Microwave-assisted linear approach toward highly substituted benzo[d]oxazol-5-yl-1 H-benzo[d]imidazole on ionic liquid support

Article abstract of DOI:10.1021/co200188g

A novel and efficient diversity-oriented synthetic approach was employed to access the benzo[d]oxazol-5-yl-1H-benzo[d]imidazole on ionic liquid support, which helps to absorb microwave irradiation. In this paper, we successfully coupled 4-hydroxy-3-nitrobenzoic acid onto ionic liquid-immobilized o-phenylenediamine, which subsequently underwent an acid mediated, ring closure reaction leading to benzimidazole derivatives. After hydrogenation of the nitro group to an amine, the resulting ionic liquid conjugate was reacted with 1,1-thiocarbonyldiimidazols to yield an ionic liquid tagged-benzoxazol. Final skeletal diversity of the present scaffold was further achieved by S-alkylation with alkyl and aryl bromides. The benzo[d]oxazol-5-yl-1H-benzo[d]imidazole was finally cleaved smoothly from the ionic liquid support with sodium methoxide in methanol under microwave irradiation. This methodology has provided access to a small, diverse library by straightforward and simple operations and could be applied readily in various drug discovery programs.

Full text of DOI:10.1021/co200188g

Research Article
pubs.acs.org/acscombsci
Microwave-Assisted Linear Approach Toward Highly Substituted
Benzo[d]oxazol-5-yl-1H-benzo[d]imidazole on Ionic Liquid Support
Kaushik Chanda, Barnali Maiti, Chih-Chung Tseng, and Chung-Ming Sun*
Laboratory of Combinatorial Drug Design, Department of Applied Chemistry, National Chiao-Tung University, Hsinchu 300-10,
Taiwan
S
* Supporting Information
ABSTRACT: A novel and efficient diversity-oriented synthetic approach was employed to access the benzo[d]oxazol-5-yl-1H-
benzo[d]imidazole on ionic liquid support, which helps to absorb microwave irradiation. In this paper, we successfully coupled 4-
hydroxy-3-nitrobenzoic acid onto ionic liquid-immobilized o-phenylenediamine, which subsequently underwent an acid
mediated, ring closure reaction leading to benzimidazole derivatives. After hydrogenation of the nitro group to an amine, the
resulting ionic liquid conjugate was reacted with 1,1-thiocarbonyldiimidazols to yield an ionic liquid tagged-benzoxazol. Final
skeletal diversity of the present scaffold was further achieved by S-alkylation with alkyl and aryl bromides. The benzo[d]oxazol-5-
yl-1H-benzo[d]imidazole was finally cleaved smoothly from the ionic liquid support with sodium methoxide in methanol under
microwave irradiation. This methodology has provided access to a small, diverse library by straightforward and simple operations
and could be applied readily in various drug discovery programs.
KEYWORDS: microwave-assisted, benzo[d]oxazol-5-yl-1H-benzo[d]imidazole, ionic liquid-immobilized
soluble support for small molecule organic synthesis by
retaining the advantages of product isolation and purification
of solid-phase synthesis along with benefits of traditional
solution phase chemistry.7 The organic substrate can be
anchored on the ionic liquid support initially while carrying
out the planned multistep synthesis without detaching the ionic
liquid for monitoring reaction progress at every stage. Since the
desired synthetic sequence can be carried out in a
homogeneous phase, the excess amounts of reagents and side
products are removed simply by washing with less polar organic
solvents. Once the desired transformations have been
accomplished, the ionic liquid support can be removed to
release the target libraries. Finally, the liberated ionic liquid can
be recycled and resubjected to other ionic liquid organic
synthetic. The importance of the ionic liquid phase organic
synthesis has been effectively utilized for the diversity-oriented
synthesis to synthesize small molecules and peptides.8 To
facilitate the design of novel bioactive compounds, the
combination of different pharmacophores into one framework
can lead to new hybrid molecules with better binding
opportunities inside target active sites. By simply changing
INTRODUCTION
■
With the introduction of chemical genetics, the study of
important biological targets has basically relied on the extensive
use of small molecules.1 The design and proficient assembly of
molecularly diverse heterocyclic libraries are key for medicinal
chemists. The small molecule focused libraries have been used
to investigate particular targets that could perturb the specific
function of the targets in a systematic manner with the
generation of information for further biomedical research.2,3
Because of the increasing demand of novel small molecules for
high-throughput screening, numerous synthetic methodologies
in combinatorial chemistry including solid support and solution
phase strategies have been developed through multidisciplinary
approaches.4 Drawbacks in solid-phase organic synthesis
(SPOS) has encouraged research in ionic liquid phase organic
synthesis.5 It has been increasingly feasible to construct the
complex molecular architectures through multistep synthetic
sequence on the basis of ever expanding range of ionic liquids.
Recently, ionic liquids (ILs) have received considerable
attention as environmentally benign reaction medium for
chemical reactions, including some enzymatic reactions in
organic chemistry.6 The most prominent feature of ionic liquids
is their tunable solubility and phase separation from organic to
aqueous phase depending on the choice of cations and anions.
Because of this property, ionic liquids have emerged as a
Received: November 9, 2011
Revised: January 11, 2012
Published: January 20, 2012
© 2012 American Chemical Society
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the substitution pattern, new scaffolds obtained from the
combinatorial techniques have been able to address the
different targets. In view of our continuous interests on
benzimidazole and benzoxazols moieties, the combination of
two pharmacophore, benzoxazol and benzimidazole moieties
into one molecule may offer interesting biological profiles.9
To demonstrate the diversity-oriented synthesis on an ionic-
liquid support, benzo[d]oxazol-5-yl-1H-benzo[d]imidazoles
were chosen as the target compounds that have very distinct
biological activity as therapeutic agents. Benzimidazoles are an
important class of heterocyclic compound in diverse
therapeutic areas including antiulcer, antihypertensive, antiviral,
anticancer, antifungal, antitubercular, antiallergic, antihista-
minic, antioxidant, and antimicrobial activities.10 Prominently,
the benzoxazol and its thio-analogues are potentilal KDR
inhibitors 1, cyclooxygenase inhibitors 2, selective 5-HT1A
serotonin receptor ligands 3 (Figure 1).11
RESULTS AND DISCUSSIONS
■
Our synthetic strategy to develop the intended molecular
framework of the benzo[d]oxazol-5-yl-1H-benzo[d]imidazole is
depicted in Scheme 1. The planned strategy commenced with
the application of the ionic liquid 1-(2-hydroxyethyl)-3-
methylimidazolium tetrafluoroborate ([hydemim][BF4])
equipped with a hydroxyl group linker as a soluble support.
Accordingly, the ionic liquid-bounded ortho-phenylenediamine
4 was synthesized from 4-fluoro-3-nitrobenzoic acid with built-
in structural diversity (R1) through a three-step protocol.13 We
envisioned to apply amide coupling and subsequent cyclization
at the primary amine functionality on ionic liquid conjugate 4
leading to an aryl imidazole skeleton, which can be further
elaborated on benzoxazol 9 and S-alkylated benzoxazol 10 as
downstream products.
The ionic liquid bound compound 4 was then N-acylated at
the primary amine with 4-hydroxy-3-nitrobenzoic acid 5 as
shown in Scheme 2. Accordingly, the anilide conjugates 6 were
obtained by the condensation of 4-hydroxy-3-nitrobenzoic acid
5 with ionic liquid conjugates 4 via DCC/HOBt activation for
12 h under refluxing N,N′-dimethylformamide (DMF).
However, the use of microwave irradiation at 160 °C
dramatically reduced the reaction time to 10 min.
By taking the advantage of the solubility profile of ionic
liquids, we further purified the reaction mixture by precipitation
with ether. For the construction of benzimidazole ring, anilide
conjugates 6 were subjected to acid-catalyzed cyclization in
presence of 10% trifluoroacetic acid under refluxing CH3CN for
5 h. To facilitate the synthesis of the target compounds, we
applied the microwave irradiation (140 °C) for the same
reaction to complete in 5 min to yield 2-arylbenzimidazole
conjugates 7. Reduction of the nitro group on conjugate 7 was
achieved by palladium on activated charcoal (10%) with
ammonium formate in methanol under microwave heating at
90 °C for 5 min. The formation of the amine conjugates 8
could also be confirmed by color change of the reaction mixture
from yellow to blue along with the change in the chemical shifts
Figure 1. Biologically active benzoxazols derivatives.
The existing synthetic strategies to benzoxazols mainly rely
on solid-phase synthetic approaches.12 In view of the potential
bioactivity of benzoxazol cores and their limited synthetic
scope, we report an application of microwave irradiation for
parallel synthesis of benzo[d]oxazol-5-yl-1H-benzo[d]-
imidazoles using ionic liquid as a phase tag, which is envisaged
to provide a homogeneous media for better reaction kinetics
and enable direct monitoring of reactions not achieved by solid-
phase approaches.
1
of aromatic regions in H NMR spectra of the crude products.
The reaction mixture was precipitated with ether to obtain the
conjugates 8. Our main goal is to construct benzoxazole ring in
conjunction with additional diversity through simple oper-
ations. The elaboration of ionic liquid bound 3-amino-4-
hydroxy benzimidazolyl derivatives 8 to the desired core
structure requires a one carbon synthon. We envisioned
thiocarbonyl diimidazole (TCDI) to be suitable as a one-
Scheme 1. Synthetic Strategy for the Benzo[d]oxazol-5-yl-1H-benzo[d]imidazole 10
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Scheme 2. General Strategy of Microwave-Assisted Synthesis of Benzimidazolyl Benzoxazols on Ionic Liquid Support
carbon electrophile to fulfill our desire for the construction of
benzoxazole ring at this penultimate step. The amine
conjugates 8 were condensed with thiocarbonyl diimidazole
in anhydrous CH3CN under microwave irradiation at 140 °C to
furnish the ionic liquid bound benzoxazole conjugates 10 in 15
min. In comparison, the same transformation required 6 h
under conventional refluxing conditions to reach full
conversion. The S-alkylation of ionic liquid conjugates
benzoxazolin-2-thione 9 is the second access point to extend
the chemical diversity. Literature survey revealed that S-
alkylation of such heterocyclic system can occur under mild
alkaline conditions, which were employed to synthesize a
number of biologically active sulfides.14 In principle, this
alkylation could take place at N- or S-terminus to afford a
mixture of products. To our delight, subjection of benzoxazolin-
2-thione 9 with various alkyl bromides in presence of
diisopropylethylamine at room temperature led to S-alkylated
conjugates 10 in good yields. The bis-heterocyclic molecules
consisting of benzimidazolyl benzoxazole were cleaved off from
ionic liquid support using 0.1 M solution of NaOMe in MeOH
at room temperature for 12 h. The same cleavage exercise was
complete in 10−15 min under microwave conditions. Ionic
liquid support was then removed by filtration after precipitation
with ether and the final compounds were quantified by HPLC
analysis indicating 76−99% crude purity of title compounds.
Purification the resulting crude products by column chroma-
tography afforded the thio analogs of bis-benzimidazolyl
benzoxazole derivatives 11 in good overall yields. By
manipulation of reaction sequence, a variety of 2-sulphanylated
benzo[d]oxazol-5-yl-1H-benzo[d]imidazole 11 were rapidly
obtained (Table 1).
However, to confirm the formation of N-or S-alkylated
product, we cleaved the ionic liquid bound benzimidazole
linked benzoxazolin-2-thione 9{2} using 0.1 M solution of
NaOMe in MeOH under the microwave condition (90 °C) for
10 min to obtain the intermediate A and characterized by the
1
study of H and 13C NMR spectroscopy and LR, HR spectra
(see Supporting Information). Exclusive formation of S-
alkylated product has been concluded by examination of its
13C NMR spectrum revealing the resonance signal at 181.9
ppm representing the CS fragment in benzoxazolin-2-thione
(A) upfield shifted to 168.0 ppm after been alkylated with
cinnamyl bromide (Figure 2).
Unlike solid-support approaches, the main advantage of
using an ionic liquid as support was its direct reaction
monitoring facility by standard analytical techniques, such as
1H, 13C NMR, and mass spectroscopy without cleaving the
ionic liquid tag. Key ionic liquid-tagged intermediates en route
1
toward the final target molecule were examined by H NMR
spectroscopy to demonstrate this advantageous in reaction
monitoring and structural characterization of products (see
Supporting Information).
Unambiguous structural assignment of nonplanar thio
analogue of benzimidazolyl benzoxazol skeleton 11 was
confirmed by signal crystal X-ray diffraction in the case of
compound 11{2,1} (Figure 3).15
The crystal structure reveals the biheterocyclic configured
with nonplanarity in the core skeleton. Moreover, it has been
found that the benzoxazole moiety is located perpendicular to
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reduction and final cyclization reactions with 1,1-thiocarbo-
nyldiimidazole. Final diversification was achieved via S-
alkylation with substituted bromides without cleavage of the
ester bond at the ionic liquid attached site under microwave
harsh conditions. This multistep synthetic strategy allowed us
to obtain IL-attached intermediates with low levels of
impurities by simple precipitation. Furthermore, it should be
noted that the thio analogs of benzo[d]oxazol-5-yl-1H-
benzo[d]imidazole are virtually unprecedented in literature.
Coupled with the use of inexpensive starting materials,
operational simplicity, and short reaction time under micro-
wave irradiation on ionic liquid support makes the method
potentially scaleable and should be applied to prepare a wide
range of analogues.
Table 1. Synthesis of Thio Analogues of Benzimidazolyl
Benzoxazol Derivatives 11 using Microwave Irradiation on
Ionic Liquid Support
EXPERIMENTAL SECTION
■
General Procedure for the Preparation of Ionic Liquid
Bound 3-(4-Hydroxy-3-nitrobenzamido)-4-(substituted
amino) Carboxylates 6. To a solution of N,N′-dicyclohex-
ylcarbodiimide (DCC) (710 mg, 3.45 mmol, 1.4 equiv) in
N,N′-dimethylformamide (DMF) was added 4-hydroxy-3-
nitrobenzoic acid 5 (585 mg, 3.20 mmol, 1.3 equiv) and 1-
hydroxybenzotriazole (HOBt) (432 mg, 3.20 mmol, 3.20
equiv) in a sequential order. The resulting slurry was stirred for
5 min at room temperature, and then ionic liquid (IL)
anchored o-phenylene diammine 4 (1.0 g, 2.46 mmol, 1.0
equiv) in DMF (5 mL) was added. The reaction mixtures were
subsequently heated with stirring in a 10 mL microwave
process vial at 160 °C for 10 min to obtain the ionic liquid
conjugate 6. After completion of the reaction, the suspension
byproducts were filtered through filter paper. The reaction
mixture was precipitated by slow addition of cold ether and
precipitated amide conjugates 6 were filtered through fritted
funnel. The crude product was washed in succession with ether
(100 mL × 3) to remove the undesired impurity and dried for
further steps.
General Procedure for the Preparation of Ionic Liquid
Bound 2-(4-Hydroxy-3-nitrophenyl)-1-alkyl-1H-benzo-
[d]imidazole Carboxylates 7. To a solution of ionic liquid-
bound 3-(4-hydroxy-3-nitrobenzamido)-4-(substituted amino)
carboxylates 6 in acetonitrile, trifluoroacetic acid (0.5 mL) and
MgSO4 (500 mg) were added, and the mixture was
subsequently heated with stirring in a 10 mL microwave
process vial at 140 °C for 5 min. After completion of the
reaction, MgSO4 was removed through Celite. The reaction
mixtures were precipitated by slow addition of excess of cold
ether (100 mL), and filtered through a fritted funnel to obtain
the ionic liquid 2-(4-hydroxy-3-nitrophenyl)-1-alkyl-1H-benzo-
[d]imidazole carboxylates 7 in high purity.
a
Isolated yields determined on weight of purified samples (%).
b
Determined by HPLC analysis (UV detection at 254 nm) of the
c
crude product (%). LRMS were detected with ESI ionization source.
Figure 2. Comparison of 13C NMR chemical shifts between
compounds A and 11{2,1} at the indicated carbon.
General Procedure for the Preparation of Ionic liquid
Polymer Bound 2-(3-Amino-4-hydroxyphenyl)-1-alkyl-
1H-benzo[d]imidazole Carboxylates 8. To a solution of 7
in methanol, Pd on charcoal (1.30 g, 12.65 mmol, 5.0 equiv.)
and ammonium formate (1.12 g, 17.72 mmol, and 7.0 equiv)
were added. The reaction mixture was subsequently heated
with stirring in a 10 mL microwave process vial (90 °C) for 5
min in the appropriate mode of pressure and temperature to
complete reduction of nitro group which was evident from
color change (yellow to greenish blue). After completion, the
reaction mixtures were then subjected to centrifugation for
removal of Pd on charcoal, and the supernatant liquid was
concentrated by rotary evaporation to remove methanol.
Acetonitrile (10 mL) was then added to salt out ammonium
the plane occupied by the benzoimidazole moiety, whereas
cinnamyl ring remains perpendicular to the plane which was
confirmed from its 3D model.
CONCLUSIONS
■
In summary, we have developed an efficient microwave-assisted
synthesis toward a bis-heterocycle library of benzimidazolyl
benzoxazols on ionic liquid support. Using this strategy, we
have synthesized a wide variety of functionalized derivatives
exploiting the readily available primary amine and substituted
bromide. The construction of benzoxazols over benzimidazole
involves the sequential amine-acid coupling, cyclization,
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Figure 3. ORTEP diagram of 1-Butyl-2-(2-(cinnamylthio)benzo[d]oxazol-5-yl)-1-1H-benzo[d]imidazole-5-carboxylic acid methyl ester 11{2,1}
(Table 1, entry 2).
formate. The reaction mixtures were filtered through fritted
funnel to remove ammonium formate to obtain the ionic liquid
bound 2-(3-Amino-4-hydroxyphenyl)-1-alkyl-1H-benzo[d]-
imidazole carboxylates 8.
2-(2-(Cinnamylthio)benzo[d]oxazol-5-yl)-1-(2-cyclohexe-
nylethyl)-1H-benzo[d]imidazole-5-carboxylic Acid Methyl
Ester 11{1,1}: H NMR (300 MHz, CDCl3) δ 8.54 (d, J =
1
1.2 Hz, 1H), 8.07 (dd, J = 8.5, 1.2 Hz, 1H), 7.95 (d, J = 1.4 Hz,
1H), 7.68 (dd, J = 8.4, 1.4 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H),
7.48−7.30 (m, 6H), 6.77 (d, J = 15.6 Hz, 1H), 6.44 (m, 1H),
5.20 (m, 1H), 4.38 (t, J = 7.1 Hz, 2H), 4.20 (d, J = 7.2 Hz, 2H),
3.98 (s, 3H), 2.37 (t, J = 7.1 Hz, 2H), 1.85−1.83 (m, 2H),
1.74−1.70 (m, 4H), 1.48−1.44 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 168.1, 166.6, 155.6, 153.2, 142.9, 142.8, 139.3, 136.5,
135.1, 133.3, 129.1, 128.5, 126.9, 126.8, 126.1, 125.2, 124.9,
124.7, 123.3, 122.7, 119.7, 110.9, 110.4, 52.6, 44.3, 38.2, 35.4,
28.6, 25.5, 22.9, 22.3; MS (ESI) m/z 550 (MH+); HRMS (ESI,
m/z) calcd for C33H32N3O3S: m/z 550.2164; Found 550.2168;
IR (KBr) 2927, 1712, 1612, 1496, 1440, 1296 cm−1.
1-Butyl-2-(2-(cinnamylthio)benzo[d]oxazol-5-yl)-1-1H-
benzo[d]imidazole-5-carboxylic Acid Methyl Ester 11{2,1}:
1H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 1.4 Hz, 1H), 8.07
(dd, J = 8.5, 1.4 Hz, 1H), 7.94 (s, 1H), 7.65 (dd, J = 8.5, 1.5 Hz,
1H), 7.62 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.5 Hz, 1H), 7.41−
7.39 (m, 2H), 7.35−7.30 (m, 3H), 6.77 (d, J = 15.6 Hz, 1H),
6.43 (m, 1H), 4.29 (t, J = 7.2 Hz, 2H), 4.20 (d, J = 7.3 Hz, 2H),
3.96 (s, 3H), 1.80 (quint, J = 7.2 Hz, 2H), 1.33−1.21 (sext, J =
7.2 Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 168.0, 166.6, 155.5, 153.2, 143.1, 142.8, 139.3, 136.6,
135.1, 129.0, 128.5, 127.0, 126.9, 126.2, 125.1, 124.8, 123.3,
122.7, 119.7, 110.8, 110.2, 52.5, 45.2, 35.3, 32.2, 20.3, 13.9; MS
(ESI) m/z 498 (MH+); HRMS (ESI, m/z) calcd for
C29H28N3O3S m/z 498.1851; Found 498.1849; IR (KBr)
2956, 1707, 1606, 1492, 1460, 1300 cm−1.
2-(2-(3,7-Dimethylocta-2,6-dienylthio)benzo[d]oxazol-5-
yl)-1-isobutyl-1H-benzo[d]imidazole-5-carboxylic Acid Meth-
yl Ester 11{3,2}: 1H NMR (300 MHz, CDCl3) δ 8.53 (d, J = 1.3
Hz, 1H), 8.05 (dd, J = 8.6, 1.3 Hz, 1H), 7.88 (s, 1H), 7.62 (dd,
J = 8.3, 1.2 Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.43 (d, J = 8.5
Hz, 1H), 5.46 (t, J = 7.1 Hz, 1H), 5.06 (m, 1H), 4.12 (d, J = 7.5
Hz, 2H), 4.02 (d, J = 7.6 Hz, 2H), 3.96 (s, 3H), 2.13−2.04 (m,
5H), 1.79 (s, 3H), 1.66 (s, 3H), 1.59 (s, 3H), 0.72 (d, J = 6.6
Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 168.0, 167.4, 155.9,
153.1, 143.2, 142.9, 142.8, 139.4, 132.3, 127.2, 126.2, 124.9,
124.7, 123.9, 122.7, 119.6, 117.4, 110.8, 110.7, 52.5, 39.9, 31.0,
29.2, 26.6, 26.1, 20.4, 18.1, 16.8; MS (ESI) m/z 518 (MH+);
HRMS (ESI, m/z) calcd for C30H36N3O3S m/z 518.2477;
Found 518.2474; IR (KBr) 2960, 1714, 1496, 1434, 1288,
1232, 1103 cm−1.
General Procedure for the Preparation of Ionic liquid
Bound 2-(2-Mercaptobenzo[d]oxazol-5-yl)-1-alkyl-1H-
benzo[d]imidazole Carboxylates 9. To a stirred solution
of ionic liquid bound 2-(3-amino-4-hydroxyphenyl)-1-alkyl-1H-
benzo[d]imidazole carboxylates conjugates 8 in CH3CN (5
mL), 1,1-thiocarbonyldiimidazole (663 mg, 3.73 mmol, 1.5
equiv) was added. The reaction mixtures were subsequently
heated with stirring in a 10 mL microwave process vial (140
°C) for 5 min in the appropriate mode of pressure and
temperature for complete cyclization. After completion, the
reaction mixture was precipitated by slow addition of excess of
cold ether (100 mL) and filtered through a fritted funnel to
obtain the ionic liquid 2-(2-mercaptobenzo[d]oxazol-5-yl)-1-
alkyl-1H-benzo[d]imidazole carboxylates 9 in high purity.
General Procedure for the Preparation of Ionic liquid
Bound 2-(2-(alkylthio)benzo[d]oxazol-5-yl)-1-alkyl-1H-
benzo[d]imidazole carboxylates 10. To a stirred solution
of ionic liquid bound 2-(2-(alkylthio)benzo[d]oxazol-5-yl)-1-
alkyl-1H-benzo[d]imidazole carboxylates conjugates 9 in N,N′-
dimethylformamide (5 mL) (DMF), N,N-diisopropylethyl
amine (480 mg, 3.71 mmol, 1.5 equiv) and various alkyl
bromides (3.71 mmol, 1.5 equiv) were added. The reaction
mixtures were subsequently stirred for 12 h under room
temperature for complete alkylation. After completion, the
reaction mixture were precipitated by slow addition of excess of
cold ether (100 mL) and filtered through a fritted funnel to
obtain the ionic liquid 2-(2-(alkylthio)benzo[d]oxazol-5-yl)-1-
alkyl-1H-benzo[d]imidazole carboxylates 10 in high purity.
General Procedure for the Cleavage of Ionic liquid
Bound 2-(2-(Alkylthio)benzo[d]oxazol-5-yl)-1-alkyl-1H-
benzo[d]imidazole Carboxylate 11. To a solution of
conjugates 10 in methanol (20 mL), NaOMe (100 mg) was
added and irradiated under pressured microwave irradiation at
(90 °C) for 12 min. 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 evaporation.
The residue was dried under vacuum, and subjected to crude
HPLC analysis with UV detection at λ = 254 nm (column,
sphereclone 5 μ Si (250 × 4.6 mm); gradient, 35% ethyl acetate
in hexane; flow rate, 1 mL/min.). The purity of crude products
was as indicated in Table 1. The obtained slurry mixtures were
purified by silica gel flash chromatography eluting with a
mixture of ethyl acetate and hexane (1:3) to obtain the pure
compounds 11 in good yields.
1-Isobutyl-2-(2-(3-methylbut-2-enylthio)benzo[d]oxazol-
5-yl)-1H-benzo[d]imidazole-5-carboxylic Acid Methyl Ester
1
11{3,3}: H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 1.2 Hz,
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1H), 8.06 (dd, J = 8.5, 1.2 Hz, 1H), 7.89 (s, 1H), 7.64 (dd, J =
8.5, 1.3 Hz, 1H), 7.59 (d, J = 8.5 Hz, 1H), 7.46 (d, J = 8.5 Hz,
1H), 5.46 (t, J = 7.6 Hz, 1H), 4.14 (d, J = 7.5 Hz, 2H), 4.03 (d,
J = 7.8 Hz, 2H), 3.98 (s, 3H), 2.10 (m, 1H), 1.79 (d, J = 6.0 Hz,
6H), 0.74 (d, J = 6.6 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ
168.1, 167.3, 155.9, 155.1, 142.9, 142.8, 139.7, 139.5, 127.2,
126.2, 124.9, 124. 122.7, 119.7, 117.6, 110.8, 110.6, 52.5, 31.1,
29.2, 26.2, 20.4, 18.4; MS (ESI) m/z 450 (MH+); HRMS (ESI,
m/z) calcd for C25H28N3O3S m/z 450.1851; Found 450.1853;
IR (KBr) 2960, 1706, 1496, 1442, 1295, 1218, 1099 cm−1.
1-Butyl-2-(2-(3,7-dimethylocta-2,6-dienylthio)benzo[d]-
oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic Acid Methyl
2.17−2.05 (m, 4H), 1.77−1.72 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 167.5, 166.1, 155.5, 152.8, 143.1, 142.2, 136.4, 131.8,
126.6, 125.9, 124.4, 123.8, 122.5, 119.6, 119.4, 111.5, 110.4,
57.8, 52.1, 34.9, 30.4, 25.2; MS (ESI) m/z 434 (MH+); HRMS
(ESI, m/z) calcd for C24H24N3O3S m/z 434.1538; Found
434.1535; IR (KBr) 2952, 1714, 1614, 1498, 1436, 1298, 1222
cm−1.
1-Cyclopentyl-2-(2-(3,7-dimethylocta-2,6-dienylthio)-
benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic
Acid Methyl Ester 11{4,2}: 1H NMR (300 MHz, CDCl3) δ 8.53
(d, J = 1.2 Hz, 1H), 7.99 (dd, J = 8.5, 1.2 Hz, 1H), 7.84 (s, 1H),
7.63−7.59 (m, 2H), 7.54 (d, J = 8.6 Hz, 1H), 5.44 (t, J = 7.6
Hz, 1H), 5.05 (m, 1H), 4.91 (q, J = 8.1 Hz, 1H), 4.02 (d, J =
7.5 Hz, 2H), 3.95 (s, 3H), 2.38−2.26 (m, 2H), 2.16−1.93 (m,
10H), 1.78 (s, 3H), 1.76−1.72 (m, 2H), 1.65 (s, 3H), 1.59 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 167.9, 167.3, 156.0, 153.1,
143.6, 143.1, 142.8, 136.8, 132.3, 126.2, 125.5, 124.2, 123.7,
123.9, 122.9, 119.6, 117.4, 111.9, 110.8, 58.2, 52.5, 37.5, 31.0,
30.8, 26.6, 26.0, 25.6, 18.1, 16.7; MS (ESI) m/z 530 (MH+);
HRMS (ESI, m/z) calcd for C31H36N3O3S m/z 530.2477,
Found 530.2480; IR (KBr) 2956, 1714, 1614, 1496, 1441,
1298, 1220 cm−1.
1
Ester 11{2,2}: H NMR (300 MHz, CDCl3) δ 8.55 (d, J = 1.4
Hz, 1H), 8.07 (dd, J = 8.5, 1.4 Hz, 1H), 7.90 (d, J = 1.1 Hz,
1H), 7.66 (dd, J = 8.4, 1.5 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H),
7.46 (d, J = 8.4 Hz, 1H), 5.47 (t, J = 6.9 Hz, 1H), 5.07 (m, 1H),
4.29 (t, J = 7.5 Hz, 2H), 4.04 (d, J = 7.5 Hz, 2H), 3.98 (s, 3H),
2.09−1.98 (m, 4H), 1.80 (s, 3H), 1.74−1.67 (m, 5H), 1.56 (s,
3H), 1.33−1.20 (sext, J = 7.2 Hz, 2H), 0.86 (t, J = 7.2 Hz, 3H);
13C NMR (75 MHz, CDCl3) δ 168.1, 167.3, 155.5, 153.2,
143.2, 143.0, 139.3, 132.3, 126.9, 126.1, 125.0, 124.8, 123.9,
122.7, 119.5, 117.4, 110.8, 110.2, 52.5, 45.2, 39.9, 32.2, 30.1,
26.7, 26.1, 20.3, 18.1, 16.7, 13.9; MS (ESI) m/z 518 (MH+);
HRMS (ESI, m/z) calcd for C30H36N3O3S m/z 518.2477;
Found 518.2480; IR (KBr) 2931, 1716, 1616.
2-(2-(Benzylthio)benzo[d]oxazol-5-yl)-1-(thiophen-2-yl-
methyl)-1H-benzo[d]imidazole-5-carboxylic Acid Methyl
1
Ester 11{5,5}: H NMR (300 MHz, CDCl3) δ 8.57 (d, J =
1.3 Hz, 1H), 8.05 (dd, J = 8.6, 1.3 Hz, 1H), 7.99 (d, J = 1.5 Hz,
1H), 7.68 (dd, J = 8.4, 1.5 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H),
7.50−7.47 (m, 2H), 7.40 (d, J = 5.5 Hz, 2H), 7.37−7.31 (m,
2H), 7.24 (d, J = 5.5 Hz, 1H), 6.95 (dd, J = 5.0, 3.5 Hz, 1H),
6.85 (d, J = 3.5 Hz, 1H), 5.62 (s, 2H), 4.60 (s, 2H), 3.98 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 167.9, 166.8, 155.4, 153.4,
142.9, 142.8, 139.2, 138.6, 135.9, 129.5, 129.2, 128.5, 127.7,
126.4, 126.3, 126.2, 126.1, 125.6, 125.2, 122.7, 119.9, 110.9,
110.6, 52.6, 44.7, 37.1; MS (ESI) m/z 512 (MH+); HRMS
(ESI, m/z) calcd for C28H22N3O3S2 m/z 512.1103, Found
512.1104; IR (KBr) 3052, 1714, 1616, 1495, 1433, 1300, 1216
cm−1.
1-(2-Cyclohexenylethyl)-2-(2-(3,7-dimethylocta-2,6-
dienylthio)benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-
1
carboxylic Acid Methyl Ester 11{1,2}: H NMR (300 MHz,
CDCl3) δ 8.56 (s, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.93 (s, 1H),
7.70 (d, J = 8.4 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.47 (d, J =
8.4 Hz, 1H), 5.46 (t, J = 7.8 Hz, 1H), 5.19 (m, 1H), 5.07 (m,
1H), 4.40 (t, J = 7.3 Hz, 2H), 4.04 (d, J = 7.7 Hz, 2H), 3.98 (s,
3H), 2.37 (t, J = 7.3 Hz, 2H), 2.09−1.96 (m, 4H), 1.83−1.80
(m, 2H), 1.79 (s, 3H), 1.73−1.71 (m, 4H), 1.68 (s, 3H), 1.60
(s, 3H), 1.49−1.44 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
167.9, 167.5, 155.8, 153.3, 143.2, 143.0, 142.9, 138.9, 133.2,
132.4, 126.7, 126.2, 125.3, 125.0, 123.9, 122.3, 119.5, 117.4,
110.9, 110.6, 52.6, 44.4, 39.9, 36.1, 31.2, 28.6, 26.7, 26.1, 25.5,
22.9, 22.3, 18.1, 16.7; MS (ESI) m/z 570 (MH+); HRMS (ESI,
m/z) calcd for C34H40N3O3S m/z 570.2790; Found 570.2793;
IR (KBr) 2970, 1710, 1608, 1502, 1440 cm−1.
1-(2-Cyclohexenylethyl)-2-(2-(3-methylbut-2-enylthio)-
benzo[d]oxazol-5-yl)-1H-benzo[d]imidazole-5-carboxylic
Acid Methyl Ester 11{1,3}: 1H NMR (300 MHz, CDCl3) δ 8.56
(d, J = 1.4 Hz, 1H), 8.08 (dd, J = 8.5, 1.4 Hz, 1H), 7.93 (d, J =
1.5 Hz, 1H), 7.69 (dd, J = 8.4, 1.5 Hz, 1H), 7.61 (d, J = 8.4 Hz,
1H), 7.48 (d, J = 8.5 Hz, 1H), 5.47 (t, J = 7.6 Hz, 1H), 5.19 (m,
1H), 4.39 (t, J = 7.3 Hz, 2H), 4.03 (d, J = 7.8 Hz, 2H), 3.98 (s,
3H), 2.37 (t, J = 7.3 Hz, 2H), 1.83−1.82 (m, 2H), 1.79 (d, J =
6.0 Hz, 6H), 1.73−1.71 (m, 2H), 1.50−1.38 (m, 4H); 13C
NMR (75 MHz, CDCl3) δ 167.5, 166.9, 154.9, 152.9, 142.5,
141.0, 139.2, 138.5, 132.7, 125.8, 125.7, 124.9, 124.5, 121.9,
119.1, 117.2, 110.4, 110.0, 52.1, 43.9, 37.7, 30.7, 28.2, 25.7,
25.0, 22.5, 21.8, 17.9; MS (ESI) m/z: 502 (MH+); HRMS (ESI,
m/z) calcd for C29H32N3O3S: m/z 502.2164; Found 502.2162;
IR (KBr): 2927, 1712, 1602, 1492, 1442, 1303 cm−1.
2-(2-(Allylthio)benzo[d]oxazol-5-yl)-1-(thiophen-2-ylmeth-
yl)-1H-benzo[d]imidazole-5-carboxylic Acid Methyl Ester
1
11{5,4}: H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 1.3 Hz,
1H), 8.05 (dd, J = 8.4, 1.3 Hz, 1H), 7.96 (d, J = 1.5 Hz, 1H),
7.69 (dd, J = 8.4, 1.5 Hz, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.42 (d,
J = 8.5 Hz, 1H), 7.24 (d, J = 5.1 Hz, 1H), 6.95 (dd, J = 5.0, 3.4
Hz, 1H), 6.84 (d, J = 3.4 Hz, 1H), 6.05 (m, 1H), 5.62 (s, 2H),
5.44 (dd, J = 16.9, 1.1 Hz, 1H), 5.25 (dd, J = 10.1, 1.1 Hz, 1H),
4.00 (d, J = 6.5 Hz, 2H), 3.97 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 167.9, 166.6, 155.4, 153.4, 142.9, 142.8, 139.2, 138.6,
132.2, 127.7, 126.3, 126.1, 125.5, 125.1, 124.5, 120.5, 120.4,
120.0, 119.9, 110.9, 110.6, 52.6, 44.7, 35.4; MS (ESI) m/z 462
(MH+); HRMS (ESI, m/z) calcd for C24H20N3O3S2 m/z
462.0946; Found 462.0949; IR (KBr) 2929, 1714, 1614, 1498,
1434, 1296 cm−1.
2-(2-(3,7-Dimethylocta-2,6-dienylthio)benzo[d]oxazol-5-
yl)-1-(thiophen-2-ylmethyl)-1H-benzo[d]imidazole-5-carbox-
ylic Acid Methyl Ester 11{5,2}: 1H NMR (300 MHz, CDCl3) δ
8.57 (d, J = 1.4 Hz, 1H), 8.05 (dd, J = 7.2, 1.4 Hz, 1H), 7.95 (d,
J = 1.5 Hz, 1H), 7.69 (dd, J = 8.4, 1.5 Hz, 1H), 7.58 (d, J = 8.4
Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.24 (d, J = 5.0 Hz, 1H),
6.95 (dd, J = 5.0, 3.4 Hz, 1H), 6.84 (d, J = 3.4 Hz, 1H), 5.62 (s,
2H), 5.40 (d, J = 7.1 Hz, 2H), 5.08 (m, 1H), 4.03 (d, J = 7.6
Hz, 2H), 3.91 (s, 3H), 2.10−2.05 (m, 3H), 1.79 (s, 3H), 1.71
(s, 3H), 1.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 167.8,
167.5, 155.4, 153.5, 143.2, 142.9, 142.0, 139.1, 138.5, 132.3,
2-(2-(Allylthio)benzo[d]oxazol-5-yl)-1-cyclopentyl-1H-
benzo[d]imidazole-5-carboxylic Acid Methyl Ester 11{4,4}:
1H NMR (300 MHz, CDCl3) δ 8.54 (d, J = 1.2 Hz, 1H), 8.01
(dd, J = 8.5, 1.2 Hz, 1H), 7.85 (s, 1H), 7.62 (m, 2H), 7.55 (d, J
= 8.6 Hz, 1H), 6.06 (m, 1H), 5.43 (dd, J = 16.9, 1.2 Hz, 1H),
5.25 (dd, J = 10.0, 1.2 Hz, 1H), 4.94 (quint, J = 8.6 Hz, 1H),
4.00 (d, J = 6.5 Hz, 2H), 3.96 (s, 3H), 2.37−2.30 (m, 2H),
120
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ACS Combinatorial Science
Research Article
127.7, 126.3, 126.2, 126.1, 126.0, 125.9, 123.9, 122.8, 119.7,
117.4, 110.9, 110.6, 52.6, 44.7, 39.9, 31.0, 26.1, 25.9, 18.1, 16.8;
MS (ESI) m/z 558 (MH+); HRMS (ESI, m/z) calcd for
C31H32N3O3S2 m/z 558.1885; Found 558.1887; IR (KBr):
2929, 1710, 1610, 1496, 1439, 1296, 1219 cm−1.
472.1695; Found 472.1696; IR (KBr) 2861, 1710, 1612, 1498,
1442, 1288, 1218 cm−1.
1-Butyl-2-(2-thioxo-2,3-dihydro-1,3-benzoxazol-5-yl)-1H-
1
benzo[d]imidazole-5-carboxylic Acid Methyl Ester (A): H
NMR (600 MHz, CDCl3) δ 8.66 (d, J = 1.5 Hz, 1H), 8.07 (dd,
J = 8.6, 1.5 Hz, 1H), 7.72 (d, J = 1.4 Hz, 1H), 7.46 (d, J = 8.6
Hz, 1H), 7.44 (d, J = 1.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H),
4.30 (t, J = 7.6 Hz, 2H), 3.94 (s, 3H), 1.79 (quint, J = 7.6 Hz,
2-(2-(Allylthio)benzo[d]oxazol-5-yl)-1-(furan-2-ylmethyl)-
1H-benzo[d]imidazole-5-Carboxylic Acid Methyl Ester
1
11{6,4}: H NMR (300 MHz, CDCl3) δ 8.56 (d, J = 1.3 Hz,
2H), 1.26 (sext, J = 7.6 Hz, 3H), 0.87 (t, J = 7.6 Hz, 3H); 13
C
1H), 8.08 (d, J = 1.9 Hz, 1H), 8.06 (dd, J = 8.4, 1.3 Hz, 1H),
7.78 (dd, J = 8.4, 1.7 Hz, 1H), 7.62 (d, J = 8.4 Hz, 1H), 7.52 (d,
J = 8.5 Hz, 1H), 7.42 (dd, J = 2.5, 1.9 Hz, 1H), 6.38 (dd, J =
3.2, 1.9 Hz, 1H), 6.31 (d, J = 3.2 Hz, 1H), 6.09 (m, 1H),
5.44(dd, J = 16.9, 1.1 Hz, 1H), 5.40 (s, 2H), 5.26 (dd, J = 10.1,
1.1 Hz, 1H), 4.00 (d, J = 6.5 Hz, 2H), 3.97 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 167.8, 166.7, 155.5, 153.5, 148.8, 145.5,
145.0, 143.7, 142.8, 139.2, 133.2, 132.2, 126.6, 125.7, 125.4,
122.4, 120.2, 120.0, 111.1, 110.9, 110.8, 52.6, 42.8, 33.6; MS
(ESI) m/z 446 (MH+); HRMS (ESI, m/z) calcd for
C24H20N3O4S m/z 446.1174; Found 446.1175; IR (KBr)
2925, 1710, 1614, 1500, 1452, 1288 cm−1.
2-(2-(3,7-Dimethylocta-2,6-dienylthio)benzo[d]oxazol-5-
yl)-1-(furan-2-ylmethyl)-1H-benzo[d]imidazole-5-carboxylic
Acid Methyl Ester 11{6,2}: 1H NMR (300 MHz, CDCl3) δ 8.57
(s, 1H), 8.06 (t, J = 8.3 Hz, 2H), 7.77 (d, J = 8.5 Hz, 1H), 7.62
(d, J = 8.5 Hz, 1H), 7.52 (d, J = 8.5 Hz, 1H), 7.42 (s, 1H), 6.38
(s, 1H), 6.31 (d, J = 3.1 Hz, 1H), 5.46 (t, J = 7.1 Hz, 1H), 5.39
(s, 2H), 5.07 (m, 1H), 4.06 (d, J = 7.6 Hz, 2H), 3.93 (s, 3H),
2.09−2.06 (m, 4H), 1.80 (s, 3H), 1.66 (s, 3H), 1.61 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 167.8, 167.4, 155.5, 153.5,
148.9, 143.7, 143.2, 142.9, 142.0, 139.2, 132.3, 126.5, 126.3,
123.9, 122.8, 119.7, 117.4, 111.1, 110.9, 110.6, 109.5, 52.6, 42.8,
39.9, 30.1, 26.7, 26.1, 25.9, 18.1, 16.7; MS (ESI) m/z 542
(MH+); HRMS (ESI, m/z) calcd for C31H32N3O4S2 m/z
542.2113; Found 542.2110; IR (KBr) 2925, 1716, 1616, 1448,
1295, 1224 cm−1.
NMR (150 MHz, CDCl3) δ 181.9, 167.4, 154.3, 150.1, 141.6,
138.4, 132.7, 126.5, 125.0, 123.9, 122.1, 111.6, 110.3, 110.2,
52.2, 44.9, 31.8, 19.9, 13.5; MS (EI) m/z 381(M+); HRMS (EI,
m/z) calcd for C20H19N3O3S1 m/z 381.1147; Found 381.1149.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
General experimental procedures and representative H NMR,
13C NMR, crude HPLC, LRMS, HRMS, and FT-IR spectral
data of compounds 11, as well as the intermediates. This
material is available free of charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: cmsun@mail.nctu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
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.
This paper is particularly supported by “Aim for the Top
University Plan” of the National Chiao Tung University and
Ministry of Education, Taiwan, R.O.C.
2-(2-(Allylthio)benzo[d]oxazol-5-yl)-1-butyl-1H-benzo[d]-
1
imidazole-5-carboxylic Acid Methyl Ester 11{2,4}: H NMR
REFERENCES
■
(300 MHz, CDCl3) δ 8.52 (d, J = 1.4 Hz, 1H), 8.04 (dd, J =
8.5, 1.4 Hz, 1H), 7.88 (d, J = 1.5 Hz, 1H), 7.64 (dd, J = 8.3, 1.5
Hz, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.44 (d, J = 8.5 Hz, 1H),
6.04 (m, 1H), 5.42 (dd, J = 16.8, 1.2 Hz, 1H), 5.24 (dd, J =
10.2, 1.2 Hz, 1H), 4.26 (t, J = 7.5 Hz, 2H), 3.98 (d, J = 6.9 Hz,
2H), 3.96 (s, 3H), 1.77 (quint, J = 7.5 Hz, 2H), 1.28−1.20
(sext, J = 7.5 Hz, 2H), 0.83 (t, J = 7.5 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 168.0, 166.6, 155.5, 153.2, 143.0, 142.7, 139.2,
132.2, 126.9, 126.2, 125.0, 124.8, 122.7, 120.0, 119.6, 110.8,
110.3, 52.5, 45.2, 35.4, 32.2, 20.3, 13.9; MS (ESI) m/z 422
(MH+); HRMS (ESI, m/z) calcd for C23H24N3O3S m/z
422.1538; Found 422.1539; IR (KBr) 2960, 2933, 1704, 1680,
1496, 1442, 1278, 1220 cm−1.
2-(2-(Benzylthio)benzo[d]oxazol-5-yl)-1-butyl-1H-benzo-
[d]imidazole-5-carboxylic Acid Methyl Ester 11{2,5}: 1H
NMR (300 MHz, CDCl3) δ 8.55 (d, J = 1.4 Hz, 1H), 8.08
(dd, J = 8.5, 1.4 Hz, 1H), 7.94 (d, J = 1.5 Hz, 1H), 7.66 (dd, J =
8.4, 1.5 Hz, 1H), 7.60 (d, J = 8.4 Hz, 1H), 7.51−7.45 (m, 3H),
7.40−7.32 (m, 3H), 4.65 (s, 2H), 4.29 (t, J = 7.3 Hz, 2H), 3.98
(s, 3H), 1.82 (quint, J = 7.3 Hz, 2H), 1.27 (sext, J = 7.3 Hz,
2H), 0.87 (t, J = 7.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
167.7, 167.0, 154.8, 153.5, 142.8, 138.6, 135.9, 129.6, 129.5,
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110.6, 52.6, 45.4, 37.1, 32.1, 20.3, 13.9; MS (ESI) m/z 472
(MH+); HRMS (ESI, m/z) calcd for C27H26N3O3S m/z
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1229.01(7) Å3, Z = 2, Dcalcd = 1.354 Mg m−3, T = 296(2) K, μ = 1.469
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