One-pot concise syntheses of benzimidazo[2,1-a]isoquinolines by a microwave-accelerated tandem process

Article abstract of DOI:10.1016/j.tetlet.2009.04.126

Direct, efficient syntheses of the benzimidazo[2,1-a]isoquinoline ring system have been achieved with 2-bromoarylaldehydes, terminal alkynes, and 1,2-phenylenediamines by a microwave-accelerated tandem process in which a Sonogashira coupling, 5-endo cyclization, oxidative aromatization, and 6-endo cyclization can be performed in a single synthetic operation.

Full text of DOI:10.1016/j.tetlet.2009.04.126

Tetrahedron Letters 50 (2009) 4167–4169
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
One-pot concise syntheses of benzimidazo[2,1-a]isoquinolines
by a microwave-accelerated tandem process
Noriko Okamoto a,b, Keisuke Sakurai a, Minoru Ishikura c, Kei Takeda b, Reiko Yanada a,
*
a Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
b Department of Synthetic Organic Chemistry, Graduate School of Medical Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan
c Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido, Ishikari-Tobetsu, Hokkaido 061-0293, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Direct, efficient syntheses of the benzimidazo[2,1-a]isoquinoline ring system have been achieved with 2-
bromoarylaldehydes, terminal alkynes, and 1,2-phenylenediamines by a microwave-accelerated tandem
process in which a Sonogashira coupling, 5-endo cyclization, oxidative aromatization, and 6-endo cycliza-
tion can be performed in a single synthetic operation.
Received 2 April 2009
Revised 25 April 2009
Accepted 30 April 2009
Available online 5 May 2009
Ó 2009 Elsevier Ltd. All rights reserved.
R2
Synthesis of the benzimidazo[2,1-a]isoquinoline ring system
has attracted a great deal of attention because of its biological
activities associated with the hybrid structure of isoquinoline1
and benzimidazole.2 Although some approaches to the ring system
have been reported,3 one of the most efficient methodologies in-
volves direct formation of the isoquinoline ring by metal-catalyzed
cyclization of alkynylbenzene derivatives. We have recently re-
ported the formation of 1,2-dihydroisoquinoline derivatives by In(-
OTf)3-catalyzed tandem cyclization of ortho-alkynylarylimines,4 in
which the starting alkynylbenzene derivatives were obtained by a
Sonogashira coupling from the corresponding aryl halides. Herein,
we report an efficient methodology for the construction of the
benzimidazo[2,1-a]isoquinoline ring system from 2-bromoarylal-
H2N
H2N
Br
R2
R1
R1
R3
+
+
N
CHO
R3
H2N
R2
R1
N
N
R3
1
Scheme 1. Tandem approach to the synthesis of benzimidazo[2,1-a]-isoquinolines
1.
dehydes, terminal alkynes, and 1,2-phenylenediamines via
a
microwave-accelerated tandem process5 in which a copper- and li-
gand-free Sonogashira coupling, 5-endo cyclization, oxidative aro-
matization, and 6-endo cyclization can be performed in a single
synthetic operation (Scheme 1).
3a: R1 = H, R2 = H
3b: R1 = H, R2 = Bu
3c: R1 = H, R2 = Ph
3d: R1 = H, R2 = Tol
–
R2
42% yield
79% yield
55% yield
Br
R2
R1
R1
Pd(OAc)2
PPh3
3e: R1 = 4-Me, R2 = Ph 54% yield
CHO
CHO
Prior to the investigation of the tandem strategy, we decided to
tune the reaction conditions for each step, and we first examined
the Sonogashira coupling reaction using o-bromobenzaldehyde
derivatives 2. O-Alkynyl aromatic aldehydes 3 were obtained in
42–79% yields, indicating the tolerance of an aldehyde group in
the coupling conditions (Scheme 2).
Since the Sonogashira coupling proceeded well, we next exam-
ined the second annulation step, in which an isoquinoline ring and
an imidazole ring can be formed in a tandem fashion starting from
2a: R1 = H
3f: R1 = 5-F, R2 = Ph
77% yield
CuI
2b: R1 = 4-Me
2c: R1 = 5-F
Et3N
Ph
Ph
Ph
N
CHO
3g: 74% yield
CHO
3i: 63% yield
S
CHO
3h: 73% yield
Scheme 2. Syntheses of o-alkynyl aromatic aldehydes.
2-ethynylbenzaldehydes
3 and 1,2-phenylenediamines 4. At-
alyzed cyclization of o-alkynylarylimines has been reported as a di-
rect method for the synthesis of isoquinolines.4,6 We therefore
screened a range of metal-catalyst systems including In(OTf)3,
Pd(OAc)2/CuI, and Pd(OAc)2 at 120 °C (runs 2–4). Among them,
Pd(OAc)2 afforded the best result under aerobic conditions. Since
the lower yields obtained for 1a may be attributed to decomposi-
tion of the products due to prolonged heating, we decided to
tempted cyclization using the protocol described by Dyker, who
used nitrobenzene both as an oxidizing agent and as a solvent,3a
resulted in lower yield of 1a (Table 1, run 1). Recently, metal-cat-
* Corresponding author.
E-mail address: ryanada@ps.hirkoku-u.ac.jp (R. Yanada).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.126

4168
N. Okamoto et al. / Tetrahedron Letters 50 (2009) 4167–4169
Table 1
Stepwise reaction of 3a with 4
catalyst
H2N
H2N
X
X
condition
+
N
solvent
CHO
reaction time
X
N
1
3a
4a: X= H, 4b: X= Me
X
Run
Catalyst
Mol (%)
4
Condition
Solvent
Time (h)
1
Yield (%)
1a
2b
3b
4b
5b
6b
—
—
10
2
2
2
4a
4a
4a
4a
4a
4b
Heatc
PhNO2
DMF
DMF
DMF
DMF
DMF
24
24
13
10
5
1a
1a
1a
1a
1a
1b
41
26
27
60
68
64
In(OTf)3
Pd(OAc)2, CuI
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Heatc
Heatc
Heatc
l
l
Wd
Wd
2
5
a
b
c
Under nitrogen atmosphere.
Under aerobic conditions.
Oil bath temperature of 120 °C. Compound 3a (concentration of 0.5 M).
Microwave irradiation at 120 °C. Compound 3a (concentration of 2.0 M).
d
conduct the reaction under microwave irradiation with the inten-
tion of minimizing the quantity of solvents and accelerating the
reaction. In fact, the reaction was greatly accelerated with micro-
wave irradiation and was completed in 5 h to give 1a in improved
yield (run 5). This microwave irradiation reaction with dimethyl
derivative 4b also gave 1b in moderate yield (run 6).
X
HX
H2N
N
H
5: X=O
6: X=S
7: X=O, 82% yield
8: X=S, 77% yield
Scheme 3.
Having in hand the optimized conditions for each step, we next
examined a one-pot synthetic strategy that would allow direct for-
mation of the benzimidazo[2,1-a]isoquinoline ring system. In an
attempt to improve the reaction conditions, we found that the
one-pot reaction of compounds 2a, phenylacetylene, and 1,2-phen-
ylenediamine 4a can proceed smoothly even in the absence of CuI
and PPh3 to give 1e in 68% yield under microwave irradiation
(Table 2, run 1).7,8 Furthermore, both Cs2CO3 and tetrabutylammo-
nium acetate (Bu4NOAc) were effective as bases, the latter being
more effective, allowing for complete conversion to 1e within
0.5 h (runs 2 and 3). Bu4NOAc might facilitate the reduction of
Pd(OAc)2 to a catalytically active Pd(0) species (Pd nanoparticle).9
To determine the general utility of this procedure, we applied these
improved conditions to other aldehydes 2, terminal alkynes, and
1,2-phenylenediamines 4. Change in the electronic nature of sub-
stituents on the aromatic rings of the aldehydes and on alkynes
did not affect the efficiency of the reaction, giving the expected
hybrid compounds 1 in moderate yields in the presence of DMF
(concentration of 5 M) after 0.5–1.0 h at 120 °C and 200 watts
(W) (runs 4–13).
Finally, we briefly examined the reactions using aminophenol 5
and aminothiophenol 6 to see whether heteroatoms other than
nitrogen can participate in the tandem reaction. When compounds
5 and 6 were treated with phenylacetylene and 1,2-phenylenedi-
amine under similar reaction conditions, only dibenzoxazepine 7
and dibenzothiazepine 8 were obtained in 82% and 77% yields,
respectively (Scheme 3).
Table 2
One-pot preparation of benzimidazo[2,1-a]isoquinoline
1
under microwave
irradiation
R2
N
4
R1
R2
2 +
Pd(OAc)2, base
DMF, µW (120 ºC)
X
N
1
X
Run
2
R1
R2
4
Base
Time (h)
1
Yielda (%)
1
2
2
3
4
5
6
7
8
9
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
H
H
H
H
H
H
H
H
Ph
Ph
Ph
Ph
Bu
Bu
Ph
p-Tol
Ph
4a
4a
4a
4a
4a
4b
4b
4a
4a
4b
Et3N
Cs2CO3
Cs2CO3
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
Bu4NOAc
5.0
3.0
3.0
0.5
0.5
0.5
1.0
0.5
0.5
0.5
1e
1e
1e
1e
1c
1d
1f
1g
1h
1i
68
70
70
80
77
70
76
78
81
83
4-Me
4-Me
Ph
10
11
2c
5-F
Br
Ph
Ph
4a
4a
Bu4NOAc
Bu4NOAc
0.5
1.0
1j
79
73
In summary, we have demonstrated a new and concise method
for one-pot construction of benzimidazo[2,1-a]isoquinolines start-
ing from 2-bromoarylaldehydes, terminal alkynes, and 1,2-pheny-
lenediamines by a microwave-promoted tandem process that
involves imine formation, copper-ligand-free Sonogashira reaction,
5-endo-trig cyclization, oxidative aromatization, and 6-endo-dig
cyclization reaction.
N
1k
CHO
2d
Br
12
Ph
Ph
4b
4a
Bu4NOAc
Bu4NOAc
1.0
0.5
1l
79
77
CHO
Acknowledgment
2e
Br
This work was supported by a Grant-in-Aid for Scientific Re-
search(C) from JSPS KAKENHI (20590027).
13
1m
CHO
S
Supplementary data
2f
a
Conditions: Aldehyde
2 (0.5 mmol), alkyne (0.55 mmol), 1,2-diamine 4
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.04.126.
(0.55 mmol), Pd(OAc)2 (0.01 mmol), and Bu4NOAc (1.0 mmol) were dissolved in
DMF (100 l), (concentration of 5.0 M). Microwave irradiation (120 °C, 200 W).
l

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4169
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