Multistep divergent synthesis of benzimidazole linked benzoxazole/ benzothiazole via copper catalyzed domino annulation

Article abstract of DOI:10.1039/c3ob27177c

An efficient, facile synthesis of structurally diverse benzimidazole integrated benzoxazole and benzothiazoles has been developed. In a multi-step synthetic sequence, 4-fluoro-3-nitrobenzoic acid was converted into benzimidazole bis-heterocycles, via the intermediacy of benzimidazole linked ortho-chloro amines. The amphiphilic reactivity of this intermediate was designed to achieve the title compounds by the reaction of various acid chlorides and isothiocyanates in a single step through the in situ formation of ortho-chloro anilides and thioureas under microwave irradiation. A versatile one pot domino annulation reaction was developed to involve the reaction of benzimidazole linked ortho-chloro amines with acid chlorides and isothiocyanates. The initial acylation and urea formation followed by copper catalyzed intramolecular C-O and C-S cross coupling reactions furnished the angularly oriented bis-heterocycles which bear a close resemblance to the streptomyces antibiotic UK-1. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3ob27177c

Organic &
Biomolecular Chemistry
View Article Online
View Journal
PAPER
Multistep divergent synthesis of benzimidazole linked
benzoxazole/benzothiazole via copper catalyzed
domino annulation†
Cite this: DOI: 10.1039/c3ob27177c
Jen-Yu Liao, Manikandan Selvaraju, Chih-Hau Chen and Chung-Ming Sun*
An efficient, facile synthesis of structurally diverse benzimidazole integrated benzoxazole and benzothi-
azoles has been developed. In a multi-step synthetic sequence, 4-fluoro-3-nitrobenzoic acid was con-
verted into benzimidazole bis-heterocycles, via the intermediacy of benzimidazole linked ortho-chloro
amines. The amphiphilic reactivity of this intermediate was designed to achieve the title compounds by
the reaction of various acid chlorides and isothiocyanates in a single step through the in situ formation
of ortho-chloro anilides and thioureas under microwave irradiation. A versatile one pot domino annula-
tion reaction was developed to involve the reaction of benzimidazole linked ortho-chloro amines with
acid chlorides and isothiocyanates. The initial acylation and urea formation followed by copper catalyzed
intramolecular C–O and C–S cross coupling reactions furnished the angularly oriented bis-heterocycles
which bear a close resemblance to the streptomyces antibiotic UK-1.
Received 8th November 2012,
Accepted 24th January 2013
DOI: 10.1039/c3ob27177c
www.rsc.org/obc
Bis-benzoxazole isolated from streptomyces sp. is shown to
interact with human topoisomerase II with antitumor activity
Introduction
Heterocyclic compounds have attracted substantial attention against various human cell lines.9,10 Introduction of a pipera-
due to their broad biological and therapeutic applications.1 In zine moiety at the C-5 position of the bis-heterocyclic ring
particular, privileged heterocycles with two or more hetero- revealed its potential role as topoisomerase inhibitor 1.11 Car-
atom containing rings have been intensively studied because bomethoxylated benzimidazoles 2 as analogues of UK-1 were
of their ability to bind to multiple receptors and because they patented for their selective cytotoxicity against cancer cell
represent the most important class of key structural units in a lines.12 Proline bis-amide substituted by benzothiazole 3
large number of bioactive molecules.2 Among these, benzimid- serves as an antagonist targeted to orexin receptors and ben-
azole, benzoxazole and benzothiazole moieties are frequently zothiazole based pyrimidine derivatives 4 are employed as
encountered in many therapeutic agents.3–5 Construction of gram positive selective antibacterial agents (Fig. 1).13,14
these privileged structures in a single molecule leads to the
Our primary interest is to focus on the construction of
formation of a novel bis-heterocyclic system which is likely to direct-linked bis-heterocyclic derivatives in which benzimid-
display unique biological properties by a synergistic effect. Syn- azole is accompanied by another heterocycle in an angular
thetic analogues possessing these core structures with direct
linkage have considerable medicinal interest and are fre-
quently identified as the most potent heterocyclic motifs for
the development of novel therapeutics.6 The linking of two
benzimidazoles at different positions has been employed as a
strategy to control the distance between the two azomethine
ring nitrogens leading to the synthesis of bis-benzimidazoles
for DNA minor groove binding.7 Benzimidazoles linked with
benzoxazoles and benzothiazoles were identified to show
significant binding affinity with protein pyruvate kinase.8
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 300-10,
Taiwan. E-mail: cmsun@mail.nctu.edu.tw
†Electronic supplementary information (ESI)
available. See DOI:
10.1039/c3ob27177c
Fig. 1 Structurally related biologically active compounds.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
fashion. Even though considerable efforts have been made to heterocycle would be carried out. The regioselective conden-
obtain derived heterocyclic compounds, there has not been a sation of primary amino functionality of the key intermediate
dedicated effort to explore structurally and functionally modi- 5 with 2-chloro-3-nitro benzoic acid leads to the aryl amides 7.
fied bis-heterocyclic compounds which linked together directly The selectivity was achieved due to the presence of the deacti-
rather than through a spacer or linker.15 The conventional vating carbonyl ester group at the para position to the second-
method for the formation of benzoxazoles involves the treat- ary amine which results in the decreasing of the
ment of 2-aminophenol with carboxylic acid derivatives or nucleophilicity and facilitates the exclusive and selective N-acy-
aldehydes under either strong acid or high temperature con- lation with the primary amine. The selectivity was inferred
ditions.16 Similarly 2-aminated benzothiazoles are derived from the 1H NMR spectra which showed an unchanged chemi-
from the substitution reaction of 2-halobenzothiazoles or cal shift of the methylene group of R1 (R1-pentyl). Transform-
2-thiobenzothiazoles with nitrogen nucleophiles.17 These ation of the aryl amides 7 into benzimidazoles 8 is conceived
methods require several reaction steps, harsh reaction con- to build up five membered rings which require an acid cata-
ditions and it is hard to prepare suitable starting materials. lyzed intramolecular nucleophilic attack to eliminate water.
Prompted by the importance of these advantageous structures, The formation of benzimidazole linked nitrochlorobenzene
it is meritorious to develop a straightforward, atom economical was confirmed by the downfield shift of the methylene group
route for the construction of these privileged structures and (R1-pentyl) in proton NMR which resulted due to the deshield-
we have successfully developed synthetic methods for bis- ing effect of the newly formed imidazole ring system. The next
benzimidazoles and benzimidazolyl benzoxazoles on polymer step in the construction of a second azole ring was the
and ionic liquid supports.18,19 As part of our ongoing efforts reduction of the nitro group into amine. Compound 9 was
devoted to the synthesis of chimeric bis-heterocycles, the treated as a common building block for the synthesis of benz-
present article describes a linear multistep synthetic route imidazole linked benzoxazoles as well as benzothiazoles and
which involves copper-catalyzed intramolecular C–O and C–S further steps were focused on exploring the amphiphilic
bond formation by the domino one pot reaction as the key 2-chloroaniline part of the arylated benzimidazoles to obtain
approach for the construction of angularly oriented benzox- the target molecules (Scheme 1). The final endeavor to the
azolyl and benzothiazolyl benzimidazoles.
present challenging task was the functionalization of the
amino group with various isothiocyanates and acid chlorides
followed by intramolecular cross coupling in a domino one pot
manner (Scheme 2).
Our attempt was initiated by the reaction of intermediate 9
with furan-2-carbonyl chloride in the presence of CuI (5 mol%),
1,10-phenanthroline (10 mol%) and Cs2CO3 (2 eq.) in toluene.
After 24 h of reflux at 110 °C, a trace level of the benzoxazole
product with the anilide intermediate 10 (24%) was formed.
However, a great amount of starting material 9 (70%) still
remained unreacted (Tables 1 and 2).20
Poor conversion of the cross coupling reaction served as a
starting point for an optimization study. A survey of various
solvents such as xylene, toluene, DMF, THF and DMSO for the
same reaction led to the same results with very little conver-
sion to the desired product and left behind the in situ gener-
ated intermediate 10. These effects prompted us to conduct
Results and discussion
The synthetic sequence commenced with the preparation of
the key building block 5 from 4-fluoro-3-nitro benzoic acid
which underwent three reaction steps such as esterification,
nucleophilic substitution and nitro reduction to furnish the
intermediate 5.19 The mono-substituted ortho-phenylenedi-
amines 5 served as key intermediates in the synthesis and also
acted as the first point of structural diversity of various alkyl
groups. For the construction of the benzimidazole linked benz-
oxazoles and benzothiazoles, 2-chloro-3-nitro benzoic acid 6
was employed as a building block through an amide linkage.
The chloro and nitro groups were positioned strategically on
which the construction of
a second angularly oriented
Scheme 1 General strategy for the synthesis of intermediate 9.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 2 One pot synthesis of benzimidazole linked benzoxazole and benzothiazole derivatives.
Table 1 Optimization of the reaction conditions
Entry
CuI (mol%)
Ligand (mol%)
Solvent
Condition (temp °C)
Time
Yielda (%)
1
2
3
4
5
6
7
8
5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
1,10-Phenanthroline (10)
1,10-Phenanthroline (10)
1,10-Phenanthroline (10)
1,10-Phenanthroline (20)
1,10-Phenanthroline (20)
1,10-Phenanthroline (10)
1,10-Phenanthroline (20)
1,10-Phenanthroline (20)
1,10-Phenanthroline (20)
1,10-Phenanthroline (20)
1,10-Phenanthroline (10)
1,10-Phenanthroline (10)
1,10-Phenanthroline (20)
1,10-Phenanthroline (30)
1,10-Phenanthroline (10)
1,10-Phenanthroline (10)
MeCN
Xylene
Toluene
Toluene
Xylene
MeCN
DMF
Xylene
Xylene
Toluene
DMF
MeCN
MeCN
MeCN
Xylene
Xylene
Reflux
Reflux
Reflux
MW (120)
MW (150)
MW (120)
MW (150)
Sealed tube (140)
Sealed tube (190)
Reflux
24 h
24 h
24 h
20 m
20 m
20 m
20 m
12 h
12 h
24 h
24 h
20 m
30 m
40 m
20 m
24 h
Traceb
Traceb
Traceb
20
40
20
30
55
80
9
10
11
12
13
14
15
16
Traceb
Traceb
15
Reflux
MW (120)
MW (140)
MW (140)
MW (160)
Sealed tube (190)
30
72
25
30
a Based on the weight of the purified compounds. b By 1H NMR, Cs2CO3 (3 eq. relative to 9).
the reaction with dielectric heating by microwave irradiation. the same conditions. Increasing the temperature to 190 °C
Reaction at various temperatures with different polar and non- accelerates the reaction to complete conversion to benzoxazole
polar solvents at various time periods still can not cause the 12 with 80% isolated yield. No reaction was observed in the
complete conversion of 9 under microwave irradiation. Then absence of the copper catalyst and it was found that employing
we examined the same reaction in xylene at 140 °C under Cs2CO3 as the base showed the best result, while other bases
sealed tube conditions to furnish 55% isolated yield and the such as TEA, DIPEA, sodium carbonate, and potassium car-
recovery of 20% intermediate 9. It is evident that the in situ for- bonate gave poorer yields under these conditions. Using 2,2′
mation of anilides 10 underwent complete cross coupling by bipyridyl as a ligand in place of 1,10-phenanthroline did not
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
Table 2 Benzimidazole linked benzoxazole 11 and benzothiazole 13
Entrya
R1NH2
R2COCl
Yieldc (%)
78
Entryb
R1NH2
R3NCS
Yieldc (%)
66
11a
13a
11b
85
13b
61
11c
11d
11e
84
72
79
13c
13d
13e
72
62
60
11f
88
78
13f
68
74
11g
13g
11h
11i
83
79
13h
13i
58
59
11j
82
13j
60
a Entries 11a–11j reaction conditions: CuI (10 mol%), 1,10-phenanthroline (20 mol%), Cs2CO3 (3 eq.), in xylene, in a sealed tube 190 °C for 12 h.
b Entries 13a–13j reaction conditions: CuI (10 mol%), 1,10-phenanthroline (30 mol%), Cs2CO3 (3 eq.), in acetonitrile, MW 140 °C for 40 min.
c Yields of purified compounds.
accomplish any better conversion to the final product. On the not improve the yield and led to a complex mixture of
basis of these optimization studies, the most favorable con- products.
dition employed for the one pot reaction was CuI (10%), 1,10-
It is inferred from the experimental observation that the
phenanthroline (20%), and Cs2CO3 (3 eq.) in xylene in a sealed lower reactivity of isothiocyanates compared to that of acid
tube. The same catalytic system could be applied for the chloride gave a lower yield of the corresponding intermediate
synthesis of benzothiazole derivatives from the intermediate 9 12 and thus affected the overall yield with slight recovery of
by reacting with various isothiocyanates. The one pot reaction the starting material. Reduced yields and harsh conditions are
was tried in various solvents under reflux and microwave required for the formation of 2-aminobenzothiazoles 13,
conditions. All these conditions did not lead to the complete because of the strong copper–sulphur bond, which further
conversion of the starting material 9 and with the yield range reduced its nucleophilicity, whereas the weak copper–oxygen
from 45–50%. Among these trials, the best condition was bond led to better yields and shorter reaction times for the for-
chosen as three equivalents of cesium carbonate and 10 mol% mation of oxazoles 11. With the optimized condition in hand
of CuI, 30 mol% of 1,10-phenanthroline with the isolated yield we next focused on the exploration of generality and scope of
of 72% and 12% of the recovered starting material 9 under this domino process. The intermediate 9 smoothly reacted
microwave irradiation. Further increasing the temperature did with various acid chlorides and isothiocyanates regardless of
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
Fig. 2 ORTEP representation of benzimidazole linked benzoxazole.
Scheme 3 Plausible mechanism for the formation of 11 and 13.
the electronic and steric properties of the substituents to
provide bis-heterocycles in good yields. It is noteworthy
to mention that the substituted benzimidazole moiety linked
to the benzene ring was well-tolerated under this reaction con-
dition, with the final products obtained in good yields. The
noticeable advantage of this protocol is that all the reactions
are insensitive to air and moisture, hence, there was no need
for an inert atmosphere. The plausible mechanism for the for-
mation of benzimidazole linked benzoxazole 11 and benzo-
thiazole 13 from the common intermediate 9 is shown in
Scheme 3.21 First, the nucleophilic addition of chloroaniline to
acid chloride and isothiocyanate furnished anilide (10a) and
urea (12a) conjugates respectively in the presence of base.
Second, the obtained intermediates were converted into final
products through intramolecular cyclization with the aid of
1,10-phenanthroline and Cs2CO3. Initial co-ordination of
copper to the intermediates (10a and 12a) leads to the oxi-
dative addition products (10c and 12c). The presence of 1,10-
phenanthroline as a ligand was employed to avoid multiple co-
ordination of copper with the amide intermediates.22 Sub-
sequently reductive elimination released the respective pro-
ducts 11 and 13 with the concomitant regeneration of the
copper catalyst.
Fig. 3 ORTEP representation of benzimidazole linked benzothiazole.
Conclusion
In summary, the developed synthetic protocol provides concise
access to the diverse bis-heterocycles comprising benzimid-
azoles, benzothiazoles and benzoxazoles. The synthetic
sequence involves acid–amine coupling, intramolecular cycliza-
tion, and reduction followed by domino, one pot azole for-
mation. The amphiphilic reactivity of 2-chloroaniline has been
exploited under Ullmann-like conditions by a catalyst–ligand–
base combination for the construction of privileged bis-hetero-
cycles. Activation of the aromatic chloro substituent for such an
intramolecular displacement is unique and would provide an
impetus for the synthesis of other heterocycles. The intramole-
cular one pot domino annulation reaction was greatly facilitated
by copper iodide/1,10-phenanthroline. The accessibility and
generality of this synthetic approach make it highly valuable in
view of the medicinal importance of these bis-heterocycles.
Assembly of these privileged heterocycles in a single molecule
will certainly provide abundant opportunities to discover more
interesting compounds with novel biological profiles.
Further the structures of the benzimidazole linked benzox-
azole and benzothiazole were unambiguously confirmed by
X-ray crystallographic analysis (Fig. 2 and 3). This novel syn-
thetic approach leads to the proficient synthesis of angularly
oriented bis-heterocycles in which the hetero-atoms are more
favorably oriented for an in situ metal chelation or binding
with electrophilic sites of the receptors in biomolecules.
Experimental section
Synthesis of key intermediate 9
Compound 5 (1.0 g, 4.8 mmol), 2-chloro-3-nitrobenzoic acid
(1.3 g, 6.7 mmol), DCC (1.4 g, 6.6 mmol), and 4-dimethyl-
aminopyridine (0.006 g, 0.05 mmol) in dry CH2Cl2 (25 mL)
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
were stirred in a round-bottomed flask for 16 h at room temp- (300 MHz, CDCl3) δH 8.56 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H), 7.94
erature. After cooling to 0 °C, the solid dicyclohexylurea (DCU) (d, J = 7.8 Hz, 1H), 7.64–7.61 (m, 2H), 7.53 (t, J = 7.8 Hz, 1H),
was filtered off and the solvent was evaporated. The crude 7.43 (s, 2H), 4.48 (m, 1H), 3.96 (s, 3H), 3.91 (s, 9H), 2.43 (m,
product was purified by precipitation and washing with 2H), 2.10 (m, 2H), 1.76 (m, 2H), 1.39 (m, 6H), 1.10 (m, 2H); 13
C
n-hexane (20 mL × 3) to afford amide 7 in 60–70% yield. Sub- NMR (75 MHz, CDCl3) δC 167.5, 163.5, 153.5, 150.5, 148.4,
sequently, amide 7 (1.0 g, 2.8 mmol) in 1,2-dichloroethane 143.7, 142.5, 141.4, 136.7, 127.2, 125.2, 124.4, 124.0, 122.7,
(50 mL) was refluxed for 16 h in 10% trifluoroacetic acid (TFA) 121.8, 121.3, 114.2, 112.1, 104.9, 61.0, 58.0, 56.3, 52.1, 33.4,
(0.43 mL, 5.61 mmol) and MgSO4 (0.5 g, 4.14 mmol). Solvent 26.1, 25.7, 25.2; MS (EI): m/z 569.25 (M+); HRMS (EI): calcd for
was removed and the crude product was purified by flash C33H35N3O6 569.2526, found 569.2523; IR (neat) 3417, 2927,
chromatography to give 8 (84–95%). For the next step, zinc dust 1716 cm−1
(15 equiv., 74.6 mmol) and ammonium formate (7 equiv., Methyl-1-cyclooctyl-2-[2-(furan-2-yl)-1,3-benzoxazol-7-yl]-1H-
.
34.8 mmol) were added to a solution of 8 (2.0 g, 4.9 mmol) in benzimidazole-5-carboxylate (11b). 1H NMR (300 MHz, CDCl3)
dry MeOH (100 mL) and the resulting reaction mixture was δH 8.56 (d, J = 1.2 Hz, 1H), 8.02 (dd, J = 8.6, 1.2 Hz, 1H),
stirred for 10 min at room temperature. Subsequently, Zn dust 7.93 (dd, J = 7.8, 1.1 Hz, 1H), 7.66–7.61 (m, 3H), 7.54 (t, J = 7.8
was filtered off through a bed of celite, the solvent was evapor- Hz, 1H), 7.24 (dd, J = 3.5, 0.5 Hz, 1H), 6.59 (dd, J = 3.5, 1.7 Hz,
ated and the product was dissolved in CH2Cl2 (100 mL). The 1H), 4.46 (m, 1H), 3.96 (s, 3H), 2.45–2.41 (m, 2H), 2.14–2.07
precipitated ammonium formate was filtered off and the solvent (m, 2H), 1.80–1.75 (m, 2H), 1.45–1.40 (m, 6H), 1.15–1.10 (m,
was evaporated to furnish 9 with 92–96% isolated yields.
2H); 13C NMR (75 MHz, CDCl3) δC 167.5, 155.8, 150.4, 147.8,
146.2, 143.0, 142.3, 141.9, 138.6, 127.1, 125.4, 124.7, 124.5,
122.6, 122.1, 115.2, 114.3, 112.4, 110.0, 52.1, 45.1, 29.2, 28.7,
21.9, 13.7; MS (EI): m/z 469 (M+); HRMS (EI): calcd for
General procedure for the synthesis of benzimidazolyl
benzoxazole (11)
To a solution of compound 9 (0.5 g, 1.34 mmol) in xylene C28H27N3O4 469.2002, found 469.1995; IR (neat): 3397, 2927,
(20 mL) was added CuI (0.025 g, 0.134 mmol), 1,10-phen- 1716 cm−1
anthroline (0.048 g, 0.268 mmol), and Cs2CO3 (1.3 g, Methyl-2-[2-(furan-2-yl)-1,3-benzoxazol-7-yl]-1-(3-phenyl-
4.03 mmol) followed by benzoyl chloride (0.282 g, 2.01 mmol) propyl)-1H-benzimidazole-5-carboxylate NMR
(11c). 1H
.
and the reaction mixture was heated at 190 °C for 12 h in a (300 MHz, CDCl3) δH 8.57 (s, 1H), 8.05 (d, J = 8.5 Hz, 1H), 7.87
sealed tube. The reaction mixture was diluted with ethyl (d, J = 7.8 Hz, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.57 (s, 1H), 7.46 (t,
acetate (100 mL) and washed with saturated aqueous sodium J = 7.8 Hz, 1H), 7.39 (d, J = 8.5 Hz, 1H), 7.20 (m, 1H), 7.09–7.07
bicarbonate solution (50 mL) to remove the solid residues. The (m, 3H), 6.89–6.87 (m, 2H), 6.55–6.53 (m, 1H), 4.21 (t, J = 7.6
aqueous layer was extracted with ethyl acetate (50 mL × 2). To Hz, 2H), 3.93 (s, 3H), 2.48 (t, J = 7.2 Hz, 2H), 2.17–2.10 (m, 2H);
the combined organic layers was added MgSO4, filtered and 13C NMR (75 MHz, CDCl3) δC 167.3, 155.5, 150.2, 147.4, 146.0,
evaporated to obtain the crude product. The crude product 142.9, 142.1, 141.7, 139.7, 138.5, 128.3, 127.8, 127.0, 126.1,
was purified by silica-gel column chromatography using EA– 125.3, 124.6, 124.5, 122.5, 122.0, 115.1, 114.0, 112.2, 109.8,
hexane (1 : 3) as an eluent to obtain pure product 11i (78%).
52.0, 44.2, 32.4, 30.5; MS (EI): m/z 477 (M+); HRMS (EI): calcd
for C29H23N3O4 477.1689, found 477.1691; IR (neat) 3405,
General procedure for the synthesis of benzimidazolyl
benzothiazole (13)
2944, 1714 cm−1
.
Methyl-1-(3,3-diphenylpropyl)-2-(2-propyl-1,3-benzoxazol-7-yl)-
To a microwave process vial of compound 9 (0.5 g, 1.34 mmol) 1H-benzimidazole-5-carboxylate (11d). 1H NMR (300 MHz,
in acetonitrile (10 mL) was added CuI (0.025 g, 0.134 mmol), CDCl3) δH 8.58 (s, 1H), 8.06 (d, J = 8.6, Hz, 1H), 7.85 (d, J =
1,10-phenanthroline (0.048 g, 0.268 mmol), and Cs2CO3 (1.3 g, 7.8 Hz, 1H), 7.6 (d, J = 7.8 Hz, 1H), 7.44 (t, J = 7.8 Hz, 1H),
4.03 mmol) followed by phenylisothiocyanate (0.543 g, 7.32–7.25 (m, 2H), 7.18–7.12 (m, 5H), 6.99–6.97 (m, 4H), 4.21
4.02 mmol) and the reaction mixture was heated at 140 °C for (t, J = 7.9 Hz, 2H), 3.96 (s, 3H), 3.77 (t, J = 7.9 Hz, 1H), 2.77 (t,
40 min under microwave irradiation. The reaction mixture was J = 7.5 Hz, 2H), 2.47–2.39 (m, 2H), 1.84–1.73 (m, 2H), 0.97 (t,
cooled to room temperature and was diluted with ethyl acetate J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC 167.5, 167.4,
(50 mL) and washed with a saturated aqueous sodium bi- 150.5, 148.1, 142.9, 142.0, 138.4, 128.6, 127.6, 127.1, 126.6,
carbonate solution (50 mL) to remove catalyst and solid 126.3, 124.7, 124.6, 124.6, 122.5, 121.7, 113.5, 109.7, 52.1, 48.4,
residues. The aqueous layer was then extracted with ethyl 43.5, 35.3, 30.2, 20.0, 13.6; MS (EI): m/z 529 (M+); HRMS (EI):
acetate (50 mL × 2). To the combined organic layers was added calcd for C34H31N3O3 529.2365, found 529.2355; IR (neat)
MgSO4, filtered and evaporated to obtain the crude product. 3409, 2940, 1716 cm−1
The obtained crude product was purified by silica-gel column Methyl-1-(3,3-diphenylpropyl)-2-[2-(3,4,5-trimethoxyphenyl)-
chromatography using EA–hexane (1 : 2) as an eluent to obtain 1,3-benzoxazol-7-yl]-1H-benzimidazole-5-carboxylate (11e). 1H
.
the title compound 13a (66%).
NMR (300 MHz, CDCl3) δH 8.59 (d, J = 0.8 Hz, 1H), 8.09 (dd, J =
8.6, 0.8 Hz, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.7Hz, 1H),
7.47 (t, J = 7.7 Hz, 1H), 7.38 (s, 2H), 7.36 (d, J = 8.6 Hz, 1H),
Spectral data
Methyl-1-cyclooctyl-2-[2-(3,4,5-trimethoxyphenyl)-1,3-benz- 7.14–7.07 (m, 6H), 6.97–6.95 (m, 4H), 4.21 (t, J = 7.8 Hz, 2H),
oxazol-7-yl]-1H-benzimidazole-5-carboxylate (11a). 1H NMR 3.97 (s, 3H), 3.93 (s, 3H), 3.89 (s, 6H), 3.78 (t, J = 7.8 Hz, 2H),
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
2.55–2.47 (m, 2H); 13C NMR (75 MHz, CDCl3: δC 167.4, 163.4, 8.10 (dd, J = 8.6, 1.1 Hz, 1H), 7.92 (dd, J = 7.7, 1.1 Hz, 1H), 7.64
153.5, 150.4, 148.1, 143.0, 142.7, 142.7, 141.4, 138.5, 128.6, (dd, J = 7.7, 1.1 Hz, 1H), 7.52 (t, J = 7.7 Hz, 1H), 7.51 (d, J =
127.1, 126.9, 126.7, 125.2, 124.8, 124.6, 122.6, 121.9, 121.4, 8.6 Hz, 1H), 7.43 (s, 2H), 5.06 (s, 1H), 4.33 (t, J = 7.0 Hz, 2H),
113.7, 109.8, 104.9, 61.0, 56.4, 52.2, 48.6, 43.7, 35.3; MS (EI): 3.96 (s, 3H), 3.92 (s, 3H), 3.91 (s, 9H), 2.36 (t, J = 7.0 Hz, 2H),
m/z 653 (M+); HRMS (EI): calcd for C40H35N3O6 653.2526, 1.70 (m, 2H), 1.57–1.56 (m, 2H), 1.30–1.29 (m, 4H); 13C NMR
found 653.2523; IR (neat) 3382, 2888, 1712 cm−1
.
(75 MHz, CDCl3) δC 167.5, 163.6, 153.5, 150.7, 148.3, 143.0,
Methyl-2-[2-(furan-2-yl)-1,3-benzoxazol-7-yl]-1-pentyl-1H-benz- 142.8, 141.5, 138.6, 132.7, 126.9, 125.1, 124.9, 124.7, 124.4,
imidazole-5-carboxylate (11f). 1H NMR (300 MHz, CDCl3) δH 122.5, 121.8, 121.5, 114.2, 110.8, 105.0, 61.0, 56.4, 52.1, 43.5,
8.57 (d, J = 0.9 Hz, 1H), 8.08 (dd, J = 8.5, 0.9 Hz, 1H), 7.91 (dd, 37.6, 27.9, 24.9, 22.3, 21.7; MS (EI): m/z 567 (M+); HRMS (EI):
J = 7.9, 0.9 Hz, 1H), 7.68–7.65 (m, 2H), 7.55–7.49 (m, 2H), 7.26 calcd for C33H33N3O6 567.2369, found 567.2365; IR (neat)
(d, J = 3.5 Hz, 1H), 6.59 (dd, J = 3.5, 1.7 Hz, 1H), 4.22 (t, J = 3417, 2935, 1716 cm−1
7.5 Hz, 2H), 3.96 (s, 3H), 1.85–1.76 (m, 2H), 1.11–1.07 (m, 4H),
.
Methyl-1-pentyl-2-[2-(phenylamino)-1,3-benzothiazol-7-yl]-1H-
0.71 (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC 167.5, benzimidazole-5-carboxylate (13a). 1H NMR (300 MHz, CDCl3)
155.8, 150.3, 147.8, 146.2, 143.0, 142.3, 141.9, 138.6, 127.1, δH 8.56 (s, 1H), 8.06 (d, J = 8.5, Hz, 1H), 7.66 (d, J = 7.6 Hz, 1H),
125.4, 124.7, 124.5, 122.6, 122.1, 115.2, 114.3, 112.4, 110.0, 7.52 (d, J = 7.7 Hz, 2H), 7.47–7.34 (m, 5H), 7.15 (t, J = 7.4 Hz,
52.1, 45.1, 29.2, 28.6, 21.9, 13.7; MS (EI): m/z 429 (M+); HRMS 1H), 4.29 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 1.86–1.79 (m, 2H),
(EI): calcd for C25H23N3O4 429.1689, found 429.1691; IR (neat) 1.22–1.20 (m, 4H), 0.80 (t, J = 6.7 Hz, 3H); 13C NMR (75 MHz,
3444, 2951, 1716 cm−1
Methyl-1-pentyl-2-[2-(3,4,5-trimethoxyphenyl)-1,3-benzoxazol- 129.5, 126.0, 124.7, 124.6, 124.6, 123.4, 122.4, 121.7, 120.6,
7-yl]-1H-benzimidazole-5-carboxylate NMR 120.5, 109.9, 52.1, 45.1, 29.4, 28.6, 22.0, 13.8; MS (EI): m/z 470
(11g). 1H
(300 MHz, CDCl3) δH 8.56 (s, 1H), 8.07 (d, J = 8.6 Hz, 1H), 7.9 (M+); HRMS (EI): calcd for C27H26N4O2S 470.1776, found
(d, J = 7.0 Hz, 1H), 7.6 (d, J = 7.0 Hz, 1H), 7.56–7.51 (m, 2H), 470.1772; IR (neat) 3261, 2954, 1716 cm−1
7.41 (s, 2H), 4.21 (t, J = 7.5 Hz, 2H), 3.93 (s, 3H), 3.89 (s, 6H), Methyl-2-{2-[(3-methylphenyl)amino]-1,3-benzothiazol-7-yl}-1-
3.88 (s, 3H), 1.78 (t, J = 7.5 Hz, 2H), 1.08–1.04 (m, 4H), 0.67 (t, pentyl-1H-benzimidazole-5-carboxylate NMR
(13b). 1H
.
CDCl3) δC 167.6, 166.9, 153.6, 152.2, 142.3, 139.5, 138.8, 131.4,
.
J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC 167.4, 163.5, (300 MHz, CDCl3) δH 8.59 (d, J = 0.9 Hz, 1H), 8.08 (dd, J = 8.5,
153.4, 150.5, 148.4, 142.9, 142.7, 141.4, 138.5, 126.8, 125.0, 0.9 Hz, 1H), 7.66 (d, J = 7.2 Hz, 1H), 7.48–7.43 (m, 2H),
124.6, 124.4, 122.5, 121.7, 121.4, 114.0, 109.9, 105.0, 60.9, 56.3, 7.37–7.35 (m, 2H), 7.31–7.26 (m, 2H), 7.00 (d, J = 7.3 Hz, 1H),
52.0, 44.9, 29.1, 28.5, 21.8, 13.6; MS (EI): m/z 529 (M+); HRMS 4.31 (t, J = 7.6 Hz, 2H), 3.98 (s, 3H), 2.37 (s, 3H), 1.87–1.80
(EI): calcd for C30H31N3O6 529.2213, found 529.2227; IR (neat) (m, 2H), 1.28–1.22 (m, 4H), 0.82 (t, J = 6.7 Hz, 3H); 13C NMR
3394, 2944, 1712 cm−1
.
(75 MHz, CDCl3) δC 167.6, 167.2, 153.7, 152.6, 142.4, 139.5,
Methyl-2-[2-(furan-2-yl)-1,3-benzoxazol-7-yl]-1-(3-methoxy- 138.8, 131.6, 129.4, 125.9, 125.5, 124.6, 124.5, 124.5, 123.4,
propyl)-1H-benzimidazole-5-carboxylate (11h). 1H NMR 122.4, 121.6, 121.5, 120.4, 117.8, 109.8, 52.1, 45.5, 29.4, 28.6,
(300 MHz, CDCl3) δH 8.35 (s, 1H), 7.85 (d, J = 8.6 Hz, 1H), 7.68 22.0, 21.5, 13.8; MS (EI): m/z 484 (M+); HRMS (EI): calcd for
(d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.41 (m, 1H), C28H28N4O2S 484.1933, found 484.1931; IR (neat) 2952, 2858,
7.33–7.29 (m, 2H), 7.04 (t, J = 3.5 Hz, 1H), 6.35 (dd, J = 3.5, 1716 cm−1
1.7 Hz, 1H), 4.17 (t, J = 6.9 Hz, 2H), 3.72 (s, 3H), 2.89 (t, J =
.
Methyl-2-[2-(butylamino)-1,3-benzothiazol-7-yl]-1-pentyl-1H-
5.6 Hz, 2H), 2.79 (s, 3H), 1.81–1.73 (m, 2H); 13C NMR (75 MHz, benzimidazole-5-carboxylate (13c). 1H NMR (300 MHz, CDCl3)
CDCl3): δC 167.4, 155.6, 150.3, 147.6, 146.1, 142.7, 142.2, 141.7, δH 8.58 (s, 1H), 8.07 (d, J = 8.5 Hz, 1H), 7.64 (d, J = 7.9 Hz, 1H),
138.6, 127.0, 125.3, 124.7, 124.5, 122.3, 122.0, 115.1, 114.0, 7.45 (d, J = 8.5 Hz, 1H), 7.44 (t, J = 7.3 Hz, 1H), 7.30 (d, J =
112.3, 110.0, 68.3, 58.3, 52.0, 41.8, 29.6; MS (EI): m/z 439 (M+); 7.6 Hz, 1H), 4.32 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 3.42 (t, J =
HRMS (EI): calcd for C24H21N3O5 431.1482, found 431.1479; IR 7.0 Hz, 2H), 1.88–1.81 (m, 2H), 1.68 (t, J = 7.3 Hz, 2H),
(neat) 3453, 2894, 1718 cm−1
.
1.49–1.37 (m, 2H), 1.24–1.23 (m, 4H), 0.95 (t, J = 7.3 Hz, 3H),
Methyl-1-(3-methylbutyl)-2-(2-phenyl-1,3-benzoxazol-7-yl)-1H- 0.82 (t, J = 6.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δC 169.7,
benzimidazole-5-carboxylate (11i). 1H NMR (300 MHz, CDCl3) 167.6, 153.8, 152.9, 142.4, 138.9, 126.0, 124.7, 124.7, 124.6,
δH 8.61 (d, J = 1.0 Hz, 1H), 8.22 (dd, J = 7.9, 1.7 Hz, 2H), 8.11 123.3, 122.4, 120.8, 119.8, 109.8, 52.1, 45.5, 45.2, 31.5, 29.5,
(dd, J = 8.5, 1.0 Hz, 1H), 7.96 (dd, J = 7.9, 0.9 Hz, 1H), 7.68 (dd, 28.7, 22.0, 20.0, 13.8, 13.7; MS (EI): m/z 450 (M+); HRMS (EI):
J = 7.9, 0.9 Hz, 1H), 7.56–7.50 (m, 5H), 4.27 (t, J = 7.8 Hz, 2H), calcd for C25H30N4O2S 450.2089, found 450.2088; IR (neat)
3.98 (s, 3H), 1.74–1.67 (m, 2H), 1.48–1.35 (m, 1H), 0.72 (s, 3H), 3424, 2956, 1712 cm−1
0.70 (s, 3H); 13C NMR (75 MHz, CDCl3) δC 167.6, 163.7, 150.5,
Methyl-2-[2-(cyclohexylamino)-1,3-benzothiazol-7-yl]-1-(3-
148.4, 143.0, 142.7, 138.5, 132.0, 129.0, 127.8, 127.0, 126.4, 125.2, methoxypropyl)-1H-benzimidazole-5-carboxylate
(13d). 1H
.
124.8, 124.6, 122.6, 122.1, 114.1, 110.0, 52.2, 43.5, 38.2, 25.7, 22.0; NMR (300 MHz, CDCl3) δH 8.59 (d, J = 1.2 Hz, 1H), 8.07 (dd, J =
MS (EI): m/z 439 (M+); HRMS (EI) calcd for C27H25N3O3 439.1896, 8.6, 1.2 Hz, 1H), 7.61 (dd, J = 7.9, 1.1 Hz, 1H), 7.51 (d, J =
found 439.1902; IR (neat) 3450, 2950, 1716 cm−1
.
8.6 Hz, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.34 (dd, J = 7.6, 1.1 Hz,
Methyl-1-[2-(cyclohex-1-en-1-yl)ethyl]-2-[2-(3,4,5-trimethoxy- 1H), 4.48 (t, J = 7.1 Hz, 2H), 3.97 (s, 3H), 3.54 (m, 1H), 3.22 (t,
phenyl)-1,3-benzoxazol-7-yl]-1H-benzimidazole-5-carboxylate J = 5.6 Hz, 2H), 3.16 (s, 3H), 2.17–2.09 (m, 2H), 2.04–2.01 (m,
(11j). 1H NMR (300 MHz, CDCl3) δH 8.58 (d, J = 1.1 Hz, 1H), 2H), 1.78–1.74 (m, 4H), 1.43–1.25 (m, 6H); 13C NMR (75 MHz,
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.

View Article Online
Paper
Organic & Biomolecular Chemistry
CDCl3) δC 168.7, 167.6, 153.9, 153.6, 142.4, 139.1, 132.0, 125.9,
Methyl-1-(3,3-diphenylpropyl)-2-{2-[(3-methylphenyl)amino]-
124.7, 124.6, 123.2, 122.4, 120.6, 120.0, 109.9, 68.6, 58.6, 54.7, 1,3-benzothiazol-7-yl}-1H-benzimidazole-5-carboxylate (13i). 1H
52.2, 42.0, 33.3, 30.1, 25.4, 24.7; MS (EI): m/z 478 (M+); HRMS NMR (300 MHz, CDCl3) δH 8.56 (s, 1H), 8.02 (d, J = 8.5 Hz, 1H),
(EI): calcd for C26H30N4O3S 478.2039, found 478.2044; IR 7.63 (d, J = 7.4 Hz, 1H), 7.35–7.11 (m, 16H), 6.98 (d, J = 8.0 Hz,
(neat) 3228, 2929, 1712 cm−1
.
1H), 4.27 (t, J = 7.9 Hz, 2H), 3.96 (s, 3H), 3.86 (t, J = 7.8 Hz,
Methyl-1-(3-methoxypropyl)-2-[2-(phenylamino)-1,3-benzothi- 1H), 2.59–2.51 (m, 2H), 2.36 (s, 3H); 13C NMR (75 MHz, CDCl3)
azol-7-yl]-1H-benzimidazole-5-carboxylate NMR δC 167.5, 167.1, 153.4, 152.5, 143.0, 142.4, 139.6, 139.5, 138.7,
(13e). 1H
(300 MHz, CDCl3) δH 8.57 (d, J = 1.1 Hz, 1H), 8.07 (dd, J = 8.5, 131.4, 129.4, 128.7, 127.5, 126.7, 126.0, 125.5, 124.7, 124.6,
1.1 Hz, 1H), 7.64 (dd, J = 6.1, 2.9 Hz, 1H), 7.54 (d, J = 7.6 Hz, 123.0, 122.4, 121.4, 121.4, 120.5, 117.6, 109.7, 63.6, 52.1, 48.5,
2H), 7.49 (d, J = 8.5 Hz, 1H), 7.42–7.34 (m, 4H), 7.14 (d, J = 43.9, 35.4, 21.5; MS (EI): m/z 608 (M+); HRMS (EI): calcd for
7.3 Hz, 1H), 4.46 (t, J = 6.9 Hz, 2H), 3.96 (s, 3H), 3.20 (t, J = C38H32N4O2S 608.2246, found 608.2248; IR (neat) 3058, 2925,
5.5 Hz, 2H), 3.14 (s, 3H), 2.00 (m, 2H); 13C NMR (75 MHz, 1714 cm−1
CDCl3): δC 167.5, 166.8, 153.6, 152.6, 142.1, 139.7, 138.9, 131.4,
.
Methyl-2-[2-(cyclohexylamino)-1,3-benzothiazol-7-yl]-1-(3,3-
(13j). 1H
129.4, 129.2, 125.9, 124.6, 124.5, 124.2, 123.1, 122.2, 121.6, diphenylpropyl)-1H-benzimidazole-5-carboxylate
120.4, 109.9, 68.4, 58.4, 52.1, 41.9, 29.9; MS (EI): m/z 472 (M+); NMR (300 MHz, CDCl3) δH 8.60 (s, 1H), 8.03 (d, J = 8.5 Hz, 1H),
HRMS (EI): calcd for C26H24N4O3S 472.1569, found 472.1573; 7.60 (d, J = 8.0 Hz, 1H), 7.30–7.20 (m, 9H), 7.16–7.13 (m, 4H),
IR (neat) 3263, 2948, 1714 cm−1
.
4.31 (t, J = 7.9 Hz, 2H), 3.98 (s, 3H), 3.89 (t, J = 7.7 Hz, 1H),
Methyl-2-{2-[(3-methoxypropyl)amino]-1,3-benzothiazol-7-yl}- 3.56–3.49 (m, 1H), 2.62–2.53 (m, 2H), 2.15–2.12 (m, 2H),
1-(3-phenylpropyl)-1H-benzimidazole-5-carboxylate (13f). 1H 1.80–1.76 (m, 2H), 1.44–1.33 (m, 6H); 13C NMR (75 MHz,
NMR (300 MHz, CDCl3) δH 8.57 (d, J = 1.1 Hz, 1H), 8.03 (dd, J = CDCl3) δC 169.2, 168.0, 154.1, 154.0, 143.5, 142.9, 139.2, 132.3,
8.5, 1.1 Hz, 1H), 7.60 (dd, J = 8.0, 0.8 Hz, 1H), 7.33–7.31 (m, 129.2, 127.9, 127.2, 126.3, 125.1, 125.0, 123.4, 122.8, 120.9,
1H), 7.30–7.29 (m, 1H), 7.27–7.20 (m, 3H), 7.13 (dd, J = 7.6, 120.3, 110.1, 55.2, 52.6, 49.0, 44.4, 35.9, 33.7, 25.8, 25.1; MS
0.8 Hz, 1H), 7.06–7.04 (m, 2H), 6.30 (s, 1H), 4.30 (t, J = 7.7 Hz, (EI): m/z 600 (M+); HRMS (EI): calcd for C37H36N4O2S 600.2559,
2H), 3.95 (s, 3H), 3.52 (m, 4H), 3.33 (s, 3H), 2.58 (t, J = 7.2 Hz, found 600.2555; IR (neat) 2927, 2854, 1714 cm−1
2H), 2.16 (m, 2H), 1.94 (m, 2H); 13C NMR (75 MHz, CDCl3) δC
.
169.4, 167.5, 153.8, 153.6, 142.3, 139.9, 138.7, 132.0, 128.6,
128.2, 126.4, 125.8, 124.6, 124.5, 123.0, 122.3, 120.5, 119.9,
Acknowledgements
109.7, 71.3, 58.2, 52.1, 44.3, 43.9, 32.6, 30.9, 28.9; MS (EI): m/z
514 (M+); HRMS (EI): calcd for C29H30N4O3S 514.2039, found The authors thank the National Science Council of Taiwan for
514.2040; IR (neat) 3226, 2925, 1714 cm−1
.
financial support and the authorities of the National Chiao
Methyl-1-(3,3-diphenylpropyl)-2-{2-[(3-methoxypropyl)amino]- Tung University for providing the laboratory facilities. This
1,3-benzothiazol-7-yl}-1H-benzimidazole-5-carboxylate (13g). 1H study was particularly supported by the “Centre for bioinfor-
NMR (300 MHz, CDCl3) δH 8.57 (s, 1H), 8.02 (d, J = 8.4 Hz, 1H), matics research of aiming for the Top University Plan” of the
7.61 (d, J = 7.4 Hz, 1H), 7.28–7.19 (m, 7H), 7.14–7.08 (m, 7H), National Chiao Tung University and Ministry of Education,
4.30 (t, J = 7.6 Hz, 2H), 3.96 (s, 3H), 3.88 (t, J = 7.9 Hz, 1H), Taiwan.
3.57–3.53 (m, 4H), 3.36 (s, 3H), 2.62–2.54 (m, 2H), 1.99–1.95
(m, 2H); 13C NMR (75 MHz, CDCl3) δC 169.3, 167.5, 153.7,
143.1, 142.4, 138.7, 131.9, 128.7, 127.5, 127.3, 126.7, 125.8,
References
124.7, 124.5, 122.9, 122.3, 120.4, 120.0, 109.6, 71.4, 58.9, 52.1,
48.5, 44.0, 43.9, 35.4, 28.9; MS (EI): m/z 590 (M+); HRMS (EI):
1 (a) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108,
3395–3442; (b) S. Fustero, M. Sánchez-Roselló, P. Barrio
and A. Simón-Fuentes, Chem. Rev., 2011, 111, 6984–7034.
2 (a) Y. Hu and J. J. Bajorath, Chem. Inf. Model., 2010, 50,
500–510; (b) R. W. Desimone, K. S. Currie, S. A. Mitchell,
J. W. Darrow and D. A. Pippin, Comb. Chem. High Through-
put Screening, 2004, 7, 473–494.
3 (a) S. Ozden, D. Atabey and H. Goker, Bioorg. Med. Chem.,
2005, 13, 1587–1597; (b) H. Goker, C. Kus and
D. W. Boykin, Eur. J. Med. Chem., 2005, 40, 1062–1069;
(c) S. Jain, A. K. Shah, J. Bariwal, S. M. Shelke, A. P. Kale,
J. R. Jagtap and A. V. Bhosale, Bioorg. Med. Chem., 2007, 15,
1181–1205.
calcd for C35H34N4O3S 590.2352, found 590.2355; IR (neat)
3226, 2925, 1714 cm−1
.
Methyl-1-(3,3-diphenylpropyl)-2-[2-(prop-2-en-1-ylamino)-1,3-
benzothiazol-7-yl]-1H-benzimidazole-5-carboxylate (13h). 1H
NMR (300 MHz, CDCl3) δH 8.54 (d, J = 1.1 Hz, 1H), 8.03 (dd, J =
8.5, 1.1 Hz, 1H), 7.28–7.14 (m, 9H), 7.13–7.08 (m, 3H), 6.94
(dd, J = 8.1, 1.5 Hz, 1H), 6.82 (dd, J = 7.4, 1.5 Hz, 1H),
5.89–5.76 (m, 2H), 5.46 (t, J = 5.4 Hz, 2H), 5.18 (q, J = 1.9 Hz,
1H), 5.13 (q, J = 1.8 Hz, 1H), 5.08 (q, J = 1.5 Hz, 1H), 5.04 (q, J =
1.5 Hz, 1H), 4.36 (s, 1H), 4.02 (t, J = 8.0 Hz, 1H), 3.96 (s, 3H),
3.78–3.75 (m, 3H), 2.42 (q, J = 7.9 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δC 167.6, 153.0, 143.8, 143.1, 142.4, 137.7, 129.9, 128.7,
128.6, 127.6, 127.5, 127.4, 126.8, 126.6, 124.4, 124.3, 122.4,
120.8, 118.4, 117.3, 109.5, 52.0, 48.4, 43.10, 35.2, 30.9; MS (EI):
m/z 558 (M+); HRMS (EI) calcd for C34H30N4O2S 558.2089,
4 S. Yoshida, S. Shiokawa, K. Kawano, T. Ito, H. Murakami,
H. Suzuki and Y. Sato, J. Med. Chem., 2005, 48, 7075–7079.
5 (a) I. Caleta, M. Kralj, M. Marjanovic, B. Bertosa, S. Tomic,
G. Pavlovic, K. Pavelic and G. K. Zamola, J. Med. Chem.,
found 558.2092; IR (neat) 3311, 2939, 1714 cm−1
.
Org. Biomol. Chem.
This journal is © The Royal Society of Chemistry 2013

View Article Online
Organic & Biomolecular Chemistry
Paper
2009, 52, 1744–1756; (b) S. Bondock, W. Fadaly and 14 A. Ali, G. E. Taylor and D. W. Graham, PCT Int. Appl.,
M. Metwally, Eur. J. Med. Chem., 2010, 45, 3692–3701. WO2001028561, 2001.
6 (a) R. E. Dolle, J. Comb. Chem., 2005, 6, 623–679; 15 (a) M. Soural, I. Bouillon and V. Krchňák, J. Comb. Chem.,
(b) R. E. Dolle, J. Comb. Chem., 2006, 7, 739–798;
(c) R. E. Dolle, B. Le Bourdonnec, A. J. Goodman,
2008, 10, 923–933; (b) J. Cao and X. Huang, J. Comb. Chem.,
2008, 10, 923–933.
G. A. Morales, J. M. Salvino and W. Zhang, J. Comb. Chem., 16 G. V. Boyd, in Science of Synthesis: Houben-Weyl Methods of
2007, 9, 855; (d) R. E. Dolle, B. Le Bourdonnec,
A. J. Goodman, G. A. Morales, C. J. Thomas and W. Zhang,
J. Comb. Chem., 2008, 10, 753.
Molecular Transformations, ed. E. Schaumann, Thieme,
Stuttgart, 2001, vol. 11, pp. 481–492.
17 G. W. Stewart, C. A. Baxter, E. Cleator and F. J. Sheen,
J. Org. Chem., 2009, 74, 3229–3231.
7 J. Mann, A. Baron, Y. Opoku-Boahen, E. Johansson,
G. Parkinson, L. R. Kelland and S. Neidle, J. Med. Chem., 18 K. Chanda, B. Maiti, C. C. Tseng and C. M. Sun, ACS Comb.
2001, 44, 138–144. Sci., 2012, 14, 115–123.
8 N. Angelopoulos, A. Hadjiprocopis and M. D. Walkinshaw, 19 C. H. Chen, M. H. Chien, M. L. Kuo, C. T. Chou, J. J. Lai,
J. Chem. Inf. Model., 2009, 49, 1547–1557.
9 S. Sato, T. Kajiura, M. Noguchi, K. Takehana, T. Kobayashi
and T. Tsuji, J. Antibiot., 2001, 54, 102–104.
10 P. S. M. Sommer, R. C. Almedia, K. Schneider, W. Beil,
R. D. Sussmuth and H. P. Fiedler, J. Antibiot., 2008, 61,
683–686.
S. F. Lin, S. Thummanagoti and C. M. Sun, J. Comb. Chem.,
2009, 11, 1038–1046.
20 (a) R. D. Viirre, G. Evindar and R. A. Batey, J. Org. Chem., 2008,
73, 3452–3459; (b) Q. Ding, X. He and J. Wu, J. Comb. Chem.,
2009, 11, 587–591; (c) E. A. D. Jaseer, J. C. Prasad, A. Dandapat
and G. Sekar, Tetrahedron Lett., 2010, 51, 5009–5012.
11 T. A. Beerman, M. M. McHugh, R. Sigmund, J. W. Lown, 21 A. Salcedo, L. Neuville and J. Zhu, J. Org. Chem., 2008, 73,
K. E. Rao and Y. Bathini, Biochim. Biophys. Acta, 1992, 1131,
53–61.
12 S. M. Kerwin, U.S Patent 7, 294, 643, 2007.
13 J. M. Bergman, P. J. Coleman, C. Cox, H. G. D. C. Lindsley,
S. P. Mercer, A. J. Roecker and D. B. Whitman, PCT Int.
Appl., WO2006127550, 2006.
3600–3603.
22 (a) D. Ma, S. Xie, P. Xue, X. Zhang, J. Dong and Y. Jiang,
Angew. Chem., Int. Ed., 2009, 48, 4222–4225; (b) G. Shen,
X. Lv and W. Bao, Eur. J. Org. Chem., 2009, 34, 5897–5901;
(c) G. Evindar and R. A. Batey, J. Org. Chem., 2006, 71,
1802–1808.
This journal is © The Royal Society of Chemistry 2013
Org. Biomol. Chem.