Synthesis of functionalized hydroxy-thiophene motifs as amido- and sulfonamido-phenol bioisosteres

Article abstract of DOI:10.1016/j.tetlet.2009.06.085

Novel highly substituted hydroxy thiophene motifs were designed and synthesized as viable amido phenol and sulfonamido phenol bioisosteres. Hydroxy group-directed regioselective bromination and palladium-catalyzed amination of thienyl bromide via Buckwald

Full text of DOI:10.1016/j.tetlet.2009.06.085

Tetrahedron Letters 50 (2009) 5005–5008
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Tetrahedron Letters
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Synthesis of functionalized hydroxy-thiophene motifs as amido- and
sulfonamido-phenol bioisosteres
*
Jianhua Chao , Arthur G. Taveras, Cynthia J. Aki
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel highly substituted hydroxy thiophene motifs were designed and synthesized as viable amido phe-
nol and sulfonamido phenol bioisosteres. Hydroxy group-directed regioselective bromination and palla-
dium-catalyzed amination of thienyl bromide via Buckwald protocol are the key elements of the
synthetic approach. The hydroxy thiophene-containing compounds displayed good binding inhibitions.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 3 May 2009
Revised 12 June 2009
Accepted 16 June 2009
Available online 21 June 2009
Keywords:
Bioisostere replacement
Phenol bioisostere
Hydroxy-thiophene
Heteroaryl Buckwald amination
Bioisostere replacement is a commonly used approach by
medicinal chemists in rational drug design.1 It is often employed
to address potential undesirable side effects or adverse metabolism
issues that could be associated with lead compounds. Sometimes,
it is explored simply for the purpose of finding new physical and
biological properties without significant changes to the core struc-
ture in an existing drug development program.
During our investigation of CXCR2 and CXCR1 chemokine
receptor antagonists, we have discovered a novel class of phenolic
cyclobutenedione compounds which exhibited potent inhibitory
activities toward one or both of these receptors, as exemplified
by structures 1 and 2 (Fig. 1), a key structural element is the amido
phenol moiety.2 Disclosed by GlaxoSmithKline scientists, a series
of N,N0-diarylurea compounds, represented by structure 3 (Fig. 1),
also displayed potent CXCR2 inhibitory activity.3 In the latter class
of antagonists, the sulfonamido phenol moiety is a prominent
feature.
With the goal of discovering new chemical series that would en-
rich our existing scope of antagonists, we searched for potential
bioisosteric replacements of the phenol group in structures 1–3.
Thiophene has frequently been utilized as a potential phenyl bio-
isostere due largely to their similarities in aromaticity and shape,
while maintaining enough structural differences to impart differ-
ent physical and biological properties. Accordingly, we envisioned
that hydroxy thiophenes 4 and 5 could be viable replacements of
the corresponding amido-6 and sulfonamido phenols 7 (Fig. 2).
The development of synthetic approaches leading to 4 and 5 is
O
O
1
R =
N
N
H
N
H
R
O
O
OH
2 R =
Cl
O
O
H2N
S
O
N
H
N
Cl
H
OH
Cl
3
Figure 1. Examples of phenolic CXCR2/CXCR1 antagonists.
1R
S
1R
N
N
2R
NH2
NH2
2R
NH2
NH2
O
OH
intro.
of N
O
OH
6
S
4
4
2
G
3
S
OH
O
N
O
8
1R
2R
S
O
1R
S
O
N
OH
OH
7
2R
5
Figure 2. Hydroxy-thiophenes as potential phenol bioisosteres.
the focus of this report. Biological data of representative hydro-
xy-thiophene analogs will only be briefly discussed.
* Corresponding author. Tel.: +1 858 401 5713; fax: +1 858 401 5321.
E-mail address: jianhua.chao@biogenidec.com (J. Chao).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.085

5006
J. Chao et al. / Tetrahedron Letters 50 (2009) 5005–5008
1R
N
Synthetic analysis of hydroxy-amino-thiophenes 4 and 5 led us
S
S
S
c or d
to a general precursor 8 (Fig. 2). 3-Hydroxy-4-amino-thiophenes
were not reported previously in the literature to the best of our
knowledge, and there was no synthetic precedent closely related
to fully functionalized thiophenes 4 and 5. Starting from 8, with
the requisite 3-hydroxy group preinstalled, it would be the most
efficient approach to the targeted motifs. The key structural
manipulation would then be the introduction of a 4-amino group.
Nitration of the commercially available methyl-3-hydroxy-2-
thiophene carboxylate 9, using concentrated H2SO4 and fuming
HNO3 produced a mixture of isomers 4-nitro 10 and 5-nitro 11 in
a 1:2 ratio and 70% yield, the desired 4-isomer being a minor prod-
uct (Scheme 1).4 When the 3-hydroxy group was masked as a
methoxy group, nitration of 15 (prepared from 14 in two steps)
afforded 5-nitro isomer 16 in 65% yield while its 4-nitro isomer
was not detected. The free 3-hydroxy group apparently played an
ortho-directing role to allow the formation of 4-nitro isomer 10;
however, the steric hinderance might have prevented regioselec-
tive formation of 10 over 11. Reduction of the nitro group in 10
and 11 was problematic which afforded amino compounds 12
and 13 in low yields, either by using SnCl2ꢀ2H2O-mediated reduc-
tion or Pd(OH)2/C-catalyzed hydrogenation (Scheme 1). This ap-
proach lacked the robustness desired for extensive elaboration.
Bromination of a 2,3-disubstituted thiophene system, when the
3-hydroxy group was masked, was similar to nitration, which gener-
ated the 5-bromo isomer regioselectively.5 However, when the 3-
hydroxy group was free, the selectivity was different from nitration.
As reported in the literature,6 and from our own studies, bromina-
tion of 9 afforded predominantly 4-bromo isomer 17 (Scheme 1).
The 3-hydroxy group plays a dominant ortho-directing role in the
electrophilic bromination of the thiophene system, and as such 4-
bromoisomerwasformednear exclusively. Totakeadvantageofthis
selective transformation, we sought to install the requisite amino
group via a 4-bromo precursor, applying the palladium-catalyzed
amination method.
MeO
a,b HO
Br
Br
Br
OMe
2R
O
O
19
O
OH
S
OMe
18
17
(19a, R1 = R2 = Me)
R1
N
R1
N
Ph
e
Ph
S
f
NH2
N
2R
2R
O
O
OH
OMe
4
20
(4a, R1 = R2 = Me)
(20a, R1 = R2 = Me)
Scheme 2. Reagents and conditions: (a) K2CO3, MeI, acetone, reflux, 6 h, 100%; (b)
NaOH, THF, rt, overnight, 96%; (c) PyBroP, DIEA, R1R2NH, CH2Cl2, rt, >90%; (d)
(ClC@O)2, DMF (cat), CH2Cl2, rt, 45 min; K2CO3, rt, 5 min; then R1R2NH, >60%; (e)
Pd(OAc)2 (3 mol %) ( )BINAP (4.5 mol %), Cs2CO3 (2.0 equiv) Ph2C@NH (1.5 equiv),
toluene (0.1 M), 110 °C, 16 h, 80% for 20a, >50% avg; (f) BBr3, CH2Cl2, ꢁ78 °C to
ꢁ15 °C, 3 h; work-up; then NaOAc, NH2OH–HCl, MeOH, rt, 1–18 h, 90% for 4a, 50–
90% avg.
alytic amination of 19, under the conditions of benzophenone imine
(1.5 equiv), Pd(OAc)2 (3 mol %), rac-BINAP (4.5 mol %), and cesium
carbonate (2.0 equiv) in refluxing toluene overnight, smoothly gen-
erated the imine adduct 20. Greater than 50% yield was achieved for
most of the substrates, and 80% in the case of N,N0-dimethyl amide
20a.9 Neither R1 nor R2 group can be a H in this amination reaction.
Subsequently, demethylation of 20 using boron tribromide provided
the hydroxy imine intermediate, which was further subjected to a
facile imine cleavage to give 3-hydroxy-4-amino-thiophene 4 in
good yield.10 The imine cleavage can be effected either by acidic
aqueous condition or the combination of NaOAc and hydroxylamine
hydrochloride in methanol. This five-step sequence is efficient and
flexible allowing easy derivatization at the 2-position of the thio-
phene (Scheme 2).
Palladium-catalyzed amination of aryl halides has been exten-
sively utilized for aryl systems, though not broadly applied to hete-
roaryls. For phenyl halides and triflates, Buckwald et al. have
reported a convenient method to convert these substrates to the cor-
responding primary anilines through the use of benzophenone
imine as an ammonia equivalent.7 The Buckwald approach appears
to be promising for our purpose. Compound 17 was first converted
to the bromo precursor 19 in three high yielding steps: methylation,
NaOH-mediated hydrolysis, and amide formation (Scheme 2).8 Cat-
Synthesis of the sulfonamido motif 5 required a little more syn-
thetic maneuvering than the amido analog 4, since 2-chlorosulfo-
nyl-3-hydroxy thiophene, equivalent to 9, was not readily
available. Installation of the 2-chlorosulfonyl group was achieved
by treatment of 3-methoxy thiophene 21 with chlorosulfonic acid,
providing 22 regioselectively and in good yields (60–83%, Scheme
3).11 2-Sulfonyl chloride 22 was converted to the corresponding sul-
fonamide 23 in above 90% yield by reacting with various amines un-
der mild conditions. Upon treatment of boron tribromide or sodium
ethanethiolate, sulfonamide 23 was demethylated to the hydroxy
compound 24, which was in turn brominated to furnish 3-hydro-
xy-4-bromide 25 regioselectively.12 This bromination occured via
the hydroxy group’s ortho-direction, similar to the conversion of
9–17. Methylation of 25 thus afforded the requisite amination pre-
cursor 26.13 Conversion of 26 to sulfonamido 5 was straightforward:
palladium-catalyzed amination using benzophenone imine pro-
vided the imine adduct 27 (50–85%),14 subsequent demethylation
and imine cleavage furnished 5 in good yields.15 To ensure efficient
and complete conversion of sulfonamido bromide 26–27, increased
amounts of Pd(OAc)2 (10 mol %) and BINAP (14 mol %) were em-
ployed in this reaction. Additionally, when substrates containing
sulfonamido group were sensitive toward boron tribromide condi-
tion, demethylation was carried out using sodium ethanethiolate
in DMF at 95 °C. The synthesis depicted in Scheme 3 represents a
practical approachtoward the sulfonamido motif 5, yields are gener-
ally high for each step and consistent in scaling up.
b or
c
S
S
S
NO2
NH2
a
MeO
MeO
MeO
O
O
O
OH
OH
OH
9
10 (4-NO2,minor)
12 (4-NH2)
11
13
(5-NO2,major)
(5-NH2)
NO2
S
S
S
f
d,e
N
MeO
N
O
O
14
O
15
OCH3
16
OCH3
OCH3
S
MeO
Br
g
9
O
OH
17
Scheme 1. Hydroxy group-directed nitration and bromination. Reagents and
conditions: (a) H2SO4 (concd), HNO3 (fuming), 0 °C, 2 h, 70%, 10–11: ꢂ 1:2; (b)
SnCl2ꢀ2H2O, EtOAc, 85 °C, 1.5 h, <10%; (c) Pd(OH)2 (20 wt % on C), H2, EtOH, 75 °C,
12 h, 20%; (d) NaOH, THF, rt, overnight, 99%; (e) (ClC@O)2, DMF (cat.), CH2Cl2, rt, 1 h;
then Me2NH in THF, 90%; (f) H2SO4 (concd), HNO3 (fuming), ꢁ5 °C, 1 h, 65%; (g) Br2,
AcOH, rt, overnight, 60%.6b
An alternative approach for the synthesis of 5 was also investi-
gated. Decarboxylation of acid 18 in H2SO4 (concd) at 60 °C within
a 4.5-h period provided 3-methoxy-4-bromo thiophene 28 in mod-
erate to good yield (Scheme 4).16 Regioselective sulfonylation of 28
by chlorosulfonic acid was possible leading to 2-sulfonyl chloride

J. Chao et al. / Tetrahedron Letters 50 (2009) 5005–5008
5007
c
O
O
S
S
S
O
S
or d
a
O
b
S
S
S
O
N
a,b
NH2
NH2
O S
N
N
H
N
H
1R
N
OMe
Cl
OMe
21
OMe
22
O
OH
R2
O
OH
OH
4a
30
23
O
O
S
S
S
S
O
O
O
O
O
O S
N
f
e
O
O
S
a,c
d
Br
OMe
Br
S
N
H
O
1R
O S
N
O
1R
S
S
N
H
N
OH
5a
N
N
1R
OH
OH
R2
R2
R2
31
26
25
24
O
S
g
O
O S
N
N
N
Cl
Ph
Ph
H
H
S
Cl
O
O
OH
32
N
NH2
h or j
S
N
O
1R
O S
1R
N
OH
OMe
Scheme 5. Reagents and conditions: (a) EtOH, 3,4-diethoxycyclobut-3-ene-1,2-
dione, K2CO3, rt, 9 h, 50%; (b)EtOH, (R)-1-phenyl-1-propylamine, rt, 1.5 h, 63%; (c)
EtOH, (R)-1-(5-methylfuran-2-yl)-1-propylamine,3b rt, 48 h, 34%; (d) 2,3-dichloro-
phenylisocyanate, CH2Cl2, rt, overnight, 73%.
R2
R2
27
5
(R1, R2 = Me: 23a, 24a, 25a, 26a, 27a, 5a)
Scheme 3. Reagents and conditions: (a) ClSO3H, CH2Cl2, ꢁ78 °C, 15 min, then rt, 2–
3 h, 60%; (b) R1R2NH, NEt3 or Pyr, CH2Cl2, rt, 94% for 23a; (c) BBr3, CH2Cl2, ꢁ78 °C to
10 °C, 4–12 h, >90% avg, 98% for 24a; (d) NaH, EtSH, DMF, 90–95 °C, 4 h, >95%; (e)
Br2, K2CO3, CH2Cl2, rt, 5 h, 70–90%, 77% for 25a; (f) K2CO3, CH3I, acetone, reflux,
3.5 h, 60–95%, 60% for 26a; (g) Pd(OAc)2 (10 mol %), ( )BINAP (14 mol %), Cs2CO3
(2.0 equiv) Ph2C@NH (1.5 equiv), toluene (0.1 M), 110 °C, 16–42 h, 85% for 27a,
>50% avg; (h) BBr3, CH2Cl2, ꢁ78 °C to 10 °C, 4 to 12 h, work-up, then NaOAc,
NH2OH–HCl, MeOH, rt, 1–2 h, 70% for 5a, 50–85% avg; (j) NaH, EtSH, DMF, 90–95 °C,
4 h, work-up, then NaOAc, NH2OH–HCl, MeOH, rt, 1–2 h, 65% avg.
lic amides and phenolic sulfonamides. The hydroxy group-directed
ortho-bromination and palladium-catalyzed amination of the re-
sulted bromide are key transformations in the synthetic approaches
(Schemes 3 and 4). These routes are efficient and versatile, allowing
rapid functionalization of the amido and sulfonamido groups for
structure–activity relationship (SAR) studies. Preliminary biological
assessments have shown that the hydroxy thiophene-containing
compounds have comparable receptor binding inhibitions to their
phenolic analogs.
29;17 however, the conversion was low yielding (38%) and incon-
sistent, plagued by unknown polar byproducts. This approach
was not suitable for large-scale synthesis. It served as a quick ac-
cess to the amination precursor 26, which can be easily prepared
from 29. In addition, it was useful when R1 and/or R2 groups were
sensitive to the reaction conditions described in Scheme 3.
Conversions of amido moiety 4 and sulfonamido moiety 5 to the
desired targets are straightforward, as illustrated in Scheme 5 with
4a and 5a. By reacting with 3,4-diethoxycyclobutene-1,2-dione,
followed by treatment of an appropriate amine, amido-hydroxy-
thiophene-amine 4a was transformed to cyclobutenedione-cen-
tered product 3018 while sulfonamido-hydroxy-thiophene-amine
5a was transformed to 31.19 When 5a was reacted with 2,3-di-
chloro-phenylisocyanate, urea 32 was formed.20 The initial studies
of these compounds in the receptor competition binding assays (vs
IL-8) showed promise, good inhibitions were realized with 30 (Ki of
CXCR2, CXCR1 = 4.5 nM, >500 nM), 31 (Ki of CXCR2, CXCR1 = 5 nM,
15 nM), and 32 (Ki of CXCR2, CXCR1 = 17 nM, 3100 nM).21 These
activities are comparable to the phenolic compounds 1 and 2,2b
and 3.3a
References and notes
1. (a) Patani, G. A.; LaVoie, E. J. Chem. Rev. 1996, 96, 3147–3176; (b) Chen, X.;
Wang, W. In Annual Reports in Medicinal Chemistry; Doherty, A. M., Ed.;
Academic Press: San Diego, CA, 2003; Vol. 38, pp 333–346.
2. (a) Merritt, J. R.; Rokosz, L. L.; Nelson, K. H.; Kaiser, B.; Wang, W.; Stauffer, T. M.;
Ozgur, L. E.; Schilling, A.; Li, G.; Baldwin, J. J.; Taveras, A. G.; Dwyer, M. P.; Chao,
J. Bioorg. Med. Chem. Lett. 2006, 16, 4107–4110; (b) Dwyer, M. P.; Yu, Y.; Chao, J.;
Aki, C.; Chao, J.; Biju, P.; Girijavallabhan, V.; Rindgen, D.; Bond, R.; Mayer-Ezel,
R.; Jakway, J.; Hipkin, R. W.; Fossetta, J.; Gonsiorek, W.; Bian, H.; Fan, X.;
Terminelli, C.; Fine, J.; Lundell, D.; Merritt, J. R.; Rokosz, L. L.; Kaiser, B.; Li, G.;
Wang, W.; Stauffer, T.; Ozgur, L.; Baldwin, J.; Taveras, A. G. J. Med. Chem. 2006,
49, 7603–7606; (c) Chao, J.; Taveras, A. G.; Chao, J.; Aki, C.; Dwyer, M.; Yu, Y.;
Purakkattle, B.; Rindgen, D.; Jakway, J.; Hipkin, W.; Fosetta, J.; Fan, X.; Lundell,
D.; Fine, J.; Minnicozzi, M.; Phillips, J.; Merritt, J. R. Bioorg. Med. Chem. Lett.
2007, 17, 3778–3783.
3. (a) Podolin, P. L.; Bolognese, B. J.; Foley, J. J.; Schmidt, D. B.; Buckley, P. T.;
Widdowson, K. L.; Jin, Q.; White, J. R.; Lee, J. M.; Goodman, R. B.; Hagen, T. R.;
Kajikawa, O.; Marshall, L. A.; Hay, D. W. P.; Sarau, H. M. J. Immunol. 2002, 169,
6435–6444; (b) Jin, Q.; Nie, H.; McCleland, B. W.; Widdowson, K. L.; Palovich,
M. R.; Elliott, J. D.; Goodman, R. M.; Burman, M.; Sarau, H. M.; Ward, K. W.;
Nord, M.; Orr, B. M.; Gorycki, P. D.; Busch-Petersen, J. Bioorg. Med. Chem. Lett.
2004, 14, 4375–4378.
4. (a) 1H NMR (400 MHz, CDCl3): d (ppm) for 10 (4-NO2), 10.15 (s, 1H), 8.50 (s,
1H), 4.03 (s, 3H); d (ppm) for 11 (5-NO2), 9.57 (s, 1H), 7.52 (s, 1H), 4.03 (s, 3H).;
(b) Barker, J. M.; Huddleston, P. R.; Wood, M. L.; Burkitt, S. A. J. Chem. Res. (S)
2001, 401–402; (c) Marques, M. A.; Doss, R. M.; Urbach, A. R.; Dervan, P. B. Helv.
Chim. Acta 2002, 85, 4485–4517.
In summary, highly functionalized hydroxy thiophenes 4 and 5
were designed and synthesized as potential bioisosteres of pheno-
5. Sanfilippo, P. J.; McNally, J. J.; Press, J. B.; Fitzpatrick, L. J.; Urbanski, M. J.; Katz,
L. B.; Giardino, E.; Falotico, R.; Salata, J.; Moore, J. B., Jr.; Miller, W. J. Med. Chem.
1992, 35, 4425–4433.
S
S
S
O
a
b
HO
Br
Br
Br
Br
S
O
6. Corral, C.; Lissavetzky, J. Synthesis 1984, 847–850.
O
Cl
7. Wolfe, J. P.; Ahman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S. L. Tetrahedron
Lett. 1997, 38, 6367–6370.
OMe
18
OMe
28
OMe
29
8. N,N0-Dimethyl-3-methoxy-4-bromo-2-thiophene carboxamide 19a: 1H NMR
(400 MHz, CDCl3) d (ppm) 7.27 (s, 1H), 3.88 (s, 3H, OMe), 3.09 (s, 6H, NMe);
m/z (M+H)+: 264, 266.
c
9. N,N0-Dimethyl-3-methoxy-4-benzophenoniminyl-2-thiophene carboxamide 20a:
1H NMR (400 MHz, CDCl3) d (ppm) 7.76 (dt, J = 1.8, 7.2, 2H), 7.48 (tt, J = 1.2,
7.2, 1H), 7.40 (br t, 2H), 7.35–7.32 (m, 3H), 7.21–7.18 (m, 2H), 6.28 (s, 1H), 3.74
(s, 3H, OMe), 3.01 (br s, 3H, NMe), 2.86 (br s, 3H, NMe); m/z (M+H)+:365.
10. N,N0-dimethyl-3-hydroxy-4-amino-2-thiophene carboxamide 4a: 1H NMR
(400 MHz, CDCl3) d (ppm) 12.91 (s, 1H, OH), 6.26 (s, 1H), 3.67 (br s, 2H,
NH2), 3.24 (s, 6H, NMe); m/z (M+H)+:187.
S
O
S
N
5
O
1R
OMe
R2
26
Scheme 4. Reagents and conditions: (a) H2SO4 (concd), 60–65 °C, 4.5 h, 83%; (b)
11. 2-Chlorosulfonyl-3-methoxy thiophene 22: A solution of 3-methoxy thiophene
21 (7.0 g, 61.31 mmol) in 50 mL of CH2Cl2 was added dropwise to a stirred
ClSO3H, CH2Cl2, rt, 1.5 h, 38%; (c) R1R2NH, NEt3 or Pyr, CH2Cl2, rt, 50% avg.

5008
J. Chao et al. / Tetrahedron Letters 50 (2009) 5005–5008
solution of chlorosulfonic acid (10.2 mL, 153.18 mmol) in 250 mL of CH2Cl2 at
were washed successively with H2O (100 mL ꢃ 2), satd NaHCO3 (100 mL ꢃ 2),
ꢁ78 °C. The mixture was stirred for 15 min at ꢁ78 °C, continued for 2 h at
room temperature, then poured carefully into 600 mL of crushed ice. The
aqueous mixture was separated, the aqueous layer was further extracted with
CH2Cl2 (200 mL ꢃ 2), and the combined organic layers were washed with brine,
dried over MgSO4. The organic solution was filtered through a 1-inch silica gel
pad, rinsing with CH2Cl2. The filtrate was concentrated in vacuo to a greenish
solid, triturated with hexanes several times, then dried on vacuum to afford
7.87 g of 22 as a fluffy green solid (60%). 1H NMR (400 MHz, CDCl3) d (ppm)
7.69 (d, J = 5.2, 1H), 6.90 (d, J = 5.6, 1H), 4.09 (s, OMe).
and brine (100 mL). The organic solution was dried (Na2SO4) and concentrated
in vacuo to
a brown solution, purified by flash column chromatography
(hexanes–CH2Cl2 = 4:1, v/v) to afford 3.37 g (83%) of 28 as a light yellow oil. 1
H
NMR (400 MHz, CDCl3) d (ppm) 7.20 (d, J = 3.6, 1H), 6.25 (d, J = 3.6, 1H), 3.88 (s,
3H, OMe).
17. 2-Chlorosulfonyl-3-methoxy-3-bromo thiophene 29: To
a stirred solution of
chlorosulfonic acid in 20 mL of CH2Cl2 at room temperature was added
dropwise in 1.5 h, via an addition funnel, a solution of 3-bromo-4-methoxy
thiophene 28 (1.02 g, 5.28 mmol) in 25 mL of CH2Cl2. Reaction was allowed to
continue for 15 min after the completion of addition. The mixture was then
filtered through a 1-inch silica gel pad, rinsing with excess volume of CH2Cl2.
The filtrate was concentrated in vacuo to give 0.59 g of 29 (38%) as a greenish
oil, which was used in the next step without purification. 1H NMR (400 MHz,
CDCl3) d (ppm) 7.65 (s, 1H), 4.19 (s, 3H, OMe).
12. N,N0-Dimethyl-3-hydroxy-4-bromo-2-thiophene sulfonamide 25a: 1H NMR
(400 MHz, CDCl3) d (ppm) 8.48 (s, 1H, OH), 7.48 (s, 1H), 2.80 (s, 6H, NMe).
13. N,N0-dimethyl-3-methoxy-4-bromo-2-thiophene sulfonamide 26a: 1H NMR
(400 MHz, CDCl3) d (ppm) 7.45 (s, 1H), 3.99 (s, 3H, OMe), 2.85 (s, 6H, NMe);
m/z (M+H)+: 300, 302.
14. N,N0-Dimethyl-3-methoxy-4-benzophenoniminyl-2-thiophene sulfonamide 27a:
1H NMR (400 MHz, CDCl3) d (ppm) 7.79–7.77 (m, 2H), 7.50 (d, J = 7.2, 2H),
7.42 (tt, J = 1.6, 7.6, 2H), 7.37–7.35 (m, 2H), 7.20–7.17 (m, 2H), 6.38 (s, 1H), 3.94
(s, 3H, OMe), 2.66 (s, 6H, NMe); m/z (M+H)+: 401.
18. Compound 30: 1H NMR (400 MHz, DMSO-d6) d (ppm) 8.54 (br s, 1H, OH), 7.76
(s, IH), 7.40–7.28 (m, 5H), 5.05 (br d, J = 7.9, 1H), 3.11 (s, 3H), 2.48 (s, 3H), 1.89–
1.86 (m, 2H), 0.87 (t, J = 7.2, 3H); m/z (M+H)+: 400.46.
19. Compound 31: 1H NMR (400 MHz, DMSO-d6) d (ppm) 8.75 (br s, 1H, OH), 7.54
(s, 1H, 6.20 (d, J = 2.7, 1H), 6.02 (d, J = 2.0, 1H), 5.11 (br d, J = 7.6, 1H), 4.10 (br s,
1H), 2.58 (s, 3H), 2.46 (s, 3H), 2.25 (s, 3H), 1.95–1.88 (m, 1H), 1.84–1.77 (m,
1H), 0.90 (t, J = 7.4, 3H); m/z (M+H)+: 440.09.
15. N,N0-Dimethyl-3-hydroxy-4-amino-2-thiophene sulfonamide 5a: 1H NMR
(400 MHz, CDCl3) d (ppm) 8.31 (s, 1H, OH), 6.35 (s, 1H), 3.71 (br s, 2H, NH2),
2.78 (s, 6H, NMe); m/z (M+H)+: 223.
16. 3-Bromo-4-methoxy thiophene 28: A mixture of thiophene 2-carboxylic acid 18
(5.0 g, 21.09 mmol) and 50 mL of concentrated sulfuric acid was heated in a
sealed tube at 58–65 °C for 4.5 h. The mixture was cooled, poured into 400 mL
of crushed ice, and extracted with CH2Cl2 (150 mL ꢃ 3). The organic extracts
20. Compound 32: 1H NMR (400 MHz, DMSO-d6) d (ppm) 9.31 (br s, 1H), 9.18 (br s,
1H), 8.07 (s, 1H), 7.40 (s, 1H), 7.31–7.25 (m, 2H), 2.65 (s, 3H), 2.50 (s, 3H); m/z
(M+H)+: 409, 411.
21. For assay conditions, see Refs. 2b and 2c.