Synthesis of 5-(ethylsulfonyl)-2-methoxyaniline: An important pharmacological fragment of VEGFR2 and other inhibitors

Article abstract of DOI:10.3762/bjoc.9.20

Background: 5-(Ethylsulfonyl)-2-methoxyaniline (5) is part of the structure in 131 compounds possessing different biological activities. In most cases, they have antitumor properties (112 compounds). Other compounds are described as cardiovascular agents, ion-channel blockers, nervous-system blockers, anti-inflammatory agents, or antidiabetic, antiosteoporotic and hypolipemic species. Compound 5 is a precursor of different protein-kinase inhibitors or enzyme modulators (EGFR, PDGFR, ckit, CDK 2 and 4, MMPs 2, 3, 9 and 13, etc.). The structure of 5 represents a fragment for several powerful inhibitors of VEGFR2, a key angiogenic receptor. Antiangiogenic inhibitors slow down or stop new blood-vessel formation from pre-existing vasculature. Some antiangiogenic drugs inhibiting the VEGFR2 receptor are successfully used in clinics for the treatment of several types of tumours in synergy with chemotherapy (e.g., Nexavar from Bayer, Sutent from Pfizer and Votrient from GlaxoSmithKline, approved by the FDA in 2005, 2006 and 2009, respectively). The structure of 5 is an important pharmacophoric fragment of potent VEGFR2 inhibitors (e.g., AAZ from PDB complex 1Y6A, enzymatic IC₅₀ = 22 nM). Up to now, 25 VEGFR2 inhibitors possessing a fragment of 5 can be found in the literature. Despite the high significance of 5-(ethylsulfonyl)-2-methoxyaniline (5) its preparation has not yet been described. Results: Here we have developed a convenient synthesis of important polyheterosubstituted aniline 5 starting from commercially available 4-methoxybenzene-1-sulfonyl chloride (1) in four steps and 59% overall yield. The target 5-(ethylsulfonyl)-2-methoxyaniline (5) and its synthetic intermediates 2-4 together with a new compound 5-(ethylsulfonyl)-2-methoxy-1,3-dinitrobenzene (4a) have been precisely physicochemically characterised.

Full text of DOI:10.3762/bjoc.9.20

Synthesis of 5-(ethylsulfonyl)-2-methoxyaniline:
An important pharmacological fragment of
VEGFR2 and other inhibitors
Miroslav Murár1, Gabriela Addová2 and Andrej Boháč*1,3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 173–179.
1Department of Organic Chemistry, Faculty of Natural Sciences,
Comenius University, Mlynská dolina, 842 15 Bratislava, Slovakia,
2Institute of Chemistry, Faculty of Natural Sciences, Comenius
University, Mlynská dolina, 842 15 Bratislava, Slovakia and 3Biomagi
Ltd. Mamateyova 26, 851 04 Bratislava, Slovakia
doi:10.3762/bjoc.9.20
Received: 14 November 2012
Accepted: 27 December 2012
Published: 25 January 2013
Email:
Associate Editor: C. Stephenson
Andrej Boháč* - andrej.bohac@fns.uniba.sk
© 2013 Murár et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
angiogenesis; pharmacophoric ligand; synthesis of
5-(ethylsulfonyl)-2-methoxyaniline; VEGFR2 tyrosine kinase inhibitors
Abstract
Background: 5-(Ethylsulfonyl)-2-methoxyaniline (5) is part of the structure in 131 compounds possessing different biological
activities. In most cases, they have antitumor properties (112 compounds). Other compounds are described as cardiovascular agents,
ion-channel blockers, nervous-system blockers, anti-inflammatory agents, or antidiabetic, antiosteoporotic and hypolipemic species.
Compound 5 is a precursor of different protein-kinase inhibitors or enzyme modulators (EGFR, PDGFR, ckit, CDK 2 and 4, MMPs
2, 3, 9 and 13, etc.). The structure of 5 represents a fragment for several powerful inhibitors of VEGFR2, a key angiogenic receptor.
Antiangiogenic inhibitors slow down or stop new blood-vessel formation from pre-existing vasculature. Some antiangiogenic drugs
inhibiting the VEGFR2 receptor are successfully used in clinics for the treatment of several types of tumours in synergy with
chemotherapy (e.g., Nexavar® from Bayer, Sutent® from Pfizer and Votrient® from GlaxoSmithKline, approved by the FDA in
2005, 2006 and 2009, respectively). The structure of 5 is an important pharmacophoric fragment of potent VEGFR2 inhibitors (e.g.,
AAZ from PDB complex 1Y6A, enzymatic IC50 = 22 nM). Up to now, 25 VEGFR2 inhibitors possessing a fragment of 5 can be
found in the literature. Despite the high significance of 5-(ethylsulfonyl)-2-methoxyaniline (5) its preparation has not yet been
described.
Results: Here we have developed a convenient synthesis of important polyheterosubstituted aniline 5 starting from commercially
available 4-methoxybenzene-1-sulfonyl chloride (1) in four steps and 59% overall yield. The target 5-(ethylsulfonyl)-2-methoxyani-
line (5) and its synthetic intermediates 2–4 together with a new compound 5-(ethylsulfonyl)-2-methoxy-1,3-dinitrobenzene (4a)
have been precisely physicochemically characterised.
173

Beilstein J. Org. Chem. 2013, 9, 173–179.
Introduction
5-(Ethylsulfonyl)-2-methoxyaniline (5) is a starting material
and a structural fragment of 131 compounds possessing
different biological activity, mostly described as antitumor
agents (112 compounds) as well as cardiovascular agents, ion-
channel blockers, nervous-system blockers, anti-inflammatory
agents, and antidiabetic, antiosteoporotic or hypolipemic
species. Compound 5 is used for the development of small
organic compounds, i.e., modulators targeting a broad spectrum
of important human protein receptors or enzymes, e.g.,
VEGFR2, EGFR, PDGFR, TEK kinase, ckit, EphB4, ErbB-2
receptor tyrosine kinase, cyclin-dependent kinases 2 and 4, neu
receptor, polo-like kinase 1, alpha and beta adrenoreceptors,
glycogen phosphorylase, IMP dehydrogenase, MMPs 2, 3, 9
and 13, etc. [1].
Figure 1: The AAZ ligand conformer from PDB complex 1Y6A and its
VEGFR2 intermolecular interaction map depicting three hydrogen
bonds and two stacked (π,π) interactions. No lipophilic interactions are
shown here. The part of the skeleton AAZ in bold represents the frag-
ment originating from the precursor 5. The interaction analysis has
been performed by software Discovery Studio Visualizer 3.1 [6].
Vascular endothelial growth factor (VEGF-A) is a homodi-
meric glycoprotein and thought to be the key signalling mole-
cule of angiogenesis, i.e., the formation of new blood vessels
from pre-existing ones. Angiogenesis is essential for cancers to a structural fragment of 5 (IC50 = 12.8; 14.7 and 87.3 nM) [7].
develop from a small size. VEGF-A binds to two VEGF recep- Several years ago Sigma-Aldrich offered 2-amino-4-(ethylsul-
tors that are expressed on the surface of vascular endothelial fonyl)phenol, which we transformed to the required 5-(ethylsul-
cells (VEGF receptor-1 and VEGF receptor-2). New vascula- fonyl)-2-methoxyaniline (5) in three simple synthetic steps
ture is formed in and around the tumour, allowing it to grow (N-acetylation, O-methylation, N-acetyl deprotection). Later on
exponentially and form life-threatening metastasis [2,3].
2-amino-4-(ethylsulfonyl)phenol was discontinued from current
commercial sources. Compound 5 is still available in small 1 g
The development of 2-anilino-5-aryloxazole containing inhibi- quantities but at a price that was unfavourable (e.g., as part of
tors of VEGFR2 receptor led to potent antiangiogenics at both the AldrichCPR collection) [8]. Nevertheless, compound 5 is
the enzymatic and cellular levels. Twenty-two derivatives of cited in the database Reaxys (Reaxys Registry Number 783509,
N-(5-(ethylsulfonyl)-2-methoxyphenyl)-5-phenyloxazol-2- 37 reactions) and SciFinder Scholar database (CAS [5339-62-
amines with determined enzymatic (IC50, VEGFR2) and 8], 191 reactions). In all cases, this compound was mentioned
cellular activities (IC50, hu-HUVEC/VEGF) were described. exclusively as a starting material or reactant [9]. Surprisingly
Among them N-(5-(ethylsulfonyl)-2-methoxyphenyl)-5-(3- the synthesis of this highly important 3-heterosubstituted aniline
(pyridin-2-yl)phenyl)oxazol-2-amine (AAZ) proved to be the 5 has not yet been published in research journals or patents, and
most promising compound (IC50: 22 nM, VEGFR2) [4]. The the properties of compound 5 have not been completely
binding mode of the AAZ ligand in the VEGFR2 receptor has described. We could find only a few of the physicochemical
been solved by X-ray crystallography and is available in the characteristics for 5. Experimental IR and 1H NMR (CDCl3)
Protein Data Bank (PDB: 1Y6A). The complex 1Y6A contains spectra are mentioned only in the SciFinder database and origi-
the intracellular tyrosine kinase domain of the VEGFR2 nated from Bio-Rad Laboratories data collection [9].
receptor, which accommodates two conformers of the AAZ
ligand [5].
Considering the above situation, we decided to develop a smart
synthesis of substituted aniline 5 from available starting ma-
Compound 5 is an important precursor for the synthesis of the terials and determine all of the important physicochemical char-
AAZ inhibitor and its derivatives. The fragment of 5 in the acteristics of the compounds from the successful synthetic
AAZ skeleton has pharmacophoric properties and ensures some pathway.
critical intermolecular interactions with the amino acid residues
of the VEGFR2 protein (e.g., PDB: 1Y6A; Asp921 and Results and Discussion
Cys917), (Figure 1).
In order to find a convenient methodology for the synthesis of
the desired compound 5, we decided to use an appropriately
Based on the above knowledge, we have recently developed substituted commercially available starting material. Sigma-
three VEGFR2 inhibitors, i.e., derivatives of AAZ that contain Aldrich offers two arylsulfonic acids possessing all three
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Beilstein J. Org. Chem. 2013, 9, 173–179.
hetero-substituents at the correct positions within a benzene we explored a second pathway starting from commercially
ring. 3-Amino-4-methoxybenzenesulfonic acid (A) and its available 4-methoxybenzene-1-sulfonyl chloride (1). Com-
demethylated precursor 3-amino-4-hydroxybenzenesulfonic pound 1 can be prepared easily from methoxybenzene (anisole)
acid (B) were selected. In particular, compound B is available in and ClSO3H in 88% yield [10]. Following the second proposed
large quantities (250 g) at a very reasonable cost. Several methodology, the starting material 1 provided 5-(ethylsulfonyl)-
attempts were carried out to transform the sulfonyl group of 2-methoxyaniline (5) in four synthetic steps and 59% overall
3-amino-4-hydroxybenzenesulfonic acid (B) to the required yield. No chromatography was needed in order to obtain the
ethylsulfonyl functionality. Sodium 3-amino-4-hydroxyben- synthetically pure product (Scheme 2).
zenesulfonate (C) was quantitatively obtained from 3-amino-4-
hydroxybenzenesulfonic acid (B) by treatment with NaOH. The Conclusion
sodium salt C was subsequently converted to the hydrochloride Even though 5-(ethylsulfonyl)-2-methoxyaniline (5) is a very
salt of 3-amino-4-hydroxybenzene-1-sulfonyl chloride (D) by important compound frequently used as a starting material,
treatment with thionyl chloride at room temperature. The amino reagent or pharmacophoric fragment, its synthesis has not yet
group of D was protected in the form of a 2-methyl- been described. Because the aniline derivative 5 possesses three
benzo[d]oxazole-5-sulfonyl chloride (E) by reaction of D with heterosubstituents on the benzene ring, a convenient starting
(EtO)3CH in the presence of p-TsOH. Reduction of sulfonyl material had to be selected for its preparation. We have devel-
chloride E to sodium sulfinate F by Na2SO3 and Na2CO3 and oped a novel and the only known preparation of 5, in 59%
its reaction with ethyl iodide proceeded as nonselective reac- overall yield in four steps starting from commercially available
tions, which excluded this methodology from further efforts 4-methoxybenzene-1-sulfonyl chloride (1). The starting ma-
(Scheme 1).
terial 1 can be obtained from well-known methoxybenzene
(anisole) by a one-step reaction of anisole with sulfuryl chlo-
These findings suggested that the free amine in B was consid- ride in 88% yield [10]. The synthesis of 5-(ethylsulfonyl)-2-
ered to be a weak point of this first synthetic route. Therefore, methoxyaniline (5) can be utilized for the development of bio-
Scheme 1: The structures of commercially available arylsulfonic acids A and B both appropriately substituted for the synthesis of product 5. An
unsuccessful synthesis of compound 5 starting from commercially more suitable 3-amino-4-hydroxybenzenesulfonic acid (B).
Scheme 2: Synthetic pathway starting from the commercially available sulfonyl chloride 1 leading to the required 5-(ethylsulfonyl)-2-methoxyaniline
(5). Reaction conditions: (a) Na2SO3 (2 equiv), NaHCO3 (2 equiv), H2O/THF (10:1), 0 °C/rt overnight, yielded 99% of 2; (b) MeOH, EtI (2.5 equiv),
reflux 2 h, 90% of 3; (c) conc. HNO3, 100 °C, 2 h, 73% of 4 (under different conditions: conc. HNO3/H2SO4 (1:1, v/v), 60 °C, 1 h, yielded 54% of
dinitro derivative 4a); (d) 10% Pd/C, H2, 2 days, 90% of 5. Compound 5 was prepared in 58.5% overall yield.
175

Beilstein J. Org. Chem. 2013, 9, 173–179.
logically active compounds as well as for different synthetic substrates. Only one of them starting from 1,4-bis(ethylsul-
purposes.
fonyl)benzene was published, with 65% yield [21]. None of the
above syntheses were performed from sodium arylsulfinate 2 as
we describe here.
Experimental
1H and 13C NMR spectra were recorded on Varian Gemini
(300 MHz and 75 MHz, respectively), chemical shifts are given 4-(Ethylsulfonyl)-1-methoxy-2-nitrobenzene (4), CAS
in parts per million (ppm), and tetramethylsilane was used as an [51572-44-2], is not commercially available from Sigma-
internal standard and DMSO-d6 as the solvent, unless other- Aldrich, Merck or Acros Organics. No direct synthesis or
wise specified. The abbreviation dm in the 1H NMR spectra experimental physicochemical properties have been described
means doublet of multiplet. It describes more complex for this compound in the SciFinder database. In the Reaxys
couplings observed at some aromatic hydrogens. IR spectra database only one mp, i.e., 119–120 °C was present [19] and
were acquired on FT-IR-ATR REACT IR 1000 (ASI Applied no spectral data were available for 4. One half reaction
Systems) with diamond probe and MTS detector. Mass spectra describing nitration of ethylsulfonylanisol with HNO3 was
were performed on LC–MS (Agilent Technologies 1200 Series mentioned in the patent literature [19]. No yield was given in
equipped with Mass spectrometer Agilent Technologies 6100 this record.
Quadrupole LC–MS) and GC–MS (Agilent Technologies
6890N gas chromatograph with a 5973 Network mass-selective 5-(Ethylsulfonyl)-2-methoxy-1,3-dinitrobenzene (4a) is an
detector (Agilent, Waldbronn, Germany)). The course of the unknown compound. No physicochemical properties or spec-
reactions was followed by TLC analysis (Merck Silica gel tral data were found either in the Reaxys or in SciFinder data-
60 F254). UV lamp (254 nm) and iodine vapours were used for bases.
the visualization of TLC spots. Melting points were measured
by using Kofler apparatus or Barnstead Electrothermal IA9200 5-(Ethylsulfonyl)-2-methoxyaniline (5), CAS [5339-62-8], is a
and are uncorrected. 4-Methoxybenzene-1-sulfonyl chloride (1) compound with only limited commercial availability. For this
was purchased from Sigma-Aldrich.
compound no synthesis can be found in the Reaxys and
SciFinder databases. There were 37 reactions in Reaxys and 191
4-Methoxybenzene-1-sulfonyl chloride (1), CAS [98-68-0], is reactions in SciFinder described. In all cases compound 5 was
a commercially available compound. This substance can be exclusively a starting material or reactant. Experimental IR and
prepared in 88% yield from readily available anisole, sulfuryl 1H NMR (CDCl3) spectra for compound 5 were mentioned in
chloride, H2SO4 and DMF according to the literature [10]. the SciFinder database and originated from Bio-Rad Labora-
Compound 1 can be alternatively obtained from anisole in 81% tories data collection [9].
yield by ClSO3H at 5 °C [11] or in 66% yield by ClSO3H in
CHCl3 [12].
Synthesis of sodium 4-methoxybenzenesulfinate (2). A stirred
mixture of H2O/THF (200 mL, 10:1, v/v) was used to dissolve
Sodium 4-methoxybenzenesulfinate (2), CAS [6462-50-6], is 18.30 g (145.2 mmol, 2.00 equiv) Na2SO3 and 12.21 g
not a commercially available compound. Sulfinate 2 can be (145.3 mmol, 2.00 equiv) NaHCO3. Then the solution was
prepared from arylsulfonyl chloride 1 by treatment with cooled in an ice bath to 0 °C. At this temperature 15.00 g
Na2SO3, NaHCO3 at 65 °C in 98% yield [13] or in 67% yield (72.6 mmol, 1.00 equiv) 1 was added portionwise to the mix-
[14]. Compound 2 has not been described. The physicochem- ture over 10 min. The reaction was stirred overnight, and the
ical properties of compound 2 were not found in the SciFinder temperature was allowed to increase to rt. The reaction mixture
database. The Reaxys database contains its 1H NMR (300 MHz, was purified by extraction with CHCl3 (3 × 50 mL). Water from
CD3OD) [15] and IR spectra [16].
the separated aqueous layer was distilled off until a white solid
material was formed. The solid mixture was triturated by
1-(Ethylsulfonyl)-4-methoxybenzene (3), CAS [7205-79-0], is MeOH (3 × 50 mL) and the remaining solid material containing
not a commercially available compound from current suppliers. the required salt 2 was dried by RVE, HV and yielded 14.10 g
The Reaxys database contains different mp values for arylethyl- (72.6 mmol, 99.9%) of 2. White solid; mp neither melting nor
sulfone 3: 40–41°C [EtOH] [16], 55–56 °C [EtOH/H2O] [17] decomposition was observed until 300 °C [MeOH]; IR (neat)
(also in SciFinder), 57 °C [18] and 59 °C [19] together with ν/cm−1: 3358 (m, br), 2959 (m), 2837 (m), 1591 (s), 1575 (m),
three 1H NMR spectra, among them one with assigned solvent 1490 (s), 1459 (m), 1441 (m), 1401 (w), 1299 (m), 1244 (s),
(CDCl3) [20]. No direct synthesis of 3 has been found in the 1188 (m), 1171 (m), 1082 (m), 1046 (m), 1029 (s), 974 (s), 835
SciFinder database. The Reaxys database describes five prepa- (m), 824 (w), 815 (m), 793 (m), 722 (w); 1H NMR (300 MHz,
rations for compound 3 from different but not very common DMSO-d6) δ 7.42 (dm, J(2,3) = 8.7 Hz, 2H, H-C(2)), 6.87 (dm,
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Beilstein J. Org. Chem. 2013, 9, 173–179.
J(2,3) = 8.7 Hz, 2H, H-C(3)), 3.74 (s, 3H, MeO-); 13C NMR Synthesis of 4-(ethylsulfonyl)-1-methoxy-2-nitrobenzene (4).
(75 MHZ, DMSO-d6) δ 159.0 (C4-O), 127.0 (C1-S), 125.5 1-(Ethylsulfonyl)-4-methoxybenzene (3) 11.30 g (56.4 mmol,
(C2), 112.8 (C3), 55.0 (MeO-); ESIMS m/z: 171.1 [M − Na]−; 1.00 equiv) was dissolved in 140 mL of HNO3 (conc. 65%,
Anal. calcd for C7H7NaO3S (194.18): C, 43.30; H, 3.63; S, w/w). The reaction mixture was heated to 100 °C and moni-
16.51; found: C, 43.15; H, 3.48; S, 16.22%.
tored by TLC. A complete conversion of starting material 4 was
observed within 2 h. Then the mixture was left to cool to rt and
carefully poured into 250 mL of ice-cold water. A white solid
material precipitated. Then the suspension was washed with
CHCl3 (3 × 60 mL). The combined organic phase was dried
over Na2SO4 and filtered, and the solution was evaporated by
RVE to yield 10.14 g (41.3 mmol, 73.3%) 4 in the form of a
pale yellow solid material. Yellow solid; mp 118.5–119.7 °C
[CHCl3] (lit. 119–120 °C [19]); IR (neat) ν/cm−1: 3076 (w),
2921 (m), 1606 (s), 1570 (w), 1532 (s, NO2), 1488 (w), 1475
Synthesis of 1-(ethylsulfonyl)-4-methoxybenzene (3). A crude (m), 1461 (m), 1350 (m), 1299 (s), 1279 (s), 1258 (m), 1236
product from the previous reaction 12.20 g (62.8 mmol, (m), 1191 (w), 1161 (m), 1145 (s), 1109 (m), 1079 (m), 1051
1.00 equiv) 2 was dissolved in 150 mL of MeOH. The solution (w), 1003 (m), 905 (w), 891 (m), 823 (m), 806 (m), 778 (m),
was stirred and heated under reflux in an Ar atmosphere. When 738 (m), 702 (m), 686 (m); 1H NMR (300 MHz, CDCl3) δ 8.37
the reaction mixture started to boil, 12.6 mL (24.50 g, (d, J(3,5) = 2.3 Hz, 1H, H-C(3)), 8.07 (dd, J(5,6) = 8.9, J(3,5) =
157.1 mmol, 2.50 equiv) EtI was added dropwise over 10 min 2.3 Hz, 1H, H-C(5)), 7.27 (d, J(5,6) = 8.9 Hz, 1H, H-C(6)), 4.07
via syringe and septum. The reaction mixture was heated under (s, 3H, MeO), 3.15 (q, J(CH2,CH3) = 7.5 Hz, 2H, SO2CH2),
reflux and monitored by TLC. After 2 h, the mixture was left to 1.32 (t, J(CH2,CH3) = 7.5 Hz, 3H, SO2CH2CH3); 13C NMR (75
cool to rt and subsequently evaporated by RVE to give a pale MHz, CDCl3) δ 156.6 (C1-O), 134.0 (C5), 130.5 (C2), 126.3
yellow solid material. The crude product 3 was triturated with (C3), 114.1 (C6), 57.2 (MeO), 50.8 (SO2CH2), 7.5
CHCl3 (3 × 30 mL), the suspension filtered and the organic (SO2CH2CH3), a signal for C4 is overlapped with one occur-
solution concentrated by RVE to 1/10 of its original volume. ring in the range of 134.0–126.3 and, therefore, cannot be
The solution crystallized by standing in a refrigerator overnight exactly assigned; GC–MS m/z: 245.1 (m, M+), 216.0 (s, M+ −
to give white crystals. The crystals were filtered off and washed Et), 214.0 (m, M+ − OMe), 200.0 (m, M+ − NO2 + H), 198.0
with cold hexane to yield 11.30 g (56.4 mmol, 89.8%) of the (m, M+ − NO2 − H), 168.1 (m, M+ − NO2 − OMe), 124.0 (m),
product 3. Pale yellow solid; mp 54.9–56.4 °C [CHCl3] (lit. 122.0 (m), 106.1 (m), 76.1 (m); Anal. calcd for C9H11NO5S
55–56 °C [EtOH/H2O] [17]); IR (neat) ν/cm−1: 2972 (m), 2934 (245.25): C, 44.08; H, 4.52; N, 5.71; S, 13.07; found: C, 43.97;
(m), 2848 (m), 1594 (m), 1578 (m), 1496 (m), 1473 (w), 1459 H, 4.78; N, 5.45; S, 13.46%.
(m), 1417 (w), 1385 (w), 1317 (m), 1296 (m), 1263 (s), 1188
(w), 1137 (s), 1113 (m), 1088 (s), 1065 (w), 1050 (w), 1022
(m), 829 (m), 806 (m), 783 (m), 737 (m), 707 (m); 1H NMR
(300 MHz, CDCl3) δ 7.83 (dm, J(2,3) = 9.0 Hz, 2H, H-C(2)),
7.03 (dm, J(2,3) = 9.0 Hz, 2H, H-C(2)), 3.89 (s, 3H, MeO), 3.09
(q, J(CH2,CH3) = 7.4 Hz, 2H, SO2CH2), 1.27 (t, J(CH2,CH3) =
7.4 Hz, 3H, SO2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 163.7
(C4-O), 130.4 (C1-S), 130.0 (C2), 114.4 (C3), 55.7 (MeO), 50.8
(SO2CH2), 7.6 (SO2CH2CH3); ESIMS m/z: 201.1 [M + H]+;
Anal. calcd for C9H12O3S (200.25): C, 53.98; H, 6.04; S, 16.01; Synthesis of 5-(ethylsulfonyl)-2-methoxy-1,3-dinitrobenzene
found: C, 53.88; H, 5.90; S, 16.42%.
(4a). 1-(Ethylsulfonyl)-4-methoxybenzene 14.92 g (74.5 mmol,
1.00 equiv) 3 was portionwise dissolved in an ice-cold mixture
of 120 mL H2SO4 (conc. 96%, w/w) and 120 mL of HNO3
(conc. 65%, w/w) at 0 °C. Afterwards the mixture was left to
warm to rt (ca 2 h). After the above steps, TLC showed us only
the presence of the starting material 3. Therefore the reaction
mixture was heated to 60 °C over 1 h. After this time TLC
showed a new product. The reaction mixture was cooled to rt
and poured into 500 mL of ice-cold water. A yellow solid ma-
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Beilstein J. Org. Chem. 2013, 9, 173–179.
terial precipitated. The obtained suspension was washed with 56.0 (MeO), 50.9 (SO2CH2), 7.8 (SO2CH2CH3); ESIMS m/z:
CHCl3 (3 × 60 mL). The combined organic phase was dried 216 [M + H]+; Anal. calcd for C9H13NO3S (215.27): C, 50.21;
over Na2SO4, filtered and evaporation by RVE to yield 11.75 g H, 6.09; N, 6.51; S, 14.90; found: C, 50.50; H, 6.15; N, 6.75; S,
(40.5 mmol, 54.4%) of 4a in the form of a yellow powder. 14.77%.
Yellow solid; mp 123.3–124.5 °C [CHCl3]; IR (neat) ν/cm−1:
3075 (m), 2974 (w), 1611 (m), 1536 (s, NO2), 1481 (m), 1457
(w), 1428 (w), 1406 (w), 1344 (m), 1314 (s), 1279 (m), 1260
(m), 1235 (w), 1211 (m), 1184 (m), 1130 (s), 1094 (m), 1047
(m), 968 (m), 927 (w), 912 (m), 890 (m), 785 (w), 772 (m), 737
(m), 711 (m), 686 (w); 1H NMR (300 MHz, CDCl3) δ 8.52 (s,
2H, H-C(4 and 6)), 4.15 (s, 3H, MeO), 3.23 (q, J(CH2,CH3) =
7.4 Hz, 2H, SO2CH2), 1.38 (t, J(CH2,CH3) = 7.4 Hz, 3H,
SO2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 151.5 (C2-O),
145.2 (C3), 134.7 (C5), 129.0 (C4), 65.3 (MeO), 50.8 Acknowledgements
(SO2CH2), 7.5 (SO2CH2CH3); ESIMS m/z: 290.1 [M]−; Anal. This work was supported by VEGA grant 2/0112/10 and
calcd for C9H10N2O7S (290.25): C, 37.24; H, 3.47; N, 9.65; S, APVV-0840-11.
11.05; found: C, 36.89; H, 3.50; N, 9.15; S, 10.97%.
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Synthesis of 5-(ethylsulfonyl)-2-methoxyaniline (5). 4-(Ethyl-
5. Protein data bank.
sulfonyl)-1-methoxy-2-nitrobenzene (4) 6.38 g (26.0 mmol,
http://www.rcsb.org/pdb/explore.do?structureId=1y6a (accessed Nov 2,
1.00 equiv) was dissolved in 150 mL of EtOH. A catalytic
amount of 10% Pd/C (64 mg, 1.00 w/w %) was added to the
solution. The mixture was stirred under an atmosphere of H2 at
34 °C and regularly analysed by TLC. After 2 days the reaction
was completed. The mixture was filtered through a small
column filled with silica gel and the solution evaporated by
RVE. The crude compound was dried by HV. Afterwards
5.01 g (23.3 mmol, 89.6%) of a solid powder was obtained as
the pure product 5 according to the 1H NMR spectrum. For mp
determination a crystallization of 5 from MeOH was performed.
Solid; mp 102.9–103.8 °C [MeOH]; IR (neat) ν/cm−1: 3459 (s,
NH2), 3366 (s, NH2), 3080 (w), 2966 (m), 2944 (m), 2924 (m),
2843 (m), 1616 (m), 1578 (m), 1504 (m), 1470 (m), 1458 (m),
1426 (m), 1375 (w), 1354 (w), 1303 (m), 1287 (s), 1277 (s),
1228 (s), 1190 (w), 1137 (s), 1108 (s), 1074 (m), 1046 (m),
1018 (s), 919 (m), 874 (m), 819 (m), 759 (m), 735 (m), 719 (s),
660 (m); 1H NMR (300 MHz, CDCl3) δ 7.25 (dd, J(3,4) = 8.4,
J(4,6) = 2.3 Hz, 1H, H-C(4)), 7.19 (d, J(4,6) = 2.3 Hz, 1H,
H-C(6)), 6.87 (d, J(3,4) = 8.4 Hz, 1H, H-C(3)), 4.15 (br s, 2H,
NH2), 3.92 (s, 3H, MeO), 3.07 (q, J(SO2CH2,CH3) = 7.4 Hz,
2H, SO2CH2), 1.24 (t, J(SO2CH2,CH3) = 7.4 Hz, 3H,
SO2CH2CH3); 13C NMR (75 MHz, CDCl3) δ 151.1 (C2-O),
137.2 (C1), 130.3 (C5), 119.3 (C4), 113.3 (C6), 109.9 (C3),
2012).
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