A facile approach for synthesis of benzofuro[2,3-c]pyridines via intramolecular cascade annulations

Article abstract of DOI:10.1002/cjoc.201400364

A facile synthesis of benzofuro[2,3-c]pyridines has been achieved under mild conditions by using ammonium acetate as the nitrogen source through intramolecular cascade annulation. This reaction could efficiently construct pyridine ring and furan ring in o

Full text of DOI:10.1002/cjoc.201400364

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DOI: 10.1002/cjoc.201400364
A Facile Approach for Synthesis of Benzofuro[2,3-c]pyridines
via Intramolecular Cascade Annulations
Ying Duan,* Ye Wang, and Dongmi Li
College of Chemistry and Chemical Engineering, Luoyang Normal University, Luoyang, Henan 471022, China
A facile synthesis of benzofuro[2,3-c]pyridines has been achieved under mild conditions by using ammonium
acetate as the nitrogen source through intramolecular cascade annulation. This reaction could efficiently construct
pyridine ring and furan ring in one step. Moreover, the key annulation step was demonstrated through dihydro-
benzofuran intermediates.
Keywords benzofuro[2,3-c]pyridines, intramolecular cascade annulation, ammonium acetate
Introduction
Scheme 1 Retrosynthetic analysis of benzofuro[2,3-c]pyridines
and proposed intramolecular cascade annulations pathway
Pyridines play important roles in agricultural
chemicals, organic materials and pharmaceuticals.[1]
Therefore, the synthesis of different kinds of pyridine
derivatives has been a hot point in organic chemistry.[2]
Among them, benzofuro[2,3-c]pyridines which serve as
an important type of pyridines, have been claimed to
have several biological activities.[3] Although there have
been several examples documented for the synthesis of
these compounds, most of them require multistep pro-
cedures to generate the pyridine and furan rings indi-
vidually,[4] or suffer from limited substrate scope and
harsh reaction conditions.[4a,4e] So far, there are a few
methods on the synthesis of benzofuro[2,3-c]pyridines
by construction of the furan and pyridine rings in a sin-
gle step.[5] Very recently, one-pot domino reaction was
reported to synthesize benzofuro[2,3-c]pyridines by Yin
and Zhang[6] when we prepared our manuscript. How-
ever, a selective access to these pyridine derivatives
from a concise and efficient method as well as eco-
nomical ingredients would be still highly desirable.
Herein, we report an efficient method for the synthesis
of benzofuro[2,3-c]pyridines. The significance of this
approach also relates to the use of commercially avail-
able starting materials and the mild conditions.
O
R'
R'
NH4OAc
+
N
O
R
O
R
+
1
2
O
O
O
R
Br
O
c
H
+
+
NH4OAc
R'
OH
d
a
b
Commercially available starting materials
Proposed intramolecular cascade annulation pathway
Ph
O
O
Ph
Ph
HOAc
NH3
O
O
HOAc
O
O
Ph
3
1a
NH4OAc
Ph
Ph
NH
HOAc
- H2O
O
NH2
O
O
Ph
II
I
Ph
Ph
Our retrosynthetic analysis for a novel route to ben-
zofuro[2,3-c]pyridines 2 is shown in Scheme 1. Benzo-
furo[2,3-c]pyridines 2 could be synthesized through
intramolecular cascade annulation of keto-enones 1 with
ammonium acetate (component a), while keto-enones
could be easily prepared from the bromomethylketones
(component b), methylketones (component c) and sali-
cylic aldehydes (component d) through nucleophilic
substitution and condensation.[7] Four components a－
Aromatization
N
O
Ph
2a
d are all commercially available and could be used for
building the architectures of benzofuro[2,3-c]pyridines
2 efficiently. Although there have been many efficient
methods to synthesize pyridines, this approach that
*
E-mail: duanying7@163.com; Tel.: 0086-0379-65515113
Received June 4, 2014; accepted September 1, 2014; published online October 8, 2014.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201400364 or from the author.
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Duan, Wang & Li
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combined four components efficiently to prepare the
ring fused pyridines with intramolecular cascade annu-
lation was rare in the previous reports. Moreover, am-
monium acetate[8] is superior to other sources of nitro-
gen owing to its low-price, convenient operation as well
as the facilitation of the acetic acid generated in the re-
action.[9] Such a synthesis would find wide application
owing to that it provides an avenue to diversely substi-
tuted benzofuro[2,3-c]pyridines.
Next, amination of 3 gives the enamine intermediate I.
Then the second annulation takes place to afford the
intermediate II, followed by the dehydrogenative aro-
matization to give the desired product benzofuro[2,3-c]-
pyridine (2a). In this process, ammonium acetate serves
as nitrogen resource and acid catalyst (acetic acid from
the ammonium acetate).[9] The crucial point is to assay
the conditions of the intramolecular cascade annulation.
To obtain the best conditions for the intramolecular
cascade annulation, we first examined the reaction of 1a
with ammonium acetate. Considering that the HOAc
was always selected as the solvent in the synthesizing
pyridines from diketones and ammonium acetate,[11] we
start our study with HOAc as the solvent. 68% yield
was achieved with the product 2a (Table 1, Entry 1).
The chemical structure of 2a was confirmed by X-ray
crystal diffraction.[12] Further investigation of alcohol
solvents such as MeOH and i-PrOH gave lower yields
(Table 1, Entries 2 and 3). Changing the solvent to
DMSO produced a slightly higher yield (Table 1, Entry
4). The annulations proceeded agonizingly in toluene
(Table 1, Entry 5). Utilizing THF as the solvent resulted
in the highest yield (Table 1, Entry 6). So the optimized
conditions for the intramolecular cascade annulation are
THF/60 ℃.
Experimental
Materials
Commercially available reagents were used through-
out without further purification.
General procedure for synthesis of keto-enones 1
Keto-enones 1a－1w were synthesized from the
corresponding 2-hydroxyl chalcones and 1-subtituted
2-bromoethanones according to slightly modified lit-
erature procedures.[7]
To a suspension of K2CO3 (1.382 g, 10 mmol) and
2-hydroxyl-substituted chalcones (5 mmol) in acetone
(60 mL) was added 1-subtituted 2-bromoethanone (7.5
mmol) at 0 ℃. The resulting mixture was warmed to
room temperature and stirred until the starting material
was completely consumed (observed by TLC, about 1
h). Water (50 mL) was added and the mixture was ex-
tracted with CH2Cl2 (30 mL×3). The organic layer was
combined and dried over Na2SO4. The solvent was re-
moved under reduced pressure and the keto-enones 1
was washed with petroleum ether and EtOAc (V∶V＝
10∶1) and dried.
Table 1 Optimization of the intramolecular cascade annulation
of 1aa
O
Ph
Solvent
Ph
+
NH4OAc
N
Ph
O
O
Ph
O
1a
2a
Entry
Solvent
AcOH
MeOH
i-PrOH
DMSO
Toluene
THF
T/℃
120
65
Yieldb/%
General procedure for synthesis of benzofuro[2,3-c]-
pyridines 2
1
2
3
4
5
6
68
35
56
71
20
77
To a solution of 1 (0.3 mmol) in THF (3.0 mL) at
room tempeture was added NH4OAc (0.231 g, 3.0
mmol). The mixture was warmed to 60 ℃ and stirred
for 24 h. Water (10 mL) and CH2Cl2 (10 mL) were
added into the reaction mixture and separated, the water
layer was then extracted with CH2Cl2 (10 mL×3), the
combined organic phases dried over anhydrous Na2SO4
and then removed in vacuo. After purification on silica
gel using petroleum ether and EtOAc (V∶V, 50∶1－
30∶1), benzofuro[2,3-c]pyridines 2 were obtained.
82
120
110
60
a
Reaction conditions: 1a (0.3 mmol), ammonium acetate (3.0
mmol), solvent (3.0 mL), 24 h. b Isolated yields.
Having identified the optimal reaction conditions,
we set out to examine the scopes and limitations of the
intramolecular cascade annulation reaction, and the re-
sults are summarized in Table 2. Both alkyl and aryl
substituent groups were good partners to give the cor-
responding benzofuro[2,3-c]pyridines 2 in moderate to
good yields. Generally, when both R2 and R3 were aryl,
the products were obtained with higher yield than other
substrates accordingly (Table 2, Entries 1－6 vs. Entries
7 and 8). The electronic property and steric effect of R3
showed limited impact on the yields (Table 2, Entries 2
and 3 as well as Entries 4－6, respectively). The inves-
tigation of the group of R2 exhibited that these sub-
Results and Discussion
Before the research, we also took the feasibility of
the proposal into account. The possible pathway of the
intramolecular cascade annulation is illustrated in
Scheme 1. The reaction pathway was proposed to begin
with the first cyclization reaction promoted by acetic
acid in stiu released from ammonium acetate to generate
the intermediate dihydrobenzofuran 3.[7a] While dicar-
bonyls condensation with NH3 (ammonia) is considered
to be an common protocol in pyridine synthesis.[8a-8h,10]
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A Facile Approach for Synthesis of Benzofuro[2,3-c]pyridines
Table 2 The synthesis of benzofuro[2,3-c]pyridines 2a
also be obtained when R1＝Me (Table 2, Entry 24).
To further demonstrate the potential synthetic appli-
cation, the intramolecular cascade annulation reaction of
1d and ammonium acetate was performed at the gram
scale. As illustrated in Eq. 1, the desired product 2i was
isolated with 74% yield.
O
R1
THF, 60 oC
R2
R3
+
NH4OAc
O
O
1
R1
R2
O
THF, 60 oC
Ar
Ph
N
NH4OAc
+
O
R3
O
2
O
1i: Ar = 4-MeOC6H4
Entry R1
R2
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
R3
Yieldb/%
1.676 g, 4.5 mmol
1
2
H
Ph
77 (2a)
70 (2b)
67 (2c)
67 (2d)
71 (2e)
73 (2f)
Ar
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Br
Br
Br
4-MeC6H4
4-BrC6H4
N
(1)
O
3
Ph
4
4-MeOC6H4
2i: 74% yield
5
3-MeOC6H4
To confirm the pathway experienced in the annula-
tion, dihydrobenzofuran 4 was synthesized using the
same method as 1 but with longer reaction time. When
dihydrobenzofuran 4 was subjected to the standard reac-
tion conditions, annulation product 5 could be isolated
with 83% yield (Eq. 2). This result illustrated that the
reaction proceeds from dihydrobenzofuran intermediate
and the pathway proposed before is reasonable.
6
2-MeOC6H4
7
Me
65 (2g)
61 (2h)
77 (84)c (2i)
75 (2j)
8
Et
9
4-MeOC6H4
4-FC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
4-ClC6H4
4-MeC6H4
4-MeC6H4
Me
Ph
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph
4-MeC6H4
67 (2k)
60 (2l)
Et
Ph
Ph
63 (2m)
70 (2n)
64 (2o)
64 (2p)
61 (75)c (2q)
65 (2r)
55 (2s)
O
O
THF, 60 oC
+
NH4OAc
Et
O
Ar
: Ar = 3,4-Cl2C6H3
Ph
4
Et
Ph
Ph
4-MeC6H4
4-MeOC6H4
Et
N
(2)
Me
O
Ar
Me
5
: 83% yield
Me
68 (2t)
Me
Ph
57 (2u)
58 (2v)
58 (2w)
70 (2x)
Conclusions
Me
4-MeC6H4
Et
In conclusion, we report an efficient method to syn-
thesize benzofuro[2,3-c]pyridines via intramolecular
cascade annulation with constructing the furan and
pyridine subset in one step. Easily-handled operation
and cheap materials made this method useful for syn-
thesis of diversely substituted benzofuro[2,3-c]pyridines.
We also proposed the pathway of this intramolecular
cascade annulation and tested the reasonableness
through the reaction of ammonium acetate with dihy-
drobenzofuran. Further investigations to extend the re-
action scope and illustrate further applications are un-
derway.
Me
24 Me
Ph
Ph
a
Reaction conditions: 1 (0.3 mmol), ammonium acetate (3.0
mmol), THF (3.0 mL), 24 h. Isolated yields. The reaction was
performed in DMSO.
b
c
strates were all performed well with the yield from 60%
to 77% (Table 2, Entries 9－16). It is noteworthy that
the reaction also proceeded well when R2 was methyl
group (Table 2, Entries 17－19), and 68% yield was
obtained while R3 was alkyl simultaneously (Table 2,
Entry 20). It was found that the substrates bearing 5-Br
substituent (R1＝5-Br) could also give desirable prod-
ucts which give a chance to achieve more benzofuro-
[2,3-c]pyridines through further coupling reactions (Ta-
ble 2, Entries 21－23). Moreover, satisfying yield could
Acknowledgement
This work was financially supported by the Natural
Science Foundation of Henan Province (No.
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