Highly efficient Ag(I)-catalyzed regioselective tandem synthesis of diversely substituted quinoxalines and benzimidazoles in water

Article abstract of DOI:10.1039/c1gc15346c

A green and operationally simple approach for the diverse synthesis of fused quinoxalines and benzimidazoles from o-alkynylaldehydes and amines having an N-tethered nucleophile using Ag(i) as the catalyst in water, is described. The X-ray crystallographic studies confirmed the proposed mechanistic pathway and the cyclized product.

Full text of DOI:10.1039/c1gc15346c

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COMMUNICATION
Highly efficient Ag(I)-catalyzed regioselective tandem synthesis of diversely
substituted quinoxalines and benzimidazoles in water†
Vineeta Rustagi, Trapti Aggarwal and Akhilesh K. Verma*
Received 31st March 2011, Accepted 9th May 2011
DOI: 10.1039/c1gc15346c
A green and operationally simple approach for the diverse
synthesis of fused quinoxalines and benzimidazoles from
o-alkynylaldehydes and amines having an N-tethered nu-
cleophile using Ag(I) as the catalyst in water, is described.
The X-ray crystallographic studies confirmed the proposed
mechanistic pathway and the cyclized product.
o-alkynylbenzaldehyde, amine and various carbon pronucle-
ophiles in the absence7 or in the presence of various alkynophilic
Lewis acid catalysts.8 To the best of our knowledge, tan-
dem synthesis of pyrrolo and indolo fused quinoxaline and
benzimidazoles from ortho-alkynylaldehydes in water has not
been explored. Most notably, reactions of water insoluble
organic compounds taking place in aqueous suspension (“on
water”) are gaining considerable attention due to their high
efficiency and straightforward synthetic protocol.9 Water, in
contrast to common organic reaction media, is an environ-
ment friendly, cheap, imflammable reaction medium which has
often had an unprecedented effect on the rate and selectivity
of organic reactions through hydrophobic interactions and
enrichment of organic substrates in the local hydrophobic
environment.10 As a part of our ongoing efforts to synthesize
N-heterocycles,11 we herein, present our findings on the synthe-
sis of isoquinolino[2,1-a]pyrrolo/indolo[2,1-c]quinoxalines and
benzimidazo[2,1-a]isoquinolines via a AgNO3-catalyzed one-
pot tandem sequence in water using o-alkynylaldehydes and
amines with tethered nucleophiles (Scheme 1). This cascade
strategy involves the formation of two new carbon–nitrogen
bonds and one new carbon–carbon bond thereby leading to
the formation of two heterocyclic rings in one-pot giving fused
polycyclic heterocycles.
Rapid advances in medicinal chemistry continue to underscore
the need of practical routes for the synthesis of heterocycles
as the majority of drug-like compounds contain heterocycles
at their core.1 Recently, transition metal-catalyzed tandem
processes provided a promising method towards this aim which
enabled the efficient conversion of simple starting materials
to complex molecules in an repetitive manner.2 Among the
various transition metals employed in tandem cyclizations,
silver-catalyzed cyclizations have gained considerable attention
because of their ability to activate various p-systems at mild
conditions and at low-catalyst loading.3
As a privileged fragment, isoquinolines are present in a
variety of natural products and in numerous pharmaceutically
important compounds.4 Quinoxalines are an important class of
benzoheterocycles5a that constitute the building blocks of some
organic semiconductors5b and a wide range of pharmacologi-
cally active compounds including anticancer5c and antimicrobial
agents.5c,5d So the molecular skeleton which integrates isoquino-
line as well as quinoxaline moieties might possess properties
of both and enhance the activity. Similarly, isoquinoline-fused
benzimidazoles have attracted considerable interest due to their
outstanding biological activities, such as anti-HIV-1, anticancer,
antimicrobial and antifungal properties.6 Thus, the development
of novel and efficient routes for rapid access to such functional-
ized isoquinolines under mild conditions is of high demand.
In this regard, some progress has been accomplished via
tandem nucleophilic addition and electrophilic cyclization using
Synthetic Organic Chemistry Research Laboratory, Department of
Chemistry, University of Delhi, Delhi, 110007, India. E-mail: averma@
acbr.du.ac.in
1
† Electronic supplementary information (ESI) available: Copies of H
Scheme 1 Tandem synthesis of fused quinoxalines and benzimidazoles.
and 13C NMR spectra for target compounds. CCDC reference number
for compound 3a is 818980 and for compound R is 819358. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c1gc15346c
For the initial experiments, we selected 2-phenylethynyl
benzaldehyde (1a) and 2-(1H-pyrrol-1-yl)aniline (2a) as model
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Table 1 Optimization of the reaction conditionsa
when the bromo substituted substrate 1d was used (entry 4).
Products 3e–g were obtained in 75, 78, 75% yields respectively
when n-butyl, cyclohexyl and trimethylsilyl were employed as
R1 (entries 5–7). Furthermore, when a heteroaromatic nucleus
was introduced in substrates 1h–j, the reaction proceeded well
and provided the desired fused scaffolds 3h–j in 85–92% yields
(entries 8–10). When 2-(3-methyl-1H-indol-1-yl)aniline 2b was
employed as the amine, the reaction proceeded well and products
3k–o were obtained in 78–93% yields (entries 11–15). When
electron-rich aromatic, heteroaromatic, substituents were used
as R1 and a fluoro group used as R4, reaction proceeded well
and provided the corresponding desired fused compounds 3l–n
in 90–93% yield (entries 12–14). A comparative decrease in yield
was observed in the case of an alicyclic substituent R1 (entry 15).
We then further employed the same protocol to examine its
scope for the reaction of benzene-1,2-diamine 2d with function-
ally varied o-alkynylaldehydes 1 (Table 3). Reaction proceeded
well with aromatic R1 group, which provided the fused benzimi-
dazole scaffolds 4a–b in 88 and 92% yield respectively (entries 1–
2). The reaction well accommodated the heteroaromatic nucleus
like pyridine, benzothiophene, quinoline coupled with aromatic,
alicyclic, alkyl substituents respectively; as o-alkynylaldehydes
1i, 1l, 1m–n which provided the desired polycyclic heteroaro-
matic products 4c–f in 75–90% yield (entries 3–6).
With these observations in hand, a plausible mechanism is
proposed (Scheme 2). 1a and 2a generate the condensation
species P which upon activation by AgNO3 results in the
nucleophilic attack from the C-2 position of the pyrrole ring
onto the imine carbon to form Q which after subsequent
aromatization affords species R. p-Complexation between the
alkyne and Ag(I) renders a regioselective 2nd intramolecular
attack of nucleophilic NH onto the alkyne to form intermediate
S, which after subsequent deprotonation leads to the formation
of cyclized product 3a.
Conditions
Yield (%)c
Entry
Catalyst
Solvent
T
◦C
Time (h)
R
3a
1
2
3
4
5
6
7
8
PdCl2
Pd(OAc)2
CuI
AgOAc
AgI
AgOTf
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
Toluene
EtOH
H2O
H2O
H2O
25
25
25
25
25
25
25
25
80
80
80
85
85
85
85
12
12
12
12
12
12
12
10
12
10
10
7
55
60
48
40
25
35
30
25
30
25
55
0
0b
0b
5b
30b
0b
52b
65b
70
60
67
25
92
92
70b
—
9
10
11
12
13
14
15
10
10
10
0
25
—
H2O
a The reactions were performed using o-alkynylaldehyde 1a (0.50 mmol),
amine 2a (0.50 mmol), 8.0 mol% of AgNO3 in 2.0 mL of solvent unless
otherwise noted. b 5.0 mol% of AgNO3 was used. c Yield of isolated
product.
substrates (Table 1). When 5.0 mol% of PdCl2, Pd(OAc)2 were
used as catalysts in CH2Cl2, the reaction was stopped at the
formation of intermediate R and no formation of the desired
product 3a was observed in 12 h (entries 1–2). Similar results
were obtained when other transition metal-catalysts like CuI,
AgOAc, AgI were used (entries 3–5). When AgOTf was used, it
provided the product 3a in only 52% yield along with 35% of
R in 12 h at rt (entry 6). When 5 mol% of AgNO3 was used in
CH2Cl2, it led to the formation of 3a in 65% yield in 12 h (entry
7). However, when 8.0 mol% AgNO3 was used, it resulted the
formation of product 3a in 70% yield in 10 h (entry 8). Screening
different solvents did not provide the desired product 3a in good
yields (entries 9–11). Surprisingly, when water was employed as
a solvent with 8.0 mol%◦of AgNO3, it provided the formation
of 3a in 92% yield at 85 C in 7 h (entry 12). It is notable that
vigorous stirring was required to promote the reaction, most
likely by increasing the area of contact between the organic and
aqueous phase.9a,12 It was noticed that when reaction duration
was increased from 7 to 10 h, it had no effect on the yield of the
product 3a (entry 13). Reducing the amount of AgNO3 from 8.0
to 5.0 mol% adversely decreased the yield of 3a to 70% (entry
14). However, in the absence of catalyst, reactants remained
unchanged during the course of the reaction (entry 15).
Under the optimized reaction conditions, we then examined
the scope of this reaction. As shown in Table 2, the reaction
was tolerant towards a variety of o-alkynylaldehydes 1 bearing
different alkynyl substituents R1. When an electron-donating
group was used as R1, then reaction was well implemented
to form intriguing cyclized products 3a–b in 92–94% yields
(entries 1–2). When an electron-rich heteroaromatic moiety like
thiophene was used as R1, it afforded the formation of product
3c in 93% yield (entry 3). A comparable yield of 3d was obtained
Scheme 2 Plausible mechanism.
The regioselective formation of 3a was confirmed by X-ray
crystallography (Fig. 1).
To support the proposed mechanism, we monitored the
progress of the reaction between 1a and 2a with 5 mol% AgNO3
in water at 85 ◦C. After 3 h, we observed the formation of
intermediate R as a major spot from the TLC along with its
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Table 2 Tandem synthesis of fused quinoxalinesa
Entry
Substrate
Amine
Product
Yield (%)b
2a
1
2
3
4
5
6
7
8
1a, R1 = Ph, R2 = H
2a
2a
2a
2a
2a
2a
2a
2a
3a
3b
3c
3d
3e
3f
92
94
93
85
75
78
75
92
1b, R1 = 4-OMePh, R2 = H
1c, R1 = 3-thienyl, R2 = H
1d, R1 = Ph, R2 = Br
1e, R1 = C(CH3)3, R2 = H
1f, R1 = cyclohexyl, R2 = H
1g, R1 = Si(CH3)3, R2 = H
3g
9
2a
2a
89
85
10
1
2
11
12
13
14
15
1a, R1 = Ph, R2 = H
2b R4 = H
2b R4 = H
2c R4 = F
2c R4 = F
2b R4 = H
3k
3l
3m
3n
3o
88
90
93
91
78
1k, R1 = p-t-bu C6H4, R2 = H
1b, R1 = p-OMe-C6H4, R2 = H
1c, R1 = 3-thienyl, R2 = H
1f, R1 = cyclohexyl, R2 = H
a The reactions were performed using o-alkynylaldehyde 1 (0.50 mmol), amine 2 (0.50 mmol), 8.0 mol % of AgNO3 in 2.0 mL of H2O at 85 ◦C for
7 h, unless otherwise noted. b Yield of isolated product.
heterocyclic ring A first, via the nucleophilic attack from the
pyrrole ring to imine carbon and not the formation of ring
B which would occur via the formation of isoquinolinium
intermediate.13
In conclusion, we have developed an environmentally benign
Ag(I)-catalyzed tandem protocol in water which provides a facile
access to fused polycyclic quinoxalines and benzimidazoles in
good to excellent yields with high regioselectivities and diversity.
These atom economical transformations in water proceeded
with high functional group tolerance. The proposed mechanistic
Fig. 1 X-Ray crystallographic structure of 3a and R (ORTEP drawing).
pathway (sequential C–N, C–C and N–C) was confirmed by the
X-ray crystallographic studies. Owing to the great diversity of
the substitution pattern, this developed chemistry can be used
for the generation of libraries of various heterocyclic systems.
Further investigations in this area are currently under way and
will be reported in due course.
oxidized form T. Both were then isolated and characterized
by NMR. Intermediate R was finally confirmed by X-ray
crystallography (Fig. 1). Isolation of intermediate R clearly
confirms that the reaction proceeds via the formation of the
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Table 3 Tandem synthesis of fused benzimidazolesa
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Entry Substrate
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1a
1k
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a The reactions were performed using o-alkynylaldehyde 1 (0.50 mmol),
amine 2d (0.50 mmol), 8.0 mol% of AgNO3 in 2.0 mL of H2O at 85 ◦
C
for 7 h, unless otherwise noted. b Yield of isolated product.
Acknowledgements
We gratefully acknowledge the Department of Science and
Technology (SR/S1/OC-66/2010) Govt. Of India for providing
financial support and USIC, University of Delhi for providing
instrumentation facilities. V.R. and T.A. are thankful to CSIR,
New Delhi for a fellowship.
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