H,
m), 4.07 (2H, br d, J 9.5 Hz, CH ) 4.00 (3H, s, CH ). m/z (EI) 329 (MH ).
þ
2
3
3-Methyl-isoquinoline-5-sulfonic acid benzylamide 11. Yellow solid
71%); m.p. 160–161 C; ꢁH (400 MHz; d DMSO) 9.31 (1H, s), 8.32
ꢁ
(
6
(
1H, d, J 8.2 Hz), 8.25 (1H, d, J 7.8 Hz), 8.25 (1H, s), 7.66 (1H, dd J
8
.2, 7.8 Hz), 7.05–7.15 (5H, m), 4.02 (2H, s, CH ) 2.68 (3H, s, CH ). m/z
2 3
þ
(EI) 313 (MH ). Found: C 65.19%, H 5.34%, N 8.68% S 9.54%.
C H N O S requires C 65.36% H 5.16%, N 8.97% S 10.26%.
1
7
16
2
2
REFERENCES
1. Compounds 3 and 4 have been previously prepared, but no spectro-
scopic data was provided. (a) Chem. Abstr. 1969, 70, 87517r;
(
b) Gracheva, I.N.; Gridneva, L.I.; Tochilkin, A.I.; Gorkin, V.Z.
Hydrazides and sulfonyl hydrazides of quinolines as blood serum
monoamine oxidase inhibitors. Pharm. Chem. J. (Engl. Transl.)
1988, 22 (11), 844–847.
2
. Available from Argonaut Technologies and Fluka. The resins have
been used directly without reconfirmation of the stated loading
3.75 ꢂ 10ꢀ mmol).
2
(
3
. (a) Hodgson, P.; Lloyd-Jones, G.C.; Murray, M.; Peakman, T.M.;
Woodward, R.L. Entropy-driven hydrogen bonding: stereodynamics
of a protonated, N,N-chiral ‘‘proton sponge.’’ Chem. Eur. J. 2000, 6
(24), 4451–4460; (b) Solution-Phase Synthesis Technical Section.
Resins and Reagents Catalog; Argonaut Technologies 2002; 104–105.
Received in the UK April 4, 2003

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