Novel approach towards 2-substituted aminobenzimidazoles on imidazolium ion tag under focused microwave irradiation

Article abstract of DOI:10.1016/j.tet.2011.06.068

We have developed an efficient, parallel synthesis of 2-substituted aminobenzimidazoles via intramolecular ring closing reactions of imidazolium ion tag immobilized o-phenylenediamine with various isothiocyanates. The methodology is based on the attachmen

Full text of DOI:10.1016/j.tet.2011.06.068

Tetrahedron 67 (2011) 6214e6220
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Novel approach towards 2-substituted aminobenzimidazoles on imidazolium
ion tag under focused microwave irradiation
*
*
Kaushik Chanda, Barnali Maiti, Wen-Sheng Chung , Chung-Ming Sun
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300, Taiwan, ROC
a r t i c l e i n f o
a b s t r a c t
Article history:
We have developed an efficient, parallel synthesis of 2-substituted aminobenzimidazoles via intra-
molecular ring closing reactions of imidazolium ion tag immobilized o-phenylenediamine with various
isothiocyanates. The methodology is based on the attachment of 4-fluoro-3-nitro benzoic acid into the
imidazolium ion tag, which enables the SNAr reactions with different amines followed by neutral re-
duction to furnish o-phenylenediamines under microwave irradiation. The substituted isothiocyanates
are reacted with o-phenylenediamines to form monothiourea, which is further activated by methyl
iodide to undergo desulfurization in one pot manner. The ionic liquid bound 2-substituted amino-
benzimidazoles were finally cleaved from the support with sodium methoxide to generate target com-
pounds in good yields and high purities with two points of structural diversity. This synthetic protocol
has promising features of extremely short reaction time, operational simplicity, good yields, as well
as widespread applications, leading to a facile and straightforward admittance to structurally diverse
2-substituted aminobenzimidazole analogues with potential bioactivities.
Received 1 February 2011
Received in revised form 9 June 2011
Accepted 21 June 2011
Available online 25 June 2011
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
un-reacted reagents and side products in which IL-bound product
remains insoluble. In recent years microwave irradiation as a non
The interest in the design and the synthesis of novel chemical
entities based on ‘privileged structures’ containing heterocyclic
moieties has grown considerably in recent years.1 The rapid syn-
thesis of bioactive heterocycles is used for lead identification and
optimization in drug discovery since their efficiency serves as both
biomimetics and reactive pharmacophores2 Because of the several
disadvantages, such as slower product conversion rate, heteroge-
neous nature, non linear kinetics associated with the solid sup-
ported synthesis,2e5 chemists have used the ionic liquid phase
organic synthesis as a viable alternative.6 In recent years, ionic
liquids (ILs) have received constant attention as eco-friendly green
reaction media7 as well as catalyst8 in organic synthesis. Due to
their several interesting properties, such as excellent thermal and
chemical stability, zero vapour pressure, non-flammability and ef-
fortless recyclability, ionic liquid serves as an appealing tool for an
organic chemist.9 With the variation of cations and anions, the
solubility of the ionic liquids is adjusted for phase separation from
organic as well as aqueous media, which would make them for
further reuse.10,11 The advantages associated with the ionic-liquid
supported synthesis are that IL-supported products can be purified
by simply washing the product mixture with solvents to remove
conventional energy source has become a unique and invaluable
technique in the rapid synthesis of small molecules. Moreover, it
has been observed that with the use of microwave irradiation,
shorter reaction times, higher yields and enhanced product purities
have been achieved.12 In continuation to our ongoing research
program aimed at the heterocyclic synthesis, we explore the ex-
peditious synthesis of biologically significant compounds through
synergies arised from the combination of MW and ILs.13
Highly substituted benzimidazole and its amino derivatives are
considered as important therapeutic scaffolds, which have long
been known as a promising class of biologically active com-
pounds.14,15 This functionality is commonly contained in meben-
dazole (Fig. 1, A) as
a potent anthelmintic drug. Similarly,
astemizole containing 2-aminobenzimidazole moiety is a second
generation anti-histamine agent with a long duration of action
(Fig. 1, B). Furthermore, the 2-aminobenzimidazole moiety has
been used selectively for inhibition of the NF-kB antigen receptor
pathway (Fig. 1, C).16 More recently, this privileged scaffold is used
as selective Raf-kinase inhibitor (Fig. 1, D).17
Different synthetic protocols are available to synthesize the 2-
aminobenzimidazole ring. This involves the SNAr reaction of
chlorobenzimidazole or methylsulfonyl benzimidazole with an
amine nucleophiles under solvent-less conditions.18 The most
common method for the synthesis of 2-aminobenzimidazole is the
cyclodesulfurization of monothioureas with desulfurizing agents,
* Corresponding authors. E-mail addresses: wschung@nctu.edu.tw (W.-S. Chung),
cmsun@mail.nctu.edu.tw (C.-M. Sun).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.06.068

K. Chanda et al. / Tetrahedron 67 (2011) 6214e6220
6215
O
Cl
CF3
HO
N
O
O
O
O
H
N
N
N
N
NHMe
N
N
OCH3
HN
C6H5
NH
NH
N
NH
N
H
N
O
OH
anticancer agent
anthelmintic drug
A
antihistamine drug
B
anticancer agent
D
C
Fig. 1. Biologically active benzofused N,N heterocycles.
such as carbodiimides, tosylchloride, mercury(II) oxide, mercury(II)
chloride, and EDPBT.19,20 Inspired by the recent development of
ionic liquid as support, we became interested in the development of
a novel and efficient method to construct benzofused N,N hetero-
cycles utilizing the ionic liquid as support and one pot hetero-
cyclisation with isothiocyantes.
completed within 10 h at ambient temperature. The application of
microwave irradiation (100 ꢀC) further reduced the reaction time to
3 min compared to that of refluxing condition (3 h). The reaction
proceeded smoothly with various amines without cleavage of the
ester bond at the ionic liquid attached site even under MW harsh
condition. Subsequently, the resulting mixture was purified again
by precipitation to obtain immobilized conjugates 4. The o-nitro
group in ionic liquid conjugates 4 was reduced with neutral con-
dition, such as Zn/HCOONH4 in methanol under microwave irra-
diation at 60 ꢀC for 5 min. Formation of the amine conjugates 5 was
confirmed by the directly observation of aromatic region change in
the conventional proton NMR. Upon completion of the reaction,
reaction mixture was filtered to remove the zinc dust. The reaction
mixture was evaporated and acetonitrile was added to salt out the
ammonium formate to obtain the compound 5. In an effort to attain
the target molecule, ionic liquid bound o-phenylenediamine 5
underwent key synthetic sequence of the efficient ring closure re-
action. It has been realized that the elaboration of intermediate 5 to
the desired core structure required one carbon electrophile, which
could be attached through reaction with isothiocyantes. In an at-
tempt to understand the scope of the cyclisation reaction, we
reported here the cyclodesulfurization of the resulted monothioura
by the condensation of amine functionality with isothiocyanates
moiety activated by methyl iodine in triethyl amine. This one pot
reaction provides a more practical route to the targeted com-
pounds. The reaction was successfully finished in conventional
refluxing condition for 5 h, whereas the application of microwave
2. Results and discussion
The synthesis of ionic liquid support 1 equipped with hydroxyl
group linker, 1-(2-hydroxyethyl)-3-methylimidazolium tetra-
fluoroborate ([hydemim][BF4]) was prepared in two steps.11e The
ionic liquid 1 was reacted with 4-fluoro-3-nitro benzoic acid 2 in
the presence of catalytic amount of 4-dimethylaminopyridine and
N,N0-dicyclohexylcarbodiimide (DCC) in anhydrous CH3CN at room
temperature for 72 h to attach the carboxylic acid to ionic liquid tag
(Scheme 1). However, this coupling reaction was finished in 12 h
under refluxing conditions. Significantly, upon application of mi-
crowave irradiation in a closed vessel system under pressure
(95 ꢀC) further reduced the reaction time to 10 min. After com-
pletion of the reaction, the suspended dicyclohexyl urea (DCU) was
filtered off and ionic liquid conjugates 3 were precipitated with
ether, which remove the excess un-reacted reagents.
To this end, the ionic liquid bound o-fluoronitrobenzene 3 was
reacted with readily available primary amines as the first building
block via an ipso-fluoro nucleophilic aromatic substitution (SNAr)
reaction to obtain IL-bound o-nitro anilines 4. The reactions were
O
O
-
BF4
NO2
DCC, cat. DMAP
CH3CN, 95 oC, 10 min,
MW.
NO2
F
+
+
OH
HO
+
N
N
N
BF4
N
O
+
-
F
1
2
3
O
O
-
-
BF4
R1-NH2
CH3CN, 100 oC, 3 min,
MW.
BF4
Zn, HCOONH4
CH3OH, 60 oC, 5 min,
NH2
+
N
+
NO2
N
O
N
N
O
R1
R1
N
H
MW.
N
H
5
4
O
O
-
BF4
R2NCS, CH3I, Et3N
CH3CN, 90 oC, 12 min,
MW.
+
R2
R2
NaOMe
CH3OH, 90 oC, 10 min,
N
N
N
N
N
O
O
N
N
N
R1
H
H
MW.
R1
6
7
Scheme 1. General strategy of microwave-assisted synthesis of 2-substituted aminobenzimidazoles on imidazolium ion tag.

6216
K. Chanda et al. / Tetrahedron 67 (2011) 6214e6220
irradiation condition (90 ꢀC) reduced the reaction time to 12 min.
After completion of the reaction, the reaction mixtures were puri-
fied by precipitation with ether to obtain 2-substituted amino-
benzimidazoles on ionic tag 6 in good yields. The proposed
multistep mechanism of the one pot formation of benzimidazole
with methyl iodide is shown in Fig. 2. The initial step of the reaction
involved the nucleophilic attack on isothiocyante moiety by the
primary amine functionality of conjugates 5 followed by the acti-
vation of the C]S bond by methyl iodide to facilitate the formation
of intermediate A. Furthermore, the intermediate A after cyclisation
and electron reorganization by triethyl amine generated the target
compound 6b as shown in Fig. 2.
Fig. 3. The two possible routes for the formation of 2-substituted aminobenzimidazoles
Further insight into the mechanism for the formation of the
intermediate A has been confirmed from the study of the 1H, 13C
NMR, and mass spectrum after cleavage. Here, we have observed
that the starting material 5 upon cleavage from the ionic liquid
support obtained D, which shows a peak at 3.81 and 52.0 ppm
corresponds to the CH group of cyclopentyl moiety in proton and
carbon NMR spectrum, respectively. It is interesting to observe
that after reaction with allyl isothiocyanates and subsequent
cleavage, the chemical shifts of CH proton of cyclopentyl moiety
remain unchanged for intermediate B as shown in Fig. 3. Here if
the secondary amine moiety of ionic liquid conjugates 5 attacked
the C]S moiety of allyl isothiocyanates to generate the in-
termediate C, the chemical shifts CH group of cyclopentyl moiety
are expected more downfield. The observed selectivity may be
because of the presence of ester functionality on the aromatic ring,
which deactivated the secondary amine and facilitated the cou-
pling of isothiocyanate exclusively with primary amine. The for-
mation of intermediates A and B has been confirmed by the
isolation and subsequent cleavage of ionic liquid support (see
Supplementary data).
The 2-substituted aminobenzimidazoles 6 were finally cleaved
from ion support using 0.1 M NaOMe solution in MeOH at room
temperature within 12 h. However, in a bid to shorten the reaction
time, we applied the microwave irradiation in a closed vessel
condition (90 ꢀC), which eventually finished in 12 min as compared
to 3 h in refluxing conditions. Upon completion of the reaction as
judged by TLC, the reaction mixture was concentrated and ionic
liquid support was precipitated by ether, which was removed by
filtration. The filtrates were evaporated and subjected to HPLC
analysis, which indicated the 71e97% crude purity of title com-
pounds. Finally column chromatography purification afforded the
2-substituted aminobenzimidazoles in good overall yields (Table 1).
on ionic liquid support.
By utilizing the desired reaction sequence, we have synthesized
various 2-substituted aminobenzimidazoles derivatives 7 with two
points of structural diversity as shown in Table 1. The data exhibit
that after five-step syntheses sequence 2-substituted amino-
benzimidazoles derivatives were rapidly synthesized on the ionic
liquid support under microwave irradiation in excellent overall
yields and purities.
The main advantage of using the ionic liquid as the support was
its direct monitoring reaction progress by standard analytical
techniques, such as proton and carbon NMR and mass spectros-
copy. Otherwise, ionic liquid bound product must be clipped off,
and purified by column to confirm their structures. Herein, we first
demonstrated the quantitative product conversion by regular
proton NMR and mass spectroscopy in each intermediate step with
an attached IL-tag. It has been found that the three protons Ha, Hb
and Hc of free IL-tag appeared at 8.64, 7.45 and 7.34 ppm, re-
spectively in spectra A (Fig. 4). The chemical shift of these three
protons were shifted to more downfield along with the appearance
of three more peaks at 8.67, 8.57 and 7.65 ppm due to the attach-
ment of 4-fluoro-3-nitro benzoic acid. Formation of o-nitroaniline
conjugates 4 were confirmed from the appearance of NH peak at
8.44 ppm in spectra C, which was further established by upfield
shift of Hf proton. Subsequent reduction of o-nitro anilines 4 to the
o-phenylenediamines 5 was observed by the shifting of Hd protons
to 7.35 ppm from 8.57 ppm. Establishment of benzimidazole ring
was evident from the appearance of Hd, He and Hf protons to the
downfield region due to electron withdrawing nature of benz-
imidazole derivatives.
CH3
S
CH3
S
N
S
C
N
N
O
OCH3
O
IL
H3C
I
NH2
NH
IL
NH
NH
O
NaOMe
O
O
-HI
CH3OH, 10 min
MW (90 oC)
NH
NH
B
A
5
Et3N
O
O
O
H
N
H
N
IL
N
IL
N
N
IL
O
O
O
NH
N
S
CH3
NH
N
6b
Fig. 2. Proposed mechanism for the formation of 2-substituted aminobenzimidazoles 6b on ionic tag.

K. Chanda et al. / Tetrahedron 67 (2011) 6214e6220
6217
Table 1
synthesis of 2-substituted aminobenzimidazole derivatives with
high efficiency, good yields, operational simplicity, as well as
broad scope of substrate tolerance at a considerably reduced time
and cost with microwave-assisted organic reactions on ionic liq-
uid support. This method could be successfully extended to other
heterocyclic compounds. High power microwave irradiation
allowed us to reduce the total reaction time to 40 min compared to
that of several hours under refluxing conditions. The key advan-
tages of ionic liquid support afford product isolation and
byproduct separation easily by ether precipitation with higher
loading capacity than other homogeneous or heterogeneous
supports. The diverse library construction and subsequent results
of biological evaluation of these compounds will be reported in
due course.
Synthesis of 2-substituted aminobenzimidazol derivatives 7aen using microwave
irradiation on ionic liquid tag
Entry
R1NH2
R2NCS
Puritya Yieldb LRMSc
(%)
(%)
7a
92
94
335d
NH2
NCS
7b
7c
97
71
91
84
300
340
NH2
NH2
NCS
O
NCS
NCS
7d
78
88
350d
NH2
4. Experimental section
4.1. General procedure for the synthesis of ionic liquid (IL)
bound 4-fluoro-3-nitro benzoic acid 3
7e
7f
86
75
91
79
316
351
NH2
NH2
NCS
4-Fluoro-3-nitro benzoic acid
2 (0.573 g, 3.14 mmol,
NCS
1.34 equiv), 1-methyl-3-ethyl imidazolium tetrafluoroborate 1
(0.50 g, 2.34 mmol, 1.0 equiv) and N,N0-dimethylamino pyridine
(DMAP) (0.005 g) are placed in a dry, nitrogen-purged 100 mL
round-bottom flask containing dry CH3CN (15 mL). To the mix-
tures was added dropwise N,N0-dicyclohexylcarbodiimide (DCC)
(0.675 g, 3.28 mmol, 1.4 equiv) dissolved in dry CH2Cl2 (5 mL) for
a period of 5 min. The reaction mixtures were stirred for another
15 min at room temperature. Then this O-acylation reaction was
carried out in a tube under microwave radiation to 95 ꢀC for
10 min at 72 W (Biotage initiator, model no: Initiator US, 355286,
10429-22T, using IR sensor as internal probe for the control of
temperature and compressed air system for cooling). After the
completion of the reaction, the insoluble DCU byproduct was
allowed to settle, and the reaction mixtures were filtered and
washed with CH3CN (50 mLꢁ3). The solvent was evaporated, and
the residue was again precipitated with cold ether, which was
filtered through fritted funnel to remove any un-reacted acid and
DCC, finally collected and dried under vacuum as a white solid. 1H
NH2
7g
7h
96
88
89
78
329
381
NCS
NCS
NH2
7i
7j
NH2
NH2
91
93
93
85
319
289
O
NCS
NCS
7k
7l
82
86
91
90
329
301
NH2
NH2
NH2
NH2
NCS
NCS
NMR (300 MHz, acetone-d6)
d
9.16 (s, 1H), 8.64 (dd, J¼7.2, 2.1 Hz,
NCS
1H), 8.49e8.44 (m, 1H), 7.92 (d, J¼1.7 Hz, 1H), 7.74 (d, J¼1.7 Hz,
7m
81
77
87
91
379
343
1H), 7.65 (dd, J¼7.2, 2.1 Hz, 1H), 4.90 (t, J¼5.8 Hz, 2H), 4.84 (t,
J¼5.8 Hz, 2H) 4.06 (s, 3H); 13C NMR (75 MHz, acetone-d6)
d 163.6,
160.1, 156.5, 137.7, 137.5, 127.9, 124.5, 123.5, 119.8, 119.5, 64.5, 48.4,
7n
36.2; MS (ESI) m/z 294 (MꢂBF4ꢂ).
NCS
a
Determined by HPLC analysis (UV detection at 254 nm) of the crude product (%.).
Determined based on the weight of purified samples after performing the col-
4.2. General procedure for the synthesis of ionic liquid (IL)
bound 4-cyclopentylamino-3-nitro benzoic acid 4b
b
umn chromatography (%).
c
LRMS were detected with ESI ionization source.
d
Compounds 7a and 7d were characterized by comparison of 1H and 13C NMR
Cyclopentyl amine (0.535 g, 6.28 mmol, 2.0 equiv) was added to
the ionic liquid bound 4-fluoro-3-nitro benzoic acid 3 (1.20 g,
3.14 mmol, 1.0 equiv) solution in dry CH3CN (10 mL) at room
temperature for 5 min. The reaction mixtures were subsequently
heated with stirring in a 10 mL microwave process vial for 3 min at
73 W in the appropriate mode of pressure and temperature. After
completion of the reaction time, the reaction mixtures were pre-
cipitated with slow addition of cold ether (100 mL), which was
filtered through a fritted funnel to obtain the ionic liquid bound 4-
cyclopentylamino-3-nitro benzoic acid 4b as a yellow solid in high
spectra with literature data.21
Finally, the cleavage of product 7 from ionic liquid support was
confirmed by observing the absence of set of three signals at 9.50,
8.00 and 7.95 ppm due to ionic liquid moiety in spectra F. Moreover,
all the intermediates of IL-supported products could be confirmed
with mass spectra (MS), which has been shown in Table 2.
3. Conclusions
purity. 1H NMR (300 MHz, acetone-d6)
d 9.21 (s, 1H), 8.69 (s, 1H),
8.39 (s, NH), 8.06 (d, J¼8.7 Hz, 1H), 7.96 (s, 1H), 7.74 (s, 1H), 74.18 (d,
J¼8.7 Hz, 1H), 4.86 (t, J¼4.5 Hz, 2H), 4.75 (t, J¼4.5 Hz, 2H), 4.20
(quint, J¼5.9 Hz, 1H), 4.08 (s, 3H), 2.23e2.09 (m, 3H), 1.81e1.61 (m,
In summary, we have accomplished a concise synthesis of
structurally diverse 2-substituted aminobenzimidazole frame-
works through one pot cyclisation reaction of isothiocyanates and
ionic-liquid supported o-phenylenediamine derivatives. The
present synthetic approach is the first of its kind towards the
5H); 13C NMR (75 MHz, acetone-d6)
d 164.6,147.5,137.7,136.4,131.3,
129.3, 124.4, 123.5, 116.2, 115.6, 63.4, 54.6, 49.0, 36.2, 33.4, 24.6; MS
(ESI) m/z 359 (MꢂBF4ꢂ).

6218
K. Chanda et al. / Tetrahedron 67 (2011) 6214e6220
Hb
Hc
A
-
BF4
+
OH
Hd
Ha
HbHc
N
N
Ha
1
9.5
9.0
8.5
8.0
7.5
7.0
6.5
ppm
Hc
Hb
O
NO2
F
Ha
Hb Hc Hf
O
N
N
B
Hd He
He
Ha
Hf
3
9.5
9.0
8.5
8.0
7.5
7.0
6.5
ppm
Hd
Hc
Hb
O
NO2
-
BF4
C
Hd
He Hb Hc
H
O
N
N
Ha
Hf
N
NH
He
Ha
Hf
Hf
4b
9.5
9.0
8.5
8.0
7.5
7.0
6.5
ppm
Hd
Hc
Hb
O
NH2
-
BF4
D
E
F
Hb He
Hc Hd
H
O
N
N
N
NH
Hf
Ha
He
Ha
5b
9.5
9.0
8.5
8.0
7.5
7.0
6.5
ppm
Hd
Hc
Hb
BF4
O
Hb He
Hc Hd
N
-
N
NH
N
N
O
H
Ha
Hf
N
He
6b
Ha
Hf
9.5
9.0
8.5
8.0
7.5
7.0
6.5
ppm
O
Hd
N
N
Hd
O
Hf
N
He
H
He
Hf
7b
9.5
9.0
8.5
8.0
7.5
7.0
6.5
ppm
Fig. 4. Stepwise monitoring of 2-substituted aminobenzimidazol derivatives by 1H NMR spectroscopy.
Table 2
(t, J¼4.5 Hz, 2H), 4.04 (s, 3H), 3.90 (quint, J¼6.0 Hz, 1H), 2.09e2.05
(m, 3H), 1.70e1.60 (m, 5H); 13C NMR (75 MHz, acetone-d6)
166.1,
Mass spectral study of ionic-liquid supported intermediates
d
144.9, 137.7, 136.1, 127.9, 124.3, 123.5, 120.4, 115.9, 109.6, 62.5, 54.5,
Entry
Products
ESI (Mass)
Yields (%)
49.3, 36.2, 33.3, 24.3; MS (ESI) m/z 329 (MꢂBF4ꢂ).
1
2
3
4
3
Mþ¼294
Mþ¼359
Mþ¼329
Mþ¼398
96
93
94
91
4b
5b
6b
4.4. General procedure for the preparation of ionic liquid
bound 2-allylamino-1-Cyclopentyl-1H-benzo[d]imidazole
carboxylates 6b
4.3. General procedure for the preparation of the ionic liquid
(IL) bound 3-amino-4-cyclopentylamino benzoic acid 5b
To a stirred solution of ionic liquid bound 3-amino-4-
cyclopentylamino benzoic acid 5b (1.10 g, 2.63 mmol, 1.0 equiv)
in dry CH3CN (5 mL), allyl isothiocyanate (0.781 g, 7.89 mmol,
3.0 equiv), CH3I (1.11 g, 7.89 mmol, 3.0 equiv) and triethyl amine
(Et3N) (0.80 g, 7.89 mmol, 3.0 equiv) were added in a sequential
order. The reaction mixtures were exposed under pressured mi-
crowave irradiation to (90ꢀ C, 1 bar) for 12 min at 70 W. Upon
cyclisation, the crude product mixtures were purified by pre-
cipitation with cold ether (100 mLꢁ3) and dried to obtain the
conjugate 6b as a pale brownish solid in high purity. 1H NMR
To a solution of 4b (1.28 g, 2.85 mmol, 1.0 equiv) in dry methanol
(10 mL), Zn (1.30 m, 20.0 mmol, 7.0 equiv) and ammonium formate
(2.7 m, 42.8 mmol, 15.0 equiv) were added. The reaction mixtures
were subsequently heated with stirring in a 10 mL microwave
process vial at 60 W for 5 min to complete reduction of nitro group.
After completion, the reaction mixtures were then subjected to
centrifugation to remove Zn and the supernatant liquid was con-
centrated by rotary evaporation to remove methanol. Acetonitrile
(10 mL) was then added to salt out ammonium formate. The re-
action mixtures were filtered through fritted funnel to remove
ammonium formate to obtain the ionic liquid bound 3-amino-4-
cyclopentylamino benzoic acid 5b as a pale brownish solid. 1H
(300 MHz, acetone-d6)
d
9.42 (s, 1H), 8.36 (s, NH), 7.89 (d, J¼1.6 Hz,
1H), 7.83e7.70 (m, 2H), 7.62e7.59 (m, 1H), 6.80 (d, J¼8.5 Hz, 1H),
5.89 (m, 1H), 5.40 (dd, J¼15.1, 1.3 Hz, 1H), 5.25 (dd, J¼10.1, 1.3 Hz,
1H), 4.66 (t, J¼4.4 Hz, 2H), 4.54 (t, J¼4.5 Hz, 2H), 3.89 (s, 3H), 3.17
(m, 1H), 1.98e1.95 (m, 3H), 1.66e1.55 (m, 5H); 13C NMR (75 MHz,
NMR (300 MHz, acetone-d6)
d
9.17 (s, 1H), 8.30 (s, NH), 7.85 (d,
acetone-d6) d 165.4, 152.0, 148.9, 137.3, 135.1, 131.8, 131.6, 124.1,
J¼1.6 Hz, 1H), 7.72 (d, J¼1.6 Hz, 1H), 7.65 (dd, J¼8.5, 1.9 Hz, 1H), 7.12
123.4, 117.6, 117.1, 63.1, 62.8, 50.0, 56.3, 47.4, 47.3, 37.2, 33.4, 33.0,
(d, J¼1.9 Hz, 1H), 6.68 (d, J¼8.5 Hz, 1H), 4.78 (t, J¼4.4 Hz, 2H), 4.64
24.3, 9.0; MS (ESI) m/z 398 (MꢂBF4ꢂ).

K. Chanda et al. / Tetrahedron 67 (2011) 6214e6220
6219
4.5. General procedure for the cleavage of ionic liquid bound
2-allylamino-1-cyclopentyl-1H-benzo[d]imidazole-5-carboxylic
acid derivatives 6b
(d, J¼8.4 Hz, 1H), 4.68 (br s, NH), 4.64 (quint, J¼8.2 Hz, 1H), 3.96 (s,
3H), 3.57 (q, J¼7.5 Hz, 2H), 2.15e2.01 (m, 4H), 2.00 (quint, J¼7.1 Hz,
2H), 1.81 (quint, J¼7.1 Hz, 2H), 1.70 (quint, J¼7.5 Hz, 2H), 1.43 (sext,
J¼7.5 Hz, 2H), 0.94 (t, J¼7.5 Hz, 2H); 13C NMR (300 MHz)
d 168.2,
To a solution of conjugates 6b (0.95 g, 2.67 mmol, 1.0 equiv) in
methanol (20 mL), NaOMe (0.10 g, 1.88 mmol, 0.7 equiv) was
added and irradiated under pressured microwave irradiation at
(90ꢀ C, 4 bar) for 10 min at 75 W. After completion of the reaction,
the crude product was precipitated with excess of cold ether
(100 mL), the ionic liquid was filtered off and subjected to evap-
oration. The residue was dried under vacuum, and subjected to
154.8, 141.1, 136.5, 123.6, 122.3, 117.9, 109.0, 55.6, 52.3, 44.0, 32.2,
29.2, 25.6, 20.5, 14.2; IR (cmꢂ1, KBr): 3322, 1709; MS (ESI) m/z 316
(MHþ); HRMS (ESI, m/z) calcd for C18H26N3O2: m/z 316.2025; found
316.2027.
4.5.6. 1-Isobutyl-2-(phenylethylamino)-1H-benzo[d]imidazole-5-
carboxylic acid methyl ester (7f). Pale yellow solid. 1H NMR
crude HPLC analysis with UV detection at
Sphereclone 5
hexane; flow rate: 1 mL/min). The slurry obtained was loaded on
silica gel column and eluted with a mixture of ethyl acetate and
hexane (2:3) to get the title compounds 7b as a brown solid in
good yields.
l
¼254 nm (column:
(300 MHz)
d
8.18 (d, J¼1.3 Hz, 1H), 7.78 (dd, J¼8.3, 1.3 Hz, 1H),
m
Si (250ꢁ4.6 mm); gradient: 35% ethyl acetate in
7.33e7.31 (m, 2H), 7.25e7.16 (m, 3H), 7.01 (d, J¼8.3 Hz, 1H), 4.35
(t, J¼6.0 Hz, 1H), 3.92 (s, 3H), 3.82 (q, J¼6.6 Hz, 2H), 3.51 (d,
J¼7.5 Hz, 2H), 3.03 (t, J¼6.6 Hz, 2H), 1.95 (sext, J¼6.0 Hz, 1H), 0.85
(d, J¼6.0 Hz, 6H); 13C NMR (300 MHz)
d 168.5, 155.5, 142.4, 139.2,
139.1, 129.3, 129.1, 127.1, 123.5, 122.2, 118.4, 107.4, 52.3, 50.3, 44.5,
35.8, 28.9, 20.5; IR (cmꢂ1, KBr): 3326, 1691; MS (EI) m/z 351 (Mþ);
HRMS (EI, m/z) calcd for C21H25N3O2: m/z 351.1947; found
351.1942.
4.5.1. 1-Cyclopentyl-2-(phenylamino)-1H-benzo[d]imidazole-5-
carboxylic acid methyl ester (7a). Pale yellow solid. 1H NMR
(300 MHz)
d
8.23 (d, J¼1.3 Hz, 1H), 7.87 (dd, J¼8.4, 1.3 Hz, 1H), 7.40
(d, J¼8.0 Hz, 2H), 7.26 (d, J¼8.4 Hz,1H), 7.20 (t, J¼8.0 Hz, 2H), 6.94 (t,
J¼7.4 Hz, 1H), 4.81 (quint, J¼8.7 Hz, 1H), 3.93 (s, 3H), 2.19e2.13 (m,
4H), 2.00 (quint, J¼7.0 Hz, 2H), 1.78 (quint, J¼7.0 Hz, 2H); 13C NMR
4.5.7. 2-(Cyclohexylamino)-1-isobutyl-1H-benzo[d]imidazole-5-
carboxylic acid methyl ester (7g). White solid. 1H NMR (300 MHz,
CDCl3)
d
8.15 (d, J¼1.4 Hz, 1H), 7.77 (dd, J¼8.3, 1.4 Hz, 1H), 7.02
(300 MHz)
d
168.2, 151.6, 141.2, 140.8, 135.9, 129.6, 123.9, 123.2,
(d, J¼8.3 Hz, 1H), 4.08 (d, J¼7.5 Hz, 1H), 3.98 (m, 1H), 3.89 (s,
3H), 3.65 (d, J¼7.4 Hz, 2H), 2.17e2.13 (m, 2H), 1.93 (sext,
J¼6.6 Hz, 1H), 1.77e1.49 (m, 4H), 1.31e1.22 (m, 4H), 0.97 (d,
123.0, 119.4, 119.3, 109.9, 56.3, 52.4, 30.2, 25.7; IR (cmꢂ1, KBr): 3270,
1707; MS (ESI) m/z 336 (MHþ).
J¼6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3)
d 168.5, 154.9, 142.5,
4.5.2. 2-Allylamino-1-cyclopentyl-1H-benzo[d]imidazole-5-
138.9, 123.4, 122.0, 118.2, 107.3, 52.2, 52.2, 50.3, 34.2, 29.1, 26.0,
25.1, 20.7; IR (cmꢂ1, KBr): 3326, 1706; MS (EI) m/z 329 (Mþ);
HRMS (EI, m/z) calcd for C19H27N3O2: m/z 329.2103; found
329.2110.
carboxylic acid methyl ester (7b). Brown solid. 1H NMR (300 MHz)
d
8.17 (d, J¼1.3 Hz, 1H), 7.79 (dd, J¼8.4, 1.3 Hz, 1H), 7.18 (d,
J¼8.4 Hz, 1H), 6.03 (m, 1H), 5.32 (dd, J¼17.1, 1.3 Hz, 1H), 5.21 (dd,
J¼10.3, 1.3 Hz, 1H), 4.78 (br s, NH), 4.60 (quint, J¼8.3 Hz, 1H), 4.21
(d, J¼5.2 Hz, 2H), 3.96 (s, 3H), 2.16e2.11 (m, 4H), 1.98 (quint,
J¼7.0 Hz, 2H), 1.80 (quint, J¼7.0 Hz, 2H); 13C NMR (300 MHz)
4.5.8. 1-(2-Cyclohexenylethyl)-2-cvyclohexylamino-1H-benzo[d]im-
idazole-5-carboxylic acid methyl ester (7h). White solid. 1H NMR
d
168.3, 154.8, 141.8, 136.8, 134.8, 123.6, 122.2, 118.4, 117.3, 109.0,
(300 MHz, CDCl3)
d
8.16 (d, J¼1.4 Hz, 1H), 7.79 (dd, J¼8.3, 1.4 Hz,
55.6, 52.3, 43.4, 29.9, 25.6; IR (cmꢂ1, KBr): 3251, 1712; MS (ESI) m/z
300 (MHþ); HRMS (ESI, m/z) calcd for C17H22N3O2: m/z 300.1712;
found 300.1711.
1H), 7.03 (d, J¼8.3 Hz, 1H), 5.41 (m, 1H), 4.12 (d, J¼7.5 Hz, 1H),
3.94 (t, J¼6.8 Hz, 2H), 3.90 (s, 3H), 3.84 (m, 1H), 2.34 (t,
J¼6.8 Hz, 2H), 2.20e2.17 (m, 2H), 1.93e1.90 (m, 4H), 1.75e1.61
(m, 2H), 1.59e1.46 (m, 8H), 1.28e1.23 (m, 2H); 13C NMR
4.5.3. 1-Cyclopentyl-2-(furan-3-yl-methylamino)-1H-benzo[d]imid-
(75 MHz, CDCl3) d 168.5, 154.6, 142.3, 138.4, 134.2, 125.4, 123.5,
azole-5-carboxylic acid methyl ester (7c). White solid. 1H NMR
122.1, 118.3, 106.9, 52.2, 52.2, 42.2, 37.0, 34.3, 29.2, 26.1, 25.6,
25.3, 23.1, 22.3. IR (cmꢂ1, KBr): 3361, 1708; MS (EI) m/z 381
(Mþ); HRMS (EI, m/z) calcd for C23H31N3O2: m/z 381.2416; found
381.2410.
(300 MHz)
d
8.18 (d, J¼1.2 Hz, 1H), 7.78 (dd, J¼8.3, 1.2 Hz, 1H),
7.37 (d, J¼1.0 Hz, 1H), 7.18 (d, J¼8.3 Hz, 1H), 6.33 (m, 2H), 5.01 (br
s, NH), 4.73 (d, J¼7.1 Hz, 2H), 4.56 (quint, J¼8.2 Hz, 1H), 3.95 (s,
3H), 2.18e2.05 (m, 4H), 1.98 (quint, J¼7.3 Hz, 2H), 1.79 (quint,
J¼7.3 Hz, 2H); 13C NMR (300 MHz)
d
168.4, 154.8, 151.8, 142.7,
4.5.9. 2-(Butylamino)-1-(3-methoxypropyl)-1H-benzo[d]imidazole-
142.3, 136.9, 123.5, 122.2, 118.7, 110.9, 109.1, 108.4, 55.6, 52.3, 41.1,
30.0, 25.5; IR (cmꢂ1, KBr): 3295, 1710; MS (ESI) m/z 340 (MHþ);
HRMS (ESI, m/z) calcd for C19H22N3O2: m/z 340.1661; found
340.1659.
5-carboxylic acid methyl ester (7i). Pale yellow solid. 1H NMR
(300 MHz, CDCl3)
d
8.12 (d, J¼1.4 Hz, 1H), 7.78 (dd, J¼8.3, 1.4 Hz,
1H), 7.02 (d, J¼8.3 Hz, 1H), 5.41 (m, NH), 4.00 (t, J¼6.0 Hz, 2H),
3.89 (s, 3H), 3.54e3.48 (m, 2H), 3.38 (s, 3H), 3.33 (t, J¼6.0 Hz, 2H),
2.01 (t, J¼6.0 Hz, 2H), 1.66 (quint, J¼7.5 Hz, 2H), 1.41 (sext,
J¼7.5 Hz, 2H), 0.94 (t, J¼7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3)
4.5.4. 2-(Benzylamino)-1-cyclopentyl-1H-benzo[d]imidazole-5-
carboxylic acid methyl ester (7d). Pale white solid. 1H NMR
d 168.4, 154.4, 142.2, 138.4, 123.6, 122.3, 117.9, 106.8, 68.0, 58.9,
(300 MHz)
d
8.19 (d, J¼1.3 Hz, 1H), 7.80 (dd, J¼8.4, 1.3 Hz, 1H), 7.44
52.3, 43.6, 38.7, 32.3, 28.7, 20.5, 14.2; IR (cmꢂ1, KBr): 3320, 1708;
MS (EI) m/z 319 (Mþ); HRMS (EI, m/z) calcd for C17H25N3O2: m/z
319.1896; found 319.1890.
(d, J¼7.9 Hz, 2H), 7.39e7.29 (m, 3H), 7.18 (d, J¼8.4 Hz,1H), 4.86 (br s,
NH), 4.75 (s, 2H), 4.54 (quint, J¼8.7 Hz, 1H), 3.93 (s, 3H), 2.19e2.13
(m, 4H), 2.00 (quint, J¼7.8 Hz, 2H), 1.79 (quint, J¼7.8 Hz, 2H); 13C
NMR (300 MHz)
d
168.3, 154.9, 141.9, 138.6, 136.8, 129.2, 128.5,
4.5.10. 1-Butyl-2-isopropylamino-1H-benzo[d]imidazole-5-
128.2, 123.6, 122.3, 118.6, 109.1, 55.7, 52.3, 48.3, 30.0, 25.5; IR (cmꢂ1
,
carboxylic acid methyl ester (7j). White solid. 1H NMR (300 MHz,
KBr): 3249,1714; MS (ESI) m/z 350 (MHþ); HRMS (ESI, m/z) calcd for
C21H24N3O2: m/z 350.1868; found 350.1866.
CDCl3)
d
8.16 (s, 1H), 7.78 (d, J¼8.3 Hz, 1H), 7.04 (d, J¼8.3 Hz, 1H),
4.31 (m, 1H), 4.09 (d, J¼7.2 Hz, 1H), 3.95 (s, 3H), 3.86 (t, J¼7.2 Hz,
2H), 1.72 (quint, J¼7.2 Hz, 2H), 1.41e1.36 (m, 2H), 1.33 (d, J¼6.5 Hz,
4.5.5. 2-(Butylamino)-1-cyclopentyl-1H-benzo[d]imidazole-5-
6H), 0.94 (t, J¼7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 168.5,
carboxylic acid methyl ester (7e). Pale white solid. 1H NMR
154.7, 142.6, 138.5, 123.5, 122.1, 118.4, 106.9, 52.2, 45.6, 42.5, 31.4,
(300 MHz)
d
8.17 (d, J¼1.4 Hz, 1H), 7.77 (dd, J¼8.4, 1.4 Hz, 1H), 7.17
23.9, 20.6, 14.1; IR (cmꢂ1, KBr): 3241, 1714; MS (EI) m/z 289 (Mþ);

6220
K. Chanda et al. / Tetrahedron 67 (2011) 6214e6220
HRMS (EI, m/z) calcd for C16H23N3O2: m/z 289.1790; found
References and notes
289.1783.
1. (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893e930; (b)
Patil, N. T.; Yamamoto, Y. Chem. Rev. 2008, 108, 3395e3442; (c) Evano, G.;
Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054e3131.
4.5.11. 1-Butyl-2-cyclohexylamino-1H-benzo[d]imidazole-5-
carboxylic acid methyl ester (7k). White solid. 1H NMR (300 MHz,
2. Koppitz, M.; Eis, K. Drug Discovery Today 2006, 11, 561e568.
3. (a) Merrifield, R. B. Science 1986, 232, 341e347; (b) Nefzi, A.; Ostresh, J. M.;
CDCl3)
d
8.16 (d, J¼1.4 Hz, 1H), 7.77 (dd, J¼8.3, 1.4 Hz, 1H), 7.01 (d,
ꢀꢁ
Houghten, R. A. Chem. Rev. 1997, 97, 449e472; (c) Krachnak, V.; Holladay, M. W.
J¼8.3 Hz, 1H), 4.21 (d, J¼7.5 Hz, 1H), 3.98 (m, 1H), 3.88 (s, 3H), 3.83
(t, J¼7.1 Hz, 2H), 2.15e2.13 (m, 2H), 1.77e1.61 (m, 5H), 1.52e1.21 (m,
Chem. Rev. 2002, 102, 61e91; (d) Lu, J.; Toy, P. H. Chem. Rev. 2009, 109, 815e838.
4. (a) Cheng, S.; Comer, D. D.; Williams, J. P.; Myers, P. L.; Boger, D. L. J. Am. Chem.
Soc. 1996, 118, 2567e2573; (b) Liu, J. F.; Kaselji, M.; Isome, Y.; Ye, P.; Sargent, K.;
Sprague, K.; Cherrak, D.; Wilson, C. J.; Si, Y.; Yohannes, D.; Ng, S. C. J. Comb.
Chem. 2006, 8, 7e10; (c) Waldo, J. P.; Mehta, S.; Neuenswander, B.; Lushington,
G. H.; Larock, R. C. J. Comb. Chem. 2008, 10, 658e663.
7H), 0.92 (t, J¼7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3)
d 168.5, 154.8,
142.6, 138.6, 123.3, 121.9, 118.2, 106.9, 52.2, 52.2, 42.5, 34.2, 31.3,
26.0, 25.3, 20.6, 14.1; IR (cmꢂ1, KBr): 3215, 1708; MS (EI) m/z 329
(Mþ); HRMS (EI, m/z) calcd for C19H27N3O2: m/z 329.2103; found
329.2113.
5. Powers, D. G.; Casebier, D. S.; Fokas, D.; Ryan, W.; Troth, J. R.; Coffen, D. L.
Tetrahedron 1998, 54, 4085e4096.
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2006, 1645e1651; (d) Donga, R. A.; Khaliq-Uz-Zaman, S. M.; Chan, T. H.; Damha,
M. J. J. Org. Chem. 2006, 71, 7907e7910; (e) Legeay, J. C.; Eynde, J. J. V.; Bazureau,
J. P. Tetrahedron Lett. 2007, 48, 1063e1068.
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Dzyuba, S. V.; Bartsch, R. A. Angew. Chem., Int. Ed. 2003, 42, 148e150; (c) Song,
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B.; Allan, D.; Headley, A. D. Chem.dEur. J. 2010, 16, 4426e4436.
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124, 14247e14254; (b) Wilkes, J. S. J. Mol. Catal. A: Chem. 2004, 214, 11e17.
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Am. Chem. Soc. 2001, 123, 218e222; (b) Wang, G.; Yu, N.; Peng, L.; Tan, R.; Zhao,
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4.5.12. 2-Allylamino-1-1sopentyl-1H-benzo[d]imidazole-5-
carboxylic acid methyl ester (7l). Pale brownish solid. 1H NMR
(300 MHz, CDCl3)
d
8.14 (d, J¼1.5 Hz,1H), 7.77 (dd, J¼8.3,1.5 Hz,1H),
7.04 (d, J¼8.3 Hz, 1H), 6.04 (m, 1H), 5.28 (dd, J¼17.1, 1.4 Hz, 1H), 5.17
(dd, J¼10.2, 1.4 Hz, 1H), 4.63 (m, NH), 4.19 (d, J¼6.7 Hz, 2H),
3.93e3.87 (m, 5H), 1.62e1.60 (m, 3H), 0.96 (d, J¼6.0 Hz, 6H); 13C
NMR (75 MHz, CDCl3)
d
168.4, 155.1, 142.3, 138.5, 135.0, 123.5, 122.3,
118.5, 116.9, 107.0, 52.3, 46.2, 41.2, 37.9, 26.3, 22.8; IR (cmꢂ1, KBr):
3220, 1714; MS (EI) m/z 301 (Mþ); HRMS (EI, m/z) calcd for
C17H23N3O2: m/z 301.1790; found 301.1788.
4.5.13. 1-Isopentyl-2-phenylpropylamino-1H-benzo[d]imidazole-5-
carboxylic acid methyl ester (7m). Pale white solid. 1H NMR
11. (a) Miao, W.; Chan, T. H. J. Org. Chem. 2005, 70, 3251e3255; (b) Cai, Y.; Zhang, Y.;
Peng, Y.; Lu, F.; Huang, X.; Song, G. J. Comb. Chem. 2006, 8, 636e638; (c) Miao,
W.; Chan, T. H. Acc. Chem. Res. 2006, 39, 897e908; (d) He, X.; Chan, T. H. Org.
Lett. 2007, 9, 2681e2684; (e) Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.;
Zanatta, N.; Bonacorso, H. G. Chem. Rev. 2008, 108, 2015e2050.
12. (a) Dallinger, D.; Kappe, C. O. Chem. Rev. 2007, 107, 2563e2591; (b) Polshettiwar,
V.; Varma, R. S. Acc. Chem. Res. 2008, 41, 629e639; (c) Dallinger, D.; Irfan, M.;
Suljanovic, A.; Kappe, C. O. J. Org. Chem. 2010, 75, 5278e5288.
(300 MHz, CDCl3)
d
8.17 (d, J¼1.4 Hz,1H), 7.81 (dd, J¼8.3, 1.4 Hz,1H),
7.33e7.19 (m, 5H), 7.02 (d, J¼8.3 Hz, 1H), 4.15 (m, 1H), 3.91 (s, 3H),
3.74 (t, J¼7.5 Hz, 2H), 3.67e3.66 (dt, J¼5.8, 6.7 Hz, 2H), 2.78 (t,
J¼7.5 Hz, 2H), 2.11 (q, J¼7.5 Hz, 2H), 1.63 (sext, J¼6.7 Hz, 1H), 1.56
(quint, J¼7.5 Hz, 2H), 0.97 (d, J¼6.7 Hz, 6H); 13C NMR (75 MHz,
CDCl3)
d 168.5, 155.2, 142.3, 141.9, 138.4, 128.9, 128.9, 126.5, 123.6,
13. (a) Maiti, B.; Chanda, K.; Sun, C. M. Org. Lett. 2009, 11, 4826e4829; (b) Lai, J. J.;
Salunke, D. B.; Sun, C. M. Org. Lett. 2010, 12, 2174e2177; (c) Yellol, G. S.; Tsai, W.
C.; Sun, C. M. Chem. Commun. 2010, 9170e9172.
122.3, 118.4, 106.9, 52.3, 43.7, 41.1, 38.9, 33.9, 31.6, 26.2, 22.8; IR
(cmꢂ1, KBr): 3221, 1711; MS (EI) m/z 379 (Mþ); HRMS (EI, m/z) calcd
for C23H29N3O2: m/z 379.2260; found 379.2264.
ꢁ
ꢁ
ꢁ
14. Valdez, J.; Cedillo, R.; A. Hernandez-Campos, A.; Yepez, L.; Hernandez-Luis, F.;
ꢁ
ꢁ
ꢁ
Navarrete-Vazquez, G.; Tapia, A.; Cortes, R.; Hernandezc, M.; Castilloa, R. Bioorg.
Med. Chem. Lett. 2002, 12, 2221e2224.
4.5.14. 2-Cyclohexylamino-1-1sopentyl-1H-benzo[d]imidazole-5-
15. (a) Mukhopadhyay, T.; Sasaki, J.; Ramesh, R.; Roth, J. A. Clin. Cancer Res. 2002, 8,
2963e2969; (b) Bonfanti, J.-F.; Doublet, F.; Fortin, J.; Lacrampe, J.; Guillemont, J.;
Muller, P.; Queguiner, L.; Arnoult, E.; Gevers, T.; Janssens, P.; Szel, H.; Willebrords,
R.; Timmerman, P.; Wuyts, K.; Janssens, F.; Sommen, C.; Wigerinck, P.; Andries, K.
J. Med. Chem. 2007, 50, 4572e4584; (c) Morningstar, M. L.; Roth, T.; Farnsworth,
D. W.; Kroeger-Smith, M.; Watson, K.; Buckheit, R. W.; Das, K.; Zhang, W.; Arnold,
E.; Julias, J. G.; Hughes, S. H.; Michejda, C. J. J. Med. Chem. 2007, 50, 4003e4015; (d)
Hasegawa, M.; Nishigaki, N.; Washio, Y.; Kano, K.; Harris, P. A.; Sato, H.; Mori, I.;
West, R. I.; Shibahara, M.; Toyoda, H.; Wang, L.; Nolte, R. T.; Veal, J. M.; Cheung, M.
J. Med. Chem. 2007, 50, 4453e4470; (e) Sørensen, U. S.; Trøbæk, D.; Christo-
phersen, P.; Hougaard, C.; Jensen, M. L.; Nielsen, E.; Peters, D.; Teuber, L. J. Med.
Chem. 2008, 51, 7625e7634.
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17. Ramurthy, S.; Subramanian, S.; Aikawa, M.; Amiri, P.; Costales, A.; Dove, J.; Fong,
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carboxylic acid methyl ester (7n). White solid. 1H NMR (300 MHz,
CDCl3)
d
8.16 (d, J¼1.3 Hz, 1H), 7.80 (dd, J¼8.2, 1.3 Hz, 1H), 7.03 (d,
J¼8.2 Hz, 1H), 4.06 (d, J¼7.5 Hz, 1H), 3.91 (m, 1H), 3.89 (s, 3H), 3.85
(t, J¼7.5 Hz, 2H), 2.18e2.15 (m, 2H), 1.79e1.59 (m, 6H), 1.58e1.48
(m, 2H), 1.28e1.25 (m, 3H), 1.00 (d, J¼6.4 Hz, 6H); 13C NMR
(75 MHz, CDCl3) d 168.5,154.7,142.6, 138.5, 123.5, 122.1,118.4,106.9,
52.3, 52.1, 41.0, 37.9, 34.3, 26.1, 26.0, 25.2, 22.9; IR (cmꢂ1, KBr): 3324,
1714; MS (EI) m/z 343 (Mþ); HRMS (EI, m/z) calcd for C20H29N3O2:
m/z 343.2260; found 343.2262.
Acknowledgements
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.
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Supplementary data
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