Solid-phase parallel synthesis of a tetrahydroindazolone library containing three unique core skeletons

Article abstract of DOI:10.1002/asia.201100145

We have developed a practical strategy for the regioselective synthesis of a 1-(hetero)aryl-3-substituted tetrahydroindazolone library. The condensation of in situ generated arylhydrazine on solid supports with 2-acylcyclohexane-1,3- diones ensured the efficiency of solid-phase parallel synthesis. In addition, we introduced three unique core skeletons containing nitrophenyl, anilyl, and pyridyl groups to maximize the molecular diversity through a diverse display of polar surface area in 3D chemical space. A 162-membered drug-like tetrahydroindazolone library was constructed in an average purity of 92 % without further purification.

Full text of DOI:10.1002/asia.201100145

FULL PAPERS
DOI: 10.1002/asia.201100145
Solid-Phase Parallel Synthesis of a Tetrahydroindazolone Library Containing
Three Unique Core Skeletons
Jonghoon Kim,[a] Heebum Song,[a] and Seung Bum Park*[a, b]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Abstract: We have developed a practical strategy for the regioselective synthesis
of a 1-(hetero)aryl-3-substituted tetrahydroindazolone library. The condensation of
in situ generated arylhydrazine on solid supports with 2-acylcyclohexane-1,3-
diones ensured the efficiency of solid-phase parallel synthesis. In addition, we in-
troduced three unique core skeletons containing nitrophenyl, anilyl, and pyridyl
groups to maximize the molecular diversity through a diverse display of polar sur-
face area in 3D chemical space. A 162-membered drug-like tetrahydroindazolone
library was constructed in an average purity of 92% without further purification.
Keywords: molecular diversity
·
polar surface area · regioselectivity ·
solid-phase synthesis · tetrahydroin-
dazolones
Introduction
For the efficient and systematic identification of bioactive
small molecules, there is a great demand for the construc-
tion of a drug-like compound library with molecular diversi-
ty, such as skeletal, stereochemical, and building-group di-
versity.[5]
The importance of molecular diversity has been clearly rec-
ognized to identify specific bioactive small molecules for the
understanding of mysterious biological processes, which is
the core of a new interdisciplinary research area, chemical
biology.[1] Since the completion of the Human Genome Proj-
ect in 2003, biomedical research communities have been fo-
cusing on the elucidation of gene functions and the associat-
ed control of gene products through the perturbation upon
treatment with small-molecule modulators.[2] The discovery
of specific small-molecule modulators can lead to the devel-
opment of potential therapeutic agents.[3] In addition, they
can serve as a biomedical research tool to elucidate a wealth
of information about complex functions of biopolymers.[4]
To address this unmet need, the organic chemistry com-
munity has developed a new algorhythm for the construc-
tion of small-molecule libraries containing natural product-
like or drug-like skeletons through combinatorial chemistry
and diversity-oriented synthesis (DOS).[5] In fact, the practi-
cal application of solid-phase organic synthesis has funda-
mentally changed the thinking process for efficient produc-
tion of a large number of small molecules due to its advan-
tages, such as simple purification, easy manipulation, amena-
bility to automation, and enforced reaction completion
when using a large excess of reagents. Therefore, the devel-
opment of a new synthetic procedure using solid-phase par-
allel synthesis can facilitate the rapid construction of a small
molecule library with diverse core skeletons. We have been
working on the construction of drug-like polyheterocycle li-
braries embedded with privileged substructures including
benzopyrans,[6] pyrroles,[7] carbohybrids,[8] and acetal-fused
pyranopyrones.[9] Our research group has also developed a
practical solid-phase parallel strategy for the divergent syn-
thesis of skeletally diversified polyheterocycles, such as dia-
zabicycle,[10] D5-2-oxopiperazine,[11] tetrahydro-b-carboline,[12]
and tetrahydro-1,4-benzodiazepine[13] from in situ generated
cyclic iminiums as a common intermediate. All these molec-
ular frameworks are derived from the structures of bioactive
[a] J. Kim, H. Song, Prof. Dr. S. B. Park
Department of Chemistry
Seoul National University
151-747 Seoul (South Korea)
Fax : (+82)2-884-4025
E-mail: sbpark@snu.ac.kr
[b] Prof. Dr. S. B. Park
Department of Biophysics and Chemical Biology
Seoul National University
151-747 Seoul (South Korea)
Fax : (+82)2-884-4025
E-mail: sbpark@snu.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100145.
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Chem. Asian J. 2011, 6, 2062 – 2072

natural products or therapeutic agents and the pilot libraries
embedded with these core skeletons were constructed
through solid-phase parallel synthesis with high purities and
molecular diversity.
dazolone library containing three unique core skeletons by
using solid-phase parallel synthesis.
As a continuation of our endeavor in molecular diversity
using diversity-oriented synthesis, we recognized tetrahy-
droindazolone as an important pharmacophore. For exam-
Results and Discussion
Tetrahydroindazolones have been generally obtained
through the simple condensation of 2-acylcyclohexane-1,3-
dione (3) with substituted hydrazine, but the regioselectivity
of this synthetic method is limited by its narrow scope of ac-
ceptable hydrazine substrates (Scheme 1).[22] As reported in
the literature, arylhydrazines 1 have been commonly used
for the regioselective synthesis of 1-aryltetrahydroindazo-
lones 4 because arylhydrazines have an adequate chemical
property to control the regiochemistry: the terminal nitro-
gen atom of arylhydrazines 1 is more nucleophilic than its
internal nitrogen atom because of the conjugation of lone-
pair electrons at the internal nitrogen atom to the aromatic
ring system. Therefore, 1-aryl-substituted tetrahydroindazo-
lones 4 can be synthesized through the condensation of 3
and 1 without the formation of 2-aryl-substituted tetrahy-
droindazolones 5.
ple, SNX-2112, which contains
a tetrahydroindazolone
moiety, is reported as a selective antitumor agent with oral
bioavailability through the competitive binding at the ade-
nosine triphosphate (ATP) binding site in the N-terninal
domain of heat shock protein
90 (HSP90). HSP90 is one of
the most abundant proteins in
cells and is known to associate
with the non-native structure
and maturation of many cellu-
lar proteins, thatꢁs why it is
called a molecular chaperone.[14]
In cancerous cells, a number of
proteins,
including
various
growth factor receptors and sig-
naling proteins, are overex-
In contrast, the regioselective synthesis of alkyl-substitut-
ed tetrahydroindazolones cannot be achieved through con-
densation of 3 and alkylhydrzines 2 because of the similar
nucleophilicities of the two nitrogen atoms in alkylhydra-
zines. To overcome this limitation, we previously developed
a divergent strategy for the orthogonal synthesis of comple-
mentary regioisomers, 1-alkyl-3-substituted tetrahydro-inda-
zolones (6) and 2-alkyl-3-substituted tetrahydroindazolones
(7) from Boc-protected alkylhydrazines 8 (see Scheme 1).[23]
The key feature of this strategy is the differentiation of nu-
cleophilicity of two internal nitrogen atoms in alkylhydra-
zines through the selective protection of the internal nitro-
gen atom with a tert-butoxycarbonyl (Boc) group, which
allows the selective formation of enehydrazines or inter-
mediate 9 followed by the acid-catalyzed deprotecion of the
Boc group and subsequent intra- or intermolecular cycliza-
tion. This divergent strategy fully controls the regioselective
synthesis of N-alkyl-3-substituted tetrahydroindazolones.
However, this novel synthetic method requires strongly
acidic conditions under microwave irradiation, which are
difficult to be applied for the practical construction of a
drug-like small-molecule library containing tetrahydroinda-
zolones when using a solid-phase parallel synthesis platform.
For the systematic construction of the tetrahydroindazo-
lone library, we pursued the development of a divergent
solid-phase parallel strategy through the robust condensa-
tion of arylhydrazines 13 immobilized on solid supports with
various 2-acylcyclohexane-1,3-diones 3. As shown in
Scheme 2, we envisioned the usage of indole aldehyde resin
as a suitable linker system because of the easy introduction
of diversity elements for the library realization through the
reductive amination of commercially available primary
amines. Along with that, final products can be liberated
from the solid support under mild acidic conditions when
using 1% TFA in dichloromethane, thus the purity of final
pressed and the stabilization of these mutant proteins are
critically regulated by HSP90.[15] Therefore, the inhibition of
HSP90 is one of the validated approaches for the treatment
of various kinds of cancers.[16] There are many reports re-
garding HSP90 inhibitors including geldanamycin,[17] its ana-
logues (17-AAG and 17-DMAG),[18] radicicol,[19] CNF-
2024,[20] etc. SNX-2112 is currently in phase III clinical
trials,[21] which validates the importance of tetrahydroindazo-
lone as a key pharmacophore in biomedical research. How-
ever, the systematic exploration of chemical space around
privileged tetrahydroindazolones has not yet been extensive-
ly pursued. Furthermore, we were interested in the diversifi-
cation of tetrahydroindazolone-based core skeletons with
the preservation of its validated molecular frameworks.
Therefore, we developed a practical procedure for the syn-
thesis of tetrahydroindazolone with excellent regioselectivity
and accomplished the construction of a novel tetrahydroin-
Abstract in Korean:
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S. B. Park et al.
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Furthermore, we aimed to
construct three discrete core
skeletons to maximize the mo-
lecular diversity in the resulting
collection of tetrahydroindazo-
lones. Based on the synthetic
strategy, we ensure the regiose-
lectivity of the resulting tetra-
hydroindazolones through the
usage of arylhydrazines, gener-
ated by the nucleophilic aro-
matic substitution of electron-
deficient aromatic rings on
solid supports with free hydra-
zine. On the basis of our pre-
liminary studies, 1-fluoro-2-ni-
troaryl and 2-chloropyridyl
moieties were suitable sub-
strates for the formation of
aryl- and heteroarylhydrazines.
The resulting aryl- and hetero-
arylhydrazines were directly
utilized for the regioselective
construction of tetrahydroinda-
zolones by condensation with
various 2-acylcyclohexane-1,3-
diones 3. In addition, the result-
ing tetrahydroindazolones con-
taining a nitro group can be
transformed into the aniline
moiety through SnCl2-assisted
Scheme 1. a) General syntheses of tetrahydroindozolones involve (left) the condensation of 1 and 3 to form 1-
aryl-3-substituted tetrahydroindazolones 4 with good regioselectivity, and (right) the condensation of alkylhy-
drazines 2 with 3 to form N-alkyl-3-substituted tetrahydroindazolones 6 and 7 with no regioselectivity. b) Or-
thogonal regioselective synthesis of N-alkyl-3-substituted tetrahydroindazolones 6 and 7 using Boc-protected
alkyl hydrazines 8.[23] Boc=tert-butoxycarbonyl.
products can be enhanced through the minimized decompo-
sition upon acid-catalyzed cleavage from solid supports.
reduction on solid supports. Therefore, we can robustly
access the three unique core skeletons with a tetrahydroin-
dazolone-based
molecular
framework. We then performed
the in silico analysis to visualize
the molecular diversity of the
resulting three core skeletons.
As shown in Figure 1, three
representative compounds 16,
17, and 18 have a unique dis-
play of polar surface charges on
the similar molecular frame-
works. In fact, the polar surface
area (PSA) and the distribution
of polar surface charges are
closely linked to noncovalent
interactions, such as hydrogen
bonding, ionic bonding, van der
Waals forces, and hydrophobic
interactions, for specific recog-
nition of small-molecule ligands
with various biopolymers. The
unique display of polar surface
charges on similar molecular
frameworks
through the introduction of dis-
was
achieved
Scheme 2. Regioselective solid-phase parallel synthetic strategy for the construction of a tetrahydroindazolone
library.
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A Tetrahydroindazolone Library Containing Three Unique Core Skeletons
three representative compounds
(16, 17, and 18) with three
unique core skeletons contain-
ing tetrahydroindazolones are
populated differently in the
chemical space with maximized
molecular diversity (see Fig-
ure 1b). By use of calculation
data, we noticed that the Prin3
factor was the most important
element related to PSA charac-
ter from among three major
principle components. Thus,
three representative compounds
were effectively differentiated
in 3D chemical space by Prin3
and the resulting small-mole-
cule library containing these
scaffolds might induce the spe-
cific interactions with various
biopolymers and facilitate the
discovery of novel small-mole-
cule modulators, which is the
crown jewel of chemical biol-
ogy.
The practical and divergent
procedures for regioselective
synthesis of tetrahydroindazo-
lones in solid-phase parallel
fashion were optimized through
the preparation of representa-
tive tetrahydroindazolones con-
taining nitrophenyl (16), anilyl
(17), and pyridyl moiety (18).
The reaction progress on solid
supports was monitored in each
step by using LCMS after cleav-
age from the solid support in
combination with the on-bead
colorimetric method. For direct
comparison of each synthetic
route, R1 and R2 were fixed
Figure 1. a) The PSA is illustrated by an isosurface diagram after an electrostatic potential and electron density
calculation and the energy-minimized conformers of representative compounds 16, 17, and 18. b) PCA of rep-
resentative compounds 16, 17, and 18.
with 4-methoxybenzyl and
a
phenyl group, respectively. As
shown in Scheme 3, the synthe-
similar moieties to common scaffolds, which was illustrated
by an isosurface diagram after calculation of electrostatic
potential and electron density. In addition, the actual trajec-
tory of three different molecular frameworks with the nitro-
phenyl (16), anilyl (17), and pyridyl (18) moiety is dissimilar
in 3D space and has quite different dihedral angles of the
heterobiaryl junction (Fklmn =54.9, 43.5, and 8.58, respective-
ly) because of intramolecular hydrogen bonding and steric
interactions on the basis of our energy-minimized conforma-
tional analysis (see Figure 1a). The computational analysis
with 15 discrete molecular descriptors and subsequent prin-
ciple component analysis (PCA) clearly demonstrated that
sis was initiated by the incorpoartion of 4-methoxybenzyla-
mine to indole aldehyde resin 10 through the reductive ami-
nation in the presence of TMOF in anhydrous THF and the
subsequent treatment of sodium cyanoborohydride
(NaCNBH3) in acetic acid at room temperature.[24] The
resin-bound secondary amine (19) was coupled with 4-
fluoro-3-nitrobenzoic acid or 6-chloronicotinic acid through
activation with HATU, which allows the introduction of ni-
trophenyl and pyridyl moiety to tetrahydroindazolones.
After the completion of the amidation step, confirmed by a
negative chloranil test, the resulting electron-deficient 4-
fluoro-3-nitrophenyl (20) and 6-chloropyridyl (21) com-
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S. B. Park et al.
FULL PAPERS
the nitro group on the aryl ring.
The further screening of reac-
tion conditions allows the com-
plete cyclization of nitroarylhy-
drazine 22 with 2-benzoyl-5,5-
dimethylcyclohexane-1,3-dione
at 1008C in DMF with micro-
wave irradiation. Finally, we
transformed the nitro group on
resin-bound tetrahydroindazo-
lone 24 to anilyl moiety 17 by
selective reduction with 1m
tin(II) chloride dihydrate in
DMF at 308C. As shown in
Scheme 3, the representative
compounds 16, 17, and 18 were
achieved upon treatment of 1%
TFA in dichloromethane for
acidolysis from solid support in
excellent purities (>90%) with-
out further purification.
After the confirmation of
molecular diversity in three
unique core skeletons and the
optimization of the solid-phase
synthetic procedure, we pur-
sued the construction of the tet-
rahydroindazolone pilot library
containing three core skeletons
by using various commercially
available primary amines as the
R1 diversity elements and in-
house prepared 2-acylcyclohex-
ane-1,3-diones 3 as the R2 di-
versity elements. To ensure the
quantity of final products, we
used 50 mg of indole aldehyde
resins per library member and
Scheme 3. Solid-phase parallel synthesis of three representative compounds 16, 17, and 18 with three unique
core skeletons containing tetrahydroindazolone: a) 4-methoxybenzyl amine, TMOF, THF, RT, 4 h, then
NaCNBH3, AcOH, RT, 2 h; b) 4-fluoro-3-nitrobenzoic acid, HATU, DIPEA, DMF, RT, 12 h; c) 6-chloronico-
tinic acid, HATU, DIPEA, DMF, RT, 12 h; d) hydrazine monohydrate, DMF, RT, 12 h; e) hydrazine monohy-
drate, pyridine, 1008C, 12 h; f) 2-benzoyl-5,5-dimethylcyclohexane-1,3-dione, DMF, microwave, 1008C, 30 min;
g) 2-benzoyl-5,5-dimethylcyclohexane-1,3-dione, DMF, 608C, 12 h; h) 1m SnCl2·ACHTNUTRGNEG(UN H2O)2 in DMF, 308C, 12 h;
i) 1% TFA in CH2Cl2, RT, 4 h. DIPEA=N,N-diisopropylethylamine, HATU=O-(7-azabenzotriazole-1-yl)-
N,N,N’,N’-tetramethyl uronium PF6, TFA=trifluoroacetic acid, THF=tetrahydrofuran, TMOF=trimethyl or-
thoformate, DMF=N,N-dimethylformamide.
pounds on solid supports were treated with free hydrazine
(NH2NH2) in DMF at room temperature or in pyridine at
1008C to furnish the in situ generation of the corresponding
nitrophenyl- (22) and pyridylhydrazine (23) on solid sup-
ports by nucleophilic aromatic ipso-substitution.
the optimized reaction conditions yielded 5–20 mg of final
products after acid-catalyzed cleavage from solid support
without further purification. In the cases of [3-(trifluorome-
thyl)phenyl]methanamine (R1 =g) or 5,5-dimethyl-2-[4-(tri-
fluoromethyl)benzoyl]cyclohexane-1,3-dione (R2 =6), we
observed the significant retardation in the intramolecular
nucleophilic cyclization of enehydrazine intermediates to
the desired tetrahydroindazolones, probably due to the de-
creased nucleophilicity of hydrazine. Thus, the condensation
reactions with these particular substrates were carried out at
a higher temperature (X=C, R=NO2, or NH2, microwave
irradiation at 1108C; X=N, 80 8C) than in the optimized
conditions to complete the cyclization. As shown in Tables 1
and 3, the drug-like small-molecule pilot library containing
For the transformation of nitrophenylhydrazine 22 or pyr-
idylhydrazine 23 to tetrahydroindazolones 24 or 25, respec-
tively, we screened the reaction conditions by changing vari-
ous solvents, additives, and reaction temperatures (data not
shown). In the case of pyridylhydrazine 23, we obtained the
desired tetrahydroindazolone 18 with high purity and yield
in DMF at 608C followed by acid-catalyzed cleavage from
solid supports by using 1% TFA in dichloromethane. How-
ever, in the case of nitrophenylhydrazine 22, the full conver-
sion of the enehydrazine intermediate to the desired tetra-
hydroindazolone 16 cannot be achieved at 608C or even at a
higher temperature in DMF, because of the significant re-
duction in the nucleophilicity of the internal amine on nitro-
phenylhydrazine 22 by the electron-withdrawing effect of
1-nitrophenyl-3-substituted tetrahydroindazolones 30
ACHTUNGTRENNUNG
{R1,R2}
and 1-pyridyl-3-substituted tetrahydroindazolones 36
ACHTUNGTRENNUNG
was synthesized in an overall five steps with nine primary
amines (a–i) at the R1 position and seven substituents (1–7)
of 2-acylcyclohexane-1,3-diones 3 at the R2 position. Under
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A Tetrahydroindazolone Library Containing Three Unique Core Skeletons
the library-to-library concept from 30
G
E
transformation of fifteen molecular descriptors to a new
matrix by using SAS 9.1 (SAS Institute, Cary, NC), the di-
mensionality of diversity matrix with fifteen orthogonal
principal components was reduced down to a 3D coordiante
system for visualizing the molecular diversity in chemical
space with three major principal components. Three princi-
pal components (Prin1, Prin2, and Prin3) represent 97.0%
of the total variance in molecular descriptors. The Prin1
factor, which explains 81.3% of the total variance, is mainly
constituted by molecular weight (MW), van der Waals
(VDW) surface, and VDW volume. The Prin2 factor, which
explains 10.5% of the total variance, is influenced by molec-
ular weight (MW), polar VDW surface area, topological
polar surface area, and H-bond acceptor surface area. The
Prin3 factor, accounting for 5.3% of the total variance, in-
cludes hydrogen-bond acceptor surface area, polar VDW
surface area, and topological polar surface area (see the
Supporting Information). As shown in Figure 2, each library
member containing different core skeletons (30, 32, and 36)
with different color codes (red, yellow, and blue) are distrib-
uted in the different regions of 3D chemical space, thus the
molecular diversity of the resulting small-molecule library is
effectively maximized through the introduction of tetrahy-
droindazolone-based three unique core skeletons.
the nitrophenyl-substituted core skeleton (29) was trans-
formed to anilyl-substituted tetrahydroindazolones (31) on
solid support upon treatment of 1m SnCl2 in DMF at 308C.
In fact, the average purity of the resulting 32
lower than 30
ACHTUNGTRENNUNG
simple alkyl or tetrahydrofuranyl moieties at the R1 posi-
tion, probably because of its harsh reduction conditions.
Therefore, the pilot library containing 32
structed by using fewer building blocks than those with 30-
{R1,R2} and 36{R1,R2}. The purities and identities of all the
A
ACHTUNGTRENNUNG
library members were assessed by the direct analysis of
crude final products by using LCMS. The presence of all the
desired compounds was unambiguously confirmed by the
molecular weight with an excellent purity range, as deter-
mined by the HPLC analysis by using a photodiode array
(PDA) detector. The purity of each library member contain-
ing three unique core skeletons (30, 32, and 36) is labeled
with different colors in Tables 1, 2, and 3, respectively. The
average purity of final crude products was 92 (30, X=C,
R=NO2, see Scheme 2), 91 (32, X=C, R =NH2), and 93%
(36, X=N). The representative final crude products of the
tetrahydroindazolone library were fully characterized by H
and 13C NMR spectroscopy along with LCMS analysis (see
Table 4 and the Supporting Information).
To visualize the importance of three unique core skele-
tons (30, 32, and 36) along with the maximized molecular di-
versity of the resulting tetrahydroindazolone library, all of
the library members were subjected to the calculation with
fifteen major molecular descriptors by using PreADMET
(BMDRC, Seoul, Korea). Through the orthogonal linear
Conclusions
In this study, we developed the practical and divergent strat-
egy for the regioselective synthesis of a 3-substituted tetra-
hydroindazolone library. Even though we previously report-
Table 1. Set of building blocks and purities [%] of tetrahydroindazolones 30.[a]
30 {R1,R2}
R1
a
b
c
d
e
f
g
h
i
methyl
phenyl
furan-2-yl
1
2
3
4
5
6
7
95
90
90
90
90
93
86
99
91
85
94
95
92
77
97
93
87
93
96
90
86
95
90
71
92
90
95
88
80
90
90
93
84
95
96
94
94
84
93
90
96
82
98
97
86
93
99
99
90
93
97
73
99
97
95
97
98
91
95
92
95
94
93
R2
3,4-dimethoxybenzyl
but-3-enyl
4-trifluoromethylpheny
isobutyl
[a] Purities were obtained by PDA-based LCMS analysis of final products without further purification.
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S. B. Park et al.
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Table 2. Set of building blocks and purities [%] of tetrahydroindazolones 32.[a]
32 {R1,R2}
R1
a
b
c
d
e
f
methyl
phenyl
3,4-dimethoxybenzyl
but-3-enyl
4-trifluoromethylpheny
furan-2-yl
1
2
3
4
5
6
92
90
90
90
90
95
90
87
91
90
91
81
94
84
95
93
94
94
87
81
90
92
90
94
98
96
95
97
96
90
92
93
90
92
92
92
R2
[a] Purities were obtained by PDA-based LCMS analysis of final products without further purification.
Table 3. Set of building blocks and purities [%] of tetrahydroindazolones 36.[a]
36 {R1,R2}
R1
a
b
c
d
e
f
g
h
i
methyl
phenyl
furan-2-yl
1
2
3
4
5
6
7
83
98
94
90
85
96
93
99
96
93
91
97
99
96
97
90
98
88
92
99
95
95
99
90
92
96
99
98
93
92
97
90
82
99
94
94
91
98
92
93
97
94
99
99
91
94
94
85
99
90
92
78
90
88
91
90
90
95
90
86
91
92
91
R2
3,4-dimethoxybenzyl
but-3-enyl
4-trifluoromethylpheny
isobutyl
[a] Purities were obtained by PDA-based LCMS analysis of final products without further purification.
ed the orthogonal synthesis of complementary regioisomers,
1-alkyl-3-substituted (6) and 2-alkyl-3-substituted tetrahy-
droindazolones (7) from Boc-protected alkylhydrazines 8,
we pursued the regioselective synthesis of 1-(hetero)aryl-3-
substituted tetrahydroindazolone through simple condensa-
tion of (hetero)arylhydrazine (12) on solid supports with 2-
acylcyclohexane-1,3-diones 3 to ensure the efficiency of our
solid-phase parallel synthetic strategy. In addition, we have
overcome the existing drawback of this condensation reac-
tion through the introduction of three unique core skeletons
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A Tetrahydroindazolone Library Containing Three Unique Core Skeletons
Table 4. Purity and mass confirmation of representative compounds in
the tetrahydroindazolone library.
Typical Solid-Phase Reaction Procedures. Step 1: Reductive Amination[24]
Individual wells of a 96-deep-well filtration block were loaded with
R1
R2
Purity
[%]
MS [M+H]+
indole aldehyde resin 10 (50 mg, loading level: 0.9 mmolgÀ1
,
Compound
0.045 mmol). R1-amines (2.2 equiv, 0.099 mmol) in a cosolvent of THF
(0.25 mL) and trimethyl orthoformate (TMOF, 0.25 mL) were dispensed
into the designated wells of the reaction block. The reaction mixture was
shaken at room temperature in a rotating oven (Robbins Scientific) for
4 h. Then, a solution of NaCNBH3 (2.2 equiv, 0.099 mmol) in AcOH
(0.01 mL) and THF (0.10 mL) were added to the reaction block. The re-
action mixture was shaken at room temperature in a rotating oven for
2 h. The resulting resins 26 were washed with DMF, MeOH, and CH2Cl2
sequentially (ꢂ3 each) and dried in vacuo.
calcd obs
30
30
N
benzyl
2-methoxy-
ethyl
methyl
phenyl
95
91
433.18 432.92
463.19 463.00
30
32
U
tetrahydro-
furan-2-yl
4-mehtyl-phe-
nethyl
3,4-dimethoxy-
benzyl
3,4-dimethoxy-
benzyl
93
90
563.24 563.14
567.29 567.25
36
36
N
benzyl
2-methoxy-
ethyl
furan-2-yl
but-3-enyl
94
97
441.18 441.12
397.22 397.09
Step 2: Acid Coupling
A reaction cocktail of 4-fluoro-3-nitrobenzoic acid (3 equiv) or 6-chloro-
nicotinic acid (3 equiv), HATU (3 equiv), and DIPEA (6 equiv) in DMF
(1.3 mL) was dispensed into each well of the reaction block charged with
resins 26. The reaction mixture was incubated in a rotating oven at room
temperature for 12 h. The resins were then washed extensively with
DMF, MeOH, and CH2Cl2 (ꢂ3 each) and dried in vacuo. The reaction
completion was confirmed by a negative chloranil test.
with a different display of polar surface area. In this proce-
dure, two different arylhydrazines were in situ generated on
solid supports after the introduction of the first diversity ele-
ment at the R1 position and subjected to the regioselective
intramolecular condensation with various 2-acylcyclohex-
ane-1,3-diones 3. We also applied the library-to-library con-
cept for the further diversification of core skeletons by
SnCl2-based solid-phase reduction. The resulting tetrahy-
droindazolone-based core skeletons (30, 32, and 36) occupy
the different regions of 3D chemical space because of their
unique display of polar surface area, a new diversity ele-
ment, along with different dihedral angles of heterobiaryl
skeletons. The optimized synthetic procedures were tolerant
toward various building blocks and the 162-membered tetra-
hydroindazolone library was constructed in parallel with
92% average purity. The biological evaluation of the library
members will be reported in due course.
Step 3a: Nucleophilic Aromatic Substitution for the Preparation of 28
A solution of hydrazine monohydrate (20 equiv) in DMF (1.3 mL) was
added to a designated well charged with resins 27. The reaction mixture
was shaken at room temperature in a rotating oven for 12 h. The resins
were then washed (ꢂ3) with DMF, MeOH, and CH2Cl2 and dried in
vacuo.
Step 3b: Nucleophilic Aromatic Substitution for the Preparation of 34
A solution of hydrazine monohydrate (20 equiv) in pyridine (1.3 mL) was
added to a designated well charged with resins 33. The reaction mixture
was shaken at 1008C in a rotating oven for 12 h. The resins were then
washed (ꢂ3) with DMF, MeOH, and CH2Cl2 and dried in vacuo.
Step 4a: Cyclization for the preparation of 29
2-Acylcyclohexane-1,3-diones 3 (3 equiv) were added to a designated
resins 28 in DMF (1.3 mL), and the reaction mixture was heated in a
capped microwave vessel under microwave irradiation (150 W, 1008C or
1108C) for 25–30 min. The resin was filtered, washed (ꢂ3) with DMF,
MeOH, and CH2Cl2, and then dried in vacuo.
Experimental Section
Step 4b: Cyclization for the Preparation of 35
General
A solution of 2-acylcyclohexane-1,3-diones 3 (3 equiv) in DMF (1.3 mL)
was added to each well charged with resins 34. The reaction mixture was
incubated in a rotating oven at 60 or 808C for 12 h. The resins were then
washed extensively with DMF, MeOH, and CH2Cl2 (ꢂ3 each) and dried
in vacuo.
All commercially available reagents and solvents were used without fur-
ther purification unless noted otherwise. All the solvents were purchased
from commercial venders. Indole aldehyde resin was obtained from No-
vabiochem. 1H and 13C NMR spectra were obtained on a Varian Inova-
500 (Varian Assoc., Palo Alto, USA). Chemical shifts were reported in
ppm from tetramethylsilane (TMS) as the internal standard or the residu-
Step 5: Reduction of the Nitro Group
al solvent peak (CDCl3, H: d=7.26, 13C: 77.23 ppm). Multiplicity was in-
1
The aromatic nitro group of resin 29 was reduced to aniline upon treat-
dicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), dd (doublet of doublet), dt (doublet of triplet), td (triplet of dou-
blets), brs (broad singlet), etc. Coupling constants are reported in hertz.
The reaction steps for library construction were performed in parallel by
using the FlexChem Synthesis System from SciGene (Sunnyvale, CA) in
a 96-deep-well filtration block. The purity of all the library members was
observed by a LCMS system equipped with a reverse-phase column (C-
18, 50ꢂ2.1 mm, 5 mm) and photodiode array (PDA) detector by using
electron spray ionization (ESI). Microwave reactions were performed by
using a CEM Discover Benchmate and microwave reaction conditions
were denoted in the Experimental Section. Yields of crude products were
calculated on the basis of the loading amount of primary amines on the
solid support. Purities of final crude products were analyzed by LCMS
equipped with a PDA detector without further purification.
ment with 1m SnCl2·ACHTNURTGNEG(UN H2O)2 in DMF (1.3 mL) at 308C for 12 h, followed
by washing (ꢂ3) with DMF, MeOH, and CH2Cl2. The resulting resin was
dried in vacuo.
Step 6: Acid-Catalyzed Cleavage
After the resulting resins in the 96-deep-well reaction blocks were dried
under high vacuum, resins were treated with 1% TFA in CH2Cl2 at room
temperature for 4 h. Then, the resins were removed by filtration and
washed several times with CH2Cl2. The filtrate was condensed under re-
duced pressure by using GeneVac (Thermo Savant) and the resulting res-
idues were diluted with 50% H2O/ACN and freeze-dried, which yielded
final products as a pale-yellow powder. The purity of the final products
was confirmed by LC/MS without further purification.
Chem. Asian J. 2011, 6, 2062 – 2072
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2069

S. B. Park et al.
FULL PAPERS
Compound 17
Yield: 58%; purity: 93%; 1H NMR
(500 MHz, CDCl3): d=8.28 (brs, 2H),
8.04 (dd, J=7.3, 1.8 Hz, 2H), 7.41–
7.38 (m, 3H), 7.31 (s, 1H), 7.22 (d, J=
8.5 Hz, 2H), 7.18 (br t, J=5.0 Hz,
1H), 7.13 (d, J=8.5 Hz, 1H), 7.09 (d,
J=8.5 Hz, 1H), 6.85 (d, J=8.5 Hz,
2H), 4.48 (d, J=5.0 Hz, 2H), 3.77 (s,
3H), 2.59 (s, 2H), 2.43 (s, 2H),
1.07 ppm
(s,
6H);
13C NMR
(125 MHz, CDCl3): d=193.5, 168.0,
159.4, 153.0, 152.7, 142.2, 135.8, 131.1,
129.7, 129.5, 129.0, 128.4, 127.9, 127.1,
126.4, 117.3, 117.1, 115.3, 114.3, 55.4,
53.0, 44.1, 36.4, 35.4, 28.2 ppm; MS
(ESI+): m/z: calcd for C30H31N4O3:
495.23 [M+H]+; found: 495.10.
Compound 18
Yield: 68%; purity: 90%; 1H NMR
(500 MHz, CDCl3): d=8.87 (s, 1H),
8.22 (d, J=8.0 Hz, 1H), 8.13 (d, J=
8.5 Hz, 1H), 8.09 (d, J=6.5 Hz, 2H),
7.43 (brd, J=7.5 Hz, 2H), 7.29 (d, J=
7.5 Hz, 2H), 6.89 (d, J=7.5 Hz, 2H),
6.70 (brs, 1H), 4.58 (d, J=4.0 Hz,
2H), 3.80 (s, 3H), 3.39 (s, 2H), 2.46 (s,
2H), 1.16 ppm (s, 6H); 13C NMR
(125 MHz, CDCl3): d=193.3, 164.9,
159.5, 154.6, 152.6, 152.5, 147.0, 137.8,
131.6, 129.8, 129.6, 129.5, 129.3, 128.3,
128.2, 117.7, 115.5, 114.4, 55.5, 53.3,
44.0, 39.7, 35.2, 28.7 ppm; MS (ESI+):
m/z: calcd for C29H29N4O3: 481.22
[M+H]+; found: 481.11.
Compound 30ACTHNUGTRNEUNG{a,1}
Yield: 67%; purity: 95%; 1H NMR
(500 MHz, CDCl3): d=8.42 (d, J=
1.5 Hz, 1H), 8.18 (dd, J=8.5, 2.0 Hz,
1H), 7.52 (d, J=8.0 Hz, 1H), 7.38–
7.31 (m, 5H), 7.02 (brt, J=5.3 Hz,
1H), 4.66 (d, J=6.0 Hz, 2H), 2.52 (s,
2H), 2.47 (s, 3H), 2.38 (s, 2H),
1.09 ppm
(s,
6H);
13C NMR
(125 MHz, CDCl3): d=193.4, 164.0,
151.7, 151.5, 145.8, 137.5, 136.4, 134.0,
132.4, 129.4, 129.2, 128.3, 128.2, 124.3,
117.3, 52.5, 44.8, 36.2, 36.0, 28.4,
13.5 ppm; MS (ESI+): m/z: calcd for
C24H25N4O4: 433.18 [M+H]+; found:
432.92.
Figure 2. PCA of representative compounds (16, 17, and 18) and chemsets (30, 32, and 36) containing three
unique tetrahydroindazolone core skeletons.
Compound 30ACTHNUGTRNEUNG{b,2}
Yield: 63%; purity: 91%; 1H NMR
(500 MHz, CDCl3): d=8.42 (d, J=
Characterization of Representative Compounds. Compound 16
1.5 Hz, 1H), 8.17 (dd, J=8.5, 2.0 Hz, 1H), 8.02 (dd, J=8.5, 2.0 Hz, 2H),
7.60 (d, J=8.0 Hz, 1H), 7.43–7.38 (m, 3H), 7.01 (brt, J=5.3 Hz, 1H),
3.70 (q, J=5.1 Hz, 2H), 3.60 (t, J=5.3 Hz, 2H), 2.59 (s, 2H), 2.48 (s,
2H), 1.11 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=192.4, 164.3,
153.1, 152.7, 145.9, 136.7, 133.8, 132.3, 131.2, 129.5, 129.3, 129.1, 128.3,
124.4, 116.2, 70.9, 59.1, 53.3, 40.4, 36.4, 35.8, 28.3 ppm; MS (ESI+): m/z:
calcd for C25H27N4O5: 463.19 [M+H]+; found: 463.00.
Yield: 63%; purity: 93%; 1H NMR (500 MHz, CDCl3): d=8.37 (d, J=
1.5 Hz, 1H), 8.18 (dd, J=8.0, 1.5 Hz, 1H), 7.97 (t, J=3.5 Hz, 2H), 7.58
(brs, 1H), 7.46 (d, J=8.0 Hz, 1H), 7.47–7.45 (m, 3H), 7.21 (d, J=7.5 Hz,
2H), 6.83 (d, J=7.5 Hz, 2H), 4.49 (d, J=5.0 Hz, 2H), 3.76 (s, 3H), 2.53
(s, 2H), 2.39 (s, 2H), 1.06 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=
192.5, 164.1, 159.3, 152.9, 152.7, 145.6, 136.6, 133.5, 132.5, 131.2, 129.7,
129.53, 129.49, 129.0, 128.3, 124.4, 116.1, 114.3, 55.5, 53.2, 44.0, 36.2, 35.7,
28.2 ppm; MS (ESI+): m/z: calcd for C30H29N4O5: 525.21 [M+H]+;
found: 525.02.
Compound 30ACTHNUGTRNEUNG{i,4}
Yield: 69%; purity: 93%; 1H NMR (500 MHz, CDCl3): d=8.43 (d, J=
2.0 Hz, 1H), 8.15 (dd, J=8.3, 1.8 Hz, 1H), 7.53 (d, J=8.0 Hz, 1H), 7.15
2070
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2062 – 2072

A Tetrahydroindazolone Library Containing Three Unique Core Skeletons
(brt, J=5.5 Hz, 1H), 6.90–6.86 (m, 2H), 6.75 (d, J=8.0 Hz, 1H), 4.18–
4.12 (m, 3H), 3.93–3.88 (m, 1H), 3.86–3.79 (m, 7H), 3.37–3.31 (m, 1H),
2008, 120, 52–61; Angew. Chem. Int. Ed. 2008, 47, 48–56; d) L. A.
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2.56 (s, 2H), 2.38 (s, 2H), 2.11–2.06 (m, 1H), 1.96 (p, J=6.1 Hz, 2H),
1.65–1.59 (m, 2H), 1.08 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=
193.5, 164.5, 154.3, 152.1, 148.8, 147.6, 146.1, 136.4, 133.7, 132.2, 130.9,
129.0, 124.5, 121.2, 116.6, 112.3, 111.1, 77.9, 68.5, 55.9, 52.4, 44.5, 36.2,
36.0, 33.2, 29.0, 28.4, 25.9 ppm; MS (ESI+): m/z: calcd for C30H35N4O7:
563.24 [M+H]+; found: 563.14.
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Compound 32ACHTUNGTRENNUNG{d,3}
Yield: 57%; purity: 90%; 1H NMR (500 MHz, CDCl3): d=8.52 (brs,
2H), 7.14–6.99 (m, 8H), 6.92 (d, J=8.0 Hz, 1H), 6.75 (d, J=8.5 Hz, 1H),
6.49 (brs, 1H), 4.22 (s, 2H), 3.81 (s, 3H), 3.80 (s, 3H), 3.68 (q, J=5.8 Hz,
2H), 2.88 (t, J=6.5 Hz, 2H), 2.58 (s, 2H), 2.41 (s, 2H), 2.33 (s, 3H),
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117.6, 116.2, 115.7, 114.0, 112.6, 111.4, 55.9, 52.2, 42.0, 36.0, 34.9, 33.0,
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[M+H]+; found: 567.32.
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Compound 36ACHTUNGTRENNUNG{a,3}
Yield: 65%; purity: 94%; 1H NMR (500 MHz, CDCl3): d=8.89 (d, J=
2.0 Hz, 1H), 8.23 (dd, J=8.5, 2.5 Hz, 1H), 8.14 (d, J=8.5 Hz, 1H), 7.90
(d, J=3.8 Hz, 1H), 7.55 (d, J=1.5 Hz, 1H), 7.37–7.30 (m, 5H), 6.74 (brs,
1H), 6.53 (dd, J=3.5, 2.0 Hz, 1H), 4.66 (d, J=5.5 Hz, 2H), 3.36 (s, 2H),
2.47 (s, 2H), 1.15 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=192.7,
164.9, 154.4, 152.2, 147.0, 146.4, 143.6, 143.1, 137.8, 137.8, 129.1, 128.3,
128.2, 128.1, 116.8, 115.8, 115.2, 111.9, 53.0, 44.5, 39.5, 35.1, 28.6 ppm; MS
(ESI+): m/z: calcd for C26H25N4O3: 441.18 [M+H]+; found: 441.12.
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Compound 36ACHTUNGTRENNUNG{b,5}
Yield: 72%; purity: 97%; 1H NMR (500 MHz, CDCl3): d=8.85 (d, J=
2.0 Hz, 1H), 8.22 (dd, J=8.8, 2.3 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 6.75
(brt, J=5.3 Hz, 1H), 5.93–5.86 (m, 1H), 5.06 (dq, J=17.3, 1.5 Hz, 1H),
4.95 (dq, J=9.8, 1.1 Hz, 1H), 3.67 (q, J=5.0 Hz, 2H), 3.58 (t, J=5.3 Hz,
1H), 3.39 (s, 3H), 3.31 (s, 2H), 3.03–3.00 (m, 2H), 2.52–2.49 (m, 2H),
2.37 (s, 2H), 1.12 ppm (s, 6H); 13C NMR (125 MHz, CDCl3): d=194.1,
165.1, 154.6, 154.4, 151.6, 146.9, 138.1, 137.8, 127.8, 118.2, 115.2, 115.1,
71.1, 59.1, 52.6, 40.0, 39.5, 35.5, 32.3, 28.8, 27.5 ppm; MS (ESI+): m/z:
calcd for C22H29N4O3: 397.22 [M+H]+; found: 397.09.
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Acknowledgements
This study was supported by the National Research Foundation of Korea
(NRF), MarineBio Technology Program funded by the Ministry of Land,
Transport, and Maritime Affairs (MLTM), Korea, and the WCU program
of the NRF funded by the Korean Ministry of Education, Science, and
Technology (MEST). We thank M. Koh at Seoul National University for
his support on in silico analysis. J.K. and H.S. are grateful for the fellow-
ships awarded by the BK21 program and the Seoul Science Fellowship.
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Received: February 14, 2011
Published online: May 20, 2011
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