A concise synthesis of N-(1,3-Thiazol-2-yl) indoline-5-sulfonic acids and sulfonyl chlorides

Article abstract of DOI:10.1081/SCC-200034827

A general and practical synthetic method was developed for indoline-5-sulfonic acids bearing a thiazole heterocycle attached to the nitrogen atom. Two select sulfonic acids were further converted to their corresponding sulfonyl chlorides, key intermediates to the indoline-5- sulfonamide pharmacophore.

Full text of DOI:10.1081/SCC-200034827

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A Concise Synthesis of
N‐(1,3‐Thiazol‐2‐yl)
Indoline‐5‐Sulfonic Acids and
Sulfonyl Chlorides
Mingbao Zhang a , Robert Dally a & William Bullock
a
a Department of Chemistry Research , Bayer
Research Center , 400 Morgan Lane, West Haven,
Connecticut, 06516, USA
Published online: 10 Jan 2011.
To cite this article: Mingbao Zhang , Robert Dally & William Bullock (2004) A
Concise Synthesis of N‐(1,3‐Thiazol‐2‐yl) Indoline‐5‐Sulfonic Acids and Sulfonyl
Chlorides, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:21, 4023-4030, DOI: 10.1081/
SCC-200034827
To link to this article: http://dx.doi.org/10.1081/SCC-200034827
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 21, pp. 4023–4030, 2004
A Concise Synthesis of N-(1,3-Thiazol-2-yl)
Indoline-5-Sulfonic Acids and
Sulfonyl Chlorides
*
Mingbao Zhang, Robert Dally, and William Bullock
Department of Chemistry Research, Bayer Research Center, West Haven,
Connecticut, USA
ABSTRACT
A general and practical synthetic method was developed for indoline-5-
sulfonic acids bearing a thiazole heterocycle attached to the nitrogen
atom. Two select sulfonic acids were further converted to their correspond-
ing sulfonyl chlorides, key intermediates to the indoline-5-sulfonamide
pharmacophore.
Key Words: Indolines; Sulfonic acids; Sulfonyl chlorides; Thiazoles.
Indoline-5-sulfonyl chlorides are key intermediates to the corresponding
indoline sulfonamides, which have shown human beta-3 adrenergic receptor
*
Correspondence: Mingbao Zhang, Department of Chemistry Research, Bayer
Research Center, 400 Morgan Lane, West Haven, CT 06516, USA; Fax: 203-812-
2452; E-mail: mingbao.zhang.b@bayer.com.
4023
DOI: 10.1081/SCC-200034827
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

4024
Zhang, Dally, and Bullock
agonist activity. In particular, studies show that substitution on the indoline
nitrogen atom with a thiazole heterocycle (Fig. 1) leads to an increase in
both potency and selectivity.[1] Previously, these indoline-5-sulfonyl chlorides
were prepared by either direct chlorosulfonation of the corresponding indo-
lines, or as in the case of N-thiazole substrates, via 5-bromoindoline by a
four-step sequence involving a low temperature Li-Br exchange and oxidative
chlorination.[2,3] In the course of a research project, we required multigram
quantities of the thiazole-substituted indoline-5-sulfonyl chlorides 1a and
1b (Fig. 1). In our hands, the four-step sequence from the corresponding
bromide was not satisfactory due to low yields and lack of reproducibility.
To take advantage of the fact that methods for converting sulfonic acids to
sulfonyl chlorides are well documented in the literature,[4] we sought to
gain access to these sulfonyl chlorides via their sulfonic acid precursors.
In this paper, we demonstrate a new synthetic approach to a wide variety of
thiazole-substituted indoline-5-sulfonic acids 2 in good yields, allowing
facile access to sulfonyl chlorides such as 1a and 1b.
The new synthetic approach is outlined in Sch. 1. We sought to install the
sulfonyl function first and assemble the thiazole ring later. This strategy per-
mitted us to access the sulfonyl chlorides 1 via the corresponding sulfonic
acids 5. This approach is attractive because it is known that room temperature
chlorosulfonylation of indoline readily installs the sulfonyl function group at
the desired 5-position to yield the key sulfonic acid precursor 3,[5] thus avoid-
ing unreliable low temperature reactions. Formation of the thiazole heterocycle
Figure 1.

N-(1,3-Thiazol-2-yl) Indoline-5-Sulfonic Acids and Sulfonyl Chlorides
4025
Scheme 1.
could then be achieved by condensing a thiourea intermediate of 3 with an
appropriate a-halo ketone RCOCH2X (X ¼ halide).
In actual practice, the key sulfonic acid precursor 3 was prepared in a
straightforward manner via chlorosulfonylation of commercially available
N-acetylindoline.[5] Thiourea 4 was then obtained by treatment of 3 with
potassium thiocyanate in 1 N HCl in 83% yield as a crystalline solid (Sch. 2).
With the thiourea 4 in hand, we first explored formation of the thiazole
heterocycle of 1a by reacting 4 with 1-chlorodecan-2-one. A solvent screen
led to the identification of water as the best solvent for this reaction. Complete
reaction was achieved in 3–4 h at reflux. The desired thiazole sulfonic acid 5a
precipitated from the reaction at room temperature. Analytically pure product
was isolated by vacuum filtration in 65% yield. When thiourea 4 was allowed
to react with 1-chloro-3-(4-fluorophenyl)acetone in the same fashion, the thia-
zole sulfonic acid 5b was obtained in 72% yield. As shown in Table 1, numer-
ous a-chloroketones (6) were reacted with the thiourea 4 under the same
conditions to yield the corresponding thiazoles 2 in good yields.
Conversion of the sulfonic acid 5a to the corresponding sulfonyl chloride
1a was first explored by treatment with neat thionyl chloride. Under these con-
ditions, the thiazole ring appeared to be attacked by the thionyl chloride, as
indicated by the disappearance of the distinct thiazole C-5 proton by

4026
Zhang, Dally, and Bullock
Scheme 2. Conditions: (i) potassium thiocyanate (5 equiv), HCl (1N), reflux;
(ii) 1-chlorodecan-2-one (for 5a), or 1-chloro-3-(4-fluorophenyl)acetone (for 5b),
water, reflux; (iii) phosphorus pentachloride (2.5 equiv), phosphorus oxychloride, 08C.
1H NMR. Both 5a and 5b were converted smoothly to the corresponding
sulfonyl chlorides 1a and 1b, in 60% and 85% isolated yields respectively,
using 2.5 equivalents of PCl5 in POCl3 at 08C.
In summary, we have developed an efficient and practical synthesis of
indoline-5-sulfonic acids with an N-thiazole heterocycle substitution. Two
select sulfonic acids were converted to their corresponding sulfonyl chlorides,
key intermediates to the indoline-5-sulfonamide pharmacophore.
EXPERIMENTAL
General. NMR spectra were obtained on a Varian 300 MHz spectrometer
in DMSO-d6. All solvents and reagents were purchased either from commer-
cial sources and used without any further purification or prepared by following
known methods.[6] Indoline-5-sulfonic acid 3 was prepared according to a
literature procedure.[5]

N-(1,3-Thiazol-2-yl) Indoline-5-Sulfonic Acids and Sulfonyl Chlorides
Table 1. Preparation of N-(1,3-thiazol-2-yl) indoline-5-sulfonic acids (2).
4027
Reaction
time (h)
Isolated
yield (%)a
Entry
Chloroketone 6
Thiazoles 2
1
6a
6b
6c
6d
6e
6f
2a
2b
2c
2d
2e
2f
4
56
70
—
57
60
36
65
2
5
3b
4
3
5.5
3
5
6
3
7
6g
2g
2
1
aReaction yields were all nearly quantitative by H NMR. The lower isolated yields
were primarily due to substantial solubility of 2 in water.
bComplex mixture was obtained.
1-(Aminocarbonothioyl)indoline-5-sulfonic acid (4). The mixture of
5-indolinesulfonic acid 3 (15 g, 75.4 mmol), potassium thiocyanate (33.6 g,
346.9 mmol) was heated at reflux in 1 N HCl (190 mL) for 8 h. The reaction
was then cooled to room temperature overnight to induce formation of a
slightly yellow precipitation, which was collected by vacuum filtration.
The wet cake was washed with water (25 mL ꢀ 2) and absolute ethanol
(25 mL), respectively. It was then air dried to afford the title compound 4
(16.1 g, 83% yield): 1H NMR (DMSO-d6) d 3.06 (t, J ¼ 8.5, 2H), 4.08
(t, J ¼ 8.5, 2H), 7.36 (d, J ¼ 8.8, 1H), 7.42 (s, 1H), 7.73 (s, broad, 2H),
8.62 (d, J ¼ 8.8, 1H). LCMS(esi): m/z 259 (M þ Hþ).

4028
Zhang, Dally, and Bullock
1-(4-Octyl-1,3-thiazol-2-yl)indoline-5-sulfonic acid (5a). A 250-mL
three-necked round-bottomed flask equipped with a mechanical stir, a reflux con-
denser were charged with thiol urea 4 (6.85 g, 26.5 mmol) and water (100 mL) to
obtain a yellow suspension to which 1-chloro-2-decanone (5.5 g, 28.9mmol) was
added. The resultant mixture was then heated at reflux for 5 h under Ar to com-
plete the reaction. It was cooled to room temperature and mixed with absolute
ethanol (100 mL) under stirring to obtain a yellowish slurry. The slurry was
filtered under vacuum to afford the desired product 5a as an off-white solid in
analytically pure form (6.8g, 65% yield): 1H NMR (DMSO-d6) d 0.84
(t, J ¼ 6.7, 3H), 1.26 (m, 10H), 1.63 (m, 2H), 2.59 (t, J ¼ 7.3, 2H), 3.25
(t, J ¼ 8.6, 2H), 4.09 (t, J ¼ 8.6, 2H), 6.06 (s, broad, 1H), 6.68 (s, 1H), 7.47
(m, 2H), 7.71 (d, J ¼ 8.8, 1H). LCMS (esi) (M þ Hþ): m/z 395. Anal. Calcd.
for C19H26N2O3S2: C, 57.84; H, 6.64; N, 7.10. Found: C, 57.54; H, 6.70; N, 6.93.
1-[4-(4-Fluorobenzyl)-1,3-thiazol-2-yl]indoline-5-sulfonic acid (5b).
The compound 5b was prepared in the same fashion as described for 5a in
1
82% yield, from the thiourea 4 and 1-chloro-3-(4-fluorophenyl)acetone: H
NMR (DMSO-d6) d 3.23 (t, J ¼ 8.5, 2H), 3.95 (s, 2H), 4.02 (t, J ¼ 8.5, 2H),
6.58 (t, J ¼ 0.8, 1H), 7.12 (tt, J1 ¼ 9, J2 ¼ 2.4, 2H), 7.35 (m, 2H), 7.44
(m, 2H), 7.78 (d, J ¼ 8.8, 1H).; LCMS (esi) (M þ Hþ): m/z 391. Anal. Calcd.
for C18H15N2O3S2: C, 55.37; H, 3.87; N, 7.17. Found: C, 55.12; H, 3.79; N, 6.98.
1-[4-(4-Fluorobenzyl)-1,3-thiazol-2-yl]indoline-5-sulfonyl chloride (1b).
1-[4-(4-Fluorobenzyl)-1,3-thiazol-2-yl] indoline-5-sulfonic acid 5b (460mg,
1.18 mmol) was dissolved in POCl3 (2.00 mL) and cooled in an ice-water
bath. To this solution was then added PCl5 (610 mg, 2.95 mmol) carefully.
The resultant mixture was then stirred for 2 h, while cooled by the ice-water
bath. It was then poured onto a copious amount of crushed ice with vigorous
stirring to induce precipitation. The greenish solid was collected by vacuum
filtration and washed with water three times. It was then dried under suction
overnight to afford the desired product as a green solid (410 mg, 85%
yield): 1H NMR (DMSO-d6) d 3.24 (t, J ¼ 8.4, 2H), 3.95 (s, 2H), 4.02
(t, J ¼ 8.3, 2H), 6.58 (s, 1H), 7.12 (t, J ¼ 8.3, 2H), 7.35 (dd, J ¼ 8.8, 5.7,
2H), 7.42 (s, 1H), 7.43 (d, J ¼ 7.0, 1H), 7.78 (d, J ¼ 8.4, 1H); LCMS (esi)
(M þ Hþ): m/z 409, 411 (Cl isotope peak).
1-(4-Octyl-1,3-thiazol-2-yl)indoline-5-sulfonyl chloride (1a). This sulfo-
nyl chloride was prepared in the same fashion as described for 1b in 60% yield
from the corresponding sulfonic acid 5a. Its 1H NMR spectrum matches that of
the literature.[3] LCMS (esi) (M þ Hþ): m/z 413, 415 (Cl isotope peak).
Indoline-5-sulfonic acids 2a–2g Indoline-5-sulfonic acids 2a–2g were
prepared in the same fashion as described for 5a from 4 and an appropriate
chloroketone. The relevant spectroscopic data are listed below:
1-(4,5,6,7-Tetrahydro-1,3-benzothiazol-2-yl)indoline-5-sulfonic acid
(2a). 1H NMR (DMSO-d6) d 1.05 (t, J ¼ 7.1, 1H), 1.79 (t, unresolved, 3H),

N-(1,3-Thiazol-2-yl) Indoline-5-Sulfonic Acids and Sulfonyl Chlorides
4029
2.62 (d, J ¼ 16.0, 3H), 3.25 (t, J ¼ 8.3, 2H), 3.43 (q, J ¼ 7.0, 1H), 4.07
(t, J ¼ 8.2, 2H), 7.45 (m, 2H), 7.64 (d, J ¼ 9.0, 1H); LCMS (esi) (M þ Hþ):
m/z 337. HRMS (esi) m/z 337.0670 ([M þ H], calcd. for [C15H16N2O3S2 þ
H], 337.0675).
1-f5-[(Dimethylamino)carbonyl]-4-methyl-1,3-thiazol-2-ylgindoline-
5-sulfonic acid (2b). 1H NMR (DMSO-d6) d 2.27 (s, 3H), 2.98 (s, 6H), 3.24
(t, J ¼ 8.2, 2H), 4.02 (t, J ¼ 8.2, 2H), 7.44 (m, 2H), 7.81 (d, J ¼ 7.9, 1H);
LCMS (esi) (M þ Hþ): m/z 368. Anal. Calcd. for C15H17N3O4S2: C,
49.03; H, 4.66; N, 11.44. Found: C, 48.78; H, 4.57; N, 11.24.
1-[5-(Methoxycarbonyl)-4-methyl-1,3-thiazol-2-yl]indoline-5-sulfonic
acid (2d). 1H NMR (DMSO-d6) d 2.57 (s, 3H), 3.26 (t, J ¼ 8.2, 2H), 7.74
(s, 3H), 4.06 (t, J ¼ 8.3, 2H), 7.47 (m, 2H), 7.87 (d, J ¼ 8.4, 1H); LCMS
(esi) (M þ Hþ): m/z 355. HRMS (esi) m/z 355.0411 ([M þ H], calcd. for
[C14H14N2O5S2 þH], 355.0417).
1
1-(4,5-Dimethyl-1,3-thiazol-2-yl)indoline-5-sulfonic acid (2e). H NMR
(DMSO-d6) d 2.19 (s, 3H), 2.25 (s, 3H), 3.24 (t, J ¼ 8.4, 2H), 4.08 (t, J ¼ 8.4,
2H), 7.47 (m, 2H), 7.58 (d, J ¼ 8.3, 1H). LCMS (esi) (M þ Hþ): m/z 311.
HRMS (esi) m/z 311.0513 ([M þ H], calcd. for [C13H14N2O3S2 þH],
311.0519).
1
1-[4-(4-Fluorophenyl)-1,3-thiazol-2-yl]indoline-5-sulfonic acid (2f). H
NMR (DMSO-d6) d 3.28 (t, J ¼ 8.3, 2H), 4.09 (t, J ¼ 8.3, 2H), 7.26 (t, J ¼ 9.0,
2H), 7.48 (m, 3H), 7.99 (m, 3H); LCMS (esi) (M þ Hþ): m/z 377. HRMS (esi)
m/z 377.0421 ([M þ H], calcd. for [C17H13FN2O3S2 þH], 377.0424).
1
1-(4,5-Diphenyl-1,3-thiazol-2-yl)indoline-5-sulfonic acid (2g). H NMR
(DMSO-d6) d 3.27 (t, J ¼ 8.1, 2H), 4.10 (t, J ¼ 8.3, 2H), 7.31 (m, 8H), 7.46
(m, 4H), 7.86 (d, J ¼ 8.8, 1H); LCMS (esi) (M þ Hþ): m/z 435. HRMS (esi)
m/z 435.0832 ([M þ H], calcd. for [C23H18N2O3S2 þH], 435.0832).
ACKNOWLEDGMENT
The authors thank Stephen O’Connor and Quanrong Shen for providing a
sample of 1-chlorodecan-2-one, and Anthony Paiva and Timothy He for
obtaining HRMS data. We are indebted to Dr. David Ladner for proofreading
this manuscript.
REFERENCES
1. Mathvink, R.J.; Barritta, A.M.; Candelore, M.R.; Cascieri, M.A.; Deng, L.;
Tota, L.; Strader, C.D.; Wyvratt, M.J.; Fisher, M.H.; Weber, A.E. Potent,
Selective Human beta 3 Adrenergic Receptor Agonists Containing

4030
Zhang, Dally, and Bullock
a Substituted Indoline-5-sulfonamide Pharmacophore. Bioorg. Med.
Chem. Lett. 1999, 9, 1869–1874.
2. Graham, S.L.; Hoffman, J.M.; Gautheron, P.; Michelson, S.R.; Scholz, T.H.;
Schwam, H.; Shepard, K.L.; Smith, A.M.; Smith, R.L.; Sondey, J.M.;
Sugrue, M.F. Topically Active Carbonic Anhydrase Inhibitors. J. Med.
Chem. 1990, 33, 749–754.
3. Fisher, M.H.; Naylor, E.M.; Parmee, E.R.; Shih, T.; Ok, H.; Weber, A.E.
Benzofuran- and Indole-2-sulfonamides. Substituted Sulfonamides as
Selective b-3 Agonists for the Treatment of Diabetes and Obesity. US
Patent 5,705,515, January 6, 1998.
4. March, J. Advanced Organic Chemistry, 4th Ed.; Wiley: New York, 1992;
499.
5. Terent’ev, A.P.; Preobrazhenskaya, M.N. Introduction of Substituents
into the Benzene Ring of Indole. VI. Synthesis of Sulfo Derivatives of
Indole and Indoline. Zhurnal Obshchei Khimii 1960, 30, 1218–1222
(English translation).
6. Tillyer, R.; Frey, L.F.; Tschaen, D.M.; Dolling, U.-H. Efficient Synthesis
of alpha-Chloro Ketones via Reaction of Organometallic Reagents with
N-Methoxy-N-methylchloroacetamide. Synlett. 1996, 225–226.
Received in Japan May 24, 2004