Ruthenium-catalyzed benzimidazoisoquinoline synthesis via oxidative coupling of 2-arylbenzimidazoles with alkynes

Article abstract of DOI:10.1016/j.tetlet.2013.05.106

Synthesis of a fused bis-heterocyclic framework, benzimidazoisoquinoline, has been achieved using Ru-catalyzed reaction of alkynes with 2-aryl benzimidazoles in the presence of Cu salts. The method provides an easy access for the generation of a library of benzimidazoisoquinoline derivatives.

Full text of DOI:10.1016/j.tetlet.2013.05.106

Tetrahedron Letters 54 (2013) 4198–4201
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Ruthenium-catalyzed benzimidazoisoquinoline synthesis via
oxidative coupling of 2-arylbenzimidazoles with alkynes
⇑
Nerella Kavitha, Genji Sukumar, Vemula Praveen Kumar, Prathama S. Mainkar, Srivari Chandrasekhar
Division of Natural Products Chemistry, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthesis of a fused bis-heterocyclic framework, benzimidazoisoquinoline, has been achieved using Ru-
catalyzed reaction of alkynes with 2-aryl benzimidazoles in the presence of Cu salts. The method provides
an easy access for the generation of a library of benzimidazoisoquinoline derivatives.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 14 February 2013
Revised 23 May 2013
Accepted 25 May 2013
Available online 4 June 2013
Keywords:
Oxidative coupling
Benzimidazoisoquinoline
C–H activation
PEG-400
Development of new procedures toward the synthesis of poly-
cyclic heterocycles is an ever demanding necessity owing to the
broad range of pharmacological applications these compounds ex-
hibit.1 Fusion of two classes of heterocycles into a single frame is a
challenging proposition, which is gaining prominence of late. The
benzimidazole class of molecules has shown their importance as
bioactive molecules2 and some of them are presently marketed
for various indications, e.g., Omeprazole, esomeprazole, and pan-
toprazole are used as antacids. Isoquinoline framed drug, viz.,
papavarine (alkaloid)3 is also used as a vasodilator and antispas-
modic. An easy access to a benzimidazoisoquinoline skeleton
(Fig. 1) would be of immense potential which has been relatively
less explored.4 With this background, we embarked onto designing
a metal catalyzed strategy to bridge 2-arylbenzimidazole and acet-
ylene functionalities through C–H and N–H activation5 (Scheme 1).
Toward this, we took advantage of recent reports6 by Miura and
co-workers & Ackermann et al. wherein the N–H and C–H activa-
tions have been achieved using Rh and Ru-catalysts.
ble 1). However, further decrease of oxidant to 0.25 or 0.1 equiv re-
sulted in lower yield of the product (entry 9, 10, Table 1).
Next, we tested the generality of this method and the results are
summarized in Table 2. 2-(4-Bromo)-phenylbenzimidazole 1b was
treated with diphenylacetylene under the optimized conditions to
get the tricyclic compound 2b in 81% yield (entry 2, Table 2). Sev-
eral other 2-arylbenzimidazoles (1c–1p) were also subjected to
coupling cyclization protocol using C–H and N–H activations to
get the corresponding benzimidazoisoquinolines (2c–2p) in good
to excellent yields. The results suggest that the nature of substitu-
tion on the 2-aryl group at para-position (Br, Cl, F, NEt2, Me, OMe,
CN, and CF3) had no impact on the product outcome (entries 2–9,
Table 2). The 2-aryl group on benzimidazole having ortho-substitu-
tion gave desired benzimidazoisoquinolines with moderate yields
(entries 10 and 11, Table 2). The substitution at meta-position
ended with a mixture of products (entry 12, Table 2). Entries 15
and 16 demonstrate that the C–H activation also happens on thio-
phene and furan substitutions on the benzimidazole ring.
In an initial attempt, benzimidazole 1a (1 mmol) was treated
with coupling partner diphenylacetylene (1 mmol) and [RuCl2(p-
cymene)]2 (0.05 mmol) in the presence of stoichiometric amounts
of oxidant in various solvents under refluxing conditions to get de-
sired product 2a7 (entries 1–6, Table 1). Excellent yields were ob-
tained when Cu(OAc)2ÁH2O (2 equiv) was used as an oxidant in
toluene (entry 6, Table 1). Interestingly, even 0.5 mmol of
Cu(OAc)2ÁH2O gave the tricyclic product in good yield (entry 8, Ta-
Further, the reactivity of unsymmetrical acetylene has also been
tested for the present method. For instance, the reaction of benz-
Benzimidazole
N
N
Isoquinoline
⇑
Corresponding author. Tel.: +91 40 27193210; fax: +91 40 27160512.
E-mail address: srivaric@iict.res.in (S. Chandrasekhar).
Figure 1. Benzimidazoisoquinoline structure.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.05.106

N. Kavitha et al. / Tetrahedron Letters 54 (2013) 4198–4201
4199
N
N
Ph
R
N
R'
N
[RuCl2(p -cymene)]2
R'
H
H
oxidant
Ph
R
1
2: R = Ph
: R = COOEt
3
Scheme 1.
imidazoles 1g and 1q with ethyl phenylpropiolate under the de-
scribed reaction conditions offered the corresponding benzimi-
dazoisoquinolines 3a and 3b, respectively, as the major isomers
(Table 3).8 The structures of these regioisomers were characterized
by NOE studies.
While demonstrating the power of this synthetic strategy for
preparing various benzimidazoisoquinolines, we also focused our
attention on developing an alternate reaction procedure wherein
the metal catalyst can be recycled. To our utmost satisfaction, all
reactions when carried out in PEG-400 as a solvent medium9 re-
sulted in the formation of desired products in similar yields only
at room temperature (see Table 2).10,11b Moreover, the recyclability
of the catalyst and PEG-400 was also accomplished successfully for
a few times with minimal loss of activity. The results pertaining to
these experiments are shown in Table 4.
Table 1
Optimization of oxidant and reaction conditionsa
Entry
Oxidant (equiv)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
9
NaOAc (2)
NaOAc (2)
Ag2CO3 (2)
Ag2CO3 (2)
Cu(OAc)2ÁH2O (2)
Cu(OAc)2ÁH2O (2)
Cu(OAc)2ÁH2O (1)
Cu(OAc)2ÁH2O (0.5)
Cu(OAc)2ÁH2O (0.25)
Cu(OAc)2ÁH2O (0.1)
DCE
Toluene
DCE
Toluene
DCE
Toluene
Toluene
Toluene
Toluene
Toluene
16
21
33
29
52
91
89
88
50
32
10
a
Reaction and conditions: 1a (1 mmol), diphenylacetylene (1 mmol), [RuCl2(p-
cymene)]2 (0.05 mmol), solvent (4 mL).
Table 2
Reaction of various benzimidazoles (1) with diphenylacetylene11
Entry
2-Aryl benzimidazole
Benzimidazoisoquinoline
Yielda (%)
Conventionalb
PEG-400c
Y
N
Y
N
N
X
X
N
H
Ph
2a: X = Y = H
Ph
1
2
3
4
5
6
7
8
9
1a: X = Y = H
88
81
79
78
74
85
79
74
76
69
61
92
87
83
80
85
84
83
87
81
73
60
1b: X = Br; Y = H
1c: X = Cl; Y = H
1d: X = F; Y = H
1e: X = NEt2; Y = H
1f: X = Me; Y = H
1g: X = OMe; Y = H
1h: X = CF3; Y = H
1i: X = CN; Y = H
1j: X = H; Y = Br
1k: X = H; Y = NO2
2b: X = Br; Y = H
2c: X = Cl; Y = H
2d: X = F; Y = H
2e: X = NEt2; Y = H
2f: X = Me; Y = H
2g: X = OMe; Y = H
2h: X = CF3; Y = H
2i: X = CN; Y = H
2j: X = H; Y = Br
2k: X = H; Y = NO2
10
11
Cl
N
N
Ph
Ph
Cl
2l1
33
35
N
N
N
N
H
12
1l
Cl
2l2
Ph
Ph
Ph
OMe
R
OMe
N
N
N
R
39
35
N
H
OMe
OMe
Ph
(continued on next page)

4200
N. Kavitha et al. / Tetrahedron Letters 54 (2013) 4198–4201
Table 2 (continued)
Entry
2-Aryl benzimidazole
Benzimidazoisoquinoline
Yielda (%)
Conventionalb
PEG-400c
13
14
1m: R = H
1n: R = OMe
2m: R = H
2n: R = OMe
78
71
83
82
N
Z
N
Z
1o: Z = O
N
H
N
2o: Z = O
15
16
69
75
73
81
Ph
2p: Z = S
Ph
1p: Z = S
a
Isolated yield.
b
Reaction and conditions: 1a–1p (1 mmol), diphenylacetylene (1 mmol), [RuCl2(p-cymene)]2 (0.05 mmol), Cu(OAc)2ÁH2O (0.5 mmol), toluene (4 mL), reflux, 12 h.11a
c
Reaction and conditions: 1a–1p (1 mmol), diphenylacetylene (1 mmol), [RuCl2(p-cymene)]2 (0.05 mmol), Cu(OAc)2ÁH2O (0.5 mmol), PEG-400/H2O (4:1), rt, 12 h.11b
Table 3
Reaction of 1g and 1q with ethyl phenylpropiolate11a
Entry
2-Aryl benzimidazole
Benzimidazoisoquinoline
Yielda (%)
N
N
OMe
OMe
N
H
N
1
68
1g
Ph
COOEt
3a
MeO
OMe
OMe
MeO
OMe
OMe
N
N
N
N
H
2
54
1q
Ph
COOEt
3b
a
Isolated yield.
to Suzuki coupling12 product 4, Heck coupling13 product 5, and
Sonogashira reaction14 product 6 (Scheme 2).
Table 4
Recyclability of [RuCl2(p-cymene)]2 and PEG-400
In conclusion, this Letter describes a general strategy toward
the synthesis of a hybrid heterocyclic framework namely benzim-
idazoisoquinoline. The highly regioselective conversion of benzim-
idazoles with unsymmetrical acetylene was also successfully
achieved. A couple of benzimidazoisoquinolines exhibited moder-
ate growth inhibitory activity in selected cancer cell lines (2m on
Entry
Substrate
Product
Isolated yield of the product
1st Run
2nd Run
3rd Run
1
2
3
la
Id
lg
2a
2d
2g
92
80
83
85
74
78
75
60
59
DU-145 showed IC50 at 20.2
lM and 2n on Hela showed IC50 at
15.21 M) and further experiments are in progress.
l
N
N
X
conditions
2b
Acknowledgments
X
conditions
(a)
Ph
Ph
N.K. and V.P.K. thank CSIR, New Delhi for research fellowships,
G.S. thanks CSIR-IICT and P.S.M. thanks DST-WOS-A for financial
assistance.
Ph
4
(b)
(c)
COOMe
5
Supplementary data
Ph
6
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
05.106.
Scheme 2. Reagents and conditions: (a) PhB(OH)2 (1 equiv), PdCl2(PPh3)2 (5 mol %),
Na2CO3 (3 equiv), 1,4-dioxane/H2O (4/1), 4 h, 80 °C, 87%; (b) methyl acrylate
(2 equiv), PdCl2(PPh3)2 (5 mol %), K2CO3 (2 equiv), DMF, 80 °C, 3 h, 76%; (c) phenyl
acetylene (1 equiv), PdCl2(PPh3)2 (5 mol %), CH3CN, Et3N, 80 °C, 4 h, 84%.
References and notes
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line 2b, which has an additional handle in the form of bromo func-
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coupling reactions. Consequently, compound 2b was transformed

N. Kavitha et al. / Tetrahedron Letters 54 (2013) 4198–4201
4201
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(1 mmol),
alkyne (1 mmol), [RuCl2(p-cymene)]2 (0.05 mmol), and
Cu(OAc)2ÁH2O (0.5 mmol) in toluene (4 mL) was heated under reflux for 12 h.
After the reaction was completed, the mixture was cooled to room
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temperature, filtered through a small pad of Celite, washed with ethyl
acetate (2 Â 5 mL), the filtrate was dried, concentrated, and purified through
silica gel column chromatography (10% acetone/hexane) to afford the desired
benzimidazoisoquinoline (2a–p and 3a–b).
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(b) Method B (PEG-400): To a solution of benzimidazole (1a–p) (1 mmol) in
5 mL PEG/H2O (4:1) were added diphenylacetylene (1 mmol), Cu(OAc)2ÁH2O
(0.5 mmol), and [RuCl2(p-cymene)]2 (0.05 mmol) and then stirred at room
temperature for 12 h. The solution was diluted with ether (10 mL), stirred for
10 min and was allowed to stand in ice–salt bath to solidify PEG-400. The ether
layer was decanted, dried over anhydrous Na2SO4, concentrated under reduced
pressure, and the residue obtained was purified by column chromatography
(10% acetone/hexane) to afford the desired benzimidazoisoquinoline (2a–p).
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and the major isomer was isolated in pure form.
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10. The reaction in PEG-400 at 100 °C produces similar results as at room
temperature without hampering the substrates and products.
11. General experimental procedure:
(a) Method
A (conventional method): A solution of benzimidazole (1a–q)