Diverse methyl sulfone-containing benzo[b] thiophene library via iodocyclization and palladium-catalyzed coupling

Article abstract of DOI:10.1021/cc900172u

Parallel solution-phase methods for the synthesis of a 72-membered benzo[b]thiophene library are reported. Medicinally interesting, drug-like, methyl sulfone-substituted benzo[b]thiophenes have been prepared by the palladium-catalyzed substitution of 3-iodobenzo[b]thiophenes by Suzuki-Miyaura, Sonogashira, Heck, carboalkoxylation, and aminocarbonylation chemistry. The key intermediates for library generation, methyl sulfone-containing 3-iodobenzo[b]thiophenes, are readily prepared by iodocyclization and oxidation methodologies from readily available alkynes.

Full text of DOI:10.1021/cc900172u

278
J. Comb. Chem. 2010, 12, 278–285
Diverse Methyl Sulfone-Containing Benzo[b]thiophene Library via
Iodocyclization and Palladium-Catalyzed Coupling
Chul-Hee Cho,† Benjamin Neuenswander,‡ and Richard C. Larock*,†
Department of Chemistry, Iowa State UniVersity, Ames, Iowa 50011, and the UniVersity of Kansas NIH
Center of Excellence in Chemical Methodologies and Library DeVelopment, Lawrence, Kansas 66047
ReceiVed NoVember 2, 2009
Parallel solution-phase methods for the synthesis of a 72-membered benzo[b]thiophene library are reported.
Medicinally interesting, drug-like, methyl sulfone-substituted benzo[b]thiophenes have been prepared by
the palladium-catalyzed substitution of 3-iodobenzo[b]thiophenes by Suzuki-Miyaura, Sonogashira, Heck,
carboalkoxylation, and aminocarbonylation chemistry. The key intermediates for library generation, methyl
sulfone-containing 3-iodobenzo[b]thiophenes, are readily prepared by iodocyclization and oxidation
methodologies from readily available alkynes.
Introduction
system with a characteristic sulfonyl group on one of the
aryl rings that plays a crucial role in COX-2 selectivity. To
date highly selective COX-2 inhibitors have been reported
to contain the following functional groups: (i) methyl
sulfonyl- or sulfonamide-substituted tricyclic compounds,
such as DuP-697,27-30 rofecoxib,27,31,32 etoricoxib,27,33 SC-
57666,34 valdecoxib,27,35 celecoxib,27,36 SC-558,36,37 and SC-
58125;27 (ii) acidic methanesulfoanilides, such as
nimesulide,27,38,39 NS-398,27,29,30,40,41 and (iii) modifications
of classical NSAIDs, such as substituted 2-phenylsulfonyl-
3-phenylindole analogues I,42-44 and substituted 2-phenyl-
sulfonyl-3-phenylbenzofuran analogues II.45 Interestingly,
the drug CH3SO2-desmethylarzoxifene (LY2066948,46
CH3SO2-DMA, III) was found to bind with high affinity to
estrogen receptors R (ERR) and ꢀ (ERꢀ) by a different mode
from the other SERMs and is a potent uterine antagonist
with minimal effects on the ovaries as determined by serum
biomarkers and histological evaluation (Figure 1).8,46-48
Most importantly, substitution at the para position of one
of the aromatic systems with a methanesulfonyl or a
sulfonamide group is essential for COX inhibition.
Benzo[b]thiophenes are of interest because of their fre-
quent occurrence in nature and their wide range of biological
and physiological effects.1-3 Benzo[b]thiophene derivatives
currently in pharmaceutical use or development include
selective estrogen receptor modulators (SERMs),4-8 tubulin-
binding agents,7,9,10 modulators of multidrug resistance,11
and anti-inflammatory12 agents to name but a few.
Traditional non-steroidal anti-inflammatory drugs (NSAIDs)
represent one of the most prescribed medications, although
the chronic use of such pharmacological agents is commonly
associated with numerous side effects. The use of cyclooxy-
genase-2 (COX-2) selective or preferential inhibitors has
opened up new horizons in the search for safer drugs for
the management of inflammation.13 Cyclooxygenases exist
as two isoforms called COX-1 and COX-2.14,15 In many
systems, COX-1 is a constitutively expressed isoform and
is responsible for the maintenance of physiological homeo-
stasis, such as renal function and gastrointestinal integrity,16
whereas COX-2 is induced in response to inflammatory
stimuli and is responsible for the progression of inflamma-
tion.17 In addition to its role in inflammatory disorders,
COX-2 is also implicated in a variety of other pathologies,
such as cancer, cardiac and cerebral ischemia, and
Parkinson’s18-22 and Alzheimer’s22-24 diseases. Thus, the
search for specific inhibitors of COX-2 by modifications of
well-known non-selective agents has been actively pursued,
and increasing attention has been devoted to the synthesis
of diaryl heterocyclic compounds.25,26
The pharmacophore of these diarylheterocyclic inhibitors
is characterized by a central carbocyclic or heterocyclic ring
system bearing two vicinal aryl moieties with one benzene
ring being substituted with a methanesulfonyl or aminosul-
fonyl group at the para position (Figure 1; see I, II, III).
For these reasons, 2,3-diarylsubstituted benzo[b]thiophenes
with a methanesulfonyl group at the meta and/or para
position have been the subject of extensive experimental
studies.
Biological evaluation of known compounds has shown that
insertion of the coxib-like scaffold gives rise to very potent
and selective COX-2 inhibitors. All structures possess 1,2-
diaryl substitution on a central hetero- or carbocyclic ring
In a continuation of our library efforts to adapt heterocy-
clization chemistry to a high-throughput synthesis format,49-54
we here report the preparation of a methyl sulfone-containing
library of multisubstituted benzo[b]thiophenes 6 by electro-
philic cyclization chemistry. We demonstrate the significance
of this methodology by elaborating the resulting sulfur-
containing 3-iodobenzothiophenes 4/5 via various palladium-
catalyzed couplings, such as Suzuki-Miyaura, Sonogashira,
* To whom correspondence should be addressed. E-mail: larock@
iastate.edu. Phone: (515) 294-4660.
† Iowa State University.
‡ University of Kansas NIH Center of Excellence in Chemical Method-
ologies and Library Development.
10.1021/cc900172u  2010 American Chemical Society
Published on Web 01/07/2010

Methyl Sulfone-Substituted Benzo[b]thiophene Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 279
Figure 1. Chemical structures of known selective COX-2 inhibitors and synthetic benzothiophene SERMs, such as CH3SO2-DMA (III).
Scheme 1. Parallel Synthesis of Multi-Substituted
Benzo[b]thiophenes
method for the parallel synthesis of multisubstituted benzo-
[b]thiophenes has also been described via known palladium-
catalyzed couplings for generation of a diverse set of building
blocks starting from 3-iodobenzo[b]thiophenes (Scheme 1).52
The strategy for library production is outlined in Scheme
2. For generation of the first methyl sulfone-substituted
benzothiophene library, we decided to explore strategies
using iodocyclization and oxidation methodologies that
would allow us considerable flexibility to introduce a
diversity of functionalities for medicinally interesting, drug-
like methyl sulfone-substituted benzo[b]thiophenes 6 in a
high-throughput manner.
Heck, carboalkoxylation and aminocarbonylation chemistry,
to methyl sulfone-containing multisubstituted benzo[b]-
thiophenes 6.
Results and Discussion
We have previously developed a general synthesis of 2,3-
disubstituted benzo[b]thiophenes by the palladium/copper-
catalyzed cross-coupling of various o-iodothioanisoles and
terminal alkynes, followed by electrophilic cyclization under
mild conditions.55 Very recently, a simple and efficient
A sequence of reactions involving Sonogashira coupling
of the bromo-iodoarenes 1, and subsequent lithiation of
compounds 2{1-7}, followed by methylthiolation with
dimethyl disulfide afforded the corresponding disulfide
Scheme 2. Library Design for a Diverse Methyl Sulfone-Substituted Benzo[b]thiophene Library (6)
Table 1. Library Data for Compounds 2{1-7} and 3{1-7}
a Isolated yields after column chromatography. All compounds 2 have been characterized by 1H and 13C NMR spectroscopy. b For 3{1-6}, n-BuLi
(3.0 equiv) and Me2S2 (2.4 equiv) were used. For 3{7}, n-BuLi (1.5 equiv) and Me2S2 (1.2 equiv) were used.

280 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Table 2. 3-Iodobenzo[b]thiophene Scaffords 4{1-7} and 5{1-6}
Cho et al.
a All reactions were carried out using alkynes 3 and 1.5 equiv of I2 in CH2Cl2 at room temperature within 0.5 h, unless otherwise indicated.
b Reactions of methyl sulfides 4 were carried out at room temperature in CH3CN/DCM (1:1) using KMnO4/MnO2. c Isolated yields after column
chromatography. All compounds 4 and 5 have been characterized by H and 13C NMR spectroscopy. d I2 (1.5 equiv, followed by an additional 1.0 equiv
1
after 12 h) was used for 24 h. The starting material 3{2} was recovered.
products 3. Initially, the electron-rich substituted dihaloarenes
1 (see Table 1) were chosen as the starting materials because
it was envisioned that the oxygen-containing groups would
provide desirable polarity in the resulting library members.
The starting materials, dihalobenzenes 1, are easily prepared
through regioselective bromination and iodination.52 In
general, the requisite precursors bearing a dibromo-substi-
tuted alkyne moiety (2) can be easily prepared from
bromophenylacetylenes (para- and meta- positions) by
palladium/copper-catalyzed Sonogashira coupling of the
corresponding dihaloarenes in good yields (Table 1).52 ortho-
Bromophenylacetylene was not chosen as suitable to avoid
competing reactions during iodocyclization. The dibromo-
substituted alkynes 2{1-6} provided the corresponding
products 3{1-6} in modest yields (Table 1, entries 1-6).
In a similar manner, the bromo-containing alkyne 2{7} also
afforded the corresponding product 3{7} in modest yields
(Table 1, entry 7).
The key cyclization step efficiently generates the methyl
sulfide-substituted 3-iodo[b]benzothiophenes 4 in 10 min
at room temperature by electrophilic cyclization of the
corresponding disulfide-containing alkynes 3{1-6} and
sulfide alkyne 3{7} using I2 in CH2Cl2 at ambient
temperature (Table 2). In all cases, good to excellent yields
of methyl sulfide-substituted 3-iodo[b]benzothiophenes 4
have been obtained, except for 4{2}. The methyl sulfides
4 were immediately converted to the corresponding
sulfones 5 by oxidation in good to excellent yields by
KMnO4 supported on MnO2 under heterogeneous condi-
tions at room temperature.56 Attempts to oxidize species
4 using standard organic solvents, for example, methylene
chloride or acetonitrile, individually under the same
reaction conditions proved unsuccessful. Both methylene
chloride and acetonitrile must be used as co-solvents for
this reaction to afford decent yields. All of the reactions
were monitored by thin layer chromatography, and the

Methyl Sulfone-Substituted Benzo[b]thiophene Library
Table 3. Library Data for Compounds 6{1-21}a
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 281
product 6
7
R3
yield (%)c
purity (%)e
ion HRMS
calcd for HRMS
found HRMS
6{1}
7{4}
2,3-dihydrobenzo[1,4]dioxin-6-yl
4-hydroxyphenylb
2-bromo-5-pyridinyl
4-carbamoylphenyl
69
98
>99
58
M+
420.0854
378.0748
441.9935
376.0830
442.1147
456.1303
484.1014
438.0834
472.0837
482.1208
505.0687
437.0881
472.0837
482.1208
505.0687
500.0963
535.0793
502.0942
535.0793
488.0764
931.0632
NDf
6{2}
7{5}
65d
58
M+
378.0753
441.9931
376.0830
442.1169
456.1303
485.1102
438.0842
473.0939
482.1201
506.0761
437.0874
473.0920
482.1192
506.0775
501.1049
536.0887
503.1037
536.0949
489.0853
NDf
6{3}
7{8}
M+H+
6{4}
7{9}
61
99
M+H+
72d
72d
77
>99
>99
98
M+NH4+
+
6{5}
7{1}
4-methoxyphenyl
6{6}
7{2}
4-(methoxymethyl)phenyl
2,3-dihydrobenzo[1,4]dioxin-6-yl
4-carbamoylphenyl
4-(methylthio)phenyl
2-morpholinopyrimidin-5-yl
4-sulfamoylphenyl
M+NH4
6{7}
7{4}
M+MeOH+
M+H+
6{8}
7{9}
57
71
65
47
95
6{9}
7{11}
7{12}
7{13}
7{6}
>99
>99
>99
99
>99
>99
99
>99
96
98
95
M+MeOH+
M+H+
6{10}
6{11}
6{12}
6{13}
6{14}
6{15}
6{16}
6{17}
6{18}
6{19}
6{20}
6{21}
M+MeOH+
M+H+
4-acetylphenyl
57
7{11}
7{2}
7{13}
7{3}
4-(methylthio)phenyl
2-morpholinopyrimidin-5-yl
4-sulfamoylphenyl
benzo[1,3]dioxol-5-yl
4-sulfamoylphenyl
4-(methylthio)phenyl
4-sulfamoylphenyl
3-fluoro-4-methoxyphenyl
4-(methylthio)phenyl
73d
57d
38
M+MeOH+
M+H+
M+MeOH+
M+MeOH+
M+MeOH+
M+MeOH+
M+MeOH+
M+MeOH+
2M+Na+
78d
18
7{13}
7{11}
7{13}
7{7}
69
34
67d
53
>99
98
7{11}
a Suzuki-Miyaura reaction: 5 mol % Pd(PPh3)4, K2CO3 (2.5 equiv), R3B(OH)2 7 (1.5 equiv), toluene/EtOH/H2O (20/5/1), reflux. See the Supporting
Information for the experimental details. b The THP ether-protected boronic acid was deprotected in situ using aq. HCl in THF at room temperature.
c Isolated yield after preparative HPLC. d Isolated yield after column chromatography. Isolated desired products 6 were characterized by 1H and 13C
NMR spectroscopy. e UV purity determined at 214 nm after preparative HPLC. f Not determined by HRMS. Identified by NMR spectroscopy.
products purified by column chromatography (see the
Supporting Information for the experimental details).
Subsequently, we proceeded to prepare a diverse library
of methyl sulfone-substituted benzothiophenes 6 by a variety
of palladium-catalyzed processes, such as Suzuki-Miyaura
coupling, Sonogashira coupling, Heck coupling, carboalkoxy-
lation, and aminocarbonylation. The Suzuki-Miyaura cou-
pling of the 3-iodobenzo[b]thiophenes 4 or 5 with appropriate
boronic acids 7 afforded the desired products 6{1-21}
(Table 3). Sonogashira coupling of the 3-iodobenzo[b]-
thiophenes 4 or 5 with appropriate terminal alkynes 8
provides the corresponding alkynes 6{22-38} under micro-
wave irradiation (Table 4). Moreover, methyl sulfone-
substituted, olefin-containing benzothiophenes 6{39-45}
have been prepared by Heck coupling of the 3-iodobenzo[b]-
thiophenes 4 or 5 with a small styrene sublibrary 9 (Table
5). Methyl sulfone-substituted, ester-containing benzo-
thiophenes 6{46-56} have been prepared by carboalkoxy-
lation of the 3-iodobenzo[b]thiophenes 4 or 5 using one
atmosphere of carbon monoxide and primary alcohols 10
(Table 6). In addition, aminocarbonylation of the 3-iodo-
benzo[b]thiophenes 4 or 5 using one atmosphere of carbon
monoxide in the presence of a palladium catalyst with
appropriate primary and secondary amines 11 afforded the
desired amide-containing products 6{57-72} (Table 7). The
sublibraries, for example, boronic acids 7, terminal alkynes
8, styrenes 9, alcohols 10, and amines 11, were chosen for
their ability to provide the requisite diversity and drug-like
properties to the scaffold (Figure 2).
Our goal in synthesizing these relatively low molecular
weight heterocycles was to examine their biological proper-
ties by high-throughput screening. The overall synthetic
process as a whole is quite functional group tolerant and
efficient. These reactions have been performed in parallel
on approximately a 35-50 mg scale, starting from the
3-iodobenzo[b]thiophenes 4 or 5. All of the crude compounds
6{1-72} were isolated by either column chromatography or
preparative HPLC. The purity of the reaction mixtures has
been analyzed by TLC, LC-MS, and HPLC.
The selected 72 sulfone-substituted benzo[b]thiophene
template 6 has been evaluated computationally for its drug-
like properties on the basis of Lipinski’s rule of five.57
Lipinski calculations have been performed based on the
commercial available of boronic acids 7, terminal alkynes
8, styrenes 9, alcohols 10, and amines 11. The molecular
weight (less than 500), clogP (less than 5), number of
hydrogen bond donors (less than 5 H) and acceptors (less
than 10 H), and the number of rotatable bonds (less than

282 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Table 4. Library Data for Compounds 6{22-38}a
Cho et al.
product 6
8
R3
yield (%)b
purity (%)d
ion HRMS
M+
2M+NH4
calcd for HRMS
found HRMS
NDe
6{22}
6{23}
6{24}
6{25}
6{26}
6{27}
6{28}
6{29}
6{30}
6{31}
6{32}
6{33}
6{34}
6{35}
6{36}
6{37}
6{38}
8{1}
8{3}
8{6}
8{1}
8{3}
8{4}
8{5}
8{2}
8{5}
8{7}
8{1}
8{4}
8{4}
8{3}
8{2}
8{4}
8{5}
hydroxymethyl
(1-hydroxy-1-methyl)ethyl
2-pyridinyl
57c
77
98
>99
>99
>99
99
378.0748
754.2153
388.0830
390.0834
418.1147
898.2576
423.0837
387.0725
440.1103
442.0605
420.0939
488.1565
472.1252
432.0939
357.0619
428.1354
393.0731
+
754.2177
388.0836
390.0843
418.1146
898.2602
423.0826
387.0701
440.1188
442.0596
420.0949
488.1577
472.1266
432.0947
357.0609
428.1372
393.0716
19
M+H+
37c
58
M+NH4+
+
hydroxymethyl
(1-hydroxy-1-methyl)ethyl
1-hydroxy-1-cyclohexyl
1-methyl-1H-imidazol-5-yl
2-hydroxyethyl
1-methyl-1H-imidazol-5-yl
3-thiophenyl
M+NH4
48c
45
98
2M+NH4
+
>99
>99
>99
97
>99
>99
>99
>99
99
M+H+
57
43
55
M+H+
+
M+NH4+
M+NH4+
M+NH4+
M+NH4+
M+NH4+
M+NH4
M+H+
hydroxymethyl
66
1-hydroxy-1-cyclohexyl
1-hydroxy-1-cyclohexyl
(1-hydroxy-1-methyl)ethyl
2-hydroxyethyl
1-hydroxy-1-cyclohexyl
1-methyl-1H-imidazol-5-yl
47c
38
56c
65
+
53
>99
>99
M+NH4
37c
M+H+
a Sonogashira reaction: 3 mol % PdCl2(PPh3)2, 3 mol % CuI, Et2NH, R3C≡CH 8 (1.2 equiv), DMF, 80 °C, 20 min, using microwave irradiation. See
the Supporting Information for the experimental details. b Isolated yield after preparative HPLC. c Isolated yield after column chromatography. Isolated
desired products 6 were characterized by 1H and 13C NMR spectroscopy. d UV purity determined at 214 nm after preparative HPLC. e Not determined
by HRMS. Identified by NMR spectroscopy.
Table 5. Library Data for Compounds 6{39-45}a
product 6
9
R3
yield (%)b
purity (%)d
ion HRMS
calcd for HRMS
found HRMS
6{39}
6{40}
6{41}
6{42}
6{43}
6{44}
6{45}
9{2}
9{1}
9{2}
9{1}
9{2}
9{3}
9{3}
3,4-dimethoxyphenyl
4-methoxyphenyl
3,4-dimethoxyphenyl
4-methoxyphenyl
3,4-dimethoxyphenyl
4-pyridinyl
64c
77c
68
57
62
61
66
95
84
>99
93
97
97
96
M+
448.1167
450.0960
481.1143
451.1038
495.0936
436.0677
392.0779
448.1181
451.1040
NDe
451.1074
495.0936
436.0691
392.0794
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
4-pyridinyl
a Heck reaction: 5 mol % Pd(OAc)2, n-Bu4NI (1.0 equiv), Na2CO3 (2.5 equiv), R3CHdCH2 9 (1.2 equiv), DMF, 80 °C. See the Supporting
Information for the experimental details. b Isolated yield after preparative HPLC. c Isolated yield after column chromatography. Isolated desired
products 6 were characterized by 1H and 13C NMR spectroscopy. d UV purity determined at 214 nm after preparative HPLC. e Not determined by
HRMS. Identified by NMR spectroscopy.

Methyl Sulfone-Substituted Benzo[b]thiophene Library
Table 6. Library Data for Compounds 6{46-56}a
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2 283
product 6
10
R3
yield (%)b
purity (%)d
ion HRMS
calcd for HRMS
found HRMS
6{46}
6{47}
6{48}
6{49}
6{50}
6{51}
6{52}
6{53}
6{54}
6{55}
6{56}
10{1}
10{3}
10{1}
10{1}
10{1}
10{2}
10{1}
10{1}
10{1}
10{1}
10{3}
methyl
3,4-dimethoxybenzyl
methyl
methyl
methyl
propyl
methyl
methyl
methyl
71c
55
>99
98
>99
>99
>99
>99
98
>99
>99
99
>99
2M+Na+
711.0979
498.1409
646.1214
377.0517
377.0517
422.1096
407.0623
424.0889
391.0310
347.0412
483.0936
711.0962
498.1409
646.1214
377.0511
377.0491
422.1108
407.0617
424.0886
391.0312
347.0421
483.0944
+
M+NH4
+
83
2M+NH4
81c
74c
47
M+H+
M+H+
+
M+NH4
41c
62c
57
M+H+
+
M+NH4
M+H+
M+H+
M+H+
methyl
3,4-dimethoxybenzyl
45
49
a Carboalkoxylation: CO (1 atm), 3 mol % Pd(OAc)2, 5 mol % dppf, TEA (2.0 equiv), R3OH 10 (1.5-5.0 equiv), DMF, 70 °C. See the Supporting
Information for the experimental details. b Isolated yield after preparative HPLC. c Isolated yield after column chromatography. Isolated desired
products 6 were characterized by H and 13C NMR spectroscopy. d UV purity determined at 214 nm after preparative HPLC.
1
Table 7. Library Data for Compounds 6{57-72}a
product 6
11
R3
yield (%)b
purity(%)d
ion HRMS
calcd for HRMS
found HRMS
6{57}
6{58}
6{59}
6{60}
6{61}
6{62}
6{63}
6{64}
6{65}
6{66}
6{67}
6{68}
6{69}
6{70}
6{71}
6{72}
11{1}
11{8}
11{10}
11{12}
11{5}
11{7}
11{8}
11{3}
11{4}
11{8}
11{2}
11{8}
11{6}
11{9}
11{6}
11{11}
2-pyridylethylamino
4-hydroxybutylamino
1-amino-4-methylpiperazino
3-(2-oxo-1-pyrrolidinyl)propylamino
3,4-(methylenedioxy)benzylamino
1-methyltryptamino
56
62
98
87
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
M+H+
473.1569
434.1096
460.1365
487.1361
496.0889
505.1256
434.1096
503.1674
486.1045
464.1202
500.1314
464.1202
503.1311
461.0841
459.1412
495.1212
473.1548
434.1100
460.1360
487.1365
496.0889
505.1248
434.1098
503.1679
486.1057
464.1190
500.1323
NDe
27
67c
48
99
65c
71
>99
>99
>99
84
>99
>99
>99
>99
>99
>99
>99
99
4-hydroxybutylamino
72c
48
1-methyl-2-pyrrolidineethanamino
5-methyl-2-furanmethanamino
4-hydroxybutylamino
1H-imidazole-1-ethanamino
4-hydroxybutylamino
4-morpholinepropanamino
4-morpholinamino
4-morpholinepropanamino
1-(4-fluorophenyl)piperazino
61
58c
17
51
84c
62c
68
503.1308
461.0833
459.1398
495.1205
57
a Aminocarbonylation: CO (1 atm), 10 mol % Pd(OAc)2, 20 mol % PPh3, TEA, R3NH2 or (R3)2NH 11 (1.5 equiv), DMF, 80 °C. See the Supporting
Information for the experimental details. b Isolated yield after preparative HPLC. c Isolated yield after column chromatography. Isolated desired
products 6 were characterized by 1H and 13C NMR spectroscopy. d UV purity determined at 214 nm after preparative HPLC. e Not determined by
HRMS. Identified by NMR spectroscopy.

284 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 2
Cho et al.
Figure 2. Sublibraries of boronic acids 7, terminal alkynes 8, styrenes 9, alcohols 10, and amines 11.
10) were calculated for each of the library members using
the SYBYL58 program. Most of the desired sulfone-
substituted benzo[b]thiophene library members were highly
Lipinski compliant. A small subset of this virtual library,
namely, 72 compounds, follows Lipinski’s rules with no
violations.
lence (GM069663) for support of this research; Johnson
Matthey, Inc. and Kawaken Fine Chemicals Co., Ltd. for
donations of palladium catalysts; and Frontier Scientific and
Synthonix for donations of boronic acids.
Supporting Information Available. Synthetic methods,
spectral assignments and copies of 1H and 13C NMR spectra
for all previously unreported starting materials and products.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Conclusions
We have successfully produced a 72-member library of
sulfone-substituted benzo[b]thiophenes 6 via palladium-
catalyzed couplings, such as Suzuki-Miyaura, Sonogashira,
Heck, carboalkoxylation, and aminocarbonylation chemistry,
starting from key intermediate sulfur-containing 3-iodoben-
zo[b]thiophenes 5. The 72 member sulfone-substituted ben-
zo[b]thiophene library 6 has been added to the Kansas
University NIH Center for Chemical Methodologies and
Library Development (KU CMLD) collection and will be
submitted to the National Institutes of Health Molecular
Library Screening Center Network (MLSCN) for evaluation
by a broad range of assays. We expect this basic methodol-
ogy to find extensive application in the fields of combinatorial
chemistry, diversity-oriented synthesis, and drug discovery.
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