Synthesis of substituted benzimidazo[2,1-a]isoquinolines and its condensed analogues using Pd(0)-catalyzed cyclization/C-H activation

Article abstract of DOI:10.1016/j.tetlet.2010.07.162

An efficient route for the synthesis of benzimidazo[2,1-a]isoquinolines and its condensed analogues has been developed via the palladium-catalyzed cyclization/C-H activation of N-allyl and N-methallyl derivatives of benzimidazoles.

Full text of DOI:10.1016/j.tetlet.2010.07.162

Tetrahedron Letters 51 (2010) 5294–5297
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Tetrahedron Letters
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Synthesis of substituted benzimidazo[2,1-a]isoquinolines and its condensed
analogues using Pd(0)-catalyzed cyclization/C–H activation
*
Sukla Nandi, Shubhankar Samanta, Susovan Jana, Jayanta K. Ray
Department of Chemistry, Indian Institute of Technology, Kharagpur 721 302, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 June 2010
Revised 7 July 2010
Accepted 30 July 2010
Available online 10 August 2010
An efficient route for the synthesis of benzimidazo[2,1-a]isoquinolines and its condensed analogues has
been developed via the palladium-catalyzed cyclization/C–H activation of N-allyl and N-methallyl deriv-
atives of benzimidazoles.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Benzimidazo[2,1-a]isoquinoline
exo-Trig
Palladium-catalyzed cyclization
C–H activation
Fused imidazo[1,2-a]heterocycles moiety which is a key struc-
tural component of bioactive molecules was widely incorporated
in the design of multiple biologically active agents and has already
been known for its antimicrobial activity along with antiviral, anti-
ulcer, antihypertension, and cardiotonic properties. The synthesis
of various benzimidazoles fused with aza-aromatic ring systems,
such as benzimidazo[2,1-a]isoquinolines (I) and pyrido[1,2-e]pur-
ines (II), as anticancer agents,1 are reported in the literature. On
the other hand the benzo[d]imidazole subunit has been exclusively
used in the design of drugs such as Pimobendan, a dihydropyridaz-
inone-benzo[d]imidazole derivative that acts as a calcium sensi-
tizer, as well as a partial inhibitor of PDE-3 and is also effective
in both acute and chronic heart failure (Fig. 1).2.
synthesis of benzimidazo[2,1-a]isoquinolines and its condensed
analogs from N-allyl and N-methallyl derivatives of
benzimidazoles.
Attention was first focused on the construction of the starting
materials for the cyclization/C–H activation by N-allylation and
N-methallylation of benzoimidazole 3 and 4 (Scheme 1). At first
the aromatic bromoaldehydes 1 (1 mmol) were treated with a mix-
ture of 1,2-phenylenediamine (1 mmol), H2O2 (30%, 4 mmol,
0.4 mL), and NH4Ce(NO3)6 (0.1 mmol, 0.0548 g) at 50 °C for
10 min10 to get the benzoimidazole 2. Benzoimidazoles were
converted to N-allylated/methallylated products 3 and 4 (for struc-
tures, see Tables 2 and 3) by the reaction with allyl bromide/meth-
allyl bromide in the presence of sodium hydride in THF at reflux
temperature.
First the intramolecular Heck reaction was performed with N-
allylated derivatives 3a in the presence of Pd(OAc)2 (10 mol %),
PPh3 (0.25 equiv), Cs2CO3 (1.2 equiv) in DMF at 95–100 °C which
affords substituted benzimidazo[2,1-a]isoquinoline derivatives 5a
in 58% yield. Compound 4a on same reaction condition gave the
condensed analog 6a in 55% yield.
There are various methods available for the synthesis of benz-
imidazo[2,1-a]isoquinolines and its condensed analogs.3–6 One of
the approaches involves Bu3SnH-mediated 6-exo-trig cyclization
of
r-aryl radicals generated from 1-allyl-2-(x-bromoaryl)benzim-
idazoles7 and another approach involves microwave-accelerated
tandem process in which a Sonogashira coupling, 5-endo cycliza-
tion, oxidative aromatization, and 6-endo cyclization can be
performed in a single synthetic operation using 2-bromoarylal-
dehydes, terminal alkynes, and 1,2-phenylenediamines as starting
materials.8 Among these, palladium-catalyzed cyclization is a very
powerful method due to its tolerance of a wide variety of func-
tional groups, thus neatly avoiding protection group chemistry.
So in continuation of our efforts on C–C bond formation reaction,9
herein we report Pd(0)-catalyzed cyclization/C–H activation for the
N
R
N
R2R1N
N
N
N
Y
N
X
I
II
* Corresponding author. Tel.: +91 3222283326; fax: +91 3222282252.
E-mail address: jkray@chem.iitkgp.ernet.in (J.K. Ray).
Figure 1. Some biologically active molecules.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.07.162

S. Nandi et al. / Tetrahedron Letters 51 (2010) 5294–5297
5295
R1
Br
H
R1
R1
Br
R1
R
CHO
+
Br
X
X
X
X
NH2
NH2
N
H2O2, CAN
X
X
NaH, THF
reflux, 4 h
N
N
solvent-free,
50oC
N
R1
R1
R
1
R1 = H or OMe
X = H or Cl
2
Br
3 R = H
4 R = Me
R = H, Me
Scheme 1. Preparation of N-allyl and N-methallyl derivatives of benzimidazoles.
Table 1
Table 2
Optimization of the reaction condition by using different types of catalysts, bases, and
Pd(0)-catalyzed intramolecular reaction of N-allylated benzoimidazole derivativesa
solventsa
R2
R2
Br
R
N
N
Br
NaOAc, PdCl2(PPh3)2
DMA, 100 oC, 2 h
N
N
Base, Catalyst
N
N
N
N
Solvent, Heat
R = H
R2 = H, OMe
5a-5c
3a R = H
4a R = Me
3a-3c
Base, Catalyst
Solvent, Heat
R = Me
R1
R1
Br
R3
X
X
N
NaOAc, PdCl2(PPh3)2
DMA, 100 oC, 2 h
X
X
N
N
R3
N
R1
R1
N
N
3d-3h
5d-5h
R3 = H, Me, F
R1 = H, OMe
X = H, Cl
Entry
Catalyst
Base
Solvent
Yield (%)
6a
5a
Entry Substrate
Product
Yield
(%)
1
2
3
4
5
6
7
8
PdCl2(PPh3)2
Pd(PPh3)4
PdCl2
NaOAc
NaOAc
NaOAc
Cs2CO3
Et3N
NaOAc
Na2CO3
NaOAc
DMA
DMA
DMA
DMF
CH3CN
CH3CN
DMA
87
56
NRb
58
15
30
52
85
50
NRb
Br
Br
Br
Br
Pd(OAc)2
55
15
26
N
N
N
1
2
3
4
5
87
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
PdCl2(PPh3)2
N
5a
45
3a
3b
3c
PhCH3
Decomp.b
Decomp.b
OMe
OMe
Decomp.: decomposition of starting material.
Reaction conditions: substrate 3a or 4a (1 mmol), catalyst (10 mol %), base
(1.2 mmol), and solvent (5 mL) at 100–110 °C for 2 h.
a
N
N
N
N
81
79
90
85
b
NR: no reaction.
5b
5c
OMe
N
N
OMe
N
N
Optimization of the reaction condition was done with 3a and 4a
as the model substrates by changing different types of catalysts,
bases, and solvents. When the reaction was carried out in acetoni-
trile poor yields were obtained (Table 1, entries 5 and 6) and in the
case of the PdCl2 catalyst no cyclized product was isolated (Table 1,
entry 3). 3a and 4a on treatment with PdCl2(PPh3)2 (10 mol %),
NaOAc (1.2 equiv) in DMA at 100–110 °C afforded 5a and 6a in
80–90% yield (Table 1, entry 1).
With the optimized reaction conditions, [PdCl2(PPh3)2
(10 mol %) as a catalyst, NaOAc (1.2 equiv) as a base, and DMA as
a solvent at 100–110 °C], we examined the generality and sub-
strate scope of this cyclization reaction of substituted N-allylated
derivatives 3a–3h to afford substituted benzimidazo[2,1-a]iso-
quinoline derivatives 5a–5h in good yields11 via 6-exo-trig cycliza-
tion as shown in Table 2. Here compounds 3a–3c gave the
products with exo cyclic double bond but in case of the compounds
3d–3h isomerised products were obtained. This difference may be
due to the steric interaction between the methyl group and the
peri hydrogen of naphthyl ring which makes the isomerised prod-
ucts unstable in case of the compounds 3a–3c (Fig 2).
N
N
N
N
5d
5e
3d
3e
3f
Br
Br
N
N
Me
N
N
Me
N
N
N
N
6
80
F
5f
F
(continued on next page)

5296
S. Nandi et al. / Tetrahedron Letters 51 (2010) 5294–5297
Table 2 (continued)
H
Me
Entry Substrate
Product
Yield
(%)
N
N
OMe
OMe
Br
N
Figure 2. Steric interaction between methyl group and peri hydrogen of naphthyl
N
7
81
ring.
N
N
5g
OMe
3g
OMe
A plausible rationale for the formation of the products (6a–6e)
is shown in Scheme 2.
Br
Cl
Cl
N
N
Cl
Cl
N
Initially an alkenyl palladium (II) intermediate was generated
by oxidative addition of Pd(0) to the sp2 C–Br bond which under-
goes addition to the inactivated double bond to produce an alkyl-
palladium which underwent cyclization with the aromatic ring
through C–H activation.12 Since no elimination is possible due to
the absence of a b-H in the alkylpalladium intermediates, C–H acti-
vation is facilitated.
8
80
N
5h
3h
a
Reagents and conditions: 3a–3h (1 equiv), PdCl2(PPh3)2 (10 mol %), NaOAc
(1.2 equiv), DMA (5 mL), 100–110 °C.
The ORTEP structure of the condensed analog of benzimi-
dazo[2,1-a]isoquinoline 6a is shown below (Scheme 3).
In conclusion, we have developed a general methodology for the
synthesis of benzimidazo[2,1-a]isoquinoline and its highly con-
densed analogs by Pd(0)-catalyzed cyclization/C–H activation. This
On the other hand N-methallylated derivatives 4a–4e with
same Heck reaction conditions afforded highly condensed analogs
of benzimidazo[2,1-a]isoquinoline 6a–6e (Table 3) in good yields11
via 6-exo-trig cyclization followed by C–H activation.
Table 3
Pd(0)-catalyzed intramolecular reaction of N-methallylated benzoimidazole derivativesa
R4
R1
R1
Me
R4
Br
NaOAc, PdCl2(PPh3)2
DMA, 100 oC, 2 h
X
X
N
N
X
X
N
N
R1
R1
4a-4e
6a-6e
R4 = H, OMe
R1 = H, OMe
X = H, Cl
Entry
1
Substrate
Product
Yield (%)
85
Me
Br
Br
Br
Br
N
N
N
N
6a
4a
Me
OMe
OMe
N
N
N
N
2
3
78
75
6b
6c
4b
Me
OMe
N
N
OMe
N
N
4c
Me
OMe
OMe
OMe
N
N
N
4
76
80
N
6d
4d
Me
OMe
Br
N
N
N
N
5
6e
4e
a
Reagents and conditions: 4a–4e (1 equiv), PdCl2(PPh3)2 (10 mol %), NaOAc (1.2 equiv), DMA (5 mL), 100–110 °C.

S. Nandi et al. / Tetrahedron Letters 51 (2010) 5294–5297
5297
N
N
Pd(II)
BH+Br-
Br
Me
Pd(0)
B:
N
N
HPdBr
N
N
BrPd
Me
N
N
N
N
PdBr
H
Pd
Br
Scheme 2. A plausible rationale for the Pd(0)-catalyzed cyclization followed by C–H activation.
Cooper, C. B.; Deshpande, M. J. Org. Chem. 2000, 65, 8059; (c) Hranjec, M.; Kralj,
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(h) Alajarin, M.; Vidal, A.; Tovar, F.; Conesa, C. Tetrahedron Lett. 1999, 40, 6127.
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A., Taylor, E. C., Eds.; Interscience Publishers: New York, 1980; Vol. 40, p 257.
7. Moriarty, E.; Aldabbagh, F. Tetrahedron Lett. 2009, 50, 5251.
Scheme 3. ORTEP structure of condensed analog of benzimidazo[2,1-a]isoquinoline
6a.
8. Okamoto, N.; Sakurai, K.; Ishikura, M.; Takeda, K.; Yanada, R. Tetrahedron Lett.
2009, 50, 4167.
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7153; (b) Jana, R.; Chatterjee, I.; Samanta, S.; Ray, J. K. Org. Lett. 2008, 10, 4795.
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11. General procedure for the synthesis of benzimidazo[2,1-a]isoquinolines and its
condensed analogs.
methodology can also be used for the synthesis of various types of
benzimidazoisoquinolines and benzimidazolequinones natural
products which have been reported to exhibit potent biological
activity.
Compounds 3 or 4 (1 equiv), PdCl2(PPh3)2 (10 mol %), NaOAc (1.2 equiv), and
DMA (5 mL) were placed in
a two-necked round-bottomed flask. After
degassing with N2, the mixture was heated at 100–110 °C for 2 h. After
cooling, the reaction mixture was diluted with saturated NH4Cl solution,
extracted with EtOAc (30 mL Â 3), and the combined organics dried (Na2SO4).
The solvent was evaporated and the crude product was purified by column
chromatography.
Acknowledgements
We thank the CSIR, New Delhi, for the fellowships, the D.S.T. for
providing funds for the project, and creating 400 MHz NMR facility
under the IRPHA program.
Spectral data of representative compounds.
Compound 5a: yellow liquid, 1H NMR (CDCl3, 200 MHz) d: 4.95 (s, 2H), 5.85 (s,
2H), 7.27–7.41 (m, 3H), 7.51–7.56 (m, 2H), 7.85–7.92 (m, 3H), 8.39–8.51 (m,
2H); 13C NMR (CDCl3, 200 MHz) d: 49.33, 109.00, 119.98, 122.35 (2C), 122.71,
123.11, 123.71, 125.96, 126.93, 127.15, 128.99, 129.32, 129.69, 131.34, 134.54,
134.86, 135.12, 143.76, 148.85; HRMS: calcd for C20H15N2 [M++H]: 283.1235,
found: 283.1231.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.07.162.
Compound 5e: pale yellow solid, mp 132 °C, 1H NMR (CDCl3, 200 MHz) d: 2.39
(s, 3H), 2.49 (s, 3H), 7.33 (t, 1H, J = 7 Hz), 7.41–7.48 (m, 3H), 7.64 (d, 1H,
J = 8 Hz), 7.74 (s, 1H), 7.95 (d, 1H, J = 8 Hz), 8.66 (d, 1H, J = 8.6 Hz); 13C NMR
(CDCl3, 200 MHz) d: 16.36, 22.08, 109.64, 117.30, 119.08, 119.48, 120.84,
121.31, 123.85, 124.26, 125.07, 129.28, 129.84, 132.30, 140.14, 143.56, 147.16;
HRMS: calcd for C17H15N2 [M++H]: 247.1235, found: 247.1231.
References and notes
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3.30 (d, 1H, J = 16.2 Hz), 3.52 (d, 1H, J = 16.2 Hz), 3.99 (s, 3H), 4.05 (s, 1H), 4.57
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