A convenient synthesis of novel 3-(heterocyclylsulfonyl)propanoic acids and their amide derivatives

Article abstract of DOI:10.1055/s-2004-834888

A large number of novel 3-(heterocyclylsulfonyl)propanoic acids and their amide derivatives were prepared in good yields and excellent purity starting from the corresponding heterocyclic compounds. At first, chlorosulfonates were generated by reaction of initial heterocycles with various sulfonating and chlorinating agents followed by their conversion into sodium sulfinates. Treatment of sulfinates with acrylic acid smoothly afforded a series of sulfonylpropionates, which were used as convenient reagents for the preparation of a large number of the corresponding carboxamide derivatives.

Full text of DOI:10.1055/s-2004-834888

PAPER
2999
A Convenient Synthesis of Novel 3-(Heterocyclylsulfonyl)propanoic Acids and
their Amide Derivatives
S
ynthesis of 3-(Hetero
i
k
ulfonyl)prop
h
a
noic
A
cids
a
A
midesil V. Dorogov, Sergey I. Filimonov, Dmitry B. Kobylinsky, Sergey A. Ivanovsky, Pavel V. Korikov,
Mikhail Y. Soloviev, Maria Y. Khahina, Elena E. Shalygina, Dmitry V. Kravchenko, Alexandre V. Ivachtchenko*
Chemical Diversity Labs, Inc., 11558 Sorrento Valley Rd., Suite 5, San Diego, CA 92121, USA
Fax +1(858)7944931; E-mail: av@chemdiv.com
Received 28 May 2004; revised 27 July 2004
sodium sulfite and the reaction of the resulting sodium
Abstract: A large number of novel 3-(heterocyclylsulfonyl)pro-
sulfinates with acrylic acid. The desired sulfonylpropi-
panoic acids and their amide derivatives were prepared in good
onates were obtained in high yields (generally, in the
range of 50–70% from the initial heterocycles) and excel-
yields and excellent purity starting from the corresponding hetero-
cyclic compounds. At first, chlorosulfonates were generated by re-
action of initial heterocycles with various sulfonating and lent purity using easy purification procedures, such as pre-
chlorinating agents followed by their conversion into sodium sulfi-
cipitation from the reaction mixtures and recrystallization.
nates. Treatment of sulfinates with acrylic acid smoothly afforded a
We used these acids as starting reagents for the prepara-
series of sulfonylpropionates, which were used as convenient re-
tion of a large library of carboxamides via the correspond-
agents for the preparation of a large number of the corresponding
ing acid chlorides.5
carboxamide derivatives.
We found this general scheme suitable for preparation of
other 3-(heterocyclylsulfonyl)propanoic acids and their
amide derivatives (Scheme 1). At the first step, chlorosul-
fonates 2a–h were obtained in good yields (39–88%) by
reacting the heterocyclic compounds 1a–h with a mixture
of chlorosulfonic acid and PCl5 (Method A) or with chlo-
rosulfonic acid (Method B) at elevated temperature. In the
case of quinoline 1g, both methods led to mixtures of re-
gioisomers, which were extremely difficult to separate us-
ing standard laboratory techniques. Therefore, we used a
modified procedure (Method C). Quinoline 1g was treated
with fuming sulfuric acid (30% SO3) at 90 °C. The result-
ing quinoline-8-sulfate was then reacted with PCl5 to af-
ford chlorosulfonate 2g (Table 1).
Key words: 3-(heterocyclylsulfonyl)propanoic acid, chlorosul-
fonates, heterocycles, parallel synthesis, libraries
Synthetic arylsulfonylalkylcarboxylic acids and their de-
rivatives are present in a wide variety of physiologically
active compounds. In particular, variously substituted de-
rivatives of 3-(phenylsulfonyl)propanoic acid were de-
scribed as antiinfective,1 oncolytic,2 antiarthritic3 and
gastrointestinal4 agents. According to these examples and
due to evident structural and bioisosteric similarity to the
mentioned physiologically active agents, the heterocyclic
analogs of 3-(phenylsulfonyl)propanoic acid represent
promising synthetic targets. Development of effective
strategies for their synthesis will provide a valuable
source of novel pharmaceutical agents.
The principal concern in the reaction of heterocyclic com-
pounds with chlorosulfonic acid is the regioselectivity of
sulfochlorination. The structures of compounds 2a–h
were established by a combination of elemental analyses,
To the best of our knowledge, no physiologically active
derivatives of 3-(heterocyclylsulfonyl)propanoic acids
were reported to date. These observations prompted us to
explore the synthetic pathways to 3-sulfonylpropanamide
derivatives of several different heterocycles, such as indo-
line 1a–d, 2,1,3-benzoxadiazole 1e, 2,1,3-benzothiadiaz-
ole 1f, quinoline 1g, and 1,4-dihydroquinoxaline-2,3-
dione 1h (Scheme 1). In this work, we report a convenient
and versatile synthetic approach to these novel heterocy-
clic structures and discuss the scope and limitations of the
chemistry involved.
1
MS and H NMR spectroscopy, and by a series of NOE
difference experiments which provided full information
about the substitution pattern. Based on the 1H NMR mea-
surements, only one major sulfochlorination product has
been formed in all the studied reactions under the de-
scribed conditions (Table 1). For example, for compound
2a, the key experiment enabled us to assign all three aro-
matic protons of the indoline ring by a single NOE differ-
ence spectrum. In this experiment, we observed the
positive NOEs between the H-7 and H-6 protons, which is
consistent with the suggested molecular structure.
Recently, we reported a convenient synthetic method for
preparation 3-(2-thienylsulfonyl)propanoic and 3-(5-bro-
mo-2-thienylsulfonyl)propanoic acids and the corre-
sponding carboxamide derivatives.5 The synthetic scheme
included sulfochlorination of thiophene or 2-bro-
mothiophene, treatment of 2-thienylchlorosulfonates with
Chlorosulfonates 2a–h were then converted into sodium
sulfinates 3a–h by treatment with an aqueous solution of
sodium sulfite and sodium bicarbonate (yield: 75–97%).
Sulfinates 3a–h were reacted with acetic acid in water to
give sulfinic acids 4a–h. Reaction of 4a–h in situ with
acrylic acid then furnished the corresponding 3-sulfonyl-
propanoic acids 5a–h in 50–75% yields. Acids 5a–h were
converted into the corresponding chlorides 6a–h by heat-
SYNTHESIS 2004, No. 18, pp 2999–3004
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Advanced online publication: 22.10.2004
DOI: 10.1055/s-2004-834888; Art ID: M04204SS
© Georg Thieme Verlag Stuttgart · New York

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M. V. Dorogov et al.
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Scheme 1 Reagents and conditions: (a) Method A: i. HSO3Cl, 30–40 °C; ii. PCl5, 80 °C (39–53%); Method B: HSO3Cl, 65–135 °C (63–
80%); Method C: i, H2SO4/SO3, 65–70 °C; ii. PCl5, 145 °C (58%); (b) Na2SO3, NaHCO3, H2O, 85–90 °C, pH 9–10 (75–97%); (c) AcOH, H2O,
20 °C; (d) H2C=CHCO2H, 20 °C (50–75%); (e) PCl5, toluene, reflux (50–75%); (f) HNR1R2, Py, DMF, 55 °C (30–95%).
ing with PCl5 in toluene (yield 50–75%). Finally, several with acids 5a–h are shown in Figure 1. The protocols are
amide libraries 7a–h were smoothly obtained using the re- straightforward and can easily be reproduced on a 10–50
action of acid chlorides 6a–h with primary and secondary g scale.
amines in DMF in the presence of pyridine. The yields of
amides were in the range of 30–95%. The developed ap-
proach to the amide libraries is compatible with the high-
All final amides within the studied heterocyclic series 7a–
h are stable crystalline compounds, which were character-
ized by LCMS and 1H NMR spectroscopy. Several exam-
throughput parallel synthesis format, and a wide variety of
ples of compounds from these libraries are shown in
different amino components can be used for this reaction.
Figure 2. All analytical data gave satisfactory results con-
The representative examples of amines used for coupling
sistent with the suggested molecular structures.
Figure 1 Representative examples of amines used as building blocks in the reaction with acids 5a–h.
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Synthesis of 3-(Heterocyclylsulfonyl)propanoic Acids and Amides
3001
Table 1 Heterocyclylsulfonyl Chlorides 2a–h
Entry
1
Product
Structure
Reaction Conditions
Yield (%)
53
Mp (°C)
171–172
2a
Method A
i. ClSO3H, 0–40 °C, 1 h
ii. PCl5, 80 °C, 1 h
2
3
2b
2c
Method A
i. ClSO3H, 30–40 °C, 1 h
ii. PCl5, 80 °C, 1 h
39
63
143–144
212–214
Method B
i. ClSO3H, 65–70 °C, 3 h
4
2d
Method B
80
175–177
i. ClSO3H, 65–70 °C, 3 h
5
6
7
8
2e
2f
Method B
i. ClSO3H, 120–130 °C, 6 h
65
70
58
75
78–80
Method B
130–135 °C, 6 h
163–165
124–126
250–252
2g
2h
Method C
i. H2SO4/SO3, 65–70 °C, 40 h
ii. PCl5, 145 °C, 1 h
Method B
i. ClSO3H, 65–90 °C, 3 h
The methylene protons of the sulfonylpropionate frag- varied according to the reactant structures, but in most
ment of acids 5a–h are usually clearly observed as triplets cases, the desired products were obtained in high yields.
in the range of 2.24–2.86 (a-protons) and 3.03–4.05 (b- The results provide further confirmation of the scope and
protons). The formation of carboxamides from the corre- generality of the applied approach to different 3-sulfonyl-
sponding acids usually causes a definite downfield shift of propionate derivatives of heterocyclic compounds: >1000
0.05–0.30 ppm for a-protons and does not substantially analogues of these molecules have been made in our lab-
influence the signals from b-protons. These characteristic oratories in the past two years by parallel synthesis meth-
signals can be used for identification of the obtained struc- ods.5
tures.
In summary, an efficient synthetic route has been devel-
oped for the preparation of a variety of 3-(heterocyclylsul-
fonyl)propanoic acids and their amide derivatives. In all
the heterocyclic series investigated, the corresponding ac-
ids and amides were generated with low levels of impuri-
ties using easy purification procedures. Product yields
Melting points were measured with a Koeffler melting point appa-
ratus and are uncorrected. H NMR spectra were recorded on a
1
Bruker AMX-400 spectrometer in DMSO-d6 using TMS as an in-
ternal standard (chemical shifts in ppm). LCMS spectra were re-
corded with a PE SCIEX API 150EX liquid chromatograph
equipped with a UV detector (lmax 215 and 254 nm) and using a C18
column (100 × 4 mm). Elution started with H2O and ended with
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M. V. Dorogov et al.
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Figure 2 Examples of 3-(heterocyclylsulfonyl)propanamides from libraries 7a–h synthesized in this work.
MeCN–H2O (95:5, v/v) and used a linear gradient at a flow rate of
0.15 mL/min and an analysis cycle time of 25 min. All reagents and
solvents were purchased from Acros Organics, Aldrich or ChemDiv
and were used without further purification.
then cooled to r.t. and extracted with CHCl3 (3 × 30 mL). The com-
bined organic fractions were evaporated in vacuo and the crude res-
idue was recrystallized from benzene–petroleum ether (bp 40–60
°C) to afford pure 2g; yield: 12.6 g (58%); mp 124–126 °C.
Heterocyclylsulfonyl Chlorides 2a–h; General and Typical Pro-
cedures
Sodium Heterocyclylsulfinates 3a–h; General Procedure
The chlorosulfonate 2a–h (0.5 mol) was added at 85–90 °C and pH
9–10 over 1 h to a stirred solution of Na2SO3 (63 g, 0.5 mol) and
NaHCO3 (4.2 g, 0.05 mol) in H2O (330 mL). The reaction mixture
was stirred at 90 °C for 30 min and then was kept at 5 °C overnight.
The formed precipitate was collected by filtration and dried to af-
ford the corresponding sodium sulfinate 3a–h in 75–97% yield. The
product was used in the next step without further purification.
Method A: Heterocyclic compound 1a or 1b (0.1 mol) was added
portionwise to chlorosulfonic acid (20 mL, 0.3 mol) at 30–40 °C
over 1–2 h. The reaction mixture was stirred at 40 °C for 15 min,
and then PCl5 (25.0 g, 0.12 mol) was added. The mixture was stirred
at 80 °C for 1 h, then cooled to r.t. and poured onto ice (500 g). The
formed precipitate was collected by filtration, washed with H2O and
dried in vacuo. The product was recrystallized from benzene–petro-
leum ether (bp 40–60 °C) to give the corresponding chlorosulfonate
2a or 2b as a white solid; yield: 39–53%.
3-(Heterocyclylsulfonyl)propanoic Acids 5a–h; General Proce-
dure
AcOH (30 mL, 0.5 mol) was added at r.t. to a stirred solution of the
appropriate sodium sulfinate 3a–h (0.5 mol) in H2O (500 mL).
Acrylic acid (36 mL, 0.5 mol) was then added to the in situ formed
solution of sulfinic acid 4a–h over 30 min. The formed precipitate
was collected by filtration and dried to afford acid 5a–h in 50–75%
yield.
Method B: The appropriate heterocyclic compound 1c–f, 1h (0.1
mol) was added portionwise to ClSO3H (20 mL, 0.3 mol) at 65–135
°C over 0.5–6 h (see Table 1 for the exact reaction conditions for in-
dividual compounds). The reaction mixture was cooled to r.t. and
poured onto ice (500 g). The formed precipitate was collected by fil-
tration, washed with H2O and dried in vacuo. The product was re-
crystallized from benzene–petroleum ether (bp 40–60 °C) to give
the corresponding chlorosulfonate 2c–f, 2h as a white solid; yield:
63–80%.
3-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]propanoic
Acid (5a)
Yield: 67%; white solid; mp 201–202 °C.
Method C: Anhyd quinoline 1g (60 g, 0.46 mol) was added drop-
wise to fuming H2SO4 (30% SO3, 120 mL) in an ice-cooled flask.
During the addition, the temperature of the reaction mixture was
kept below 90 °C. The resulting dark solution was heated at 90 °C
for 40 h, then allowed to cool to r.t. and poured cautiously into ice-
cold H2O (500 mL). The formed colorless prisms were collected by
filtration, washed with H2O and dried to afford pure 8-quinoline-
sulfonic acid; yield: 67 g (54%); mp >300 °C (dec.). A portion of 8-
quinolinesulfonic acid (20 g, 0.088 mol) was added to PCl5 (20 g,
0.096 mol). The resulting mixture was refluxed at 145 °C for 1 h,
1H NMR (300 MHz, DMSO-d6): d = 2.23 (s, 3 H, CH3CO), 2.77 (t,
2 H, J = 7.5 Hz, CH2CO, 3.03 (t, 2 H, J = 7.5 Hz, SO2CH2), 3.98
(m, 1 H, NCH2), 4.08 (m, 1 H, NCH2), 3.15 (m, 1 H, ArCH2), 3.22
(m, 1 H, ArCH2), 6.93 (s, 1 Harom, H-4), 6.99 (d, 1 Harom, J = 8.2 Hz,
H-7), 7.37 (d, 1 Harom, J = 8.2 Hz, H-6), 11.45 (s, 1 H, CO2H).
LCMS: m/z = 298 (M + H+).
Anal. Calcd for C13H15NO5S: C, 52.52; H, 5.09; N, 4.71; S, 10.78.
Found: C, 52.55; H, 5.11; N, 4.76; S, 10.83.
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Synthesis of 3-(Heterocyclylsulfonyl)propanoic Acids and Amides
3003
3-[(1-Acetyl-2-methyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]pro-
panoic Acid (5b)
Yield: 67%; white solid; mp 191–192 °C.
J = 7.5 Hz, H-7), 8.40 (d, 1 Harom, J = 8.1 Hz, H-4), 8.50 (d, 1 Harom
,
J = 7.8 Hz, H-5), 9.10 (d, 1 Harom, J = 6.5 Hz, H-2), 12.25 (s, 1 H,
CO2H).
1H NMR (300 MHz, DMSO-d6): d = 1.33 (d, 3 H, J = 5.7 Hz,
NCHCH3), 2.29 (s, 3 H, CH3CO), 2.54 (t, 2 H, J = 7.7 Hz, CH2CO),
2.79 (m, 1 H, ArCH2), 3.49 (m, 1 H, ArCH2), 3.34 (t, 2 H, J = 7.7
Hz, SO2CH2), 4.69 (m, 1 H, NCH), 7.69 (dd, 1 Harom, J6,4 = 1.9 Hz,
J6,7 = 8.9 Hz, H-6), 7.72 (d, 1 Harom, J4,6 = 1.9 Hz, H-4), 8.20 (d, 1
LCMS: m/z = 266 (M + H+).
Anal. Calcd for C12H11NO4S: C, 54.33; H, 4.18; N, 5.28; S, 12.09.
Found: C, 54.35; H, 4.22; N, 5.28; S, 12.10.
3-[(1,4-Dimethyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-6-
yl)sulfonyl]propanoic Acid (5h)
Yield: 60%; white solid; mp 273–275 °C.
Harom, J7,6 = 8.9 Hz, H-7), 12.00 (s, 1 H, CO2H).
LCMS: m/z = 312 (M + H+).
Anal. Calcd for C14H17NO5S: C, 54.01; H, 5.50; N, 4.50; S, 10.30.
Found: C, 54.06; H, 5.52; N, 4.54; S, 10.34.
1H NMR (300 MHz, DMSO-d6): d = 2.55 (t, 2 H, J = 7.1 Hz,
CH2CO), 3.55 (t, 2 H, J = 7.1 Hz, SO2CH2), 3.65 (s, 3 H, NCH3),
3.68 (s, 3 H, NCH3), 7.60 (dd, 1 Harom, J7,8 = 8.3 Hz, J7,5 = 1.0 Hz,
H-7), 7.76 (d, 1 Harom, J8,7 = 8.3 Hz, H-8), 7.77 (d, 1 Harom, J5,7 = 1.0
Hz, H-5), 12.25 (s, 1 H, CO2H).
3-[(1-Acetyl-5-bromo-2,3-dihydro-1H-indol-7-yl)sulfonyl]pro-
panoic Acid (5c)
Yield: 70%; white solid; mp 189–191 °C.
LCMS: m/z = 327 (M + H+).
1H NMR (300 MHz, DMSO-d6): d = 2.20 (s, 3 H, CH3CO), 2.55 (t,
2 H, J = 7.5 Hz, CH2CO), 3.30 (t, 2 H, J = 8.3 Hz, ArCH2), 3.65 (t,
2 H, J = 7.5 Hz, SO2CH2), 4.15 (t, 2 H, J = 7.8 Hz, NCH2C), 7.60
(s, 1 Harom, H-4), 8.80 (s, 1 Harom, H-6), 12.00 (s, 1 H, CO2H).
Anal. Calcd for C12H11NO4S: C, 47.85; H, 4.32; N, 8.58; S, 9.83.
Found: C, 47.88; H, 4.35; N, 8.64; S, 9.87.
3-(Heterocyclylsulfonyl)propanoic Acid Chlorides 6a–h; Gen-
eral Procedure
LCMS: m/z = 377 (M + H+).
Acid 5a–h (0.1 mol) was added at r.t. over 40 min to a solution of
PCl5 (31.7 g, 0.15 mol) in toluene (300 mL). The mixture was heat-
ed at reflux until complete dissolution of the components. The mix-
ture was cooled and the solvent was evaporated in vacuo. The
residue was recrystallized from benzene to afford pure chlorides
6a–h as white solids; yield: 50–75%.
Anal. Calcd for C13H14BrNO5S: C, 41.50; H, 3.75; Br, 21.24; N,
3.72; S, 8.52. Found: C, 41.55; H, 3.80; Br, 21.26; N, 3.76; S, 8.56.
3-[(1-Acetyl-5-bromo-2-methyl-2,3-dihydro-1H-indol-7-yl)sul-
fonyl]propanoic Acid (5d)
Yield: 75%; white solid; mp 130–132 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.26 (d, 3 H, J = 5.7 Hz,
CCH3), 2.00 (s, 3 H, CH3CO), 2.24 (t, 2 H, J = 7.7 Hz, CH2CO),
2.75 (m, 1 H, ArCH2), 3.45 (m, 1 H, ArCH2), 3.03 (t, 2 H, J = 7.7
Hz, SO2CH2), 4.40 (m, 1 H, NCH), 6.81 (s, 1 Harom, H-4), 6.90 (s, 1
Harom, H-6), 11.45 (s, 1 H, CO2H).
3-(Heterocyclylsulfonyl)propanoic Acid Amides 7a–h; General
Procedure
Parallel solution-phase reactions were performed using a laboratory
synthesizer ‘CombiSyn-012-3000’.6 In each of twelve individual
reaction units, amine HNR1R2 (1.5 mmol), pyridine (1.45 mL, 1.8
mmol) and DMF (3 mL) were loaded. Appropriate chloride 6a–h
(1.5 mmol) was added at 10 °C with stirring. The reaction mixtures
were stirred at 55 °C for 1 h, then cooled to r.t. H2O (50 mL) was
added to each reaction unit, the formed precipitates were collected
by filtration and recrystallized from MeOH to yield the correspond-
ing members of amide libraries 7a–h. The products were >96% pure
(as measured by LCMS), and the reaction yields varied between 30
and 95%.
LCMS: m/z = 391 (M + H+).
Anal. Calcd for C14H16BrNO5S: C, 43.09; H, 4.13; Br, 20.47; N,
3.59; S, 8.22. Found: C, 43.12; H, 4.16; Br, 20.49; N, 3.63; S, 8.27.
3-(2,1,3-Benzoxadiazol-4-ylsulfonyl)propanoic Acid (5e)
Yield: 54%; white solid; mp 175–176 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.65 (t, 2 H, J = 7.6 Hz,
CH2CO), 3.75 (t, 2 H, J = 7.6 Hz, SO2CH2), 7.80 (t, 1 Harom, J = 7.4
Hz, H-6), 8.15 (d, J = 7.6 Hz, 1 Harom, H-7), 8.35 (d, 1 Harom, J = 7.2
Hz, H-5), 12.25 (s, 1 H, CO2H).
Selected Data
3-[(1-Acetyl-2,3-dihydro-1H-indol-5-yl)sulfonyl]-N-[2-(3,4-di-
ethoxyphenyl)ethyl]propanamide (7a{1})
LCMS: m/z = 257 (M + H+).
Yield: 68%; white solid; mp 127–130 °C.
Anal. Calcd for C9H8N2O5S: C, 42.19; H, 3.15; N, 10.93; S, 12.51.
Found: C, 42.22; H, 3.19; N, 10.95; S, 12.52.
1H NMR (300 MHz, DMSO-d6): d = 1.40 (t, 6 H, J = 7.5 Hz, 2
CH3), 2.20 (s, 3 H, CH3CO), 2.40 (t, 2 H, J = 7.0 Hz, ArCH2), 2.60
(t, 2 H, J = 7.7 Hz, CH2CO), 3.20 (q, 2 H, J = 7.0 Hz, CH2NH), 3.25
(t, 2 H, J = 8.0 Hz, ArCH2), 3.30 (t, 2 H, J = 7.7 Hz, SO2CH2), 4.00
3-(2,1,3-Benzothiadiazol-4-ylsulfonyl)propanoic Acid (5f)
Yield: 54%; white solid; mp 175–176 °C.
(m, 4 H, 2 OCH2), 4.20 (t, 2 H, J = 7.8 Hz, NCH2), 6.60 (d, 1 Harom
,
1H NMR (300 MHz, DMSO-d6): d = 2.86 (t, 2 H, J = 7.7 Hz,
CH2CO), 3.03 (t, 2 H, J = 7.7 Hz, SO2CH2), 7.88 (t, 1 Harom, J = 7.4
Hz, H-6), 8.07 (d, 1 Harom, J = 7.5 Hz, H-5), 8.17 (d, 1 Harom, J = 7.2
Hz, H-7), 11.45 (s, 1 H, CO2H).
J = 7.4 Hz,), 6.70 (d, 1 Harom, J = 7.4 Hz, ), 6.65 (s, 1 Harom, H-2¢),
7.80 (d, 1 H, J = 6.5 Hz, CONH), 7.60 (d, J = 7.9 Hz, 1 Harom, H-7),
7.65 (s, 1 Harom, H-4), 8.20 (d, 1 Harom, J = 7.9 Hz, H-6).
LCMS: m/z = 489 (M + H+).
LCMS: m/z = 273 (M + H+).
Anal. Calcd for C9H8N2O4S2: C, 39.70; H, 2.96; N, 10.29; S, 23.55.
Found: C, 39.72; H, 2.99; N, 10.33; S, 23.57.
1-Acetyl-5-({3-[4-(2,5-dimethylphenyl)piperazin-1-yl]-3-oxo-
propyl}sulfonyl)-2-methylindoline (7b{1})
Yield: 50%; white solid; mp 195–198 °C.
3-(Quinolin-8-ylsulfonyl)propanoic Acid (5g)
Yield: 68%; white solid; mp 198–200 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.55 (t, 2 H, J = 7.8 Hz,
CH2CO), 4.05 (t, 2 H, J = 7.8 Hz, SO2CH2), 7.65 (dd, 1 Harom
J = 8.5 Hz, H-3), 7.70 (t, 1 Harom, J = 7.9 Hz, H-6), 8.30 (d, 1 Harom
1H NMR (300 MHz, DMSO-d6): d = 1.33 (d, 3 H, NCHCH3), 2.20
(s, 6 H, 2 ArCH3), 2.25 (s, 3 H, CH3CO), 2.70 (t, 2 H, J = 7.5 Hz,
CH2O), 2.80 [m, 4 H, NCH2CH2), 3.60 (m, 4 H, NCH2CH2), 3.30 (t,
2 H, J = 6.8 Hz, ArCH2), 3.35 (t, 2 H, J = 7.7 Hz, SO2CH2), 4.20 (t,
1 H, J = 7.6 Hz, NCH), 6.70 (d, 1 Harom, J = 7.4 Hz, H-3¢), 6.75 (s,
,
,
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M. V. Dorogov et al.
PAPER
N-(1,3-Benzodioxol-5-ylmethyl)-3-[(1,4-dimethyl-2,3-dioxo-
1 Harom, H-6¢), 6.95 (d, 1 Harom, J = 7.4 Hz, H-4¢), 7.60 (d, 1 Harom
J = 8.0 Hz, H-7), 7.65 (s, 1 Harom, H-4), 8.20 (d, 1 Harom, J = 8.0 Hz,
,
1,2,3,4-tetrahydroquinoxalin-6-yl)sulfonyl]propanamide
H-6).
(7h{1})
Yield: 58%; white solid; mp 197–199 °C.
LCMS: m/z = 484 (M + H+).
1H NMR (300 MHz, DMSO-d6): d = 2.55 (t, 2 H, J = 7.1 Hz,
CH2CO), 3.55 (t, 2 H, J = 7.1 Hz, SO2CH2), 3.65 (s, 3 H, NCH3),
3.68 (s, 3 H, NCH3), 4.13 (d, 2 H, J = 5.9 Hz, NCH2), 5.95 (s, 2 H,
OCH2), 6.70 (m, 3 Harom), 7.60 (dd, 1 Harom, J7,8 = 8.3 Hz, J7,5 = 1.0
Hz, H-7), 7.76 (d, 1 Harom, J8,7 = 8.3 Hz, H-8), 7.77 (d, 1 H, J5,7 = 1.0
Hz, H-5), 8.29 (t, 1 H, J = 5.9 Hz, CONH).
Ethyl 4-({3-[(1-Acetyl-5-bromo-2-methyl-2,3-dihydro-1H-in-
dol-7-yl)sulfonyl]propanoyl}amino)piperidine-1-carboxylate
(7d{1})
Yield: 45%; white solid; mp 184–187 °C.
1H NMR (300 MHz, DMSO-d6): d = 1.25 (t, 3 H, J = 6.7 Hz,
CH2CH3), 1.25 (d, 3 H, NCHCH3), 1.70 (m, 2 H, CH2), 2.90 (m, 2
H, CH2), 3.60 (m, 2 H, CH2), 2.20 (s, 3 H, CH3CO), 2.50 (t, 2 H,
J = 7.7 Hz, CH2CO), 2.80 (m, 1 H, NCHCH3), 3.25 (t, 2 H, J = 7.7
Hz, SO2CH2), 3.80 (m, 2 H, CH2), 4.20 (t, 2 H, J = 6.5 Hz, CH2),
4.05 (q, 2 H, J = 7.0 Hz, OCH2), 7.60 (s, 1 Harom, H-4), 7.80 (d, 1 H,
J = 6.5 Hz, CONH), 8.70 (s, 1 Harom, H-6).
LCMS: m/z = 460 (M + H+).
Acknowledgment
We thank Dr. Konstantin V. Balakin and Dr. Yan A. Ivanenkov
(Chemical Diversity Labs, Inc.) for discussion and help in the pre-
paration of the manuscript.
LCMS: m/z = 545 (M + H+).
3-(2,1,3-Benzothiadiazol-4-ylsulfonyl)-N-cycloheptylpropan-
amide (7f{1})
Yield: 65%; white solid; mp 191–194 °C.
References
(1) Munroe, J. E.; Shepherd, T. A.; Jungheim, L. N.; Hornback,
W. J.; Hatch, S. D.; Muesing, M. A.; Wiskerchen, M.-A.; Su,
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885. (b) Baxter, A. D.; Bhogal, R.; Bird, J.; Keily, J. F.;
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(3) Becker, D. P.; Barta, T. E.; Bedell, L.; DeCrescenzo, G.;
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Kurashina, Y.; Iizuka, K. Jpn. J. Pharmacol. 1993, 63, 219;
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1H NMR (300 MHz, DMSO-d6): d = 1.35 (m, 4 H), 1.55 (m, 6 H),
1.70 (m, 2 H), 3.55 (m, 1 H), 2.50 (t, 2 H, J = 7.3 Hz, CH2CO), 3.80
(t, 2 H, J = 7.3 Hz, SO2CH2), 7.60 (d, 1 H, J = 6.6 Hz, CONH), 7.90
(t, 1 Harom, J = 7.2 Hz, H-6), 8.30 (d, 1 Harom, J = 7.2 Hz, H-7), 8.35
(d, 1 Harom, J = 1.3 Hz, H-5).
LCMS: m/z = 368 (M + H+).
N-(3,4-Dimethoxyphenyl)-3-(quinolin-8-ylsulfonyl)propan-
amide (7g{1})
Yield: 55%; white solid; mp 103–106 °C.
1H NMR (300 MHz, DMSO-d6): d = 2.70 (t, 2 H, J = 7.4 Hz,
CH2CO), 3.70 (s, 6 H, 2 OCH3), 4.10 (t, 2 H, J = 7.4 Hz, SO2CH2),
6.65 (d, 1 Harom, J = 7.4 Hz, H-6¢), 6.85 (d, 1 Harom, J = 7.2 Hz, H-
5¢), 7.20 (s, 1 Harom, H-2¢), 7.65 (dd, 1 Harom, J = 8.5 Hz, J = 1.2 Hz,
H-5), 7.70 (t, 1 Harom, J = 7.7 Hz, H-6), 8.25 (d, 1 Harom, J = 7.7 Hz,
H-7), 8.45 (d, 1 Harom, J = 1.0 Hz, H-4), 8.50 (d, 1 Harom, J = 1.0 Hz,
H-5), 9.15 (d, 1 Harom, J = 7.5 Hz, H-2), 9.7 (s, 1 H, CONH).
(5) Tyuneva, I. V.; Filimonov, S. I.; Soloviev, M. Y.; Balakin,
K. V.; Skorenko, A. V.; Dorogov, M. V. Proc. Inst. Higher
Edu.: Chem. Techn. (Russia) 2003, 46, 77; Chem. Abstr.
2004, 141, 54130.
LCMS: m/z = 401 (M + H+).
(6) Baru, M.; Ivachtchenko, A. Russian Patent 2180609, 2002;
Chem. Abstr. 2003, 138, 14907.
Synthesis 2004, No. 18, 2999–3004 © Thieme Stuttgart · New York