Multidisciplinary synthetic approach for rapid combinatorial library synthesis of triaza-fluorenes

Article abstract of DOI:10.1021/cc1000902

A new multidisciplinary synthetic approach comprising polymer-support synthesis, microwave-assisted synthesis, and multicomponent condensation facilitates synthesis of triaza-fluorenes library with a set of advantages such as rapid process, simple purification, and structural diversity in one shot. Microwave-assisted multistep synthetic protocol was used to construct the benzimidazole ring on soluble polymer support using activated aryl-fluorides. The PEG anchored aryl fluoride was condensed with selective primary amines via an ipso-fluoro displacement reaction followed by reduction of nitro group. The subsequent cyclization with cyanogen bromide is used as a key step to furnish immobilized benzimidazoles. Finally multicomponent condensation of resulted polymer bound benzimidazoles with various aldehydes and 1,3-diones under microwave irradiations provides rapid access for triaza-fluorenes with high purity and excellent yields. Microwave irradiation greatly accelerates the rate of all reactions while polymer support facilitates purifications by simple precipitation technique. This strategy dramatically increases efficiency of overall multistep synthesis.

Full text of DOI:10.1021/cc1000902

J. Comb. Chem. 2010, 12, 723–732
723
Multidisciplinary Synthetic Approach for Rapid Combinatorial
Library Synthesis of Triaza-Fluorenes
Ya-Shan Hsiao, Gorakh S. Yellol, Li-Hsun Chen, and Chung-Ming Sun*
Department of Chemistry, National Chiao Tung UniVersity, Hsinchu 300-10, Taiwan
ReceiVed May 26, 2010
A new multidisciplinary synthetic approach comprising polymer-support synthesis, microwave-assisted
synthesis, and multicomponent condensation facilitates synthesis of triaza-fluorenes library with a set of
advantages such as rapid process, simple purification, and structural diversity in one shot. Microwave-
assisted multistep synthetic protocol was used to construct the benzimidazole ring on soluble polymer support
using activated aryl-fluorides. The PEG anchored aryl fluoride was condensed with selective primary amines
via an ipso-fluoro displacement reaction followed by reduction of nitro group. The subsequent cyclization
with cyanogen bromide is used as a key step to furnish immobilized benzimidazoles. Finally multicomponent
condensation of resulted polymer bound benzimidazoles with various aldehydes and 1,3-diones under
microwave irradiations provides rapid access for triaza-fluorenes with high purity and excellent yields.
Microwave irradiation greatly accelerates the rate of all reactions while polymer support facilitates purifications
by simple precipitation technique. This strategy dramatically increases efficiency of overall multistep synthesis.
Introduction
The role played by an organic chemist is one of the main
drivers in drug discovery process.1 Along with the develop-
ment of new synthetic methods and technologies, the precise
nature of this role is particularly the fast access toward the
novel compounds. Rapid synthesis, construction of diverse
library in automated format, short step processes, easy
workup procedure, and simple isolation and purification
methods along with environmental friendly chemistry, are
the main objectives to speed up the current organic synthesis.
Several advanced techniques like microwave synthesis,2 ionic
liquid synthesis,3 sonication,4 polymer-support synthesis,5
multicomponent condensation,6 and combinatorial synthesis7
are established to accelerate the synthetic organic chemistry.
However, success in this arena still requires more embel-
lishments that will meet the plethora of hurdles that initial
drug discovery process must surmount. The separated efforts
Figure 1. Multidisciplinary synthetic approach.
through each technique are insufficient to execute this
natorial synthesis. Controlled microwave irradiation has
proven to be a powerful tool both for speeding up reaction
optimizations and for the efficient preparation of new target
compounds related to drug discovery projects.2,11 One of the
many advantages of microwave heating in chemical synthesis
is the dramatic reduction in reaction time, intended its use
in multicomponent condensations for the construction of
heterocycles.12 Multicomponent synthesis is an evolutionary
approach of introducing structural diversity in a single step
synthetic operation. Over the years, combinatorial synthesis
research interest turned to multicomponent condensation
reaction because it provides the fast diversified access for
multifunctionalized ring systems.13 Hence, multicomponent
reactions are well-suited for both combinatorial chemistry
and high-speed parallel synthesis, and therefore, they possess
high exploratory power.
obligation.8 Driving through this modern organic synthesis,
integrating a variety of advanced technologies for the rapid
generation of numerous multifunctionalized molecule librar-
ies can provide the high speed path for modern drug
discovery (Figure 1). Multidisciplinary synthetic approach
is an integrated concept which supports the coagulation of
different disciplines of synthetic organic chemistry along with
their advantages to facilitate the drug discovery.9 Hence in
addition to the advent of combinatorial synthesis, we are now
focused on application of advanced techniques in synthetic
methodologies.10
Over the last number of years, scientists have been
exploring the microwave heating for enhancing the combi-
* To whom correspondence should be addressed. E-mail:
cmsun@mail.nctu.edu.tw.
10.1021/cc1000902  2010 American Chemical Society
Published on Web 07/21/2010

724 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Hsiao et al.
Figure 2. Azafluorene ring containing bioactive natural products and synthetic molecules.
Results and Discussions
In the recent past, polymer supported organic synthesis
has been extensively used as a platform for the rapid
generation of molecular libraries.14 Molecules attached with
a polymer can be easily isolated from the reaction mixture
by precipitation or phase extraction techniques. Although
solid polymer supported organic synthesis has demonstrated
its utility, it still exhibits several limitations like solvation
problem, nonlinear kinetic behavior and irregular distribution
in the chemical reaction due to the heterogeneous nature of
reactions. Soluble polymer supports provides alternative
strategies in essence avoids the difficulties of solid-phase
synthesis while preserving its positive aspects like easy
workup, effortless product purification in addition to enabling
homogeneous reaction conditions.15 Among the various
soluble polymers, polyethylene glycol (PEG) has proven to
be the most versatile and successful support to simplify and
speed up the synthesis.16 Research in soluble polymer support
synthesis has led to the development of newer methodologies
in combinatorial synthesis to screen small molecule libraries
for drug lead discovery.
In an effort to investigate multidisciplinary synthetic
approach for drug-like molecules, we targeted tricyclic triaza-
fluorene ring construction with various substitutions. Fluorene
and aza-fluorene derivatives possesses a broad spectrum of
biological properties. These compounds have been described
as propyl hydroxylase inhibitor,17 antidiabetics,18 anti-
inflammatory,19 antiviral,20 antimicrobial,21 antineoplastic,22
and potent immunosuppressive agents.23 Aza-fluorenes also
emerged as an integral backbones of calcium channel
blockers.24 Some of the analogs of aza-fluorene compound
show potent antitumor activity.25 Aza-fluorene heterocycles
are the subunit of several natural alkaloids and active
pharmaceuticals (Figure 2).17,26
Taking into consideration the advantages of multicompo-
nent reaction, microwave synthesis, and soluble polymer-
support synthesis, along with biological importance of
azafluorene ring system, the ultimate goal of our research is
to develop rapid, efficient, and simple multidisciplinary
approach to construct the structurally diverse library of
molecules containing aza-fluorene skeleton. Our current work
was divided into two major parts. The first part is to
synthesize the polymer supported benzimidazole skeleton
from 4-fluoro-3-nitro-benzoic acid by microwave accelerated
linear four steps sequence. The second part involves the
microwave enhanced multicomponent condensation of re-
sulted polymer supported benzimidazoles with aldehydes and
1,3-diketones for the high speed library synthesis of triaza-
fluorenes.
In previous synthesis, Kurth et al. reported the fluorene
synthesis in linear fashion from isothiocyanate ester using
barium hydroxide.27 The strategy to assemble fluorene
framework by Martin group was the reaction of aniline with
chloro-benzimidazole.28 However Lunn achieved the aza-
fluorene ring construction by pyrolytic rearrangement.23
Almost all the synthetic routes to these medicinally pertinent
heterocycles suffer from one of the limitations, such as (i)
prolonged reaction time, (ii) low yields, (iii) thermal
decomposition of substrates, reagents, or products, (iv)
narrow scope for substrates, and (iv) tedious work up
procedures.29 In our earlier work, we have reported30 the
microwave assisted PEG-supported synthesis of 2-(aryl
amino)benzimidazoles, bis-benzimidazole and benzimida-
zolyl quinoxalinones. Herein we disclose a soluble polymer
supported microwave synthesis of triaza-fluorenes in excel-
Scheme 1. Multistep Polymer Supported Microwave Synthesis of Amino-benzimidazoles

Combinatorial Library Synthesis of Triaza-Fluorenes
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 725
1
Figure 3. Comparison of H NMR spectra of polymer bound compound 4 and 5.
Scheme 2. Microwave-Assisted Soluble Polymer Supported Multicomponent Reaction
Scheme 3. Observed By-products in Excess of Reagents in Multicomponent Reaction
lent yields and high purity. Since PEG has received attention
as soluble polymer support in a wide variety of reactions,
we have decided to investigate the possibility of using PEG,
which has an average molecular weight of 2000 and can
functionalize at both ends, as a soluble polymeric support
in microwave heating.
Initially, 4-fluoro-3-nitrobenzoic acid 1 was anchored on
polymer by standard esterification conditions. 4-fluoro-3-
nitrobenzoic acid 1 treated with PEG in the presence of DCC
and DMAP in dichloromethane at reflux for 18 h to afford
PEG-bound 4-fluoro-3-nitrobenzoate 2 with 86% yield.
Nevertheless, to speed up the process, we attempted the
reaction of PEG and 4-fluoro-3-nitro-benzoic acid 1 under
microwave irradiation at 150 °C for 15 min to prepare PEG-
bound 4-fluoro-3-nitrobenzoate 2 through ester linkage
(Scheme 1). The reaction proceeded to completion as
evidenced by the disappearance of the absorption of the acid
hydroxyl group and the appearance of the absorption of the
ester group at 1729 cm-1 in the IR spectrum. To introduce
the additional diversity in the skeleton, variety of primary
amines were coupled to PEG linked 4-fluoro-3-nitrobenzoate
2 by nucleophilic aromatic substitution. The reactions were
completed within 18 h in dichloromethane at room temper-
ature to afford PEG supported nitroarenes 3. Microwave
heating used in the same reaction greatly reduced the reaction
time to 5-10 min. The time required for the completion of
reaction under microwave heating depends upon the type of
primary amines used. Common linear-chain aliphatic amines
and aromatic amines with strong electron donating groups
gave good yield in short reaction time (5 min) while aromatic
amines with strong electron withdrawing groups requires 10
min to furnish the targeted compounds. All supported amines
3 were purified by precipitation using cold ether. Subse-
quently, reduction of nitro group was achieved in microwave
by using zinc and ammonium formate in methanol. The
reduction was completed within 2 min to furnish the aniline

726 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Hsiao et al.
Table 1. Reaction Substrate Scope
derivative 4. The reduction in a thermal heating was carried
out with the same stoichiometric amounts of reagents in
refluxing methanol and took 30 min for completion. After
the reaction was completed, the heterogeneous material was
removed by filtration and the PEG-bound amines were again
purified by precipitation.
The next task of this endeavor was the construction of
benzimidazole ring through cyclization of soluble supported
anilines 4 using cyanogen bromide. Initially, the compound
4 was refluxed in dichloromethane with cyanogen bromide
furnished the desired cyclization product PEG linked ami-
nobenzimidazole 5 after 18 h with 60% yield. The same
reaction when carried out under microwave heating at 100
°C was completed in only 15 min to furnish PEG linked
amino-benzimidazole 5 in 78% yield. Mechanistically, the
bromo substitution from cyanogen bromide by the less
hindered more reactive primary aniline affords cyanoaniline.
Subsequent cyclization through secondary aniline followed
by aromatization furnishes the 2-amino-benzimidazoles.
Progress of one-pot cyclization was easily monitored by
regular proton NMR spectroscopy as shown in Figure 3. The
peaks corresponding to aromatic protons at 7.40 (Ha), 7.58
(Hb), and 6.66 (Hc) ppm of compound 4 are shifted to
downfield region and appeared at 8.12 (Ha), 8.00 (Hb), and
7.30 (Hc) ppm, respectively, in benzimidazole 5. Addition-
ally, the appearance of the peak from amine protons at 8.48
ppm was the evidence for the cyclization of the imidazolene
ring. When both microwave results and conventional pre-
heated oil bath results were compared, we observed a clear
improvement in yields and reaction time with microwave
heating. Moreover the products were purified simply by
precipitation in cold ether.
The main objective of our studies is the investigation of
multidisciplinary approach comprising the soluble polymer
supported multicomponent reaction under microwave ir-
radiation. For comparison point of view, we performed the
multicomponent condensation under both microwave irradia-
tion and classical heating conditions. The mixture of PEG-
supported amino-benzimidazoles 5, aldehydes 6, and 1,3-
diones/3-oxoesters 7 was subjected to condensation in
refluxing toluene (Scheme 2). The reaction was completed
after 18 h to furnish triaza-fluorenes 9 in 61% yield.
Moreover, the reagent equivalents also play an important role
in this condensation reaction. If excess aldehyde was used,
imine 10 was isolated as the byproduct while in case of
excess 1,3-dione or 3-oxoesters, amide 11 was the byproduct
which diminish the yield of the condensed products 8
(Scheme 3). However, to investigate the multidisciplinary
effect, the equimolar amounts of PEG-supported amino-
benzimidazole 5, aldehyde 6, 1,3-dione 7 and 10 mol %
piperidine in toluene was subjected to microwave irradiation
at 100 °C (4 bar). The time required for the completion of
reaction was more than 30 min because microwave absorp-
tion coefficient of toluene is very small. Hence, to optimize
the appropriate reaction medium, various solvents were
screened and based on the outcome, methanol was selected
as the optimum solvent for multicomponent reaction.
a ESI mass, molecular peak obtained as [M + 1]. b Total isolated
yield after both steps. c Crude HPLC purity after PEG cleavage.
methanol was treated under microwave irradiation at 100
°C (4 bar). The reaction was efficiently promoted by
microwave irradiation to furnish polymer supported triaza-
fluorenes 8. The reaction time was strikingly shortened to
15-20 min from 18 h required under traditional heating
condition and the yield was increased to 92% from 61%
(Scheme 2). Moreover, no byproduct (10 and 11) were
observed and no decomposition of polymer bound intermedi-
ates were detected during this one pot coupling reaction.
Consequently, the equimolar amount of PEG-linked ben-
zimidazole 5, aldehyde 6, 1,3-dione 7, and piperidine in

Combinatorial Library Synthesis of Triaza-Fluorenes
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 727
temperature within 12 h. The crude mixture was concen-
trated; the polymer was precipitated out with excess of cold
ether and removed by filtration. The filtrate was dried and
subjected to HPLC analysis (Table 1), which depicted high
purity and excellent yield of all the compounds without
further purification. The completion of cleavage from the
polymer support was verified by observing an upfield shift
of N-methylene protons at para-position of the polymer
disconnected site from 4.4 to 3.6 ppm in addition to the
disappearance of characteristic set of peaks corresponding
to polymer protons.
The structure of the final compounds was also unambigu-
ously confirmed on the basis of X-ray crystallographic study.
The X-ray crystallographic data of 9p are in full agreement
with its structure (see Supporting Information). The 4-ni-
trophenyl ring attached to main core was situated at C4 and
bears antiparallel orientation. The carbonyl group is at C6
position and alkyl substitution on N1, all clearly confirmed
the expected structure of 9p (Figure 4).
To examine the efficiency and the generality of this novel
three component condensation reaction, 10 amino-benzimi-
dazole derivatives, 10 aldehydes, and 7 1,3-diones were
investigated. Based on the optimized reaction conditions, a
series of penta-substituted-dihydrofluorene derivatives were
synthesized by equimolecular amounts of aldehydes, 1,3-
diones or 3-oxoesters and PEG supported 2-aminobenzimi-
dazoles in methanol at 100 °C at 4 bar pressure under
microwave irradiation. After irradiation for 15-20 min, the
immobilized triaza-fluorene derivatives 8 were obtained in
quantitative yields. Subsequent removal of polymer support
furnished triaza-fluorenes 9 in good to excellent yields
(Scheme 2). The results were summarized in Table 1. The
protocol was applied to the aryl aldehydes with either
electron-withdrawing groups or electron-donating groups and
Figure 4. ORTEP diagram of compound 9p.
Therefore, microwave irradiation exhibited several advan-
tages over the conventional heating by significantly reducing
the reaction time and dramatically improving the reaction
yield. Gratifyingly, the procedure is easy to operate and the
workup procedure is simple precipitation in ether. Regular
proton NMR spectroscopy was used to monitor multicom-
ponent coupling reaction. In 1H NMR spectrum of condensed
compounds 8, the peaks due to benzimidazoles aromatic
protons at 8.12 (Ha), 8.00 (Hb) and 7.30 (Hc) ppm shifted
to the upfield region and appeared at δ 7.65 (Ha), 7.83 (Hb),
and 7.32 (Hc), respectively. Moreover the absence of peak
of amine protons and the appearance of characteristic signal
at 6.45 ppm because of a proton on newly created pyrimidine
ring were the clear indications for the formation of polymer
supported triaza-fluorenes 8.
Finally, polymer support was cleaved in a potassium
cyanide solution in methanol to deliver methyl ester of penta-
substituted triaza-fluorenes 9 in good yields (Table 1). In
most of the cases, a cleavage reaction was completed at room
Scheme 4. Mechanistic Pathway of Multicomponent Reaction

728 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Hsiao et al.
aliphatic aldehydes. As can be seen from Table 1, the
electronic effect of the substituted benzaldehydes has an
insignificant impact on the conversion. The feasibility of
employing aliphatic aldehydes instead of aryl aldehydes in
the reaction was also investigated. Providentially, aliphatic
aldehydes also condensed providing products in good yield.
Additionally, different types of 1,3-diones and 3-oxoesters
were used to examine this protocol and to increase the
diversity in the scaffold. It was observed that when 1,3-
diones were used the multicomponent reaction proceeded
little faster than 3-oxoesters were employed. Also the
yields were superior when 1,3-diones were used. These
results were correlated to the higher reactivity of 1,3-
diones than 3-oxoesters.
The observed outcome of the multicomponent condensa-
tion reaction can be explained on the basis of the plausible
mechanism depicted in Scheme 4. The first generally
proposed step is the formation of the unsaturated diones 11
through Knoevenagel condensation of aldehyde and 1,3-
dione. The unsaturated diones 11 were detected and identified
in the reaction mixture by mass spectroscopy and TLC
analysis. Michael addition type reaction of benzimidazole 5
with unsaturated diones 11 could afford 12 which on further
proton transfer rearrange to adduct 13. Intermolecular
cyclization to 14 and subsequent proton transfer provide 15
which upon dehydration could furnish triaza-fluorenes 8.
We have successfully integrated three disciplines of the
synthetic organic chemistry along with their advantages for
the high speed library synthesis of triaza-fluorenes. Rate of
each step is accelerated by microwave irradiation. Soluble
polymer support enables the homogeneous reaction condi-
tions and also speeds up the separation and purification
simply by precipitation technique. Hence this method
dramatically shortens the time required for overall reaction
sequence and increases efficiency of the total process.
together multiple facets of synthetic chemistry has great
expectations in terms of the potential to transform the future
of drug discovery.
Experimental Section
General Methods. Dichloromethane and toluene were
distilled from calcium hydride before use. All reactions were
performed under an inert atmosphere with unpurified reagents
and dry solvents. Analytical thin-layer chromatography
(TLC) was performed using 0.25 mm silica gel coated
Kiselgel 60 F254 plates. Flash chromatography was performed
using the indicated solvent and silica gel 60 (230-400 mesh).
All the microwave experiments were performed in a Biotage
initiator under optimized reaction conditions of power and
equipped with an infrared pyrometer for the control of
temperature and compressed air system for cooling was used.
Chemical shifts are reported in parts per million (ppm) on
the scale from an internal standard.
Synthesis of Dimethyl 9-Butyl-7-ethyl-5-phenyl-5-hydro-
5a,8,9-triaza-fluorene-3,6-dicarboxylate (9a). Activated ester
was prepared by dissolving 4-fluoro-3-nitrobenzoic acid 1
(0.185 g, 1.0 mmol) in dry dichloromethane and DCC (0.206
g, 1.0 mmol) as well as 4-dimethylaminopyridine (DMAP)
(0.033 g) were added to the solution. After 10 min, the
solution of PEG (2000) (1.2 g, 0.6 mmol) in dry dichlo-
romethane (10 mL) was added. The reaction mixtures were
subjected to microwave irradiation at 100 °C for 15 min.
The precipitating reaction mixture and washing with excess
cold ether (50 mL × 3) afford PEG bounded 4-fluoro-3-
nitrobenzoate 2 in 86% (2.0 g) yield. 1-aminobutane (0.09
g, 1.2 mmol) was added to a solution of PEG bounded
4-fluoro-3-nitrobenzoate 2 in dichloromethane. After irradia-
tion in a microwave reactor at 150 °C for 10 min, the PEG
bound 4-(butylamino)-3-nitrobenzoate 3 was purified as the
same procedure described previously with 88% yield. Zinc
(1.0 g, 15.0 mmol) and ammonium formate (0.63 g, 10.0
mmol) were added to a solution of 3 (1.84 g, 0.76 mmol) in
methanol, and the reaction mixture was subjected to micro-
wave irradiation at 80 °C for 2 min. The mixture was filtered
with Celite to remove zinc and the filtrate was collected and
concentrated under reduced pressure. Then dichloromethane
(25 mL) was added to precipitate ammonium formate, and
the mixture was again passed through a thin layer of Celite
to remove ammonium formate. To a solution of PEG-bound
3-amino-4-(butylamino)benzoate 4 (0.80 g, 0.35 mmol) in
dichloromethane, cyanogen bromide (BrCN) (0.075 g, 0.7
mmol) was added. The reaction mixture was irradiated by
microwave at 100 °C for 15 min. The solvent was removed
under reduced pressure and washed with ether to deliver PEG
bound amino-benzimidazole 5 with 78% (0.64 g) yield.
Benzaldehyde 6a (0.028 g, 0.26 mmol), methyl 3-oxopen-
tanoate 7a (0.034 g, 0.26 mmol) and piperidine (0.005 g,
0.03 mmol) were added to a solution of PEG bound amino-
benzimidazole 5 (0.64 g, 0.26 mmol) in methanol. The
reaction mixture was irradiated under microwave at 100 °C
for 15 min using 180 W power (4 bar). The reaction is
monitored by thin layer chromatography and 1H NMR
spectroscopy. After completion, the reaction mixture was
washed with cold ether. The precipitate was filtered and dried
Conclusion
Multicomponent condensation of polymer-bound benz-
imidazole, aldehydes, and 1,3-diones under microwave
irradiation afforded the novel library of triaza-fluorene
molecules. It has been demonstrated that the microwave
heating is very effective in speeding up both the soluble
supported multistep synthesis, as well as in accelerating the
rate of subsequent multicomponent reaction. Noteworthy,
soluble supported intermediates and soluble support itself
are stable during microwave harsh irradiation. Monitoring
reaction progress in each step by regular proton NMR is
feasible by using PEG as a soluble polymer support. Great
substrate scope, high yields, short reaction time, pure
products and easy work up are advantages of this procedure
in comparison to other methods. In multidisciplinary syn-
thetic approach, we have successfully used multicomponent
reaction to introduce the structural diversity in one pot,
applied the microwave irradiation to accelerate the rate of
reactions and soluble polymer support for the speedy and
simple purifications of products. This approach provides a
high speed path for the rapid synthesis of molecular libraries
with high degree of structural diversity. The powerful
potential of multidisciplinary synthetic approach, bringing

Combinatorial Library Synthesis of Triaza-Fluorenes
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 729
well to furnish the PEG bound triaza-fluorene 8a in 92%
yield. The 1 M solution of potassium cyanide (0.325 g, 0.5
mmol in 5 mL) in methanol was added to a solution of PEG-
bound triaza-fluorene 8a (0.70 g, 0.25 mmol) in methanol
(5 mL). The mixture was stirred at ambient temperature for
12 h. After completion of reaction, the inorganic material
was removed by filtration and then filtrate was concentrated
under reduced pressure. The polymer was precipitated out
with excess of cold ether and removed by filtration. The
filtrate was dried and subjected to HPLC analysis which
depicts high purity. The title compound 9a was obtained in
85% (0.123 g) overall yield of two steps after column
chromatography purification.
1H NMR (300 MHz, CDCl3): δ 7.85 (dd, J ) 8.3, 1.2 Hz,
1H), 7.69 (d, J ) 1.2 Hz, 1H), 7.43 (dd, J ) 8.3, 1.4 Hz, 2H),
7.40 (s, 1H), 7.29-7.20 (m, 3H), 7.07 (d, J ) 8.3 Hz, 1H),
6.42 (s,1H), 4.14 (dt, J ) 14.1, 7.0 Hz, 2H), 3.90 (s, 3H), 3.66
(s, 3H), 3.03 (dd, J ) 19.5, 7.3 Hz, 1H), 2.83 (dd, J ) 19.5,
7.3 Hz, 1H), 1.82 (q, J ) 7.4 Hz, 2H), 1.48-1.35 (m, 2H),
1.25 (t, J ) 7.3 Hz, 3H), 1.00 (t, J ) 7.4 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 167.1, 167.0, 150.3, 142.4, 135.2, 129.0,
128.9(2C), 128.4, 127.5(2C), 125.3, 110.8, 108.0, 99.2, 57.6,
52.6, 51.1, 42.1, 35.0, 30.6, 30.4, 25.6, 20.2, 14.1, 13.4. MS
(ESI): m/z 448 (M + H)+. HRMS (ESI) Calcd for
C26H30N3O4: m/z 448.2236. Found: 448.2234 (M + 1)+. IR
(neat): 2954, 1716, 1602, 1521, 1241 cm-1. HPLC: 81%.
Dimethyl 9-(3-Methoxypropyl)-7-ethyl-5-phenyl-5-hy-
dro-5a,8,9-triaza-fluorene-3,6-dicarboxylate (9d). 1H NMR
(300 MHz, CDCl3): δ 7.86 (dd, J ) 8.4, 1.4 Hz, 1H), 7.68 (d,
J ) 1.4 Hz, 1H), 7.41 (dd, J ) 6.9, 1.5 Hz, 2H), 7.29-7.18
(m, 3H), 7.14 (d, J ) 8.4 Hz, 1H), 6.42 (s, 1H), 4.22 (dt, J )
6.7, 2.9 Hz, 2H), 3.90 (s, 3H), 3.66 (s, 3H), 3.39 (dt, J )
6.2, 2.3 Hz, 2H), 3.31 (s, 3H), 3.00 (m, 1H), 2.84 (m, 1H),
2.22-2.06 (m, 2H), 1.25 (t, J ) 7.4 Hz, 3H). 13C NMR (75
MHz, CDCl3): δ 166.7, 166.6, 164.2, 149.8, 142.0, 135.1,
128.8, 128.4(2C), 127.9, 127.0(2C), 124.8, 123.7, 110.2, 107.5,
98.8, 68.9, 58.5, 57.1, 52.0, 50.6, 39.0, 29.9, 28.3, 12.9. MS
(ESI): m/z 464 (M + H)+. HRMS (ESI) Calcd for C26H30N3O5:
m/z 464.2185. Found: 464.2182 (M + 1)+. IR (neat): 2952,
2879, 1710, 1600, 1525 cm-1. HPLC: 80%.
Dimethyl 9-(3-Methoxypropyl)-7-ethyl-5-(2-fluorophe-
nyl)-5-hydro-5a,8,9-triaza-fluorene-3,6-dicarboxylate (9e).
1H NMR (300 MHz, CDCl3): δ 7.88 (dd, J ) 8.3, 1.3 Hz,
1H), 7.80 (d, J ) 1.3 Hz, 1H), 7.43 (dt, J ) 7.4, 1.6 Hz,
1H), 7.17 (m, 1H), 7.13 (d, J ) 8.3 Hz, 1H), 7.07-6.97 (m,
2H), 6.75 (s, 1H), 4.21 (t, J ) 6.6 Hz, 2H), 3.91 (s, 3H),
3.64 (s, 3H), 3.37 (t, J ) 5.8 Hz, 2H), 3.31 (s, 3H),
3.07-2.88 (m, 2H), 2.10 (quint, J ) 6.2 Hz, 3H), 1.27 (t, J
) 7.4 Hz, 3H). 13C NMR (75 MHz, CDCl3): δ 167.0, 165.7,
161.3, 158.0, 150.1, 135.4, 130.1, 129.9, 129.3, 129.1, 125.5,
125.1, 124.4, 115.8, 110.3, 107.9, 97.7, 69.3, 58.9, 52.5, 51.1,
50.8, 39.5, 30.3, 28.8, 13.4. MS (ESI): m/z 482 (M + H)+.
HRMS (ESI) Calcd for C26H29FN3O5: m/z 482.2091. Found:
482.2089 (M + 1)+. IR(neat): 2948, 2873, 1716, 1604, 1243,
763 cm-1. HPLC: 95%.
Methyl6-Oxo-8,8-dimethyl-11-butyl-5-phenyl-5,6,7,8,9,11-
hexahydro-7H-4b,10,11-triaza-benzo[b]fluorene-3-car-
boxylate (9b). 1H NMR (300 MHz, CDCl3): δ 7.89 (dd, J )
8.4, 1.4 Hz, 1H), 7.70 (d, J ) 1.4 Hz, 1H), 7.41 (d, J ) 7.3
Hz, 2H), 7.25 (t, J ) 7.6 Hz, 2H), 7.18 (m, 1H), 7.14 (d, J )
8.4 Hz, 1H), 6.51 (s, 1H), 4.17 (t, J ) 7.6 Hz, 2H), 3.88 (s,
3H), 2.57 (d, J ) 17.5 Hz, 1H), 2.50 (d, J ) 17.5 Hz, 1H),
2.28 (d, J ) 16.2 Hz, 1H), 2.17 (d, J ) 16.2 Hz, 1H), 1.85
(quint, J ) 7.3 Hz, 2H), 1.44 (sextet, J ) 7.3 Hz, 2H), 1.09
(s, 3H), 1.01 (t, J ) 7.3 Hz, 3H), 0.98 (s, 3H). 13C NMR
(75 MHz, CDCl3): δ 194.7, 166.8, 162.8, 150.9, 141.6, 134.7,
129.6, 128.9(2C), 128.3, 127.4(2C), 125.5, 124.8, 111.4, 109.0,
108.4, 55.8, 52.6, 51.1, 46.7, 42.4, 32.8, 30.7, 29.8, 27.7, 20.3,
14.1. MS (ESI): m/z 458 (M + H)+. HRMS (ESI) Calcd for
C28H32N3O3: m/z 458.2444. Found: 458.2443 (M + 1)+.
IR(neat): 2954, 2865, 1712, 1612, 1589 cm-1; HPLC: 99%.
3-Methyl 6-tert-Butyl 9-(3-methoxypropyl)-7-methyl-
5-butyl-5-hydro-5a,8,9-triaza-fluorene-3,6-dicarboxy-
late (9f). 1H NMR (300 MHz, CDCl3): δ 7.90 (dd, J ) 8.4
Hz, 1.4 Hz, 1H), 7.80 (d, J ) 1.4 Hz, 1H), 7.15 (d, J ) 8.4
Hz, 1H), 5.57 (t, J ) 4.0 Hz, 1H), 4.13 (t, J ) 6.7 Hz, 2H),
3.94 (s, 3H), 3.33 (dt, J ) 6.5 Hz, 3.5 Hz, 2H), 3.29 (s,
3H), 2.40 (s, 3H), 2.04 (quint, J ) 6.5 Hz, 2H), 1.87 (m,
1H), 1.66 (m, 1H), 1.53 (s, 9H), 1.32 (m, 1H), 1.13 (sextet,
J ) 7.2 Hz, 2H), 0.89 (m, 1H), 0.75 (t, J ) 7.2 Hz, 3H). 13
C
NMR (75 MHz, CDCl3): δ 167.3, 166.9, 159.4, 150.7, 135.6,
129.4, 125.1, 124.1, 110.1, 108.0, 99.2, 79.8, 69.3, 59.0, 53.2,
52.6, 39.3, 34.2, 28.9(3C), 28.7, 26.1, 24.9, 23.0, 14.3. MS
(ESI): m/z 472 (M + H)+. HRMS (ESI) Calcd for
C26H38N3O5: m/z 472.2811. Found: 472.2814 (M + 1)+.
IR(neat): 2956, 2929, 1720, 1604, 1376 cm-1. HPLC: 62%.
Methyl 6-Oxo-11-butyl-5-(3-nitrophenyl)-5,6,7,8,9,11-
hexahydro-7H-4b,10,11-triaza-benzo[b]fluorene-3-car-
1
boxylate (9c). H NMR (300 MHz, CDCl3): δ 8.10 (t, J )
Dimethyl 9-Isobutyl-7-(methoxymethyl)-5-(2-chlorophe-
nyl)-5-hydro-5a,8,9-triaza-fluorene-3,6-dicarboxylate (9g).
1H NMR (300 MHz, CDCl3): δ 7.98 (d, J ) 1.2 Hz, 1H),
7.86 (dd, J ) 8.4, 1.2 Hz, 1H), 7.50 (dd, J ) 7.4, 2.0 Hz,
1H), 7.31 (dd, J ) 7.4, 1.7 Hz, 1H), 7.22-7.11 (m, 2H),
7.08 (d, J ) 8.4 Hz, 1H), 6.91 (s, 1H), 4.75 (d, J ) 16.2
Hz, 1H), 4.69 (d, J ) 16.2 Hz, 1H), 3.98 (dd, J ) 7.4, 17.2
Hz, 1H), 3.96 (dd, J ) 7.4, 17.2 Hz, 1H), 3.89 (s, 3H), 3.63
(s, 3H), 3.52 (s, 3H), 2.33 (m, 1H), 0.98 (d, J ) 6.7 Hz,
6H). 13C NMR (75 MHz, CDCl3): δ 166.9, 166.5, 159.3,
150.7, 139.8, 135.2, 132.3, 130.5, 129.9, 129.8, 129.0, 128.2,
125.6, 124.6, 111.3, 108.4, 99.9, 73.6, 59.5, 54.3, 52.6, 51.2,
49.8, 28.2, 20.5, 20.4. MS (ESI): m/z 498 (M + H)+. HRMS
(ESI) Calcd for C26H29ClN3O5: m/z 498.1796. Found:
1.8 Hz, 1H), 8.06 (ddd, J ) 8.2, 1.8, 1.0 Hz, 1H), 7.94 (dd,
J ) 8.3, 1.3 Hz, 1H), 7.90 (ddd, J ) 7.8, 1.8, 1.0 Hz, 1H),
7.59 (d, J ) 1.3 Hz, 1H), 7.48 (t, J ) 7.8 Hz, 1H), 7.20 (d,
J ) 8.3 Hz, 1H), 5.65 (s, 1H), 4.25 (dt, J ) 11.3, 7.0 Hz,
2H), 3.88 (s, 3H), 2.74 (dt, J ) 17.6, 5.2 Hz, 1H), 2.60 (ddd,
J ) 17.6, 9.1, 5.2 Hz, 1H), 2.38 (d, J ) 7.4 Hz, 2H),
2.06-1.96 (m, 2H), 1.89 (quint, J ) 7.4 Hz, 2H), 1.45
(sextet, J ) 7.4 Hz, 2H), 1.03 (t, J ) 7.4 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 195.0, 166.6, 165.4, 150.6, 149.0, 143.7,
134.7, 133.8, 129.8, 129.1, 126.0, 125.1, 123.4, 121.9, 111.0,
109.2, 108.8, 55.4, 52.7, 42.6, 37.4, 33.0, 30.7, 21.9, 20.3, 14.1.;
MS (ESI): m/z 475 (M + H)+. HRMS (ESI) Calcd for
C26H27N4O5: m/z 475.1981. Found: 475.1984 (M + 1)+.
IR(neat): 2937, 1720, 1608, 1508, 1386, 767 cm-1. HPLC: 99%.

730 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5
Hsiao et al.
498.1800 (M + 1)+. IR(neat): 2954, 1720, 1602, 1525, 1095,
101.4, 100.3, 73.9, 59.5, 57.3, 54.5, 52.6, 51.3, 30.7, 30.5,
30.2, 26.1, 25.6. MS (ESI): m/z 534 (M + H)+. HRMS (ESI)
Calcd for C29H32N3O7: m/z 534.2240. Found: 534.2243 (M
+ 1)+. IR(neat): 2933, 2857, 1718, 1596, 1521, 1243, 763
cm-1. HPLC: 99%.
765 cm-1. HPLC: 97%.
3-Methyl 6-tert-Butyl 9-Isopropyl-7-methyl-5-(2-chlo-
rophenyl)-5-hydro-5a,8,9-triaza-fluorene-3,6-dicarboxy-
1
late (9h). H NMR (300 MHz, CDCl3): δ 8.08 (d, J ) 1.4
Hz, 1H), 7.82 (dd, J ) 8.4, 1.4 Hz, 1H), 7.58 (dd, J ) 7.6,
1.8 Hz, 1H), 7.30 (dd, J ) 7.6, 1.5 Hz, 1H), 7.21 (d, J )
8.4 Hz, 1H), 7.21-7.11 (m, 2H), 6.79 (s, 1H), 5.15 (quint,
J ) 7.0 Hz, 1H), 3.9 (s, 3H), 2.51 (s, 3H), 1.62 (d, J ) 6.7
Hz, 3H), 1.58 (d, J ) 6.7 Hz, 3H), 1.41 (s, 9H). 13C NMR
(75 MHz, CDCl3): δ 166.7, 166.1, 148.6, 138.9, 133.2, 131.9,
130.9, 129.6, 129.4, 129.3, 129.2, 127.4, 124.6, 123.4, 111.0,
109.0, 100.4, 79.9, 54.7, 52.1, 46.0, 28.4(3C), 24.6, 20.3,
20.1. MS (ESI): m/z 496 (M + H)+. HRMS (ESI) Calcd for
C27H31ClN3O4: m/z 496.2003. Found: 496.2006 (M + 1)+.
IR(neat): 2971, 2927, 1720, 1662, 1590, 1089, 763 cm-1.
HPLC: 92%.
Methyl 6-Oxo-8,8-dimethyl-11-benzyl-5-ethyl-5,6,7,8,9,11-
hexahydro-7H-4b,10,11-triaza-benzo[b]fluorene-3-car-
1
boxylate (9l). H NMR (300 MHz, CDCl3): δ 7.91 (d, J )
1.2 Hz, 1H), 7.86 (dd, J ) 8.3, 1.2 Hz, 1H), 7.27-7.28 (m,
5H), 7.01 (d, J ) 8.3 Hz, 1H), 5.84 (t, J ) 3.0 Hz, 1H),
5.37 (d, J ) 15.6 Hz, 1H), 5.25 (d, J ) 15.6 Hz, 1H), 3.92
(s, 3H), 2.54 (d, J ) 17.4 Hz, 1H), 2.46 (d, J ) 17.4 Hz,
1H), 2.33 (s, 2H), 2.10 (m, 1H), 1.92 (m, 1H), 1.16 (s, 3H),
1.12 (s, 3H), 0.72 (t, J ) 7.4 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 195.4, 166.8, 165.4, 152.3, 135.4, 134.5, 129.6,
129.3(2C), 128.5, 127.7(2C), 125.5, 125.1, 110.9, 109.2,
106.2, 52.7, 52.6, 51.4, 46.6, 45.9, 32.7, 30.0, 27.9, 25.5,
7.8. MS (ESI): m/z 491 (M+). HRMS (ESI) Calcd for
C31H29N3O3: m/z 492.2209. Found: 492.2207 (M + 1)+.
IR(neat): 2962, 2923, 1712, 1612, 1396 cm-1. HPLC: 94%.
Dimethyl 9-Cyclopentyl-5-ethyl-7-ethyl-5-hydro-5a,8,9-
triaza-fluorene-3,6-dicarboxylate (9i). 1H NMR (300 MHz,
CDCl3): δ 7.86 (dd, J ) 8.4, 1.4 Hz, 1H), 7.81 (d, J ) 1.4
Hz, 1H), 7.15 (d, J ) 8.4 Hz, 1H), 5.64 (t, J ) 3.8 Hz, 1H),
5.09 (quint, J ) 8.7 Hz, 1H), 3.92 (s, 3H), 3.73 (s, 3H),
2.93 (dq, J ) 12.3, 7.4 Hz, 1H), 2.75 (dq, J ) 12.3, 7.4 Hz,
1H), 2.14-1.94 (m, 8H), 1.76-1.66 (m, 2H), 1.18 (t, J )
7.4, 3H), 0.70 (t, J ) 7.4 Hz, 3H). 13C NMR (75 MHz,
CDCl3): δ 167.4, 167.2, 167.0, 151.4, 134.0, 129.7, 124.7,
123.8, 110.2, 109.3, 95.4, 54.6, 53.7, 52.6, 51.1, 30.5, 29.4,
29.3, 27.2, 25.6, 25.5, 13.5, 8.1. MS (ESI): m/z 412 (M +
H)+. HRMS (ESI) Calcd for C23H30N3O4: m/z 412.2236.
Found: 412.2234 (M + 1)+. IR(neat): 2960, 2873, 1720,
1673, 1467 cm-1. HPLC: 85%.
Methyl 6-Oxo-11-(4-methoxybenzyl)-8,8-dimethyl-5-bu-
tyl-5,6,7,8,9,11-hexahydro-7H-4b,10,11-triaza-benzo[b]fluo-
1
rene-3-carboxylate (9m). H NMR (300 MHz, CDCl3): δ
7.87 (s, 1H), 7.83 (d, J ) 8.6 Hz, 1H), 7.23 (d, J ) 8.6 Hz,
2H), 7.03 (d, J ) 8.3 Hz, 1H), 6.84 (d, J ) 8.6 Hz, 2H),
5.80 (t, J ) 3.2 Hz, 1H), 5.30 (d, J ) 15.4 Hz, 1H), 5.20 (d,
J ) 15.4 Hz, 1H), 3.91 (s, 3H), 3.76 (s, 3H), 2.53 (d, J )
17.3 Hz, 1H), 2.45 (d, J ) 17.3 Hz, 1H), 2.31 (s, 2H),
2.06-1.80 (m, 2H), 1.34-1.20 (m, 2H), 1.14 (s, 3H), 1.11
(s, 3H), 0.90-0.80 (m, 2H), 0.73 (t, J ) 7.2 Hz, 3H). 13C
NMR (75 MHz, CDCl3): δ 195.0, 166.9, 165.2, 159.8, 152.2,
134.5, 129.5, 129.3(2C), 127.5, 125.5, 125.0, 114.7(2C),
110.9, 109.2, 106.8, 55.7, 52.6, 51.9, 51.4, 46.6, 45.5, 32.8,
32.6, 30.0, 27.8, 25.8, 22.9, 14.5. MS (ESI): m/z 502 (MH+).
HRMS (ESI) Calcd for C30H36N3O4: m/z 502.2706. Found:
502.2704 (M + 1)+. IR(neat): 2954, 1718, 1616, 1594, 823
cm-1. HPLC: 98%.
Methyl 6-Oxo-8,8-dimethyl-11-cyclohexyl-5-(4-meth-
oxy phenyl)-5,6,7,8,9,11-hexahydro-7H-4b,10,11-triaza-
benzo[b]fluorene-3-carboxylate (9j). 1H NMR (300 MHz,
CDCl3): δ 7.84 (d, J ) 8.3 Hz, 1H), 7.72 (s, 1H), 7.34 (d,
J ) 8.3 Hz, 2H), 7.30 (d, J ) 8.3 Hz, 1H), 6.77 (d, J ) 8.3
Hz, 2H), 6.46 (s, 1H), 4.75 (t, J ) 12.2 Hz, 1H), 3.90 (s,
3H), 3.73 (s, 3H), 2.54 (s, 2H), 2.28 (d, J ) 16.3 Hz, 1H),
2.18 (d, J ) 16.3 Hz, 1H), 2.17 (m, 2H), 2.06-1.81 (m,
4H), 1.62-1.54 (m, 2H), 1.39-1.25 (m, 2H), 1.10 (s, 3H),
1.00 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 194.7, 166.8,
162.5, 159.4, 150.5, 134.0, 133.8, 129.9, 128.6(2C), 125.0,
124.3, 114.2(2C), 111.4, 110.5, 109.0, 55.8, 55.7, 55.5, 52.6,
51.2, 46.6, 32.9, 30.8, 30.5, 30.0, 27.6, 26.2, 26.1, 25.6. MS
(ESI): m/z 514 (MH+). HRMS (ESI) Calcd for C31H36N3O4:
m/z 514.2706. Found: 514.2708 (M + 1)+. IR(neat): 2931,
2861, 1716, 1614, 1589, 850 cm-1. HPLC: 99%.
3-Methyl 6-tert-Butyl 9-(2-thienylmethyl)-7-methyl-5-
(4-nitrophenyl)-5-hydro-5a,8,9-triaza-fluorene-3,6-dicar-
boxylate (9n). 1H NMR (300 MHz, CDCl3): δ 8.13 (d, J )
8.7 Hz, 2H), 7.84 (dd, J ) 8.4, 1.4 Hz, 1H), 7.61 (d, J )
8.7 Hz, 2H), 7.60 (d, J ) 1.4 Hz, 1H), 7.26 (dd, J ) 5.1,
1.2 Hz, 1H), 7.14 (dd, J ) 3.4, 1.2 Hz, 1H), 7.11 (d, J )
8.4 Hz, 1H), 6.97 (dd, J ) 5.1, 3.4 Hz, 1H), 6.47 (s, 1H),
5.53 (d, J ) 14.8 Hz, 1H), 5.42 (d, J ) 14.8 Hz, 1H), 3.89
(s, 3H), 2.54 (s, 3H), 1.44 (s, 9H). 13C NMR (75 MHz,
CDCl3): δ 166.7, 166.1, 158.7, 149.4, 148.8, 147.9, 137.4,
134.4, 129.1, 128.6(2C), 127.7, 127.4, 126.6, 125.8, 124.8,
124.3(2C), 110.5, 108.8, 101.1, 80.7, 57.7, 52.7, 40.8, 30.1,
28.8(2C), 25.1. MS (ESI): m/z 561 (M + H)+. HRMS (ESI)
Calcd for C29H29N4O6S: m/z 561.1808. Found: 561.1804 (M
+ 1)+. IR(neat): 2923, 2852, 1714, 1608, 1521, 1346, 819
cm-1. HPLC: 96%.
Dimethyl 9-Cyclohexyl-7-(methoxymethyl)-5-(1,3-ben-
zodioxol-4-yl)-5-hydro-5a,8,9-triaza-fluorene-3,6-dicar-
1
boxylate (9k). H NMR (300 MHz, CDCl3): δ 7.83 (dd, J
) 8.4, 1.4 Hz, 1H), 7.70 (d, J ) 1.4 Hz, 1H), 7.31 (d, J )
8.4 Hz, 1H), 6.92 (dd, J ) 8.0, 1.7 Hz, 1H), 6.84 (d, J )
1.7 Hz, 1H), 6.68 (d, J ) 8.0 Hz, 1H), 6.38 (s, 1H), 5.86
(dd, J ) 4.9, 1.2 Hz, 2H), 4.75 (m, 1H), 4.68 (s, 2H), 3.90
(s, 3H), 3.68 (s, 3H), 3.52 (s, 3H), 2.21-2.12 (m, 2H),
2.01-1.78 (m, 6H), 1.55-1.46 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 166.9, 166.7, 158.2, 150.1, 148.4, 147.8, 136.0,
134.3, 129.4, 125.1, 124.0, 121.1, 111.0, 110.2, 108.3, 107.8,
Methyl 6-Oxo-11-(2-thienylmethyl)-5-propyl-5,6,7,8,9,11-
hexahydro-7H-4b,10,11-triaza-benzo[b]fluorene-3-car-
1
boxylate (9o). H NMR (300 MHz, CDCl3): 7.90 (d, J )
8.3 Hz, 1H), 7.88 (s, 1H), 7.22 (d, J ) 4.9 Hz, 1H), 7.17 (d,
J ) 8.3 Hz, 1H), 7.10 (d, J ) 3.2 Hz, 1H), 6.94 (dd, J )

Combinatorial Library Synthesis of Triaza-Fluorenes
Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 5 731
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4.9, 3.2 Hz, 1H), 5.77 (t, J ) 3.4 Hz, 1H), 5.47 (d, J ) 15.8
Hz, 1H), 5.41 (d, J ) 15.8 Hz, 1H), 3.92 (s, 3H), 2.74 (dt,
J ) 17.6, 4.7 Hz, 1H), 2.60-2.46 (m, 2H), 2.60 (dd, J )
17.6, 9.1, 5.2 Hz, 1H), 2.07-2.02 (m, 2H), 1.40-1.28 (m,
2H), 0.97-0.82 (m, 2H), 0.75 (t, J ) 7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3): δ 195.8, 166.9, 166.8, 151.3, 137.4, 134.0,
127.6, 127.3, 126.6, 125.5, 125.1, 110.9, 108.9, 108.0, 52.7,
51.7, 40.8, 37.7, 35.1, 32.8, 30.1, 22.2, 16.9, 14.3. MS (ESI):
m/z 436 (M + H)+. HRMS (ESI) Calcd for C24H26N3O3S:
m/z 436.1695. Found: 436.1692 (M + 1)+. IR(neat): 3060,
3008, 2950, 1697, 1614 cm-1. HPLC: 99%.
Methyl 6-Oxo-11-(2-thienylmethyl)-5-propyl-5,6,7,8,9,11-
hexahydro-7H-4b,10,11-triaza-benzo[b]fluorene-3-car-
boxylate (9p). 1H NMR (300 MHz, CDCl3): δ 8.10 (d, J )
8.6 Hz, 2H), 7.92 (dd, J ) 8.4, 1.3 Hz, 1H), 7.55 (d, J )
1.3 Hz, 1H), 7.54 (d, J ) 8.6 Hz, 2H), 7.18 (d, J ) 8.4 Hz,
1H), 6.60 (s, 1H), 5.26 (s, 1H), 4.28 (m, 2H), 3.87 (s, 3H),
2.52 (s, 2H), 2.47 (t, J ) 6.9 Hz, 2H), 2.27 (d, J ) 16.4 Hz,
1H), 2.12 (m, 2H), 2.10 (d, J ) 16.4 Hz, 1H), 1.85 (m, 2H),
1.60 (m, 2H), 1.50 (m, 2H), 1.08 (s, 3H), 0.94 (s, 3H). 13C
NMR (75 MHz, CDCl3): δ 194.6, 166.6, 163.6, 150.8, 148.2,
147.7, 134.5, 133.9, 129.0, 128.2(2C), 125.9, 125.1(2C),
124.3(2C), 111.0, 108.9, 107.6, 55.5, 52.7, 51.1, 46.8, 41.2,
36.8, 32.9, 29.6, 28.4, 27.7, 25.6, 23.1, 22.4. MS (ESI): m/z
555 (M + H)+. HRMS (ESI) Calcd for C32H34N4O5: m/z
555.0916. Found: 436.0961 (M + 1)+. IR(neat): 3060, 3008,
2950, 1697, 1614 cm-1. HPLC: 97%.
(8) Schreiber, S. L. Science 2000, 287, 1964–1969.
(9) Our recent work focused on the bringing the different
disciplines of organic synthesis on one platform with their
advances and apply their integrated effect to speed up library
synthesis of drug-like compounds. This concept is termed as
“multidisciplinary synthetic approach” by its profound nature
in organic synthesis which could bring the two or more
disciplines of organic synthesis on one path to facilitate initial
drug discovery process. Some of the reports already available
which supports the multidisciplinary synthetic approach. See:
(a) Zhang, W.; Chen, C. H.; Lu, Y.; Nagashima, T. Org. Lett.
2004, 6, 1473–1476. (b) Bai, L.; Wang, J. X. AdV. Synth. Cat.
2008, 350, 315–320. (c) Dallinger, D.; Gorobets, N. Y.;
Kappe, C. O. Org. Lett. 2003, 5, 1205–1208. (d) Bai, L.;
Wang, J. X. Curr. Org. Chem. 2005, 9, 535–553. (e)
Leadbeater, N. E.; Torenius, H. M.; Tye, H. Mol. DiVersity
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Acknowledgment. The authors thank the National Science
Council of Taiwan for the financial assistance and the
authorities of the National Chiao Tung University for
providing the laboratory facilities.
Supporting Information Available. 1H and 13C NMR, IR,
and mass spectra of compounds 9a-9p. This material is
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