Microwave-assisted tandem transformation on an ionic-liquid support: Efficient synthesis of pyrrolo/pyridobenzimidazolones and isoindolinone-fused benzimidazoles

Article abstract of DOI:10.1002/asia.201100277

A tandem transformation that involves the formation of three bonds and two heterocyclic rings in a one-pot fashion through amino-alkylation of an ionic-liquid-immobilized diamine with keto acids followed by successive double intramolecular cyclizations to afford a tricyclic framework has been explored. This tandem cyclization has been utilized to develop a rapid and efficient method to synthesize various pyrrolo[1,2-a]benzimidazolones and pyrido[1,2-a]benzimidazolones on an ionic-liquid support by using focused microwave irradiation. The application of this tandem cyclization was further extended to the aromatic keto acids to provide isoindolinone-fused benzimidazoles, a structurally heterogeneous library with skeletal diversity. The outcome of the cascade reaction was confirmed by the X-ray crystallographic study of the product directly attached to the ionic-liquid support. Use of the ionic liquid as a soluble support facilitates purification by simple precipitation along with advantages like high loading capacity, homogeneous reaction conditions, and monitoring of the reaction progress by regular conventional spectroscopic methods, whereas application of microwave irradiation greatly accelerates the rate of the reactions. Copyright

Full text of DOI:10.1002/asia.201100277

DOI: 10.1002/asia.201100277
Microwave-Assisted Tandem Transformation on an Ionic-Liquid Support:
Efficient Synthesis of Pyrrolo/Pyridobenzimidazolones and Isoindolinone-
Fused Benzimidazoles
Suman Thummanagoti, Gorakh S. Yellol, and Chung-Ming Sun*[a]
Abstract:
A
tandem transformation
using focused microwave irradiation.
The application of this tandem cycliza-
tion was further extended to the aro-
matic keto acids to provide isoindoli-
none-fused benzimidazoles, a structur-
ally heterogeneous library with skeletal
diversity. The outcome of the cascade
reaction was confirmed by the X-ray
crystallographic study of the product
directly attached to the ionic-liquid
support. Use of the ionic liquid as a
soluble support facilitates purification
by simple precipitation along with ad-
vantages like high loading capacity, ho-
mogeneous reaction conditions, and
monitoring of the reaction progress by
regular conventional spectroscopic
methods, whereas application of micro-
wave irradiation greatly accelerates the
rate of the reactions.
that involves the formation of three
bonds and two heterocyclic rings in a
one-pot fashion through amino-alkyla-
tion of an ionic-liquid-immobilized dia-
mine with keto acids followed by suc-
cessive double intramolecular cycliza-
tions to afford a tricyclic framework
has been explored. This tandem cycli-
zation has been utilized to develop a
rapid and efficient method to synthe-
Keywords: heterocycles
·
ionic
liquids microwave chemistry
·
·
size various pyrrolo
lones and pyridoACHTUNGTRENNUNG
lones on an ionic-liquid support by
ACHTUNGTRENNUNG
supported synthesis · tandem reac-
tions
Introduction
ated with heterogeneous reaction conditions such as unequal
distribution of the reaction sites and inefficient coupling
rates have led to alternative soluble-support methodologies
with the aim of restoring homogeneous reaction conditions
and easily separating the desired compound from the sup-
port. The successful implementation of soluble polyethylene
glycol (PEG), polyvinyl alcohol, and other soluble polymers
in small-molecule synthesis retains more advantages over
conventional solution-phase chemistry.[4] However, the use
of soluble polymer supports suffers from the drawbacks of
low loading capacity and low aqueous solubility. The draw-
backs associated with solid- and soluble-polymer-supported
synthesis urge chemists to search for alternative tools in
their arsenal to restore facile, convenient, and nonpolluting
synthetic protocols. The recently emergent ionic liquids
(ILs) and their intriguing properties as environmentally
benign reaction media have attracted considerable interest
in numerous chemical reactions and biomedical applica-
tions.[5] Depending on the choice of anions and cations, the
solubility of the ILs can be tuned readily to control the
phase trafficking in organic and aqueous phases. These at-
tractive features—together with high loading capacity and
high thermal as well as chemical stability—make ionic liq-
uids attractive for use as soluble supports in organic synthe-
To enhance the traditional paradigm of small-molecule dis-
covery, diversity-oriented synthesis has evolved into the sys-
tematic generation of a large number of druglike molecules
that are available for screening and to identify lead com-
pounds for pharmaceutical research and drug develop-
ment.[1] To meet the growing demand for new, small mole-
cules in high-throughput screening for drug discovery, sub-
stantial effort has been dedicated to develop solid-phase
and solution-phase chemistries.[2] Highly successful and read-
ily automated insoluble-solid-supported synthesis has been
applied in numerous areas.[3] However, the problems associ-
[a] S. Thummanagoti, G. S. Yellol, Prof. Dr. C.-M. Sun
Department of Applied Chemistry
National Chiao Tung University
Hsinchu 300-10 (Taiwan)
Fax : (+886)3-5736007
E-mail: cmsun@mail.nctu.edu.tw
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100277. It includes detailed
1
experimental procedures as well as H and 13C NMR, mass, IR, and
HPLC spectra of compounds 10, 11, 14, 16, 18, and 9.
Chem. Asian J. 2011, 6, 2471 – 2480
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
2471

FULL PAPERS
sis. The substrate anchored on ILs is suitable for monitoring
the reaction progress by conventional spectroscopic analysis.
Moreover, for the reactions conducted in the homogeneous
phase, the excess amounts of reagents and byproducts are
removed by simple washing with a low-polar organic sol-
vent. The recovered IL can be recycled in the synthetic pro-
cess. This liquid-phase strategy has been demonstrated by
several groups to synthesize small molecules and peptides in
combinatorial fashion.[6]
Diversity-oriented synthesis together with combinatorial
parallel synthesis has been significantly affected by the in-
troduction of microwave synthesis.[7] The use of microwaves
in ionic-liquid-supported reactions has attracted the atten-
tion of many researchers in recent days. Ionic liquids absorb
the microwave energy efficiently, through which the reaction
rate can be accelerated remarkably. The synergies that arise
from the combined use of microwaves and IL is certainly ef-
fective in meeting the increasing demand for environmental-
ly benign chemical processes.[8]
roloimidazolones exhibited properties as cognition-enhanc-
ing pharmaceuticals,[12] whereas the expanded series of pyr-
rolobenzimidazolone derivatives (III) were evaluated for
their anticonvulsant properties.[13] Substituted pyrimidoben-
zimidazole (IV) derivatives have been investigated to treat
disorders of the central nervous system.[14]
In continuation with our effort to develop a rapid and ef-
ficient method for medicinally interesting compounds with
multidisciplinary synergetic approaches,[15] here we report
the tandem transformation that leads to the efficient synthe-
sis of pyrroloACTHNUTRGENNUG[1,2-a]benzimidazolone, pyridoACHTUNGTERN[NUGN 1,2-a]benzimi-
dazolone, and isoindolinone-fused benzimidazolone deriva-
tives on an ionic-liquid support by means of focused micro-
wave irradiation.
Results and Discussions
3-Hydroxyethyl(1-methylimidazolium)tetrafluoroborate (1),
readily available from the reaction of 1-methylimidazole
and 2-bromoethanol,[16] was used as a suitable ionic-liquid
(IL) support for an intended multistep synthetic sequence.
The synthetic strategy to develop a distinct molecular frame-
work commenced with the loading of 4-fluoro-3-nitrobenzo-
ic acid (2) onto IL 1 through esterification, in which the IL
acts as a soluble support for growing molecules. The esterifi-
cation reaction was carried out in the presence of N,N’-dicy-
clohexylcarbodiimide (DCC) and a catalytic amount of
N,N’-dimethylaminopyridine (DMAP) in acetonitrile for
20 minutes in the microwave cavity at 808C to furnish IL-
immobilized fluronitrobenzoate 3 (Scheme 1). The same
esterification reaction under conventional heating required
48 hours. By taking advantage of the distinct solubility fea-
ture of the IL-anchored substrate, the excess amounts of re-
agents and the reaction byproducts can easily be removed
by using less-polar organic solvents in which the IL conju-
gate substrate is insoluble. Accordingly, IL conjugate 3 was
purified and obtained in good yields after washing with di-
ethyl ether.
To illustrate the rapid and efficient synthetic methodology
on an ionic-liquid support, structurally fused benzimidazole
with 2-pyrrolodinones, 2-pyridinones, and isoindolones were
examined as the target compounds that occupy an important
place in current therapeutic agents.[9] Irrespective of the
target, the growing existence of imidazole-fused heterocy-
cles in many drug entities has proven the remarkable ability
of imidazole nuclei to serve both as biomimetics and reac-
tive pharmacophores.[10] Batracyclin (I) and isoindolo
ACTHNUTRGNE[NUG 2,1-
The immobilized fluoronitrobenzoate 3 was treated with
various primary amines to substitute the fluorine atom
through an ipso-fluoro nucleophilic substitution reaction
under focused microwave irradiation. The ipso-fluoro dis-
placement reaction was carried out in acetonitrile at 808C
for about 10 minutes to obtain the IL-supported nitroamine
4. In contrast, this reaction took 4 hours under reflux condi-
tions. Various amines were used to create the substitutional
diversity in the targeted framework. It is worth mentioning
that that IL-linked ester functionality is stable under the mi-
crowave heating conditions and not cleaved by various
amines. The ipso-fluoro displacement was monitored and
confirmed by conventional proton NMR spectroscopy. To
reduce the nitro functional group, IL-anchored substrate 4
was treated with zinc and ammonium formate in methanol
for 30 minutes under reflux conditions. This metal reduction
also smoothly occurred on the IL support to afford IL–dia-
mine conjugate 5 with good yields in 5 minutes at 808C. The
a]benzimidazoles (II) as topoisomerase II inhibitors have
shown in vivo antitumor activity against murine leukemia P-
388 and colon adenocarcinoma 38 cell lines.[11] Similarly, pyr-
Abstract in Chinese:
2472
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2471 – 2480

Microwave-Assisted Transformation
pound 7 was attributed to the
activation of acid functionality
in the presence of a stoichio-
metric amount of TFA. The
structure was confirmed to be
compound 8 after removing the
IL support in sodium methox-
ide solution. On the other
hand, the coupling of keto acid
with IL diamine conjugate 5
and successive intramolecular
cyclizations were successfully
achieved by using 20 mol%
TFA with magnesium sulfate in
dichloroethane under focused
microwave irradiation at 1108C
over 10 minutes (Scheme 1).
The reaction mixture was puri-
fied again by precipitation in di-
ethyl ether and separated by fil-
tration to offer IL-supported
pyrrolo/pyridobenzimidazolone
derivatives
9 in good yields
(72–85%). For comparison, the
same reaction was carried out
under conventional reflux con-
ditions, which took 24 hours to
furnish the same product in di-
chloroethane. In the particular
case of R2 as the alkyl group,
this tandem reaction affords cy-
clized benzimidazolone deriva-
tives 9 even with stoichiometric
amounts of TFA. The formation
of pyrrolo/pyridobenzimidazo-
lone derivatives 9 was detected
directly with the IL support by
Scheme 1. Ionic-liquid-supported synthesis of pyrrolo/pyridobenzimidazolones.
1
reduction was confirmed by the upfield shifting of aromatic
protons in the proton NMR spectrum of compound 5.
means of spectroscopic analysis. In the H NMR spectrum
of compound 9, the absence of peaks that correspond to
amine and acid protons together with the emergence of
peaks due to alkyl protons present on the keto acid moiety
suggested the successful cyclization of IL diamine conjugate
5 with keto acid 6. Additionally, the stereogenic quaternary
carbon appeared at d=89.5 ppm in the C13 NMR spectrum
of compound 9 along with the amide carbonyl carbon ab-
sorbance peak at d=175 ppm. The formation of an amide
bond was further confirmed by IR spectroscopy, which de-
picts the amide frequency band around 1720 cmÀ1. Due to
the ketonic nature of tert-amide carbonyl functionality, it
may be a little higher.
The synthetic pathway that leads to pyrrolo/pyridobenzi-
midazolones through cascade reactions includes amino-alky-
lation and a subsequent double intramolecular cyclization
process. The important mechanistic steps involved in the
tandem transformation pathway for the formation of the tri-
cyclic skeleton are depicted in Scheme 2. The tandem reac-
tion is supposed to start from the acid-catalyzed imine for-
The next challenge was the synthesis of pyrrolo/pyrido-
benzimidazolone derivatives from IL conjugate 5 through
one-pot tandem transformations. Aliphatic g-keto acids as
well as d-keto acids were used to produce structurally di-
verse heterocyclic skeletons along with substitutional diver-
sity depending on the groups present on the keto acids. The
g-keto acids can provide a five-membered ring, whereas d-
keto acids undergo elaborate cyclization to a six-membered
ring to provide a skeletally different tricyclic framework.
Accordingly, IL diamine conjugate 5 was treated with vari-
ous g- and d-keto acids 6 in the presence of trifluoroacetic
acid (TFA) under microwave irradiation. During the optimi-
zation of conditions for the intended cascade cyclization, it
was observed that the coupling of keto acid with ortho-phe-
nylenediamine is dependent on the amount of acid used. We
observed the coupling of the acid moiety with diamine func-
tionality with a stoichiometric amount of TFA afforded 2-
alkyl-substituted benzimidazoles 7. The formation of com-
Chem. Asian J. 2011, 6, 2471 – 2480
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2473

C.-M. Sun et al.
FULL PAPERS
the X-ray crystallographic study
of compound 10 f. Figure 1 de-
picts the ORTEP diagram of
compound 10 f (X-ray crystallo-
graphic data are specified in the
Supporting Information). The
crystal structure of compound
10 f indicates that the phenyl
group is present at the C26
carbon of the pyridobenzimida-
zole skeleton, which further
proved its structure.
Scheme 2. Plausible mechanistic steps involved in the synthesis of pyrrolo/pyridobenzimidazolones.
mation through condensation of conjugate diamine 5 with
keto acids 6 by excluding water molecules. The formation of
an amide bond by amine–acid coupling was less likely in the
presence of the comparatively more reactive ketone func-
tionality, which readily reacts with amine to form an imine
bond. The subsequent tandem transformation led to intra-
molecular cyclization through the attack of a secondary
amine on an electrophilic imine carbon towards pentacyclic
aza-ring formation to afford a benzimidazole derivative. The
resulting benzimidic secondary amine and acid functionality
present in one skeleton are in a more favorable position for
cyclization to form a more stable five- or six-membered
cyclic lactic ring. The intramolecular cyclization to form an
amide was assisted by the liberation of a water molecule by
the dehydrating agent magnesium sulfate, thereby resulting
in pyrrolo/pyridobenzimidazolones 9.
Figure 1. ORTEP diagram of compound 10 f.
Finally, the removal of the ionic-liquid support from 9 was
carried out in sodium methoxide/methanol solution under
microwave irradiation at 1108C over 10 minutes to furnish
pyrrolo/pyridobenzimidazolone derivatives 10 and 11. The
cleaved IL was precipitated from the reaction mixtures by
the addition of diethyl ether; the desired products were sep-
arated by filtration. The recovered IL was recycled in the
synthetic process. The filtrate was concentrated and the
crude final compounds were subjected to HPLC analysis.
Further column chromatography purification furnished
To extend the scope of the present cascade process, selec-
tive ionic-liquid-conjugated diamines were planned to react
with a-ketobenzoic acids under the same reaction conditions
to offer scaffold diversity and to provide a structurally dis-
tinct library. Accordingly, IL-supported diamine 5 was treat-
ed with 2-acylbenzoic acid 12 with 20 mol% TFA in di-
chloroethane under microwave irradiation at 1108C
(Scheme 3). IL-supported isoindolobenzimidazolones 13
pyrrolo
ACHTUNGTRENNUNG
10 and pyridoACHTUNGTRENNUNG
zolones 11 in good yields
(Table 1). A variety of 4-keto
acids and 5-keto acids were
used in combination with the
N-alkyl substitution on the dia-
mine moiety for this tandem
transformation to furnish pyrro-
lo/pyridobenzimidazoles
with
substitutional diversity, as de-
picted in Table 1. In addition to
the spectroscopic analysis, the
final structure and outcome of
the tandem transformation was
unambiguously confirmed by Scheme 3. Synthesis of isoindolinone-fused benzimidazole derivatives.
2474
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2471 – 2480

Microwave-Assisted Transformation
Table 1. Pyrrolo/pyridobenzimidazolone derivatives.
The confirmation of the structure of compound 13 and
the outcome of the tandem transformation on aromatic ke-
tobenzoic acid is feasible directly on the ionic-liquid sup-
port. The absence of peaks that correspond to amine and
acid protons together with the emergence of the new peaks
due to aromatic protons of the 2-acetyl benzoic acid moiety
1
in the H NMR spectrum of compound 13 along with the
R1
R2
Mass[a] LRMS[b] Yield
[%][c]
amide frequency band around 1720 cmÀ1 in the IR spectra
suggested the cyclization of diamine conjugate 5 with 2-ace-
tylbenzoic acid 12 on the ionic tag. Moreover, the structure
of isoindolobenzimidazolone was unambiguously confirmed
by the X-ray crystallographic study of compound 13a direct-
ly with the ionic-liquid support. Figure 2 depicts the ORTEP
diagram of compound 13a (X-ray crystallographic data is
specified in the Supporting Information). To the best of our
knowledge, this is the first report of an X-ray crystallograph-
ic study on molecules linked with an ionic-liquid support.
Compound
10a
10b
302
350
97
79
85
80
10c
440
96
83
10d
10e
364
366
94
98
75
72
10 f
10g
416
412
74
95
74
75
10h
10i
392
394
382
396
86
93
68
85
72
75
77
75
10j
10k
11a
11b
11c
288
316
318
94
84
99
84
82
80
Figure 2. ORTEP diagram of isoindolobenzimidazolone 13a.
11d
364
94
83
The subsequent removal of the ionic-liquid support from
13 furnished isoindolobenzimidazolones 14 in good yield
over two steps (Table 2).
11e
11 f
356
378
85
95
86
75
The scope of this method was further broadened by incor-
poration of the additional sulfur element in the scaffold.
The IL-supported pyrrolobenzimidazolone 9 f and pyrrolo-
benzimidazolone 9e were treated with Lawssonꢁs reagent in
toluene under focused microwave conditions at 1508C. The
thio derivative of the IL-supported pyrido- and pyrroloben-
zimidazolones (15 and 17) were obtained in good yields
over 10 minutes, whereas the same reaction took 24 hours
under reflux conditions in toluene (Scheme 4). Further re-
moval of the polymer support afforded thiopyrrolobenzimi-
dazolone 16 and thiopyridobenzimidazolone 18. The struc-
tures of thio compounds 16 and 18 were confirmed by
proton NMR spectroscopy along with mass and IR analysis.
It is worth mentioning that the time taken to attain the
desired reaction temperatures for all the reactions under mi-
crowave exposure is substantially shortened on account of
11g
11h
430
432
85
70
77
70
[a] Mass (low-resolution (LR) MS) was detected as [M]+. [b] HPLC
purity of unpurified samples. [c] Yields were determined from the weight
of purified samples [%].
were obtained in good yields within 10 minutes; they were
purified by a simple precipitation method. The same reac-
tion took 24 hours under reflux conditions for compete cyc-
lization.
Chem. Asian J. 2011, 6, 2471 – 2480
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2475

C.-M. Sun et al.
FULL PAPERS
drogen.[17] In our current synthetic approach, we have suc-
cessfully integrated the advantages of IL with microwave
synthesis to afford a rapid synthesis of pyrrolo/pyridobenzi-
midazolones with high purity and yields. In addition, the
total in-pot reaction time for the multistep synthesis was
drastically reduced to around 1.2 hours under microwave ir-
radiation conditions. For classical thermal reaction condi-
tions, the total in-pot reaction time is around 125 hours.
There was also a significant decrease in total reloading time
by using IL as a support, which facilitates the purification in
each step.
Table 2. Synthesis of isoindolobenzimidazolones.
Compound
R1
R2
Mass[a] LRMS[b] Yield [%][c]
14a
350
364
78
93
85
82
14b
14c
402
398
85
71
80
78
Conclusion
14d
In summary, we have developed a rapid and efficient solu-
tion-phase approach to synthesize pyrrolo
ACHTUNGTREN[NUGN 1,2-a]benzimida-
[a] Mass (LRMS) was detected as [M]+. [b] HPLC purity of unpurified
samples. [c] Yields were determined from the weight of purified samples
[%].
zolones, pyrido[1,2-a]benzimidazolones, and isoindolinone-
AHCTUNGTRENNUNG
fused benzimidazoles with two points of diversity on an
ionic-liquid support under microwave conditions. Here we
have demonstrated a novel tandem reaction that efficiently
affords different-sized fused heterocyclic skeletons. This cas-
cade transformation mainly consists of three sequential
steps: condensation of an amine functionality with keto car-
bonyl to afford imine, intramolecular cyclization through
the imine bond to form an imidazole ring, and a second in-
tramolecular cyclization to form various-sized fused lactam
rings. Ionic liquid was explored as a high-loading liquid sup-
port for multistep organic synthesis in a homogeneous phase
under microwave conditions. It is noteworthy that a synergy
arises from the combined use of microwave heating with the
ionic-liquid support and can be very effectively used to
speed up the multistep synthesis of biologically interesting
heterocycles.
the high-polar microwave absorbance medium created by
the ionic-liquid support. The solubility of the ionic-liquid
support throughout the sequence of reactions was not influ-
enced by the growing chain. Thus separation and purifica-
tion procedures become greatly simplified so that the gener-
al procedure involved precipitation and washing with low-
polar organic solvents. Moreover, the ionic-liquid support is
stable under microwave heating conditions. The reaction
progress was monitored through regular proton NMR spec-
troscopy without releasing the intermediates from the sup-
port. The previous syntheses of pyrrolo/pyridobenzimidazo-
lone derivatives are a time-consuming and tedious process
in moderate overall yields and the R1 group is limited to hy-
Scheme 4. Synthesis of thio analogues of pyrido/pyrrolobenzimidazolone.
2476
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2471 – 2480

Microwave-Assisted Transformation
(ESI): m/z: 302 [M+]; HRMS (ESI): m/z: calcd for C17H22N2O3:
Experimental Section
302.1630; found: 302.1625 [M+]; IR (neat): n˜ =2360, 1720, 1614 cmÀ1
;
HPLC: 97%.
General Methods
Methyl 3a-Methyl-1-oxo-4-phenethyl-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrroloACTHNUTRGNEUNG[1,2-a]imidazole-7-carboxylate (10b)
Dichloroethane was distilled from calcium hydride before use. All reac-
tions were performed under an inert atmosphere with unpurified re-
agents and dry solvents. Analytical thin-layer chromatography (TLC) was
performed with 0.25 mm silica gel-coated Kieselgel 60 F254 plates. Flash
column chromatography was performed using the indicated solvent and
silica gel 60 (Merck, 230–400 mesh). 1H (300 MHz) and 13C NMR
(75 MHz) spectra were recorded with a Bruker DX-300 spectrometer.
Chemical shifts are reported in parts per million (ppm) on the d scale
from an internal standard. High-resolution mass spectra (HRMS) were
recorded with a JEOL TMS-HX 110 mass spectrometer. Microwave ex-
periments were performed with a CEM Discover microwave system in a
closed vessel. The temperature for reaction was set by instrument.
1H NMR (300 MHz, CDCl3): d=7.98 (d, J=1.8, 1H), 7.81 (dd, J=8.1,
1.8 Hz, 1H), 7.35–7.17 (m, 5H), 6.4 (d, J=8.1 Hz, 1H), 3.89 (s, 3H),
3.63–3.54 (m, 1H), 3.38 (m, 1H), 3.03–2.89 (m, 2H), 2.73 (m, 1H), 2.41
(dd, J=16.9, 8.5 Hz, 1H), 2.18 (dd, J=16.9, 8.5 Hz, 1H), 1.90 (m, 1H),
1.44 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=173.8, 166.9, 147.0,
138.5, 129.1, 128.7, 128.6 (3C), 127.6, 126.7, 119.0, 115.7, 104.4, 88.9, 51.5,
44.9, 35.5, 34.7, 32.9, 22.5 ppm; IR (neat): n˜ =2360, 1697, 1616 cmÀ1; MS
(ESI): m/z: 350 [M+]; HRMS (ESI): m/z: calcd for C21H22N2O3:
350.1630; found: 350.1619 [M+]; HPLC: 79%.
Methyl 4-(3,3-Diphenylpropyl)-3a-methyl-1-oxo-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrroloACTHNUTRGNEUNG[1,2-a]imidazole-7-carboxylate (10c)
General Procedure for the Synthesis of the Pyrrolo/Pyrido/
Isoindolobenzimidazolones
1H NMR (300 MHz, CDCl3): d=7.96 (d, J=1.8 Hz, 1H), 7.72 (dd, J=
8.1, 1.8 Hz, 1H), 7.22–7.32 (m, 10H), 6.12 (d, J=7.8 Hz, 1H), 3.84 (t, J=
7.4 Hz, 1H), 3.84 (s, 3H), 3.30–3.10 (m, 2H), 2.79 (m, 1H), 2.56–2.24 (m,
5H), 1.41 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=173.5, 166.9,
147.3, 143.7, 143.6, 128.9, 128.7 (4C), 127.6 (3C), 127.5 (3C), 126.6, 119.1,
115.6, 104.7, 88.9, 51.6, 48.6, 41.3, 36.5, 34.2, 33.1, 22.3 ppm; IR (neat):
n˜ =2360, 1718, 1612 cmÀ1; MS (ESI): m/z: 440 [M+]; HRMS (ESI): m/z:
calcd for C28H28N2O3: 440.2100; found: 440.2095 [M+]; HPLC: 96%
Ionic liquid 1 (0.5 g, 2.3 mmol) in acetonitrile (5 mL) was added to the
solution of 2 (0.51 g, 2.7 mmol, 1.2 equiv) in acetonitrile (5 mL), followed
by the addition of DCC (0.57 g, 2.7 mmol, 1.2 equiv) and a catalytic
amount of DMAP (0.002 g). The reaction mixture was irradiated with mi-
crowaves at 808C for 20 min. The precipitated dicyclohexyl urea (DCU)
was filtered through a fritted Celite plug. The Celite plug was rinsed with
acetonitrile, and the combined organic phase was concentrated under
vacuum. The crude reaction mixtures were precipitated by slow addition
of an excess amount of diethyl ether (100 mL). The precipitated ester
conjugate was then filtered and washed to obtain IL-supported com-
pound 3 in good yield. Various primary amines (6.7 mmol, 3.0 equiv) in
acetonitrile (5 mL) were added to a solution of 3 in acetonitrile (5 mL),
and the reaction mixtures were irradiated in a microwave cavity at 808C
for 10 min to afford IL-immobilized nitroamines 4. Upon concentration
under reduced pressure, the crude residue was precipitated by addition
of ether (100 mL). The precipitated IL conjugate 4 was then filtered
through a fritted funnel and washed several times to remove the byprod-
ucts and dried. Zinc (7.0 equiv) and ammonium formate (NH4COOH)
(15.0 equiv) were added to the solution of nitroamine 4 in methanol and
irradiated in a microwave cavity at 808C for 5 min. The insoluble zinc
was removed by filtration, and the filtrate was concentrated under re-
duced pressure. The residue was purified by crystallization in ether to
afford ionic-liquid-supported dimaine 5. Various aliphatic g- or d-keto
acids 6 (1.5 equiv) were added together with dry MgSO4 and 20 mol%
trifluoroacetic acid to the solution of 5 in ethylenedichloride (9 mL). The
reaction mixture was subjected to microwave irradiation for 10 min at
1108C to offer the IL-supported conjugates 9. The crude reaction mixture
was filtered through the fritted funnel, and the reaction mixture was pre-
cipitated by slow addition of cold ether (60 mL). The precipitated ionic-
liquid conjugate was then filtered through a fritted funnel and washed
several times with ether to get the ionic-liquid-supported pyrrolo/pyrido-
benzimidazoles 9. The solution of 0.1m NaOMe in MeOH (10 mL) was
added to the solution of IL-supported conjugates 9 in methanol. The re-
action mixture was subjected to microwave irradiation for 10 min at
1108C. The reaction mixture was precipitated by addition of ether. The
precipitate of IL was separated by filtration. The filtrates were concen-
trated under reduced pressure, and the crude pyrrolo/pyridobenzimida-
zoles were subjected to HPLC purification (68–99%). The residue was
further purified by column chromatography over silica gel with ethylace-
tate/n-hexane (1:1) as an eluent to obtain the pure pyrrolo/pyridobenzi-
midazoles 10 and 11 in good yields (72–85%).
Methyl 4-Isobutyl-1-oxo-3a-phenyl-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrroloACTHNUTRGNEUNG[1,2-a]imidazole-7-carboxylate (10d)
1H NMR (300 MHz, CDCl3): d=8.06 (d, J=1.8 Hz, 1H), 7.76 (dd, J=
8.4, 1.8 Hz, 1H), 7.37–7.36 (m, 5H), 6.35 (d, J=8.4 Hz, 1H), 3.83 (s, 3H),
3.18 (m, 1H), 2.89–2.53 (m, 5H), 1.95 (m, 1H), 1.25 ppm (t, 6H);
13C NMR (75 MHz, CDCl3): d=173.9, 166.9, 148.0, 137.6, 129.3, 129.2,
128.8 (2C), 128.5, 125.4 (2C), 119.1, 114.7, 104.4, 91.4, 51.6, 51.5, 36.5,
33.6, 27.9, 20.5, 20.3 ppm; IR (neat): n˜ =2360, 1720, 1612 cmÀ1; MS (ESI):
m/z: 364 [M+]; HRMS (ESI): m/z: calcd for C22H24N2O3: 364.1787;
found: 364.1782 [M+]; HPLC: 94%.
Methyl 4-(2-Methoxyethyl)-1-oxo-3a-phenyl-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrroloACTHNUTRGNEUNG[1,2-a]imidazole-7-carboxylate (10e)
1H NMR (300 MHz, CDCl3): d=8.07 (d, J=1.5 Hz, 1H), 7.78 (dd, J=
8.1, 1.5 Hz, 1H), 7.41–7.31 (m, 5H), 6.39 (d, J=8.1 Hz, 1H), 3.84 (s, 3H),
3.44–3.36 (m, 2H), 3.34–3.25 (m, 5H), 3.21 (m, 1H), 2.80–2.49 ppm (m,
3H); 13C NMR (75 MHz, CDCl3): d=174.5, 166.8, 146.8, 138.2, 129.1,
129.0, 128.8 (2C), 128.3, 125.2 (2C), 118.9, 114.8, 103.8, 90.9, 70.1, 58.7,
51.5, 42.3, 36.4, 33.2 ppm; IR (neat): n˜ =2362, 1718, 1610 cmÀ1; MS (ESI):
m/z: 366 [M+]; HRMS (ESI): m/z: calcd for C21H22N2O4: 366.1580;
found: 366.1584 [M+]; HPLC: 98%.
Methyl 4-[2-(Cyclohex-1-en-1-yl)ethyl]-1-oxo-3a-phenyl-2,3,3a,4-
tetrahydro-1H-pyrroloACTHNUGRTNEUNG[1,2-a]benzimidazole-7-carboxylate (10 f)
1H NMR (300 MHz, CDCl3): d=8.06 (d, J=1.8 Hz, 1H), 7.79 (dd, J=
8.1, 1.8 Hz, 1H), 7.41–7.34 (m, 5H), 6.34 (d, J=8.1 Hz, 1H), 5.39 (s, 1H),
3.86 (s, 3H), 3.31–3.06 (m, 3H), 2.68–2.52 (m, 3H), 1.95–1.84 (m, 6H),
1.64–1.48 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=174.9, 167.4,
147.1, 138.9, 134.8, 129.8, 129.7, 128.9 (2C), 128.6, 125.7 (2C), 124.2,
119.3, 115.3, 104.4, 91.4, 52.1, 42.7, 36.9, 36.7, 33.8, 28.8, 25.6, 23.2,
22.6 ppm; IR (neat): n˜ =2360, 1720, 1612 cmÀ1; MS (ESI): m/z: 416 [M+];
HRMS (ESI): m/z: calcd for C26H28N2O3: 416.2100; found: 416.2097 [M+
]; HPLC: 74%.
Methyl 4-Butyl-3a-methyl-1-oxo-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrrolo
G
Methyl 4-Phenethyl-3a-phenyl-1-oxo-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrroloACTHNUTRGNEUNG[1,2-a]imidazole-7-carboxylate (10g)
1H NMR (300 MHz, CDCl3): d=7.90 (d, J=1.8 Hz, 1H), 7.72 (dd, J=
8.4, 1.8 Hz, 1H), 6.34 (d, J=8.4 Hz, 1H), 3.8 (s, 3H), 3.29–3.08 (m, 2H),
2.84–2.71 (m, 2H), 2.39–2.33 (m, 2H), 1.65–1.53 (quint, J=7.3 Hz, 2H),
1.4 (s, 3H), 1.37 (sext, J=7.2 Hz, 2H), 0.93 ppm (t, J=7.3 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=173.6, 166.7, 147.5, 129.1, 127.5, 118.7,
115.5, 104.4, 88.9, 51.5, 42.6, 36.4, 33.0, 30.6, 22.2, 20.3, 13.6 ppm; MS
1H NMR (300 MHz, CDCl3): d=8.11 (d, J=1.5 Hz, 1H), 7.83 (dd, J=
1.5, 8.1 Hz, 1H), 7.40–7.37 (m, 5H), 7.31–7.24 (m, 3H), 7.13–7.10 (m,
2H), 6.39 (d, J=8.1 Hz, 1H), 3.9 (s, 3H), 3.46 (m, 1H), 3.32 (m, 1H),
3.01 (m, 1H), 2.87 (m, 1H), 2.66–2.52 (m, 2H), 2.45 (m, 1H), 2.20 ppm
(m, 1H); 13C NMR (75 MHz, CDCl3): d=174.4, 166.9, 146.4, 138.5,
Chem. Asian J. 2011, 6, 2471 – 2480
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2477

C.-M. Sun et al.
FULL PAPERS
138.5, 129.3, 129.2, 128.9 (2C), 128.6 (3C), 128.5 (2C), 126.6, 125.1, 119.1,
114.9, 104.0, 90.9, 51.6, 45.3, 35.6, 34.0, 33.2 ppm; IR (neat): n˜ =2360,
1716, 1612 cmÀ1; MS (ESI): m/z: 412 [M+]; HRMS (ESI): m/z: calcd for
C26H24N2O3: 412.1787; found: 412.1794 [M+]; HPLC: 95%.
Methyl 5-Butyl-4a-methyl-1-oxo-1,2,3,4,4a,5-
hexahydrobenzo[4,5]imidazo[1,2-a]pyridine-8-carboxylate (11b)
G
ACHTUNGTRENNUNG
1H NMR (300 MHz, CDCl3): d=8.38 (d, J=1.5 Hz, 1H), 7.74 (dd, J=
8.1, 1.5 Hz, 1H), 6.37 (d, J=8.1 Hz, 1H), 3.85 (s, 3H), 3.23–3.02 (m, 2H),
2.67–2.46 (m, 2H), 2.20 (m, 1H), 2.06–1.79 (m, 3H), 1.60 (quintet, J=
7.5 Hz, 2H), 1.43–1.35 (m, 2H), 1.37 (s, 3H), 0.95 ppm (t, J=7.3, 3H);
13C NMR (75 MHz, CDCl3): d=167.2, 166.3, 145.1, 129.9, 128.9, 119.1,
117.2, 104.0, 84.0, 51.5, 42.7, 32.8, 31.1, 30.6, 22.0, 20.4, 16.9, 13.8 ppm; IR
(neat): n˜ =2358, 1708, 1658 cmÀ1; MS (ESI): m/z: 316 [M+]; HRMS
(ESI): m/z: calcd for C18H24N2O3: 316.1787; found: 316.1784 [M+];
HPLC: 84%
Methyl 4-Butyl-3a-(4-ethylphenyl)-1-oxo-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrroloACHTUNGTRENNUNG[1,2-a]imidazole-7-carboxylate (10h)
1H NMR (300 MHz, CDCl3): d=8.04 (d, J=1.8 Hz, 1H), 7.77 (dd, J=
1.8, 8.1 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.32 (d,
J=8.1 Hz, 1H), 3.85 (s, 3H), 3.22–3.09 (m, 2H), 3.01 (m, 1H), 2.97–2.57
(m, 4H), 1.54 (m, 1H), 1.37–1.24 (m, 4H), 1.20 (t, J=7.6 Hz, 3H),
0.89 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=174.3,
167.0, 147.1, 145.4, 135.5, 129.3, 128.5, 128.3 (2C), 125.3 (2C), 118.7,
114.8, 103.8, 91.0, 51.6, 42.9, 36.6, 33.5, 30.4, 28.3, 20.3, 15.3, 13.8 ppm; IR
(neat): n˜ =2360, 1720, 1612 cmÀ1; MS (ESI): m/z: 392 [M+]; HRMS
(ESI): m/z: calcd for C24H28N2O3: 392.2100; found: 392.2091 [M+];
HPLC: 86%.
Methyl 5-(2-Methoxyethyl)-4a-methyl-1-oxo-1,2,3,4,4a,5-
hexahydrobenzoACTHNUTRGNENGU[4,5]imidazoACHUTNGTREN[NNGU 1,2-a]pyridine-8-carboxylate (11c)
1H NMR (300 MHz, CDCl3): d=8.36 (d, J=1.5 Hz, 1H), 7.72 (dd, J=
8.1, 1.5 Hz, 1H), 6.42 (d, J=8.1 Hz, 1H), 3.81 (s, 3H), 3.52–3.46 (m, 2H),
3.36–3.31 (m, 3H), 3.33 (s, 3H), 2.62–2.43 (m, 2H), 2.21 (m, 1H), 2.01–
1.78 (m, 3H), 1.36 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=167.1,
166.4, 144.8, 129.8, 128.6, 119.4, 117.2, 104.0, 83.9, 70.6, 58.9, 51.5, 42.8,
32.7, 30.6, 22.0, 16.9 ppm; IR (neat): n˜ =2360, 1702, 1654 cmÀ1; MS (ESI):
m/z: 318 [M+]; HRMS (ESI): m/z: calcd for C17H22N2O4: 318.1580;
found: 318.1579 [M+]; HPLC: 99%.
Methyl 3a-(4-Ethylphenyl)-4-(2-methoxyethyl)-1-oxo-2,3,3a,4-tetrahydro-
1H-benzo[d]pyrroloACHTUNGTRENNUNG[1,2-a]imidazole-7-carboxylate (10i)
1H NMR (300 MHz, CDCl3): d=8.05 (d, J=1.5 Hz, 1H), 7.77 (dd, J=
8.1, 1.5 Hz, 1H), 7.29 (d, J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H), 6.37 (d,
J=8.1 Hz, 1H), 3.85 (s, 3H), 3.48–3.32 (m, 4H), 3.30 (s, 3H), 3.29–3.14
(m, 2H), 2.77–2.51 (m, 4H), 1.19 ppm (t, J=7.5 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=174.5, 166.9, 146.9, 145.4, 135.6, 129.2, 128.5, 128.3
(2C), 125.4 (2C), 119.0, 114.9, 103.8, 91.0, 70.2, 58.8, 51.6, 43.1, 36.4, 33.3,
28.3, 15.3 ppm; IR (neat): n˜ =2360, 1720, 1612 cmÀ1; MS (ESI): m/z: 394
[M+]; HRMS (ESI): m/z: calcd for C23H26N2O4: 394.1893; found:
394.1884 [M+]; HPLC: 93%.
Methyl 4a-Methyl-1-oxo-5-phenethyl-1,2,3,4,4a,5-
hexahydrobenzoACTHNUTRGNENGU[4,5]ImidazoACHUTNGTREN[NNGU 1,2-a]pyridine-8-carboxylate (11d)
1H NMR (300 MHz, CDCl3): d=8.42 (d, J=1.8 Hz, 1H), 7.78 (dd, J=
8.1, 1.8 Hz, 1H), 7.31–7.17 (m, 5H), 6.44 (d, J=8.1 Hz, 1H), 3.83 (s, 3H),
3.45 (m, 1H), 3.30 (m, 1H), 2.95–2.88 (m, 2H), 2.60–2.34 (m, 2H), 1.98–
1.71 (m, 3H), 1.50 (m, 1H), 1.35 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=167.1, 166.4, 144.7, 138.6, 129.9, 128.9 (2C), 128.7, 128.5
(2C), 126.6, 119.4, 117.1, 103.9, 83.9, 51.5, 45.0, 35.1, 32.2, 30.5, 22.0,
16.8 ppm; IR (neat): n˜ =2360, 1706, 1654 cmÀ1; MS (ESI): m/z: 364 [M+];
HRMS (ESI): m/z: calcd for C22H24N2O3: 364.1787; found: 364.1795 [M+
]; HPLC: 94%.
Methyl 3a-(4-Fluorophenyl)-4-isobutyl-1-oxo-2,3,3a,4-tetrahydro-1H-
benzo[d]pyrrolo [1,2-a]imidazole-7-carboxylate (10j)
1H NMR (300 MHz, CDCl3): d=8.05 (d, J=1.5 Hz, 1H), 7.8 (dd, J=8.4,
1.5 Hz, 1H), 7.33 (dd, J=7.8, 0.9 Hz, 2H), 7.04 (t, J=7.8 Hz, 2H), 6.4 (d,
J=8.4 Hz, 1H), 3.84 (s, 3H), 3.14 (m, 1H), 2.85 (dd, J=14.4, 8.4 Hz,
1H), 2.72 (dd, J=14.4, 8.4 Hz, 1H), 2.70–2.53 (m, 3H), 2.93 (m, 1H),
0.92 (d, J=6.8 Hz, 3H), 0.90 ppm (d, J=6.8 Hz, 3H); 13C NMR
(75 MHz, CDCl3): d=173.8, 166.8, 147.7, 133.8, 133.7, 129.3, 128.3, 127.5,
127.3 119.3, 115.9, 115.6, 114.8, 104.5, 90.8, 51.6, 51.5, 36.5, 33.4, 27.8,
20.5, 20.2 ppm; IR (neat): n˜ =2360, 1720, 1612 cmÀ1; MS (ESI): m/z: 382
[M+]; HRMS (ESI): m/z: calcd for C22H23FN2O3: 382.1693; found:
382.1700 [M+]; HPLC: 68%.
Methyl 4a-Methyl-1-oxo-5-(thiophen-2-ylmethyl)-1,2,3,4,4a,5-
hexahydropyridoACTHNUTRGNEUNG[1,2-a]benzimidazole-8-carboxylate (11e)
1H NMR (300 MHz, CDCl3): d=8.41 (d, J=1.5 Hz, 1H), 7.66 (dd, J=
8.4, 1.5 Hz, 1H), 7.21 (d, J=4.8 Hz, 1H), 7.01 (d, J=3.6 Hz, 1H), 6.95
(dd, J=4.8, 3.6 Hz, 1H), 6.36 (d, J=8.4 Hz, 1H), 4.52 (s, 2H), 3.84 (s,
3H), 2.68–2.47 (m, 2H), 2.25–2.18 (m, 2H), 2.12–1.83 (m, 2H), 1.75 ppm
(s, 3H); 13C NMR (75 MHz, CDCl3): d=167.0, 166.4, 144.5, 141.1, 130.2,
128.4, 126.9, 125.1, 124.9, 120.3, 117.3, 105.4, 84.2, 51.6, 42.3, 32.7, 30.6,
21.9, 16.9 ppm; IR (neat): n˜ =2360, 1706, 1656 cmÀ1; MS (ESI): m/z: 356
[M]+; HRMS (ESI): m/z: calcd for C19H20N2O3S: 356.1195; found:
356.1193 [M+1]+; HPLC: 85%.
Methyl 3a-(4-Fluorophenyl)-4-(3-methylbutyl)-1-oxo-2,3,3a,4-tetrahydro-
1H-pyrroloACHTUNGTRENNUNG[1,2-a]benzimidazole-7-carboxylate (10k)
1H NMR (300 MHz, CDCl3): d=8.06 (d, J=1.5 Hz, 1H), 7.79 (dd, J=
8.4, 1.5 Hz, 1H), 7.4 (dd, J=8.6, 1.1 Hz, 2H), 7.04 (t, J=8.6 Hz, 2H),
6.32 (d, 8.4 Hz, 1H), 3.86 (s, 3H), 3.24–3.13 (m, 2H), 3.01 (m, 1H), 2.67–
2.53 (m, 3H), 1.57 (m, 1H), 1.42 (m, 1H), 1.26 (m, 1H), 0.92 (d, J=
6.8 Hz, 3H), 0.90 ppm (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=174.3, 166.9, 164.6, 161.3, 146.6, 134.3, 129.5, 127.3, 127.2, 119.0, 115.9,
115.7, 114.9, 104.0, 90.5, 51.7, 41.5, 36.9, 36.7, 33.3, 26.1, 22.7, 22.4 ppm;
IR (neat): n˜ =2360, 1718, 1610 cmÀ1; MS (ESI): m/z: 396 [M+]; HRMS
(ESI): m/z: calcd for C23H25FN2O3: 396.1849; found: 396.1841 [M+];
HPLC: 85%.
Methyl 5-Butyl-1-oxo-4a-phenyl-1,2,3,4,4a,5-
hexahydrobenzoACTHNUTRGNENGU[4,5]imidazoACHUTNGTREN[NNGU 1,2-a]pyridine-8-carboxylate (11 f)
1H NMR (300 MHz, CDCl3): d=8.3 (d, J=1.5 Hz, 1H), 7.71 (dd, J=8.1,
1.5 Hz, 1H), 7.34–7.26 (m, 5H), 6.22 (d, J=8.1 Hz, 1H), 3.85 (s, 3H),
3.13–2.89 (m, 3H), 2.43 (m, 1H), 2.18–2.05 (m, 2H), 1.88 (m, 1H), 1.64
(m, 1H), 1.42 (m, 1H), 1.29–1.15 (m, 3H), 0.84 ppm (t, J=7.0 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=167.5, 167.2, 143.7, 138.6, 130.9, 129.0
(2C), 128.9, 128.7, 124.9 (2C), 118.6, 115.4, 103.3, 86.5, 51.4, 42.3, 30.8,
30.2, 29.9, 20.2, 14.7, 13.6 ppm; IR (neat): n˜ =2360, 1708, 1664 cmÀ1; MS
(ESI): m/z: 378 [M+]; HRMS (ESI): m/z: calcd for C23H26N2O3:
378.1943; found: 378.1940 [M+]; HPLC: 95%.
Methyl 5-Ethyl-4a-methyl-1-oxo-1,2,3,4,4a,5-
hexahydrobenzoACHTUNGTRENNUNG[4,5]imidazoACHUTNGTREN[NUNG 1,2-a]pyridine-8-carboxylate (11a)
1H NMR (300 MHz, CDCl3): d=8.39 (d, J=1.8 Hz, 1H), 7.76 (dd, J=
8.4, 1.8 Hz, 1H), 6.39 (d, J=8.4 Hz, 1H), 3.86 (s, 3H), 3.32–3.18 (m, 2H),
2.68–2.47 (m, 2H), 2.26 (m, 1H), 2.08–1.81 (m, 3H), 1.40 (s, 3H),
1.26 ppm (t, J=7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=167.3,
166.4, 144.5, 129.9, 128.8, 119.0, 117.2, 103.7, 83.9, 51.6, 37.0, 32.8, 30.6,
22.5, 16.9, 14.5 ppm; IR (neat): n˜ =2362, 1714, 1654 cmÀ1; MS (ESI): m/z:
288 [M+]; HRMS (ESI): m/z: calcd for C16H20N2O3: 288.1474; found:
288.1465 [M+]; HPLC: 94%.
Methyl 5-[2-(1-Cyclohexenyl)ethyl]-1-oxo-4a-phenyl-1,2,3,4,4a,5-
hexahydrobenzoACTHNUTRGNENGU[4,5]imidazoACHUTNGTREN[NNGU 1,2-a]pyridine-8-carboxylate (11g)
1H NMR (300 MHz, CDCl3): d=8.54 (d, J=1.5 Hz, 1H), 7.74 (dd, J=
8.1, 1.5 Hz, 1H), 7.38–7.32 (m, 5H), 6.26 (d, J=8.1 Hz, 1H), 5.34 (s, 1H),
3.86 (s, 3H), 3.20 (m, 1H), 3.10–3.99 (m, 2H), 2.46 (m, 1H), 2.19–2.02
(m, 3H), 1.95–1.86 (m, 5H), 1.69–1.47 ppm (m, 6H); 13C NMR (75 MHz,
CDCl3): d=168.1, 167.7, 143.9, 139.2, 134.9, 131.5, 129.6 (2C), 129.5,
129.4, 125.5 (2C), 124.1, 119.2, 115.9, 103.8, 86.9, 52.0, 42.2, 36.4, 31.3,
2478
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2471 – 2480

Microwave-Assisted Transformation
30.7, 28.9, 25.6, 23.2, 22.6, 15.2 ppm; IR (neat): n˜ =2360, 1708, 1664 cmÀ1
;
Methyl 4-[2-(1-Cyclohexenyl)ethyl]-3a-methyl-1-thioxo-2,3,3a,4-
tetrahydro-1H-benzo[d]pyrrolo[1,2-a]imidazole-7-carboxylate (16)
MS (ESI): m/z: 430 [M+]; HRMS (ESI): m/z: calcd for C27H30N2O3:
430.2256; found: 430.2259 [M+]; HPLC: 85%.
ACHTUNGTRENNUNG
1H NMR (300 MHz, CDCl3): d=8.73 (d, J=1.7 Hz, 1H), 7.87 (dd, J=
8.4, 1.7 Hz, 1H), 6.50 (d, J=8.4 Hz, 1H), 5.48 (s, 1H), 3.84 (s, 3H), 3.41
(m, 1H), 3.26–3.16 (m, 3H), 2.50–2.34 (m, 2H), 2.25 (t, J=7.6 Hz, 2H),
1.99–1.97 (m, 4H), 1.67–1.51 (m, 4H), 1.47 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=196.8, 166.8, 148.7, 134.0, 130.6, 127.5, 123.9, 119.1,
117.2, 105.5, 95.7, 51.8, 47.3, 42.3, 38.0, 36.7, 25.4, 25.1, 22.7, 22.1,
20.3 ppm; IR (neat): n˜ =2360, 1708, 1610 cmÀ1; MS (ESI): m/z: 370 [M+];
HRMS (ESI): m/z: calcd for C21H26N2O2S: 370.1715; found: 370.1711
[M+]; HPLC: 51%.
Methyl 5-Cyclooctyl-1-oxo-4a-phenyl-1,2,3,4,4a,5-hexahydropyridoACTHNUTRGNE[UNG 1,2-
a]benzimidazole-8-carboxylate (11h)
1H NMR (300 MHz, CDCl3): d=8.55 (d, J=1.8 Hz, 1H), 7.67 (dd, J=
8.1, 1.8 Hz, 1H), 7.42–7.34 (m, 5H), 6.29 (d, J=8.1 Hz, 1H), 3.84 (s, 3H),
3.45 (t, J=9.0 Hz, 1H), 3.08 (m, 1H), 2.44 (m, 1H), 2.17–1.98 (m, 2H),
1.95–1.52 (m, 12H), 1.39–1.25 ppm (m, 4H); 13C NMR (75 MHz, CDCl3):
d=167.6, 167.4, 141.3, 139.4, 131.5, 129.1 (3C), 128.4, 125.1 (2C), 117.7,
115.4, 105.0, 86.4, 53.3, 51.5, 33.1, 30.3, 30.7, 30.4, 30.3, 26.7, 26.4, 25.5,
24.8, 14.2 ppm; IR (neat): n˜ =2360, 1706, 1666 cmÀ1; MS (ESI): m/z: 432
[M+]; HRMS (ESI): m/z: calcd for C27H32N2O3: 432.2413; found:
432.2409 [M+]; HPLC: 70%.
Methyl 4a-Methyl-5-(thiophen-2-ylmethyl)-1-thioxo-1,2,3,4,4a,5-
hexahydropyridoACTHNUTRGNEUNG[1,2-a]benzimidazole-8-carboxylate (18)
1H NMR (300 MHz, CDCl3): d=9.69 (d, J=1.5 Hz, 1H), 7.80 (dd, J=
8.4, 1.5 Hz, 1H), 7.03 (d, J=3.9 Hz, 1H), 7.23 (d, J=4.8 Hz, 1H), 6.96
(dd, J=4.8, 3.9 Hz, 1H), 6.46 (d, J=8.4 Hz, 1H), 4.56 (s, 2H), 3.84 (s,
3H), 3.22–3.15 (m, 2H), 2.33 (m, 1H), 2.20 (m, 1H), 1.97–1.79 (m, 2H),
1.46 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=195.5, 166.8, 145.8,
140.6, 131.4, 130.4, 127.0, 125.3, 125.0, 120.4, 119.5, 105.9, 86.9, 51.8, 42.5,
41.8, 32.2, 21.8, 16.6 ppm; IR (neat): n˜ =2360, 1706, 1602 cmÀ1; MS (ESI):
m/z: 372 [M+H]+; HRMS (ESI): m/z: calcd for C19H20N2O2S2: 372.0966;
found: 372.0971 [M+1]+; HPLC: 90%.
Methyl 5-Butyl-4b-methyl-11-oxo-4b,11-dihydro-5H-
benzoACHTUNGTRENNUNG[4,5]imidazoACHTUNGTRENNUNG[2,1-a]isoindole-8-carboxylate (14a)
1H NMR (300 MHz, CDCl3): d=8.06 (d, J=1.5 Hz, 1H), 7.87 (d, J=
7.5 Hz, 1H), 7.78 (dd, J=8.4, 1.5 Hz, 1H), 7.67–7.75 (m, 3H), 6.38 (d, J=
8.4 Hz, 1H), 3.84 (s, 3H), 3.39 (t, J=7.6 Hz, 2H), 1.72 (s, 3H), 1.50
(quint, J=7.5 Hz, 2H), 1.24 (sext, J=7.5 Hz, 2H), 0.87 ppm (t, J=
7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=171.4, 167. 4, 150.1, 147.9,
133.7, 132.9, 130.4, 129.9, 129.6, 125.8, 122.4, 119.7, 118.2, 105.1, 89.4,
52.1, 43.8, 31.1, 23.4, 20.7, 14.2 ppm; IR (neat): n˜ =2360, 1720, 1612 cmÀ1
;
Methyl 2-[3-(4-Fluorophenyl)-3-oxopropyl]-1-isobutyl-1H-benzimidazole-
5-carboxylate (9)
MS (ESI): m/z: 350 [M+]; HRMS (ESI): m/z: calcd for C21H22N2O3:
350.1630; found: 350.1624 [M+]; HPLC: 78%.
1H NMR (300 MHz, CDCl3): d=8.39 (d, J=1.2 Hz, 1H), 8.10–8.05 (m,
2H), 7.96 (dd, J=8.7, 1.2 Hz, 1H), 7.31 (d, J=8.7 Hz, 1H), 7.13 (t, J=
8.5 Hz, 2H), 4.03 (d, J=7.8, 2H), 3.94 (s, 3H), 3.75 (t, J=7.2 Hz, 2H),
3.2 (t, J=7.2 Hz, 2H), 2.3 (septet, J=6.8 Hz, 1H), 0.99 ppm (d, J=
6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3): d=196.9, 167.7, 164.2, 155.9,
141.9, 138.8, 132.9, 130.8, 130.7, 123.9, 123.7, 121.3, 115.9, 115.6, 109.3,
51.9, 51.2, 35.7, 29.3, 21.5, 20.2 ppm (2C); IR (neat): n˜ =2368, 1714,
1679 cmÀ1; MS (ESI): m/z: 382 [M+]; HRMS (ESI): m/z: calcd for
C22H23FN2O3: 382.1693; found: 382.1697 [M+]; HPLC: 92%.
Methyl 4b-Methyl-5-(3-methylbutyl)-11-oxo-4b,11-dihydro-5H-
isoindoloACHTUNGTRENNUNG[2,1-a]benzimidazole-8-carboxylate (14b)
1H NMR (300 MHz, CDCl3): d=8.06 (d, J=1.5 Hz, 1H), 7.88 (d, J=
7.5 Hz, 1H), 7.79 (dd, J=8.4, 1.5 Hz, 1H), 7.77 (d, J=7.5 Hz, 1H), 7.65–
7.60 (m, 2H), 6.36 (d, J=8.4 Hz, 1H), 3.84 (s, 3H), 3.41 (t, J=7.8 Hz,
2H), 1.73 (s, 3H), 1.59–1.24 (m, 3H), 0.9 ppm (d, J=13.8 Hz, 6H);
13C NMR (75 MHz, CDCl3): d=170.9, 166.9, 149.4, 147.4, 133.3, 132.1,
129.9, 129.4, 129.2, 125.4, 121.9, 119.2, 117.7, 104.5, 88.9, 51.6, 41.9, 37.2,
26.1, 23.1, 22.5, 22.4 ppm; IR (neat): n˜ =2360, 1720, 1614 cmÀ1; MS (ESI):
m/z: 364 [M+]; HRMS (ESI): m/z: calcd for C22H24N2O3: 364.1787;
found: 364.1791 [M+]; HPLC: 93%.
Crystallographic Data
CCDC 817573 (10 f) and 817574 (13a) contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
Methyl 5-[2-(Cyclohex-1-en-1-yl)ethyl]-4b-methyl-11-oxo-4b,11-dihydro-
5H-isoindoloACHTUNGTRENNUNG[2,1-a]benzimidazole-8-carboxylate (14c)
1H NMR (300 MHz, CDCl3): d=8.06 (d, J=1.5 Hz, 1H), 7.87 (d, J=
7.5 Hz, 1H), 7.81 (dd, J=8.1, 1.5 Hz, 1H), 7.78 (d, J=7.8 Hz, 1H), 7.59–
7.53 (m, 2H), 6.38 (d, J=8.1 Hz, 1H), 5.48 (s, 1H), 3.89 (s, 3H), 3.48 (t,
J=7.8 Hz, 2H), 2.19–1.9 (m, 2H), 1.89–1.85 (m, 4H), 1.72 (s, 3H), 1.55–
1.37 ppm (m, 4H); 13C NMR (75 MHz, CDCl3): d=170.9, 166.9, 149.2,
147.5, 134.3, 133.3, 132.0, 129.9, 129.4, 129.1, 125.3, 123.7, 121.9, 119.2,
117.7, 104.5, 88.8, 51.6, 42.9, 36.5, 28.7, 25.0, 23.1, 22.6, 21.9 ppm; IR
(neat): n˜ =2358, 1720, 1612 cmÀ1; MS (ESI): m/z: 402 [M+]; HRMS
(ESI): m/z: calcd for C25H26N2O3: 402.1943; found: 402.1953 [M+1]+;
HPLC: 85%.
Acknowledgements
Financial support from the National Science Council (NSC) of Taiwan
and the authorities of the National Chiao Tung University, Taiwan for
providing laboratory facilities are gratefully acknowledged.
[1] a) S. A. Patil, R. Patil, D. D. Miller, Curr. Med. Chem. 2009, 16,
2531–2565; b) P. Gund, E. Maliski, F. Brown, Curr. Opin. Drug
Discov. Devel. 2009, 12, 337–338; c) K. C. Nicolaou, R. Hanko, W.
Hartwig, Handbook of Combinatorial Chemistry, Wiley-VCH, Wein-
heim, 2002.
[2] a) A. Moulin, M. Bibian, A. L. Blayo, S. El Habnouni, J. Martinez,
J. A. Fehrentz, Chem. Rev. 2010, 110, 1809–1827; b) D. E. Bergbreit-
er, J. Tian, C. Hongfa, Chem. Rev. 2009, 109, 530–582; c) V. Polshet-
tiwar, R. S. Varma, Acc. Chem. Res. 2008, 41, 629–639; d) H. M.
Geysen, F. Schoenen, D. Wagner, R. Wagner, Nat. Drug Discov.
2003, 2, 222–230.
Methyl 4b-Methyl-11-oxo-5-phenethyl-4b,11-dihydro-5H-
benzoACHTUNGTRENNUNG[4,5]imidazoACHTUNGTRENNUNG[2,1-a]isoindole-8-carboxylate (14d)
1H NMR (300 MHz, CDCl3): d=8.1 (d, J=1.5 Hz, 1H), 7.87–7.79 (m,
2H), 7.54–7.50 (m, 2H), 7.40 (m, 1H), 7.20–7.10 (m, 3H), 7.06–7.03 (m,
2H), 6.39 (d, J=8.4, 1H), 3.90 (s, 3H), 3.68–3.62 (m, 2H), 2.87–2.70 (m,
2H), 1.71 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=170.9, 166.9,
149.1, 147.3, 138.2, 133.4, 131.8, 129.7, 129.4, 129.3, 128.7 (2C), 128.5
(2C), 126.6, 125.3, 121.7, 119.6, 117.9, 104.6, 88.8, 51.7, 45.6, 34.9,
22.9 ppm; IR (neat): n˜ =2362, 1712, 1619 cmÀ1; MS (ESI): m/z: 398 [M+];
HRMS (ESI): m/z: calcd for C25H22N2O3: 398.1630; found: 398.1629 [M+
]; HPLC: 70%.
[3] a) T. E. Nielsen, M. Meldal, Curr. Opin. Drug Discovery Dev. 2009,
12, 798–810; b) O. J. Plante, E. R. Palmacci, P. H. Seeberger, Science
2001, 291, 1523–1527; c) P. H. Seeberger, S. Danishefsky, Acc.
Chem. Res. 1998, 31, 685–695.
[4] a) C. Crauste, C. Perigaud, S. Peyrottes, J. Org. Chem. 2009, 74,
9165–9172; b) H. Zhi, C. Lue, Q. Zhang, J. Luo, Chem. Commun.
Chem. Asian J. 2011, 6, 2471 – 2480
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2479

C.-M. Sun et al.
FULL PAPERS
2009, 2878–2880; c) C. M. Sun in Combinatorial Chemistry Methods
and Protocols (Ed.: L. Bellavance), The Humana Press Inc., NJ,
2002, p. 345.
[11] a) J. Guillaumel, S. Leonce, A. Pierre, P. Renard, B. Pfeiffer, P. B.
Arimondo, C. Monneret, Eur. J. Med. Chem. 2006, 41, 379–386;
b) K. Dzierzbicka, P. Trzonkowski, P. L. Sewerynek, A. Mysliwski, J.
Med. Chem. 2003, 46, 978–986.
[12] a) A. H. Gouliaev, Binau J. Moster, M. Vedso, A. Senning, Org.
Prep. Proced. Int. 1995, 27, 273–303; b) M. Pinza, C. Farina, A.
Cerri, U. Pfeiffer, M. T. Riccaboni, S. Banfi, R. Biagetti, O. Pozzi,
M. Magnani, L. Dorigotti, J. Med. Chem. 1993, 36, 4214–4220.
[13] a) F. Gualtieri, D. Manetti, M. N. Romanelli, C. Ghelardini, Curr.
Pharm. Des. 2002, 8, 125–138; b) A. Chimirri, A. De Sarro, G. De
Sarro, R. Gitto, M. Zappala, Farmaco 2001, 56, 821–826.
[5] a) B. Wu, D. Hu, Y. Yu, Y. Kuang, X. Zhang, J. Chen, Chem.
Commun. 2010, 46, 7954–7956; b) I. A. Ignatyev, P. G. N. Mertens,
C. Van Doorslaer, K. Binnemans, D. E. de Vos, Green Chem. 2010,
12, 1790–1795; c) M. L. Salum, C. J. Robles, R. Erra-Balsells, Org.
Lett. 2010, 12, 4808–4811; d) R. Cai, Y. Liu, S. Gu, Y. Yan, J. Am.
Chem. Soc. 2010, 132, 12776–12777; e) P. Wasserscheid, T. Welton,
Ionic Liquids in Synthesis, Wiley-VCH, Weinheim, Germany, 2003.
[6] a) B. Ni, A. D. Headley, Chem. Eur. J. 2010, 16, 4426–4436; b) B.
Ni, Q. Zhang, K. Dhungana, A. D. Headley, Org. Lett. 2009, 11,
1037–1040; c) A. Goswami, T. Ito, N. Saino, K. Kase, C. Matsuno, S.
Okamoto, Chem. Commun. 2009, 439–441; d) W. Miao, T. H. Chan,
Acc. Chem. Res. 2006, 39, 897–908.
[14] a) B. E. Maryanoff, W. Ho, D. F. McComsey, A. B. Reitz, P. P. Grous,
S. O. Nortey, R. P. Shank, B. Dubinsky, R. J. Taylor, J. F. Gardocki, J.
Med. Chem. 1995, 38, 16–20; b) A. B. Reitz, S. O. Nortey, P. Sanfi-
lippo, M. K. Scott, US patent 6358946, 2002.
[7] a) C. O. Kappe D. Dallinger, Nat. Rev. Drug Discov. 2006, 5, 51–63;
b) A. De La Hoz, A. Diaz-Ortiz, A. Moreno, Chem. Soc. Rev. 2005,
34, 164–178; c) C. O. Kappe, A. Stadler, Microwaves in Organic
Synthesis, Wiley-VCH, Weinheim, 2005.
[8] a) V. Polshettiwar, R. S. Varma, Pure Appl. Chem. 2008, 80, 777–
790; b) J. Hoffmann, M. Nuchter, B. Ondruschka, P. Wasserscheid,
Green Chem. 2003, 5, 296–299.
[9] a) S. Das, R. Frohlich, A. Pramanik, Org. Lett. 2006, 8, 4263–4266;
b) F. Carlo, G. Stefania, P. Carlo, M. Marisa, G. Carla, US patent
7544705, 2009; c) M. Hayakawa, H. Kaizawar, K. I. Kawaguchi, N.
Ishikawa, T. Koizumi, T. Ohishi, M. Yamano, M. Okada, M. Ohta,
S. I. Tsukamoto, F. Raynaud, M. D. Waterfield, P. Parker, P. Work-
man, Bioorg. Med. Chem. 2007, 15, 403–412.
[15] a) G. S. Yellol, T. W. Chung, C. M. Sun, Chem. Commun. 2010, 46,
9170–9172; b) J. J. Lai, D. B. Salunke, C. M. Sun, Org. Lett. 2010, 12,
2174–2177; c) Y. S. Hsiao, G. S. Yellol, L. H. Chen, C. M. Sun, J.
Comb. Chem. 2010, 12, 723–732; d) K. Chanda, B. Maiti, G. S.
Yellol, M. H. Chien, M. L. Kuo, C. M. Sun, Org. Biomol. Chem.
2011, 9, 1917–1926.
[16] F. Yi, Y. Peng, G. Song, Tetrahedron Lett. 2005, 46, 3931–3933.
[17] a) N. T. Patil, A. K. Mutyala, P. G. V. V. Lakshmi, B. Gajula, B. Srid-
har, G. R. Pottireddygari, T. P. Rao, J. Org. Chem. 2010, 75, 5963–
5975; b) A. Cul, A. Daıch, B. Decroix, G. Sanzb, L. V. Hijfte, Tetra-
hedron 2004, 60, 11029–11039; c) S. Caccamese, G. Principato, Tet-
rahedron: Asymmetry 1996, 7, 2577–2584.
[10] a) L. D. Luca, Curr. Med. Chem. 2006, 13, 1–23; b) M. Boiani, M.
Gonzalez, Mini-Rev. Med. Chem. 2005, 5, 409–424; c) Z. Jin, Nat.
Prod. Rep. 2005, 22, 196–229.
Received: March 17, 2011
Published online: June 30, 2011
2480
www.chemasianj.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 2011, 6, 2471 – 2480