Construction of a polyheterocyclic benzopyran library with diverse core skeletons through diversity-oriented synthesis pathway

Article abstract of DOI:10.1021/cc100044w

In this study, a divergent and practical solid-phase parallel diversity-oriented synthesis (DOS) strategy was successfully applied for the construction of five discrete core skeletons embedded with privileged benzopyranyl substructure. The diversity of these core skeletons was expanded through the introduction of various substituents at the R, R¹, and R² positions from a single key intermediate in five different pathways. More importantly, we efficiently maximized the molecular diversity through the transformation of the core skeleton itself by using the library-to-library concept and created a distinctively different collection of small molecules with the same building blocks. A 434-member polyheterocyclic benzopyran library was constructed on a scale of about 10 mg with the potential for further diversification. Without further purification, the average purity of the library is 85%.

Full text of DOI:10.1021/cc100044w

548
J. Comb. Chem. 2010, 12, 548–558
Construction of a Polyheterocyclic Benzopyran Library with Diverse
Core Skeletons through Diversity-Oriented Synthesis Pathway
Sangmi Oh,† Hwan Jong Jang,† Sung Kon Ko,† Yeonjin Ko,† and
Seung Bum Park*,†,‡
Department of Chemistry and Department of Biophysics and Chemical Biology,
Seoul National UniVersity, Seoul 151-747, Korea
ReceiVed March 18, 2010
In this study, a divergent and practical solid-phase parallel diversity-oriented synthesis (DOS) strategy was
successfully applied for the construction of five discrete core skeletons embedded with privileged benzopyranyl
substructure. The diversity of these core skeletons was expanded through the introduction of various
substituents at the R, R1, and R2 positions from a single key intermediate in five different pathways. More
importantly, we efficiently maximized the molecular diversity through the transformation of the core skeleton
itself by using the library-to-library concept and created a distinctively different collection of small molecules
with the same building blocks. A 434-member polyheterocyclic benzopyran library was constructed on a
scale of about 10 mg with the potential for further diversification. Without further purification, the average
purity of the library is 85%.
Introduction
ficient DOS pathway for the construction of eleven discrete
core skeletons embedded with privileged benzopyran
substructure via various chemical transformations.7 Herein,
we report the use of our DOS pathway and the solid-phase
parallel synthesis to construct a library of natural product-
like small molecules that contain benzopyran substructure
and have maximum skeletal diversity.
Benzopyran is a well-known privileged substructural
motif observed in many biologically active natural prod-
ucts, and it plays a pivotal role in the regulation of various
biopolymers.8 As shown in Figure 1, naturally occurring
small benzopyran-containing molecules have huge skeletal
diversity through the conjunction of the privileged ben-
zopyran motif in their core skeletons, which allows
discrete biological activities associated with their novel
polycycles, such as antiproliferative activity against vari-
Since the completion of the human genome project in
2003, biomedical communities have been focused on the
elucidation of the gene function and the associated control
of gene products with small-molecule modulators.1 The
systematic endeavors of scientists in various disciplines
led to the birth of a new interdisciplinary research field,
chemical biology.2 The core components of chemical
biology are the identification of novel small-molecule
modulators as perturbing agents in biological systems and
the application of these small bioactive molecules to
pinpoint the control of specific gene products.3 Therefore,
there is a great demand for drug-like small molecules with
wide bioactivity ranges for the identifying specific small-
molecule modulators. To address this issue, the organic
chemistry community has investigated diversity-oriented
synthesis (DOS)sa new synthesis strategy to efficiently
populate the chemical space with skeletally and stere-
ochemically diverse small molecules through complexity-
generating reactions.4 The natural product-like and/or
drug-like small-molecule collections constructed using
DOS have proved to be effective for identifying bioactive
small-molecule modulators and therapeutic agents.5 Our
research group has been working on the development of
new DOS pathways and library realization using our new
methodology. We are particularly interested in the con-
struction of novel polyheterocyclic core skeletons embed-
ded with privileged substructural motifs, such as ben-
zopyran, pyridine, pyrazole, pyrazolopyrimidine, and
pyrimidine.6 We previously reported a concise and ef-
Figure 1. Examples of benzopyran-containing natural products. A,
Epicalyxin F that shows antiproliferative activity against carcinoma
cells; B, tetrahydrocannabinol that shows agonistic effect on
cannabinoid receptors, CB1 and CB2; C, rhododaurichromanic acid
A that exhibits phytotoxic properties; D, an ellagic acid derivative
that shows an inhibitory effect on glucose transport assay; E, (+)-
alboatrin that exhibits potent anti-HIV and anti-inflammatory
activities.
* To whom correspondence should be addressed. E-mail: sbpark@
snu.ac.kr.
† Department of Chemistry.
‡ Department of Biophysics and Chemical Biology.
10.1021/cc100044w  2010 American Chemical Society
Published on Web 06/01/2010

Construction of a Polyheterocyclic Benzopyran Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 549
Figure 2. Synthetic strategy for the construction of five discrete core skeletons embedded with benzopyran substructure: path A, Suzuki
coupling; path B, Stille coupling and subsequent Diels-Alder reaction; path C, asymmetric hydrogenation; path D, aromatization; path E,
click chemistry.
Scheme 1. Synthetic Scheme for Benzopyran Intermediate
ous carcinoma cells;9 agonistic effect on the cannabinoid
3R{R1} Loaded on Solid Supports
receptors, CB1 and CB2;10 inhibitory effect on cellular
glucose transport;11 phytotoxic properties;12 and potent
anti-HIV and anti-inflammatory activities.13 There have
been many studies of the synthesis of benzopyran deriva-
tives, but previous reports focused on limited diversifica-
tions of the appendices on the arene region of benzopyrans
with a few core structures or simple substituent changes
in the pyran region.14 Therefore, it is worthwhile to
construct a collection of drug-like small molecules with
diverse benzopyran-containing core skeletons. These ef-
forts will pave the way to demonstrate previously unre-
vealed advantages of the DOS approach; skeletally diverse
core skeletons embedded with privileged substructures aid
the search for specific small-molecule modulators for
diverse protein receptors in biological systems.
a DTBMP, triflic anhydride, CH2Cl2, 0 °C, 30 min. b 2,6-Lutidine,
CH2Cl2/THF, room temp. c TMSCl, CH2Cl2, room temp. d TfOH, CH2Cl2,
room temp.
To construct a benzopyran-containing small-molecule
library, we selected five discrete core skeletons from our
original DOS pathway. These synthetic methods should be
applicable for the solid-phase parallel synthesis format
without any loss of their molecular diversity. As shown in
Figure 2, we planned to access these five discrete core
skeletons through various chemical transformations from key
intermediate 2, such as palladium-mediated Suzuki coupling
(path A), Stille-type vinylation and subsequent Diels-Alder
reaction (path B), and Negishi-type alkynylation and sub-
sequent Huisgen 1,3-dipolar [3 + 2] cycloaddition, that is,
click chemistry (path E).15 These synthetic routes were
optimized in the solid-phase for the efficient construction of
benzopyran-containing small molecules in parallel synthesis
format. We also pursued the further diversification of
Diels-Alder adducts 5R{R1,R2} from path B transformed
into two structurally discrete core skeletons, 6R{R1,R2} and
7R{R1,R2}, through a library-to-library approach using
substrate-controlled asymmetric hydrogenation (path C) and
aromatization (path D) with a high degree of diastereose-
lectivity in the solution-phase and solid-phase parallel
synthesis, respectively.
Results and Discussion
Construction of Small Molecule Library with New
Benzopyran-containing Core Skeleton 4R{R1,R2} through
Path A. To maximize the molecular diversity of our
proposed library, we initiated the synthetic route from eight
different chromanone moieties 1R{R1}, synthesized from four
different hydroxyacetophenones through the cyclization with
acetone [R1 ) methyl] or cyclopentanone [R1 ) -(CH2)4-]
in the presence of pyrrolidine catalyst. As shown in Scheme
1, the resulting chromanone underwent triflation using triflic
anhydride in the presence of the proton sponge 2,6-di-tert-
butyl-4-methylpyridine (DTBMP) to yield the key isolable
intermediate, vinyl triflate 2R{R1}. After activation of (4-
methoxyphenyl)diisopropylsilylpropyl polystyrene resins by
treating TfOH, eight different vinyl triflated intermediates

550 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Oh et al.
Table 1. Classification of Loaded Intermediates 3R{R1} on Solid Supports
Table 2. Purity and Mass of Representative Compounds 4R{R1,R2} in Path A
ID
R
R1
R2
puritya(%)
MS(calcd)
MSb(found)
4a{1,17}
4b{1,8}
4c{1,8}
4d{1,8}
7-hydroxy
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
methyl
methyl
methyl
methyl
4-chloro-2-methylphenyl
4-fluorophenyl
4-fluorophenyl
96
99
99
99
299.08
301.12
345.13
381.11
298.86
300.99
345.03
380.96
4-fluorophenyl
a Purities were obtained by LC/MS analysis (PDA data) of final products without further purification. b Mass analysis were performed with electron
spray ionization (ESI) method.
2R{R1} were immobilized on these activated resins in the
presence of 2,6-lutidine to afford intermediates 3R{R1} on
solid supports (see Table 1). The average loading level was
about 0.9 mmol/g, measured by the weight gain of the loaded
resins and cross-checked against the weight of cleaved
products from loaded resins.
144-member small-molecule collection was synthesized on
a scale of 10-20 mg. The identity and purity of the final
products were determined using an LC/MS instrument,
injected with an aliquot of the crude cleavage product. As
shown in Tables 2 and 3, the presence of all the desired
compounds was unambiguously confirmed by their molecular
mass and their average purity was 87% without any purifica-
tion steps. The purities of the individual compounds are
shown in different colors.
Construction of Small-Molecule Library with Polyhet-
erocyclic Core Skeletons 5R{R1,R2}-7R{R1,R2} through
Paths B-D Using Library-to-Library Approach. We
previously reported the DOS pathway, which contains
palladium-mediated Stille-type vinylation on vinyl triflate
intermediate and subsequent endo-selective Diels-Alder
reaction with substituted maleimides as dienophiles to yield
diastereoselective benzopyran-containing heterocyclic com-
pounds 5R{R1,R2}. In this study, eight different vinyl triflate
intermediates 3R{R1} underwent palladium-mediated Stille-
type vinylation on the solid support to maximize the
molecular diversity of the final products. After extensive
washing, the resulting dienes were subjected to an in situ
Diels-Alder reaction with various maleimides on the solid
support (see Scheme 2). Among the 35 commercially
The common vinyl triflate moiety on intermediate 3R{R1}
is an excellent substrate for a palladium-mediated C-C
cross-coupling reaction; therefore, we first introduced various
substituted aryl rings via the Suzuki coupling of aryl boronic
acids. Among the many conditions tested in the solid phase,
Pd(PPh3)4 and Na2CO3 in aqueous 1,4-dioxane demonstrated
a robust chemical transformation of 3R{R1} with various
substituted aryl boronic acids, resulting in high yields of the
desired product 4R{R1,R2} (see Table 2). Under this reaction
condition, we synthesized benzopyran-containing small
molecules [4a{R1,R2}-4d{R1,R2}] using 18 different aryl
boronic acids in combination with eight vinyl triflate
intermediates 3R{R1} after cleaving the desired product from
the solid support by using HF/pyridine in tetrahydrofuran
(THF) and subsequent quenching with TMSOEt. The Suzuki-
type diversification at the R2 position introduced the new
privileged heterobiaryl structural motif in the new benzopy-
ran-containing core skeleton 4R{R1,R2}, and the resulting

Construction of a Polyheterocyclic Benzopyran Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 551
Table 3. Sets of Building Blocks and Purities of Compounds 4R{R1,R2}
Scheme 2. Synthetic Scheme of Paths B-D and 3-D Structural Difference of Three Distinct Core Skeletons (5-7)a
a 3-D structure of each molecules, 5a{1,3} in red, 6a{1,3} in yellow, and 7a{1,3} in green, were superimposed with three points of each benzopyran (1O,
2C, and 7C) by using Discovery Studio 1.7 software (Accelrys Software Inc.).
Table 4. Purity and Mass of Representative Compounds in Paths B-D
ID
R
R1
R2
puritya (%)
MS(calcd)
MSb(found)
5a{1,3}
5b{2,3}
5c{2,3}
5d{1,3}
6a{2,3}
6b{2,3}
6c{2,3}
7a{2,3}
7b{1,3}
7-hydroxy
methyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
phenyl
96
92
99
97
80
92
99
99
87
376.15
432.18
478.20
486.15
404.19
434.20
480.22
396.12
400.12
376.08
432.07
478.06
486.01
404.05
434.00
480.10
395.91
400.23
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
7-hydroxy
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
7-hydroxy
-(CH2)4-
-(CH2)4-
methyl
-(CH2)4-
-(CH2)4-
-(CH2)4-
-(CH2)4-
methyl
8-hydroxy-7-methoxy
a Purities were obtained by LC/MS analysis (PDA data) of final products without further purification. b Mass analyses were performed with the
electron spray ionization (ESI) method.
available maleimides tested for this reaction, we selected 17
substituted maleimides for the actual library synthesis to
ensure high yield and purity without any loss of molecular
diversity. After HF/pyridine cleavage and subsequent quench-
ing with TMSOEt, we obtained a 136-member diastereo-
merically enriched small-molecule collection [5a{R1,R2}-
5d{R1,R2}] with a novel polyheterocyclic core skeleton contain-
ing privileged benzopyran substructure on a scale of 10 mg
each. Their average purity (see Table 4 and 5), measured by
LC/MS analysis of the crude products, was around 85%.
To expand the molecular diversity of the small-molecule
collection, we applied the library-to-library approach to
transform the polyheterocyclic core skeleton 5R{R1,R2} into
two discrete core skeletons, 6R{R1,R2} and 7R{R1,R2}, using
robust chemical transformations such as Pd/C-based hydro-
genation (path C) and DDQ-mediated aromatization (path
D), respectively. We previously confirmed that this substrate-
controlled asymmetric hydrogenation of polyheterocyclic
monoene 5R{R1,R2} under mild reaction conditions using
heterogeneous catalyst Pd/C can yield diastereochemically

552 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Oh et al.
Table 5. Sets of Building Blocks and Purities of Compounds 5R{R1,R2}-7R{R1,R2}
enriched polyheterocycles 6R{R1,R2} in excellent yields (see
Scheme 2). The shape of the resulting core skeleton
6R{R1,R2} is structurally discrete and more concave than that
of its precursor 5R{R1,R2} because of the conversion at the
monoene site of sp2 carbon to sp3 carbon through asymmetric
hydrogenation. We initially tried to carry out the hydrogena-
tion reaction on solid supports using homogeneous catalysts
in organic solvents such as hydrazine16 and RhCl(PPh3)3,17
but we failed to obtain the desired hydrogenated compounds.
We then decided to carry out the hydrogenation reaction
using Pd/C and a hydrogen balloon in solution-phase parallel
synthesis after the cleavage of the monoene products
5R{R1,R2} from the solid support. Unfortunately, the outcome
of the asymmetric hydrogenation was substrate-dependent.
Therefore, we proceeded with solution-phase heterogeneous
hydrogenation with monoene precursors 5R{R1,R2} generated
with only nine maleimides to yield a 54-member collection
of small molecules [6a{R1,R2}-6c{R1,R2}] with a new core
skeleton through the transformation of the core skeleton
without any changes in the substituents. The average purity
of 6R{R1,R2} in path C was about 81% from 3R{R1} without
further purification, and the purities of the individual
compounds are shown in different colors in Table 5.
monoene precursor 5R{R1,R2} and provide a new flatter core
skeleton 7R{R1,R2} with the same substituents (see Scheme
2). Unfortunately, this transformation failed in the case of
compounds containing the biphenyl group, 5c and 5d, and
gave a complex mixture of products. Therefore, we pro-
ceeded the DDQ-mediated aromatization with 5a{R1,R2} and
5b{R1,R2} with nine substituted maleimides as building
blocks and obtained a 36-member collection of small
molecules [7a{R1,R2} and 7b{R1,R2}] with a new rigid and
flat core skeleton. The purities of the individual final
compounds are shown in Table 5 in different colors; the
average purity, measured by LC/MS analysis of the crude
products, was 84%.
Construction of Small-Molecule Library with New
Benzopyran-containing Core Skeleton 8R{R1,R2} through
Path E. For our synthetic path E, we introduced terminal
alkyne to the vinyl triflate intermediates 3R{R1} on the solid
support through a palladium-mediated Negishi-type cross-
coupling reaction. It was not easy to perform this reaction
in the parallel block synthesis format because it required
anhydrous conditions, so we pursued this transformation
using resin-loaded vinyl triflate intermediates 3R{R1} in each
separate reaction vessel. After Negishi-type alkynylation, the
resulting terminal alkynyl moiety on the benzopyran core
skeletons was subjected to Huisgen 1,3-dipolar [3 + 2]
cycloaddition, namely, Click chemistry, in the presence of
BrCu(PPh3)3,18 a Cu-catalyst soluble in organic solvent, and
DIPEA to yield a new triazole-containing core skeleton
8R{R1,R2} using solid-phase parallel synthesis (see Table 6).
We utilized 8 different azide compounds for the Click
The additional transformation of the polyheterocyclic core
skeleton 5R{R1,R2} was pursued via a DDQ-mediated
aromatization reaction using the library-to-library approach.
Compared to heterogeneous hydrogenation, which introduces
the sp3 carbon center in an asymmetric fashion, the aroma-
tization using 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)
can remove the existing stereogenic carbon centers of the

Construction of a Polyheterocyclic Benzopyran Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 553
Table 6. Purity and Mass of Representative Compounds 8R{R1,R2} in Path E
ID
R
R1
R2
puritya (%)
MS(calcd)
MSb(found)
8a{1,1}
8a{2,1}
8c{1,1}
8d{2,1}
7-hydroxy
8-hydroxy-7-methoxy
6-(3-hydroxyphenyl)
6-chloro-8-(3-hydroxyphenyl)
methyl
-(CH2)4-
methyl
benzyl
benzyl
benzyl
benzyl
87
91
79
92
334.15
360.16
410.19
470.16
334.42
360.30
410.11
470.08
-(CH2)4-
a Purities were obtained by LC/MS analysis (PDA data) of final products without further purification. b Mass analyses were performed with the
electron spray ionization (ESI) method.
discrete core skeletons, 6R{R1,R2} and 7R{R1,R2}, using
Table 7. Sets of Building Blocks and Purities of Compounds
8R{R1,R2}
substrate-controlled heterogeneous catalytic hydrogenation
and DDQ-mediated aromatization, respectively. This library-
to-library strategy allows the construction of a novel small-
molecule collection with three discrete benzopyran-contain-
ing core skeletons using the same building blocks. We
successfully applied our DOS pathway for the construction
of a full-scale benzopyran library with five discrete core
skeletons using solid-phase parallel synthesis, and we gener-
ated a 434-member drug-like small-molecule library with
85% average purity. Extensive biological evaluation of this
benzopyran library will lead to a valuable research tool in
the search for small-molecule modulators and potential
therapeutic agents. The corresponding biological results will
be reported in due course.
Experimental Section
General Information. All reagents in this synthetic
chemistry and produced a 64-member collection of triazole-
containing benzopyranyl compounds 8R{R1,R2} after HF/
pyridine cleavage from the solid support and subsequent
quenching with TMSOEt. The purities of the individual final
compounds are shown in Table 7 in different colors; the
average purity, measured by LC/MS analysis of crude
products, was 85%.
procedure were purchase from Sigma-Aldrich [MO, U.S.A.]
and TCI [Japan] and were used without further purification
unless noted otherwise. The progress of reaction was
monitored using thin-layer chromatography (TLC) (silica gel
60 F254 0.25 mm), and components were visualized by
observation under UV light (254 nm) or by treating the TLC
plates with anisaldehyde staining solution followed by
heating. Silica gel 60 (0.040-0.063 mm) used in flash
column chromatography was purchased from Merck [Ger-
many]. All reactions were conducted in oven-dried glassware
under dry argon atmosphere, unless otherwise specified.
CH2Cl2 was distilled from CaH2 immediately prior to use.
THF and toluene were distilled in the presence of sodium
metal. Other solvents and organic reagents were purchased
from commercial vendors and used without further purifica-
Conclusion
In this study, we successfully demonstrated the practical
construction of a small-molecule library with five discrete
core skeletons embedded with privileged benzopyranyl
substructure through creative recombination. In particular,
we focused on the expansion of the molecular diversity in
solid-phase parallel synthesis using the library-to-library
approach. Skeletal diversity was efficiently achieved through
the application of various chemical transformations on the
key intermediates, vinyl triflates 3R{R1}, such as palladium-
mediated Suzuki-type arylation, Stille-type vinylation and
subsequent diastereoselective Diels-Alder reaction, and
Negishi-type alkynylation and subsequent Huisgen 1,3-
dipolar [3 + 2] cycloaddition, to yield three discrete core
skeletons, 4R{R1,R2}, 5R{R1,R2}, and 8R{R1,R2}, respec-
tively. The excellent endo-selectivity of dienophiles in the
Diels-Alder reaction yielded a diastereochemically enriched
polyheterocycle, 5R{R1,R2}, which was transformed into two
1
tion unless otherwise mentioned. H and 13C NMR spectra
were recorded on a Varian Inova-500 [Palo Alto, U.S.A.]
or Bruker Avance DPX-300 [Germany], and chemical shifts
were measured in parts per million (ppm) relative to internal
tetramethylsilane (TMS) standard or specific solvent signal.
Multiplicity was indicated as follows: s (singlet); d (doublet);
t (triplet); q (quartet); m (multiplet); dd (doublet of doublet);
dt (doublet of triplet); td (triplet of doublet); bs (broad
singlet), and so forth. Coupling constants were reported in
hertz (Hz). Routine mass analysis were performed on a LC/
MS system equipped with a reverse phase column (C-18,

554 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Oh et al.
50 × 2.1 mm, 5 µm) and electron spray ionization (ESI).
The HRMS analyses were conducted at the Mass Spectro-
metry Laboratory of Seoul National University by direct
injection on a JEOL JMS AX505WA spectrometer using the
fast atom bombardment (FAB) method.
General Procedure for the Synthesis of Compound 2.
After silyl protection of hydroxyl group in compound 1, each
compound (1.0 equiv) and 2,6-di-tert-butyl-4-methylpyridine
(DTBMP, 1.3 equiv) were dissolved in anhydrous CH2Cl2.
To this solution, triflic anhydride (Tf2O, 1.2 equiv) was added
at 0 °C with ice-bath under N2 atmosphere. After the reaction
mixture was stirred for 10 min at the same temperature, the
resulting solid was filtered off and the filtrate was concen-
trated in vacuo. The remaining residue was redissolved in
ethyl acetate and washed with sat. NaHCO3 solution and
brine. The combined organic layer was dried over anhydrous
MgSO4, filtrated, and evaporated in vacuo. The resulting
mixture was purified with silica gel flash column chroma-
tography to provide product. After the deprotection of silyl
group, compound 2a˜d{1-2} were obtained in good yields.
General Procedure for the Synthesis of Compound 1.
Hydroxyacetophenone derivative (1.0 equiv) was dissolved
in EtOH. Pyrrolidine (3.0 equiv) was added to the solution,
followed by the addition of either acetone (10 equiv) or
cyclopentanone (3.0 equiv). The reaction mixture was then
heated to reflux for about 24 h. After the completion of
reaction monitored by TLC, the reaction mixture was
concentrated in Vacuo. The residue was redissolved in ethyl
acetate and washed several times with 1N HCl aqueous
solution. After washing with brine, the combined organic
layer was dried over anhydrous MgSO4, filtrated, and
evaporated in vacuo. The resulting mixture was purified with
silica gel flash column chromatography to provide desired
products [1a{1}-1d{2}]. Among these compounds, 1a˜b{1-2}
were previously reported.7
6-(3-Hydroxyphenyl)-2,2-dimethylchroman-4-one (1c{1}).
Colorless crystal (86%); 1H NMR (300 MHz, CDCl3): δ 8.06
(d, J ) 2.3 Hz, 1H), 7.66 (dd, J ) 8.6 and 2.3 Hz, 1H),
7.26-7.21 (m, 1H), 7.09-7.05 (m, 2H), 6.93 (d, J ) 8.6
Hz, 1H), 6.77 (dd, J ) 7.7 and 1.4 Hz, 1H), 2.73 (s, 2H),
1.44 (s, 6H); 13C NMR (75 MHz, CDCl3): δ 193.3, 159.7,
156.3, 141.2, 135.0, 133.4, 130.1, 124.6, 120.0, 118.9, 118.8,
114.3, 113.6, 79.5, 48.8, 26.6; MS (ESI-) m/z calculated for
C17H15O3 [M - H]-: 267.10; Found: 267.02.
7-Hydroxy-2,2-dimethyl-2H-chromen-4-yltrifluoromethane-
1
sulfonate (2a{1}). Colorless liquid (88%); H NMR (300
MHz, CDCl3): δ 7.11 (d, J ) 8.4 Hz, 1H), 6.41 (dd, J ) 8.4
and 2.3 Hz, 1H), 6.35 (d, J ) 2.3 Hz, 1H), 5.47 (s, 1H),
5.13 (s, 1H), 1.50 (s, 6H); 13C NMR (75 MHz, CDCl3): δ
158.4, 155.2, 142.5, 122.9, 115.4, 109.6, 108.4, 104.1, 78.3,
27.9; MS (ESI-) m/z calculated for C12H10F3O5S [M - H]-:
323.02; Found: 322.87.
7-Hydroxyspiro(chromene-2,1′-cyclopentane)-4-yl trifluo-
romethanesulfonate (2a{2}). Colorless liquid (84%); 1H
NMR (300 MHz, CDCl3): δ 6.87 (d, J ) 8.4 Hz, 1H), 6.27
(dd, J ) 8.4 and 2.3 Hz, 1H), 6.15 (d, J ) 2.3 Hz, 1H), 5.35
(s, 1H), 2.16-2.12 (m, 2H), 1.86-1.83 (m, 2H), 1.66-1.60
(m, 4H), 1.25-1.17 (m, 3H), 1.06 (d, J ) 6.8 Hz, 18H); 13
C
6-(3-Hydroxyphenyl)spiro(chroman-2,1′-cyclopentan)-4-
NMR (75 MHz, CDCl3): δ 158.9, 154.9, 142.7, 122.2, 114.5,
112.9, 110.4, 108.7, 88.4, 39.1, 23.3, 17.9, 12.6; MS (ESI+)
m/z calculated for C23H34F3O5SSi [M + H]+: 507.18; Found:
507.46 (It was identified as a TIPS protected form).
1
one (1c{2}). Colorless crystal (82%); H NMR (300 MHz,
CDCl3): δ 8.13 (d, J ) 2.3 Hz, 1H), 7.71 (dd, J ) 8.6 and
2.3 Hz, 1H), 7.32-7.26 (m, 1H), 7.14-7.12 (m, 2H), 6.99
(d, J ) 8.6 Hz, 1H), 6.83 (dd, J ) 8.1 and 1.8 Hz, 1H), 5.94
(bs, 1H), 2.89 (s, 2H), 2.14-2.06 (m, 2H), 1.95-1.87 (m,
2H), 1.77-1.63 (m, 4H); 13C NMR (75 MHz, CDCl3): δ
193.7, 160.1, 156.3, 141.2, 134.9, 133.4, 130.1, 124.8, 120.8,
119.1, 118.9, 114.3, 113.6, 90.2, 47.0, 37.5, 23.9; MS (ESI-)
m/z calculated for C19H17O3 [M - H]-: 293.12; Found:
292.86.
8-Hydroxy-7-methoxy-2,2-dimethyl-2H-chromen-4-yl tri-
fluoromethanesulfonate (2b{1}). Colorless liquid (90%); 1H
NMR (300 MHz, CDCl3): δ 6.81 (d, J ) 8.6 Hz, 1H), 6.53
(d, J ) 8.6 Hz, 1H), 5.55 (s, 1H), 4.67 (bs, 1H), 3.93 (s,
3H), 1.58 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 149.6,
142.7, 140.9, 134.3, 120.0, 117.5, 116.6, 112.8, 110.8, 104.0,
79.0, 56.4, 28.1; MS (ESI-) m/z calculated for C13H12F3O6S
[M - H]-: 353.03; Found: 352.94.
6-Chloro-8-(3-hydroxyphenyl)-2,2-dimethylchroman-4-
1
one (1d{1}). Colorless crystal (84%); H NMR (500 MHz,
8-Hydroxy-7-methoxyspiro(chromene-2,1′-cyclopentane)-
4-yl trifluoromethanesulfonate (2b{2}). Colorless liquid
(84%); 1H NMR (300 MHz, CDCl3): δ 6.76 (d, J ) 8.6 Hz,
1H), 6.49 (d, J ) 8.6 Hz, 1H), 5.56 (s, 1H), 4.68 (bs, 1H),
3.88 (s, 3H), 2.26-2.22 (m, 2H), 1.98-1.92 (m, 2H),
1.78-1.64 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 149.6,
142.8, 140.9, 134.5, 115.9, 112.7, 111.5, 104.1, 89.4, 56.4,
39.4, 23.7; MS (ESI-) m/z calculated for C15H14F3O6S [M -
H]-: 379.05; Found: 378.81.
CDCl3): δ 7.84 (d, J ) 2.6 Hz, 1H), 7.49 (d, J ) 2.6 Hz,
1H), 7.31-7.28 (m, 1H), 7.08 (d, J ) 7.7 Hz, 1H), 7.01 (s,
1H), 6.87 (dd, J ) 8.0 and 2.1 Hz, 1H), 5.23 (s, 1H), 2.75
(s, 2H), 1.45 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 192.2,
155.6, 137.7, 136.8, 133.2, 129.6, 126.4, 125.5, 122.0, 121.8,
116.5, 115.1, 80.1, 48.7, 26.7; MS (ESI-) m/z calculated for
C17H14ClO3 [M - H]-: 301.06; Found: 300.85.
6-Chloro-8-(3-hydroxyphenyl)spiro(chroman-2,1′-cyclo-
pentan)-4-one (1d{2}). Colorless crystal (81%); 1H NMR (300
MHz, CDCl3): δ 7.84 (d, J ) 2.6 Hz, 1H), 7.46 (d, J ) 2.6
Hz, 1H), 7.31-7.26 (m, 1H), 7.04 (d, J ) 7.7 Hz, 1H), 6.98
(s, 1H), 6.84 (dd, J ) 8.0 and 2.1 Hz, 1H), 2.85 (s, 2H),
2.10-2.05 (m, 2H), 1.74-1.61 (m, 6H); 13C NMR (125
MHz, CDCl3): δ 192.5, 156.1, 137.9, 137.4, 133.5, 130.6,
126.5, 126.0, 122.3, 122.1, 118.1, 114.2, 90.6, 46.8, 36.9,
24.0; MS (ESI-) m/z calculated for C19H16ClO3 [M - H]-:
327.08; Found: 327.86.
6-(3-Hydroxyphenyl)-2,2-dimethyl-2H-chromen-4-yl tri-
fluoromethanesulfonate (2c{1}). Colorless liquid (81%); 1H
NMR (500 MHz, CDCl3): δ 7.44-7.41 (m, 2H), 7.28 (t, J
) 8.0 Hz, 1H), 7.09 (d, J ) 8.0 Hz, 1H), 6.99 (t, J ) 2.5
Hz, 1H), 6.89 (d, J ) 8.0 Hz, 1H), 6.81 (dd, J ) 8.0 and 2.5
Hz, 1H), 5.68 (s, 1H), 5.36 (s, 1H), 1.54 (s, 6H); 13C NMR
(125 MHz, CDCl3): δ 156.1, 153.3, 142.5, 141.9, 134.2,
130.4, 130.3, 120.1, 119.4, 119.0, 117.4, 116.5, 114.4, 113.8,

Construction of a Polyheterocyclic Benzopyran Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 555
78.2, 28.1; MS (ESI-) m/z calculated for C18H14F3O5S [M -
H]-: 399.05; Found: 399.19.
treated with HF/Pyridine/THF (5/5/90) for 4 h at room
temperature, and then ethoxytrimethylsilane was added and
allowed to react for 1 h to quench excessive HF (HF/pyridine
protocol). After removing resins by filtration, the filtrate was
condensed in vacuo using a GeneVac EZ-2 Plus to obtain
the desired product 4.
Compound 4a{1,17}. 1H NMR (500 MHz, CDCl3): δ 7.22
(d, J ) 2.2 Hz, 1H), 7.19-7.16 (m, 1H), 7.06 (d, J ) 8.1
Hz, 1H), 6.45-6.35 (m, 2H), 6.23 (dd, J ) 8.3 and 2.5 Hz,
1H), 5.32 (s, 1H), 5.28 (s, 1H), 2.13 (s, 3H), 1.49 (d, J )
16.4 Hz, 6H); 13C NMR (125 MHz, CDCl3): δ 156.9, 154.3,
138.8, 136.7, 133.4, 133.2, 131.2, 130.1, 127.0, 126.4, 126.1,
115.9, 107.9, 104.2, 76.7, 28.2, 27.8, 19.8; HRMS (FAB+)
m/z calculated for C18H17ClO2 [M]+: 300.0917; Found:
300.0914.
6-(3-Hydroxyphenyl)spiro(chromene-2,1′-cyclopentane)-
4-yl trifluoromethanesulfonate (2c{2}). Colorless liquid
(83%); 1H NMR (300 MHz, CDCl3): δ 7.42-7.39 (m, 2H),
7.29-7.24 (m, 1H), 7.08 (d, J ) 7.5 Hz, 1H), 6.98 (s, 1H),
6.87 (d, J ) 9.0 Hz, 1H), 6.80 (dd, J ) 7.8 and 1.7 Hz, 1H),
5.71 (s, 1H), 4.98 (bs, 1H), 2.28-2.23 (m, 2H), 1.98-1.92
(m, 2H), 1.79-1.66 (m, 4H); 13C NMR (75 MHz, CDCl3):
δ 156.0, 153.2, 142.3, 141.8, 134.0, 130.1, 129.9, 120.7,
119.9, 119.2, 117.9, 117.2, 117.0, 114.1, 113.6, 88.4, 39.4,
23.5; MS (ESI-) m/z calculated for C20H16F3O5S [M - H]-:
425.07; Found: 425.09.
6-Chloro-8-(3-hydroxyphenyl)-2,2-dimethyl-2H-chromen-
4-yl trifluoromethanesulfonate (2d{1}). Colorless crystal
(81%); 1H NMR (500 MHz, CDCl3): δ 7.28 (d, J ) 2.5 Hz,
1H), 7.26 (s, 1H), 7.20 (d, J ) 2.5 Hz, 1H), 7.04 (d, J ) 7.5
Hz, 1H), 6.97 (t, J ) 2.0 Hz, 1H), 6.83 (dd, J ) 8.0 and 2.0
Hz, 1H), 5.71 (s, 1H), 1.51 (s, 6H); 13C NMR (125 MHz,
CDCl3): δ 155.6, 149.1, 141.7, 137.7, 132.4, 131.7, 129.6,
126.5, 122.0, 120.8, 119.7, 118.2, 116.4, 115.0, 78.4, 27.9;
MS (ESI-) m/z calculated for C18H13ClF3O5S [M - H]-:
433.01; Found: 432.89.
1
Compound 4b{1,8}. H NMR (500 MHz, CDCl3): δ
7.31-7.28 (m, 2H), 7.08-7.04 (m, 2H), 6.43 (dd, J ) 33.3
and 8.5 Hz, 2H), 5.49 (s, 1H), 5.48 (s, 1H), 3.87 (s, 3H),
1.52 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 163.6, 161.6,
147.9, 140.7, 134.6, 134.5, 134.1, 130.5, 130.4, 127.3, 116.7,
116.3, 115.4, 115.3, 115.2, 103.6, 103.5, 56.3, 56.2, 27.7;
HRMS (FAB+) m/z calculated for C18H17FO3 [M]+: 300.1162;
Found: 300.1166.
6-Chloro-8-(3-hydroxyphenyl)spiro(chromene-2,1′-cyclo-
pentane)-4-yl trifluoromethanesulfonate (2d{2}). Colorless
crystal (76%); 1H NMR (500 MHz, CDCl3): δ 7.28 (d, J )
3.0 Hz, 1H), 7.26 (d, J ) 2.0 Hz, 1H), 7.19 (d, J ) 2.5 Hz,
1H), 7.01 (dd, J ) 7.5 and 1.5 Hz, 1H), 6.95 (dd, J ) 2.5
and 1.5 Hz, 1H), 6.82 (dd, J ) 8.5 and 2.5 Hz, 1H), 5.75 (s,
1H), 2.21-2.01 (m, 2H), 1.76-1.59 (m, 6H); 13C NMR (125
MHz, CDCl3): δ 155.5, 149.0, 141.7, 137.7, 132.0, 131.8,
129.5, 126.5, 121.9, 120.7, 118.9, 118.7, 116.4, 114.9, 88.8,
39.3, 23.5; MS (ESI-) m/z calculated for C20H15ClF3O5S [M
- H]-: 459.03; Found: 458.91.
General Procedure for the Loading Step of Solid-Phase,
Compound 3. (4-Methoxyphenyl)-diisopropylsilylpropyl poly-
styrene resins (1.5 mmol/g, 1.0 equiv) were swelled in
CH2Cl2 with TMSCl (4.0 equiv) for 15 min to remove
residual water in solid supports. After filtration and then
washing with CH2Cl2, the resins were treated with 3% (v/v)
trifluoromethanesulfonic acid (6.0 equiv) in CH2Cl2 for 15
min. Then the resins were filtered, washed three times with
CH2Cl2, and then suspended in CH2Cl2. 2,6-Lutidine (8.0
equiv) and each compound 2 (3.5 equiv) were added
sequentially, and then the reactor was shaken for 12 h. After
filtration, the resulting resins were washed with CH2Cl2 and
THF (three times each) and then dried in vacuo to provide
benzopyran intermediates 3a˜d{1-2}.
General Procedure of Suzuki Coupling for Compound
4 (Path A). Benzopyran-loaded resins 3 (1.0 equiv) were
separated into each well of a 96-deep-well filtration block,
and solutions of 18 different boronic acids (3.0 equiv) in
1,4-dioxane were dispensed into the designated wells of the
reaction block. Then, the solution of Pd(PPh3)4 (0.1 equiv)
in 1,4-dioxane and 10% aqueous Na2CO3 solution were
added to the reaction block. The reaction mixture was shaken
at 70 °C in a rotating oven for 24 h, followed by washing
with THF, CH2Cl2, DMF, and MeOH (three times each).
After drying in vacuo, the resins in the reaction blocks were
Compound 4c{1,8}. 1H NMR (500 MHz, CDCl3): δ 7.36
(dd, J ) 8.3 and 2.2 Hz, 1H), 7.33 (dd, J ) 8.8 and 5.4 Hz,
2H), 7.21 (t, J ) 8.0 Hz, 1H), 7.15 (d, J ) 2.5 Hz, 1H),
7.08 (t, J ) 8.8 Hz, 2H), 7.02-6.98 (m, 1H), 6.94 (d, J )
8.3 Hz, 1H), 6.89-6.87 (m, 1H), 6.74-6.70 (m, 1H), 5.62
(s, 1H), 4.97 (bs, 1H), 1.51 (s, 6H); 13C NMR (125 MHz,
CDCl3): δ 163.7, 161.7, 156.0, 153.3, 142.8, 134.4, 134.1,
133.5, 130.6, 130.1, 129.8, 128.2, 124.2, 122.6, 119.5, 117.5,
115.6, 113.8, 76.3, 27.8; HRMS (FAB+) m/z calculated for
C23H20FO2 [M + H]+: 347.1447; Found: 347.1447.
1
Compound 4d{1,8}. H NMR (500 MHz, CDCl3): δ
7.33-7.23 (m, 3H), 7.19 (d, J ) 2.7 Hz, 1H), 7.14-7.07
(m, 3H), 7.04 (dd, J ) 2.5 and 1.5 Hz, 1H), 6.89 (d, J ) 2.5
Hz, 1H), 6.84-6.80 (m, 1H), 5.65 (s, 1H), 5.00 (bs, 1H),
1.46 (s, 6H); 13C NMR (125 MHz, CDCl3): δ 163.8, 161.8,
155.4, 149.0, 138.8, 134.1, 133.7, 131.5, 130.6, 130.2, 129.4,
125.6, 124.6, 122.2, 116.6, 115.7, 114.5, 76.5, 27.5; HRMS
(FAB+) m/z calculated for C23H19ClFO2 [M + H]+: 381.1058;
Found: 381.1057.
General Procedure of Diels-Alder Reaction for Com-
pound 5 (Path B). Benzopyran-loaded resins 3 (1.0 equiv)
were separated into each well of a 96-deep-well filtration
block, and a solution of tributyl(vinyl)tin (3.0 equiv) and
Pd(PPh3)4 (0.1 equiv) in 1,4-dioxane was dispensed into each
well of the reaction block. The reaction mixture was shaken
at 70 °C in a rotating oven for 36 h. Then, the resulting
resins were washed with THF, CH2Cl2, hexane, and MeOH
(three times each), and treated with 0.2 M solution of
diethyldithiocarbamate in THF twice to remove the residual
palladium catalyst on solid supports. Seventeen different
maleimides (3.0 equiv) in toluene were dispensed into the
designated wells of the reaction block, and the reaction
mixture was shaken at 40 °C in a rotating oven for 48 h.
After washing with toluene, CH2Cl2, THF, and DMF
sequentially (three times each), the resulting resins were dried

556 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Oh et al.
in vacuo, and the desired product 5 was cleaved from solid
supports by using HF/pyridine cleavage protocol.
After the reaction completion, the reaction mixture was
filtrated and then evaporated in vacuo to provide the desired
product 6.
1
Compound 5a{1,3}. H NMR (500 MHz, DMSO-d6): δ
1
Compound 6a{2,3}. H NMR (500 MHz, acetone-d6): δ
9.46 (s, 1H), 7.40 (d, J ) 8.6 Hz, 1H), 7.38-7.28 (m, 3H),
6.86-6.82 (m, 2H), 6.30 (dd, J ) 8.6 and 2.5 Hz, 1H),
6.27-6.22 (m, 1H), 6.11 (d, J ) 2.5 Hz, 1H), 3.68 (dd, J )
8.3 and 4.9 Hz, 1H), 3.38 (d, J ) 6.9 Hz, 1H), 2.71 (ddd, J
) 14.7, 7.5, and 1.3 Hz, 1H), 2.65 (d, J ) 3.4 Hz, 1H),
2.35-2.27 (m, 1H), 1.73 (s, 3H), 1.21 (s, 3H); 13C NMR
(125 MHz, DMSO-d6): δ 179.3, 176.6, 158.9, 153.7, 133.3,
133.1, 129.5, 128.8, 127.3, 124.2, 115.5, 113.0, 109.8, 104.8,
104.7, 75.8, 44.6, 43.0, 42.4, 29.3, 26.4, 25.8; MS (ESI+)
m/z calculated for C23H22NO4 [M + H]+: 376.15; Found:
376.08.
8.05 (s, 1H), 7.33-7.21 (m, 3H), 6.93 (d, J ) 8.6 Hz, 1H),
6.69-6.57 (m, 2H), 6.35 (dd, J ) 8.3 and 2.5 Hz, 1H), 6.14
(d, J ) 2.5 Hz, 1H), 3.47 (dd, J ) 9.5 and 5.6 Hz, 1H),
3.41-3.33 (m, 1H), 3.33-3.25 (m, 1H), 2.57-2.51 (m, 1H),
2.45 (dd, J ) 14.1 and 10.6 Hz, 1H), 2.40 (t, J ) 6.7 Hz,
1H), 2.03-1.91 (m, 3H), 1.90-1.67 (m, 5H), 1.67-1.58 (m,
1H), 1.55-1.44 (m, 1H); 13C NMR (125 MHz, acetone-d6):
δ 178.5, 175.8, 157.1, 154.5, 133.4, 128.5, 127.8, 127.0,
116.0, 107.9, 103.3, 86.9, 41.6, 40.1, 39.3, 38.1, 37.0, 28.7,
25.5, 23.9, 23.7, 21.1; HRMS (FAB+) m/z calculated for
C25H25NO4 [M]+: 403.1784; Found: 403.1784.
1
Compound 5b{2,3}. H NMR (500 MHz, CDCl3): δ
1
Compound 6b{2,3}. H NMR (500 MHz, CDCl3): δ
7.35-7.25 (m, 3H), 7.02-6.95 (m, 3H), 6.53 (d, J ) 8.8
Hz, 1H), 6.34-6.27 (m, 1H), 5.55 (s, 1H), 3.88 (s, 3H), 3.58
(dd, J ) 8.7 and 5.3 Hz, 1H), 3.38 (dt, J ) 8.4, 6.6, and 1.6
Hz, 1H), 3.06 (ddd, J ) 14.9, 7.5, and 1.6 Hz, 1H),
2.91-2.82 (m, 1H), 2.62 (d, J ) 4.4 Hz, 1H), 2.34-2.26
(m, 1H), 2.11-1.74 (m, 5H), 1.73-1.62 (m, 1H), 1.44-1.34
(m, 1H); 13C NMR (125 MHz, CDCl3): δ 178.4, 175.6, 147.3,
140.4, 135.6, 133.3, 132.0, 129.0, 128.5, 126.5, 117.5, 116.0,
113.2, 105.8, 88.7, 56.3, 44.9, 42.8, 42.2, 39.9, 36.0, 25.4,
23.9, 23.5; HRMS (FAB+) m/z calculated for C26H25NO5
[M]+: 431.1733; Found: 431.1731.
Compound 5c{2,3}. 1H NMR (500 MHz, CDCl3): δ 7.67
(d, J ) 2.2 Hz, 1H), 7.32 (dd, J ) 8.3 and 2.2 Hz, 1H),
7.28-7.19 (m, 4H), 7.09 (d, J ) 7.6 Hz, 1H), 7.01-6.98
(m, 1H), 6.95-6.90 (m, 3H), 6.75 (dd, J ) 8.0 and 1.6 Hz,
1H), 6.50-6.45 (m, 1H), 5.47-5.20 (bs, 1H), 3.59 (dd, J )
8.6 and 5.4 Hz, 1H), 3.45-3.33 (m, 1H), 3.10 (ddd, J )
14.9, 7.5, and 1.6 Hz, 1H), 2.88-2.78 (m, 1H), 2.67 (d, J )
5.4 Hz, 1H), 2.38-2.29 (m, 1H), 2.15-2.06 (m, 1H),
2.02-1.92 (m, 2H), 1.90-1.76 (m, 2H), 1.73-1.60 (m, 1H),
1.48-1.39 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 178.5,
175.7, 156.3, 152.5, 142.7, 134.2, 133.9, 132.0, 130.1, 129.0,
128.5, 128.2, 126.5, 122.1, 121.3, 119.6, 119.4, 119.3, 114.0,
113.9, 87.4, 45.1, 42.9, 42.3, 39.9, 36.2, 25.7, 23.8, 23.5;
HRMS (FAB+) m/z calculated for C31H27NO4 [M]+:
477.1940; Found: 477.1946.
7.30-7.21 (m, 3H), 6.61 (dd, J ) 7.5 and 1.8 Hz, 2H), 6.57
(d, J ) 8.6 Hz, 1H), 6.52-6.45 (m, 1H), 5.44 (s, 1H), 3.86
(s, 3H), 3.45-3.31 (m, 2H), 3.27-3.14 (m, 1H), 2.74-2.62
(m, 1H), 2.42 (dd, J ) 14.1 and 10.6 Hz, 1H), 2.24-2.16
(m, 2H), 2.15-2.08 (m, 1H), 2.07-1.99 (m, 1H), 1.99-1.70
(m, 5H), 1.69-1.58 (m, 1H), 1.56-1.49 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 178.5, 175.6, 146.1, 141.1, 134.2,
132.1, 128.9, 128.4, 126.4, 117.4, 116.8, 105.0, 87.9, 56.6,
41.4, 40.1, 39.6, 39.0, 37.4, 28.9, 25.1, 24.1, 23.9, 21.3;
HRMS (FAB+) m/z calculated for C26H27NO5 [M]+:
433.1889; Found: 433.1887.
1
Compound 6c{2,3}. H NMR (500 MHz, CDCl3): δ
7.29-7.24 (m, 2H), 7.19 (t, J ) 7.8 Hz, 1H), 7.17-7.13
(m, 3H), 7.01 (d, J ) 8.3 Hz, 1H), 6.94-6.91 (m, 1H),
6.81-6.76 (m, 1H), 6.70 (dd, J ) 7.7 and 2.1 Hz, 1H),
6.54-6.48 (m, 2H), 5.92 (bs, 1H), 3.50-3.41 (m, 1H), 3.36
(dd, J ) 9.5 and 5.4 Hz, 1H), 3.24-3.15 (m, 1H), 2.66-2.56
(m, 1H), 2.53-2.43 (m, 1H), 2.24-2.16 (m, 2H), 2.16-2.08
(m, 1H), 2.08-2.00 (m, 1H), 1.99-1.86 (m, 2H), 1.86-1.69
(m, 3H), 1.68-1.58 (m, 1H), 1.57-1.45 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 179.1, 176.2, 156.5, 153.2, 143.0,
133.2, 132.0, 130.0, 129.0, 128.6, 126.9, 126.5, 125.9, 124.3,
119.1, 117.8, 113.9, 113.8, 87.0, 41.5, 40.3, 39.8, 38.7, 37.6,
29.4, 25.3, 24.1, 23.9, 21.5; HRMS (FAB+) m/z calculated
for C31H29NO4 [M]+: 479.2097; Found: 479.2093.
General Procedure of Aromatization Reaction for
Compound 7 (Path D). Before the cleavage step of
compound 5 synthesized by Diels-Alder reaction, a solution
of 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ, 5.0 equiv)
in 1,4-dioxane was added to each well, and then the reaction
mixture was shaken at 75 °C in a rotating oven for 24 h.
After washing with THF, CH2Cl2, DMF, and MeOH (three
times each), the resulting resins were dried in vacuo, and
the desired product 7 was cleaved from solid supports by
using HF/pyridine cleavage protocol.
Compound 5d{1,3}. 1H NMR (500 MHz, CDCl3): δ 7.43
(d, J ) 2.5 Hz, 1H), 7.34-7.27 (m, 3H), 7.25-7.21 (m,
1H), 7.20 (d, J ) 2.5 Hz, 1H), 7.06-7.02 (m, 2H),
6.95-6.91 (m, 2H), 6.80-6.76 (m, 1H), 6.48-6.42 (m, 1H),
6.30 (bs, 1H), 3.62 (dd, J ) 8.6 and 5.1 Hz, 1H), 3.39-3.31
(m, 1H), 3.09 (ddd, J ) 15.0, 7.5, and 1.7 Hz, 1H), 2.55 (d,
J ) 3.9 Hz, 1H), 2.37-2.27 (m, 1H), 1.78 (s, 3H), 1.24 (s,
3H); 13C NMR (125 MHz, CDCl3): δ 178.2, 176.0, 155.6,
148.0, 138.2, 133.2, 131.9, 130.0, 129.4, 129.3, 128.9, 126.6,
126.1, 123.0, 121.4, 121.2, 120.8, 116.9, 114.7, 75.7, 45.7,
42.3, 42.0, 28.6, 26.0; HRMS (FAB+) m/z calculated for
C29H24ClNO4 [M]+: 485.1394; Found: 485.1391.
1
Compound 7a{2,3}. H NMR (500 MHz, DMSO-d6): δ
9.99 (bs, 1H), 8.12 (d, J ) 8.1 Hz, 1H), 7.82 (d, J ) 7.8
Hz, 1H), 7.66 (d, J ) 8.6 Hz, 1H), 7.50 (t, J ) 7.1 Hz, 2H),
7.42 (t, J ) 6.5 Hz, 3H), 6.51 (d, J ) 8.6 Hz, 1H), 6.31 (s,
1H), 2.55-2.36 (m, 2H), 2.13-2.00 (m, 2H), 1.99-1.85 (m,
4H); 13C NMR (125 MHz, DMSO-d6): δ 172.3, 171.8, 166.0,
158.8, 142.4, 142.3, 137.4, 136.0, 134.2, 133.5, 133.1, 133.0,
132.2, 131.3, 131.2, 117.6, 115.8, 109.6, 94.8, 44.6, 29.9;
General Procedure of Hydrogenation Reaction for
Compound 6 (Path C). Solution of each compound 5 (1.0
equiv) and 10% Pd/C (10 mol %) in MeOH/THF (1:1) was
purged with hydrogen. Then, the reaction mixture was stirred
under this hydrogen atmosphere for 3 h at room temperature.

Construction of a Polyheterocyclic Benzopyran Library
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4 557
HRMS (FAB+) m/z calculated for C25H19NO4 [M]+:
397.1314; Found: 397.1306.
153.1, 144.8, 142.5, 134.5, 133.9, 131.2, 130.0, 129.4, 129.2,
129.1, 128.4, 128.3, 128.1, 123.8, 123.2, 122.3, 121.0, 118.8,
117.6, 114.2, 114.0, 76.1, 54.6, 27.4; HRMS (FAB+) m/z
calculated for C26H24N3O2 [M + H]+: 410.1869; Found:
410.1871.
Compound 7b{1,3}. 1H NMR (500 MHz, CDCl3): δ 8.01
(d, J ) 8.0 Hz, 1H), 7.91 (d, J ) 8.0 Hz, 1H), 7.53-7.50
(m, 2H), 7.44-7.40 (m, 3H), 7.19 (d, J ) 9.0 Hz, 1H), 6.66
(d, J ) 9.0 Hz, 1H), 5.59 (bs, 1H), 3.95 (s, 3H), 1.99 (s,
6H); 13C NMR (125 MHz, CDCl3): δ 167.2, 166.8, 149.3,
140.6, 139.8, 136.9, 135.1, 131.9, 131.6, 129.3, 128.5, 127.7,
127.2, 127.0, 123.5, 115.0, 114.9, 105.8, 80.4, 56.5, 27.3;
HRMS (FAB+) m/z calculated for C24H19NO5 [M]+:
401.1263; Found: 401.1269.
Compound 8d{2,1}. 1H NMR (500 MHz, CDCl3): δ 7.56
(s, 1H), 7.41-7.33 (m, 3H), 7.33-7.29 (m, 2H), 7.24 (d, J
) 2.7 Hz, 1H), 7.21 (t, J ) 8.2 Hz, 1H), 7.15 (d, J ) 2.7
Hz, 1H), 7.03-6.97 (m, 2H), 6.86-6.82 (m, 1H), 6.18 (s,
1H), 5.59 (s, 2H), 2.18-1.98 (m, 2H), 1.70-1.63 (m, 2H),
1.63-1.49 (m, 4H); 13C NMR (125 MHz, CDCl3): δ 156.0,
148.9, 144.7, 138.4, 134.5, 132.0, 131.1, 130.0, 129.4, 129.3,
129.1, 128.4, 128.3, 125.7, 124.2, 123.7, 123.6, 122.0, 121.5,
116.6, 114.7, 87.2, 77.4, 54.6, 38.4, 23.6, 23.5; HRMS
(FAB+) m/z calculated for C28H25ClN3O2 [M + H]+:
470.1635; Found: 470.1630.
General Procedure of Click Chemistry for Compound
8 (Path E). Ethynyl magnesium bromide (8.0 equiv) in THF
(0.5 M) was added to anhydrous ZnCl2 (10 equiv), and then
this reaction mixture was stirred vigorously at 0 °C for 30
min under anhydrous condition. Benzopyran-loaded resins
3 (1.0 equiv) were separated into each well of a 96-deep-
well filtration block, and the prepared zinc reagent solution
and Pd(PPh3)4 (0.1 equiv) in 1,4-dioxane solution were
sequentially added into each well charged with resins. After
vigorous shaking for 12 h, the resulting resins were filtrated
and sequentially washed with CH2Cl2, THF, acetone, and
EtOH (three times each). Then, resultants were treated with
0.2 M solution of diethyldithiocarbamate in THF twice and
dried in vacuo. After this reaction, each alkynylated ben-
zopyran-loaded resin was separated into each well of a 96-
deep-well filtration block, and 8 different azides (3.0 equiv)
in toluene were dispensed into the designated wells of the
reaction block. After the addition of BrCu(PPh3)3 (0.2 equiv)
in toluene and DIPEA (6.0 equiv) into the reaction block,
the reaction mixture was shaken at room temperature in a
rotating oven for 36 h. The resulting resins were sequentially
washed with toluene, THF, CH2Cl2, DMF, and MeOH (three
times each), dried in vacuo, and the desired product 8 was
cleaved from solid supports by using HF/pyridine cleavage
protocol.
Acknowledgment. This study was supported by (1) the
National Research Foundation of Korea (NRF), (2) Marine-
Bio Technology Program funded by the Ministry of Land,
Transport, and Maritime Affairs (MLTM), Korea, and (3)
the WCU program of the NRF funded by the Korean
Ministry of Education, Science, and Technology (MEST).
S.O., H.J.J., S.K.K, and Y.J.K are grateful for a fellowship
award from the BK21 program.
Supporting Information Available. Experimental pro-
cedures and spectral data correspond to representative
compounds (1H, 13C NMR, and LC/MS). This material is
available free of charge via the Internet at http://pubs.acs.org.
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6.80 (dd, J ) 8.1 and 2.5 Hz, 1H), 6.09 (s, 1H), 5.50 (s,
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