Ionic liquid-supported synthesis of sulfonamides and carboxamides

Article abstract of DOI:10.1021/co200149m

An ionic liquid-supported aldehyde was designed and converted to ionic liquid-supported secondary aryl amines through reductive amination. The reaction of ionic liquid-supported aryl amines with sulfonyl chlorides and acid chlorides, respectively, followed by cleavage using trifluoroacetic acid (TFA) afforded sulfonamides and caboxamides. To introduce additional diversity in the synthesis of sulfonamides and caboxamides, ionic liquid-supported iodosubstituted aryl amine was synthesized using the same strategy, and underwent Suzuki coupling reaction, followed by reaction with a methanesulfonyl chloride to generate the corresponding biaryl sulfonamide. The advantages of the protocol over solid-phase synthesis are homogeneous reaction medium, high loading, easy separation of products, and characterization of intermediates.

Full text of DOI:10.1021/co200149m

Research Article
pubs.acs.org/acscombsci
Ionic Liquid-Supported Synthesis of Sulfonamides and
Carboxamides
Manoj Kumar Muthayala,† Bhupender S. Chhikara,‡ Keykavous Parang,*,‡ and Anil Kumar*,†
†Department of Chemistry, Birla Institute of Science and Technology, Pilani, 333031, India
‡Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, 02881, United
States
S
* Supporting Information
ABSTRACT: An ionic liquid-supported aldehyde was designed and converted to
ionic liquid-supported secondary aryl amines through reductive amination. The
reaction of ionic liquid-supported aryl amines with sulfonyl chlorides and acid
chlorides, respectively, followed by cleavage using trifluoroacetic acid (TFA)
afforded sulfonamides and caboxamides. To introduce additional diversity in the
synthesis of sulfonamides and caboxamides, ionic liquid-supported iodosubstituted
aryl amine was synthesized using the same strategy, and underwent Suzuki coupling
reaction, followed by reaction with a methanesulfonyl chloride to generate the
corresponding biaryl sulfonamide. The advantages of the protocol over solid-phase
synthesis are homogeneous reaction medium, high loading, easy separation of
products, and characterization of intermediates.
KEYWORDS: carboxamides, ionic liquids, parallel synthesis, sulfonamides, Suzuki coupling reaction
vapor pressure, wide liquid range, and high thermal stability,
and possess highly conductive solvation ability for a variety of
organic substrates and catalysts including Lewis acids and
enzymes.
INTRODUCTION
■
For the last several years, solid-phase synthesis has been utilized
to generate large molecular libraries of small organic molecules
in synthetic organic chemistry.1−3 A significant number of
organic reactions on various solid supports and a variety of
linkers have been explored for the discovery of active
compounds in pharmaceutical research.4−11 Despite the success
of solid-phase approaches for the generation of large libraries in
combinatorial or parallel organic synthesis, they are associated
with several disadvantages such as low-loading efficiency,
difficulty in characterization of intermediates, prolonged
validation-time in conversion of solution-phase protocols to
solid-phase methods, inability to affect compound purification
prior to the final cleavage from the solid support, use of large
excesses of reagents, and difficulty and high cost of synthesis of
compounds in adequate quantities for biological evaluation.
Thus, particularly for smaller focused arrays, more attention has
increasingly turned to the identification. Consequently,
alternative solution-phase approaches that do not suffer from
these limitations have been reported over the last few decades
such as using fluorous-assisted synthesis,12−16 PEG/solid-PEG
supported synthesis,17−19 soluble polymer supported syn-
thesis,20 polymer supported solution phase synthesis,21
polymer-bound reagents, and scavengers and liquid phase
combinatorial synthesis.22 Ionic liquid supported synthesis has
become the subject of major interest in the past few years due
to easy preparation of ionic liquid supports. Under this
approach, the reaction progress may be readily monitored by
TLC and spectroscopic techniques. Room temperature ionic
liquids are known to be green alternatives to the volatile
organic solvents and have other useful properties, such as low
In view of pharmacological importance of sulfonamides and
amides, their synthesis has been an area of high interest in
medicinal chemistry research. The amide bond is a key building
unit in many natural and synthetic compounds. A number of
small molecules with amide functionality have been shown to
possess various biological activities such as antibacterial,23
antitumor,24 antiviral, Kv1.5 channel inhibitors,25 and VEGFR-
2 kinase inhibitors.26 Sulfonamide moiety is a common
pharmacophore in various biologically important molecules.
Sulfonamides are pharmacologically significant as therapeutic
agents as shown in sulfa antibiotics, serotonin antagonists,
antifungal,27,28 antibacterial,29 and antitubercular30 agents.
Isoquinoline sulfonamides inhibit protein kinases by competing
with ATP. In view of their importance in drug discovery, several
solid-phase routes have been reported for the synthesis of a
large number of structurally diversified sulfonamides and
amides.31−33
To explore the synthetic utility of the ionic liquid-supported
synthesis and to develop new and ecofriendly reaction
methodologies,34−37 herein, we describe the preparation and
use of acid labile ionic liquids that facilitate a convenient
method for ionic liquid-supported synthesis of sulfonamides
and amides.
Received: September 8, 2011
Revised: October 19, 2011
Published: October 20, 2011
© 2011 American Chemical Society
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Scheme 1. Synthesis of Ionic Liquid-Supported Aldehyde Group
Scheme 2. Synthesis of Sulfonamides and Amides from Ionic Liquid-Supported Aldehyde 6
a
Table 1. Optimization of Reductive Amination Conditions.
RESULTS AND DISCUSSION
■
b
Ionic liquid-supported aldehyde group 6 was prepared by
selective monoalkylation of 4-hydroxybenzaldehyde (2) with 1-
chloro-3-bromopropane (1), followed by reaction with 1-
methylimidazole (4) under reflux and ion exchange (Scheme
1). The chloride anion of ionic liquid-supported aldehyde
entry
reducing agent
temp (°C)
time (h)
yield (%)
1
2
3
4
5
6
7
8
NaBH4
35
60
60
35
40
40
60
60
7
7
8
6
5
5
6
6
66
75
NaBH4
c
NaBH4
72
d
NaBH4
60
−
group was exchanged with hexafluorophosphate (PF6 ) in dry
NaBH(OAc)3
NaBH(OAc)3
NaBH3CN
NaBH3CN
87
d
acetone. The ionic liquid-supported aldehyde group was
converted to ionic liquid-supported secondary amines through
reductive amination and further substitution of amino func-
tional groups.
83
85
d
79
a
Reaction conditions: Ionic liquid-supported aldehyde (6) (1 mmol),
aniline (1 mmol), reducing agent (1.1 mmol), room temperature,
[bmim][BF4] (1.0 mL). Isolated yield. Toluene used as a solvent in
To demonstrate the application of designed ionic liquid-
supported aldehyde for the synthesis of diverse classes of
compounds, ionic liquid-supported liquid phase synthesis of
sulfonamides and amides is shown here (Scheme 2). Initially,
reaction conditions were optimized for the reductive amination
of ionic liquid-supported aldehyde group 6 with aniline using
different borohydrides to afford the intermediate ionic liquid
supported secondary amines as summarized in Table 1. Among
different screened borohydrides, NaBH(OAc)3 was found to
give the highest yield of supported amine in [bmim][BF4] ionic
liquid at 40 °C (entry 5, Table 1). Thus, NaBH(OAc)3 was
used with five different aromatic amines for the reductive
amination reactions.
Six anilines were reacted with 6 to give ionic liquid-supported
amines (8a−f) in 80−83% yield (Scheme 2). The excess of
anilines was removed from the ionic liquid by extraction with
ethyl acetate and then NaBH(OAc)3 and [bmim][BF4] were
removed by water washing leaving behind the supported
secondary amines (8). All the ionic liquid-supported anilines
b
c
d
place of [bmim][BF4]. Methanol used as a solvent.
1
were characterized by IR, H NMR, and mass spectrometry. In
IR spectra, a peak around 1690−1700 cm−1 for stretching of
aldehyde carbonyl disappeared and a broad peak appeared in
the range of 3100−3200 cm−1 for secondary NH stretching. In
NMR, a characteristic peak appeared around 4.10 ppm for
CH2NH group along with other aromatic protons of the phenyl
ring.
Next, ionic liquid-supported secondary amines (8) were
reacted with sulfonyl chlorides (9) to give ionic liquid-
supported sulfonamides (11). After removal of excess of
sulfonyl chloride from the reaction mixture, the ionic liquid-
supported sulfonamides were cleaved using TFA to give
sulfonamides 13−23 in high yields (82−91%) as shown in
Table 2.
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Table 2. Synthesis of Sulfonamides
a
b
Isolated yields after column chromatography. Overall yield (from ionic liquid supported aldehyde 6).
To demonstrate the utility of 6 in supported liquid phase
synthesis, ionic liquid-supported secondary amines (8) were
reacted with acid chlorides (10) to give ionic liquid-supported
amides (12). The excess of acid chlorides were removed by
ethyl acetate extraction followed by cleavage with TFA to afford
desired amides 24−30. All the amides were isolated in good
yields (81−87%, Table 3) and excellent purities following final
purification.
The use of ionic liquid supported-aldehyde group avoids the
cumbersome conditions and makes the environmentally clean
protocol for the synthesis of useful sulfonamides and
carboxamides with the experimental ease. Functionalization of
substituted ionic liquid-supported secondary amines followed
by sulfonylation or acylation can be used to generate library of
structurally diversified sulfonamides and carboxamides, respec-
tively. The protocol represented here would improve the
paradigm of sulfonamide and carboxamides and provide
insights for potential application of ionic liquid-supported
aldehydes and amines for generation of other compounds.
The scope of the ionic liquid-supported aldehyde 6 was
further extended to increase functional diversity. Compound 6
was converted to ionic liquid-supported iodosubstituted aryl
amine 8e as described above (Scheme 1). The ionic liquid-
supported aryl amine 8e was transformed to ionic liquid-
supported biaryl secondary amines 31 using Suzuki coupling
reaction conditions (Scheme 3). The ionic liquid-supported
secondary amine with biphenyl was characterized with 1H
NMR and mass spectrometry. The resulting secondary amine
was transformed to the corresponding sulfonamide (32) by
reaction with methanesulfonyl chloride using the standardized
reaction conditions and finally cleaved to give sulfonamide
EXPERIMENTAL PROCEDURES
■
General. 1-Methyl imidazole, 1-chloro-3-bromopropane, 4-
hydroxybenzaldehyde, KPF6, and sodium triacetoxyborohydride
were purchased from Sigma-Aldrich and were used without
further purification. Aryl amines, sulfonyl chlorides, and acid
chlorides were purchased from S. D. Fine Chemicals Ltd.,
Mumbai. Silica gel (100−200 mesh) was used for column
chromatography. Thin-layer chromatography (TLC) was
performed on Merck-precoated silica gel 60-F254 plates. All
the other solvents and chemicals were obtained from
commercial sources and purified using standard methods.
The products were analyzed by NMR and mass spectroscopic
1
(22). Structure of both 31 and 32 was confirmed by H NMR
and 13C NMR spectroscopy (Supporting Information).
In conclusion, a new acid-labile ionic liquid-supported
aldehyde was developed to facilitate the rapid and parallel
solution-phase synthesis of sulfonamides and carboxamides.
1
techniques. The H and 13C NMR spectra were recorded on a
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Table 3. Synthesis of Carboxamides
a
b
Isolated yields after column chromatography. Overall yield (from ionic liquid supported aldehyde 6).
Scheme 3. Ionic Liquid-Supported Suzuki Reaction and Synthesis of Sulfonamide
Varian (500 MHz) spectrometer in DMSO-d6 with 1H resonant
frequency of 500 MHz and 13C resonant frequency of 126
MHz. The chemical shifts are expressed in parts per million (δ)
and coupling constants (J) in Hz. The Mass spectra were
recorded on QSTAR ELITE LX/MS/MS from Applied
Biosystems.
Synthesis of Ionic Liquids-Supported Aldehyde. 1-
Methylimidazole, 4 (4.43 g, 0.054 mol), was mixed with 4-(3-
chloropropyloxy)benzaldehyde, 3 (9.75 g, 0.05 mol), and
heated at 80 °C for 6 h. After the completion of the reaction, a
thick liquid was obtained. The reaction mixture was cooled
down to room temperature, and unreacted 1-methylimidazole
and 4-(3-chloropropyloxy)benzaldehyde were removed by
extraction with diethyl ether/ethyl acetate (2 × 25 mL, 1:1
v/v). The ionic liquid layer was concentrated under vacuum on
a rotatory evaporator to give chloride salt 5. Ion exchange was
carried out in dry acetone (50 mL) using potassium
hexafluorophosphate (7.67 g) at room temperature for 48 h.
Acetone was evaporated; resulting solution was dissolved in
water (25 mL) and extracted with DCM (3 × 50 mL). The
DCM layer was dried over anhydrous sodium sulfate and
evaporated under reduced pressure to afford pure 6 (yield
18.30 g, 96%).
General Procedure for the Synthesis of Ionic Liquid
Supported Amines. Compound 6 (1 g, 2.5 mmol) was
refluxed with corresponding amine 7 (3.0 mmol) in methanol
or ethanol for overnight. The obtained solid was reduced using
sodium triacetoxyborohydride (700 mg, 3.3 mmol) in [bmim]-
[BF4] for 5 h at 40 °C. The excess of amine was removed by
extracting with ethyl acetate (3 × 20 mL). The inorganic
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and the organic layer was dried on a rotatory evaporator to give
ionic liquid-supported amine 8.
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General Procedure for the Synthesis of Sulfonamides/
Carboxamides. To the stirred reaction mixture of 8 (1
mmol) and triethylamine (1.5 mmol) in dichlorormethane (3.0
mL) at 0 °C was added sulfonyl chloride/acid chloride (1.2
mmol) dropwise. The reaction mixture was brought to room
temperature and stirred for 7−10 h (Table 1). After completion
of the reaction, the mixture was washed with diethyl ether (3 ×
10 mL) and water (2 × 10 mL), respectively. The sulfonamide/
carboxamide-supported on ionic liquid was cleaved using
trifluoroacetic acid (TFA, 1 mL). The resulting solution was
neutralized with 10% aqueous NaHCO3 solution and extracted
with hexane/ethyl acetate (1:1 v/v) (2 × 10 mL). The
combined organic extracts were concentrated under reduced
pressure and purified by column chromatography on silica gel
(60−120 mesh) using hexane and ethyl acetate as eluents.
General Procedure for Suzuki Coupling on Ionic
Liquid Support. To a solution of ionic liquid-supported 4-
iodoaniline (0.67 mmol) in water (5.0 mL) at 80 °C under
nitrogen was added phenylboronic acid (0.19 mmol) and
Cs2CO3 (1.34 mmol). The resulting mixture was stirred at 80
°C for 15 min, followed by the addition of Pd(OAc)2 (0.097
mmol). The reaction mixture was then stirred vigorously for 23
h at 80 °C under nitrogen atmosphere. After completion of the
reaction, the mixture was washed with water (3 × 15 mL), and
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ASSOCIATED CONTENT
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(15) Curran, D. P. Fluorous reverse phase silia gel. A new tool for
preparative separations in synthetic organic and organofluorine
chemistry. Synlett 2001, No. 09, 1488−1496.
S
* Supporting Information
Experimental procedure for synthesis of 4-(3-chloropropoxy)-
benzaldehyde, chemical structures of ionic liquid-supported
amines and ionic liquid supported sulfonamides and amides,
and spectroscopic and physical data of synthesized compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
■
Corresponding Author
(19) Barrett, A. G. M.; Hopkins, B. T.; Kobberling, J. ROMPgel
̈
*Address: Department of Biomedical and Pharmaceutical
Sciences, College of Pharmacy, University of Rhode Island,
41 Lower College Road, Kingston, RI 02881, U.S.A. (K.P.);
Department of Chemistry, Birla Institute of Technology and
Science, Pilani, Rajasthan (INDIA), PIN-333 031 (A.K.).
Phone: +1-401-874-4471 (K.P); +-91-1596-245073 (A.K.).
Fax: +1-401-874-5787 (K.P.); +91-1596-244183 (A.K.). E-
mail: kparang@uri.edu (K.P.); anilkumar@bits-pilani.ac.in
(A.K.).
reagents in parallel synthesis. Chem. Rev. 2002, 102 (10), 3301−3324.
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synthesis. Acc. Chem. Res. 2000, 33 (8), 546−554.
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C.; Hoffman, P. S.; Macdonald, T. L. Biological activity of modified
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ACKNOWLEDGMENTS
■
We thank the Council of Scientific and Industrial Research
(CSIR), New Delhi (01(2214)/08/EMR-II), and U.S. National
Science Foundation, Grant Number CHE 0748555 for the
financial support.
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