Formal [3+2] cycloaddition of 1-cyanocyclopropane 1-ester with pyridine, quinoline or isoquinoline: A general and efficient strategy for construction of cyanoindolizine skeletons

Article abstract of DOI:10.1039/c4cc03267e

An efficient and straightforward synthetic protocol has been developed for the preparation of cyanoindolizine derivatives via a cycloaddition reaction between 1-cyanocyclopropane 1-ester and pyridine or benzopyridine for the generation of a wide range of structurally interesting and pharmacologically significant compounds. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc03267e

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Formal [3+2] cycloaddition of 1-cyanocyclopropane
1-ester with pyridine, quinoline or isoquinoline:
a general and efficient strategy for construction
of cyanoindolizine skeletons†
Cite this: Chem. Commun., 2014,
50, 9068
Received 2nd May 2014,
Accepted 24th June 2014
Juanjuan Liu, Lanxiang Zhou, Weijian Ye and Cunde Wang*
DOI: 10.1039/c4cc03267e
www.rsc.org/chemcomm
An efficient and straightforward synthetic protocol has been developed which affords formal [2+3]-cycloaddition with alkenes,15 alde-
for the preparation of cyanoindolizine derivatives via a cycloaddition hydes,16 ketones,17 isocyanates,18 imines,19 diazenes,20 pyrazo-
reaction between 1-cyanocyclopropane 1-ester and pyridine or benzo- lines,21 azomethine imine ylides,22 nitrones,23 acetylenes,24
pyridine for the generation of a wide range of structurally interesting nitriles25 to structure various five-membered carbo- and heterocycles.
and pharmacologically significant compounds.
To the best of our knowledge, no example using 1-cyanocyclo-
propane 1-ester and pyridine as starting materials to construct the
Indolizines are important classes of organic compounds that are cyanoindolizine core was reported. These products were described
not only widely used as synthetic building blocks and various kinds as potent central nervous system (CNS) depressant agents, anti-
of functional materials,1 but they also occur in numerous natural cancer, anti-inflammatory, and antimalarial agents as shown in
products and pharmaceuticals as privileged scaffolds.2 Among Fig. 1.2,5,7 Herein we report a facile and straightforward method to
them, the cyanoindolizines have attracted more attention recently. synthesize substituted cyanoindolizines from 1-cyanocyclopropane
Cyanoindolizine derivatives were investigated extensively as highly 1-esters and pyridines via an iodine-catalyzed formal [3+2] cyclo-
potent non-nucleoside inhibitors of HIV-1 reverse transcriptase,3 a addition reaction.
xanthine oxidase with inhibitory activities for the prevention or
The starting materials, 2-aroyl-3-aryl-1-cyanocyclopropane
treatment of a disease associated with the abnormal serum uric carboxylates, were prepared in good yields under mild conditions
acid level,4 anticancer agents,2,5 potent inhibitors of Acinetobacter according to the reported procedure.26 In order to explore the
baumannii OXA-24 carbapenemase,6 anti-inflammatory, and anti- synthesis of title cyanoindolizines via the [3+2] cycloaddition reac-
malarial agents.7
tions of substituted cyclopropane with pyridines, the reaction
The synthesis of indolizine derivatives has made much progress,8 between ethyl 2-(p-bromophenyl)-3-(p-chlorobenzoyl)-1-cyano cyclo-
most traditionally synthetic strategies require starting from pyridinium pentanecarboxylate and pyridine was chosen as a model reaction
N-methylides8b,9 or pyridines with specific C2 functionalization.10 to optimize the reaction conditions. The results are summarized
In contrast, only some annulation reactions of the pyridine ring in Table 1.
that involve [3+2] cycloaddition have recently been reported.11,12 In
To start, the reaction was conducted with 1 equiv. of ethyl
recent years, some previous studies revealed that donor–acceptor 3-( p-bromophenyl)-2-(p-chlorobenzoyl)-1-cyanocyclopropane carbo-
cyclopropanes are versatile building blocks in Lewis acid-promoted nate and 1 equiv. of pyridine using a catalytic amount of the Lewis
formal cycloadditions for the construction of various cyclic acid AlCl3, ZnCl2, BF3Et2O, FeCl3 and I2 in toluene at 120 1C.
skeletons.13 The formal [3+2] cycloaddition reaction of donor–
acceptor (D–A) cyclopropanes has emerged as a powerful
method for the simple access to useful molecules for materials
or biological applications. The ring-opening of the strained
substituted cyclopropanes can give easily a 1,3-dipolar inter-
mediate upon thermolysis or under catalysis by Lewis acids14
School of Chemistry and Chemical Engineering, Yangzhou University,
180 Siwangting Street, Yangzhou 225002, P. R. China. E-mail: wangcd@yzu.edu.cn;
Fax: +86-514-8797-5244; Tel: +86-514-8797-5568
† Electronic supplementary information (ESI) available: Reaction conditions and
spectra. CCDC 978204, 978827, 970814, 939543 and 939542. For ESI and crystallo-
Fig. 1 Examples of bioactive cyanoindolizines.
graphic data in CIF or other electronic format see DOI: 10.1039/c4cc03267e
9068 | Chem. Commun., 2014, 50, 9068--9071
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Table 1 Optimization of reaction conditions in the synthesis of 2a
Table
2
Synthesis of cyanoindolizine derivatives from pyridine and
1-cyanocyclopropane 1-ester
Entry
R
R1
R2
Yielda (%)
1
2
3
4
5
6
7
8
p-Br
o-Cl
p-CH3
m-Br
m-Br
p-OCH3
o-Cl
p-Cl
p-Cl
p-Cl
H
p-Cl
p-Cl
H
p-Cl
p-Cl
p-Cl
H
H
H
H
H
H
H
H
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
84 (2a)
79 (2b)
81 (2c)
63 (2d)
76 (2e)
80 (2f)
75 (2g)
85 (2h)
76 (2i)
71 (2j)
84 (2k)
82 (2l)
75 (2m)
76 (2n)
Entry
Catalyst
Solvent
T (1C)
t (h)
Yielda (%)
1
2
3
4
5
6
7
8
10% AlCl3
10% ZnCl2
10% BF3
10% FeCl3
10% I2
20% I2
50% I2
100% I2
200% I2
20% I2
20% I2
20% I2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
120
120
120
120
120
120
120
120
120
120
60
20
20
20
20
20
20
20
20
20
20
20
20
20
20
8
0
0
0
0
53
84
78
73
71
74
9
62
74
64
26
54
83
p-Br
9
p-CH3
o-OCH3
p-Br
p-Cl
m-Br
o-Cl
10
11
12
13
14
9
H
H
H
10
11
12
13
14
15
16
17
90
20% I2
20% I2
20% I2
20% I2
130
140
120
120
120
a
Isolated yield.
15
24
to good yields. Pleasingly, simple benzo-fused pyridines (quino-
line and isoquinoline) were found to work well, leading to more
complex cycloadducts in variable yields. Thus, quinoline and
isoquinoline afforded substituted pyrrolo[1,2-a]quinoline and
pyrrolo[2,1-a]isoquinoline in yields of ca. 80%, respectively, upon
reaction with 1-cyanocyclopropane 1-ester (Tables 3 and 4).
Generally, 1-cyanocyclopropane 1-ester with a range of sub-
stituents such as methyl, methoxy, chloro, and bromo at ortho-,
meta- or para-positions of phenyl groups all worked well to give
1-cyanoindolizine derivatives. Substrates with para-position
phenyl groups gave the products in higher yields than those
with ortho-, or meta-position phenyl groups. Besides pyridine
and 4-(dimethylamino)pyridine, substrate quinoline and iso-
quinoline also reacted well with 1-cyanocyclopropane 1-esters
to give 1-cyanobenzoindolizine derivatives.
20% I2
a
Isolated yield.
As a result, the use of Lewis acid AlCl3, ZnCl2, BF3Et2O, or FeCl3
did not lead to [3+2] cycloaddition at all (Table 1, entries 1–4).
Pleasingly, while molecular iodine was used as a Lewis acid
the 3-( p-bromophenyl)-2-( p-chlorobenzoyl)-1-cyanoindolizine (2a)
was obtained as the only isolable product in 53% yield (entry 5).
When the amount of iodine was increased further to 20 mol%, the
reaction was complete after 20 h and the isolated yield was the best,
84% (entry 6). The yield was reduced slightly when the amount of
iodine was increased from 50 mol% to 200% (entries 7–9). Switching
the solvent to DMF decreased the yield to 74% (entry 10). When
conducted at 60 1C, the reaction nearly did not take place (entry 11).
While the reaction was carried out at 90 1C, the reaction was
incomplete after 20 h and the isolated yield was only 62% (entry 12).
Lower yield was obtained when the reaction was conducted at
130–140 1C (entries 13 and 14). Additionally, the lower yields of 2a
were also observed when this reaction was carried out at 8–15 h
(entries 15 and 16), or 24 h (entry 17). A series of experiments revealed
that the optimal results were obtained when the reaction of
1-cyanoindolizine 2a and pyridine together with 20 mol% iodine
was carried out in toluene, the resultant mixture was stirred for 20 h at
120 1C, whereby the yield of 2a reached 84% (Table 1, entry 6).
Having established the optimal conditions for the synthesis
of 1-cyanoindolizine 2a, to determine the scope of the protocol,
a number of available 1-cyano-cyclopropanecarboxylates were
condensed with pyridine or 4-(dimethylamino)pyridine under
optimized reaction conditions. The results are summarized in
Table 2. Both electron-deficient and electron-rich aromatic
groups were similarly viable affording the products in moderate
Table 3 Synthesis of 1-cyanobenzoindolizine derivatives from isoquino-
line and 1-cyanocyclopropane 1-ester
Entry
R
R1
Yielda (%)
1
2
3
4
p-Br
m-Br
p-Br
H
H
77 (3a)
69 (3b)
79 (3c)
68 (3d)
p-Br
H
o-OCH3
a
Isolated yield.
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Table 4 Synthesis of 1-cyanobenzoindolizine derivatives from quinoline
and 1-cyanocyclopropane 1-ester
Scheme 1 Synthesis of 3-cyanoindolizine derivatives from 1-cyanocyclo-
R1
Yielda (%)
propane 1-ester and pyridine.
Entry
R
1
2
3
o-CH3
m-Br
p-CH3
p-Cl
H
p-Cl
65 (4a)
64 (4b)
72 (4c)
Table 5 Iodine-catalyzed synthesis of 3-cyanoindolizine derivatives
R1
R2
Yielda (%)
a
Entry
Isolated yield.
1
2
3
4
5
6
7
8
H
p-Br
H
H
H
H
p-Cl
H
H
H
p-CH3
o-CH3
p-Br
p-Br
o-Cl
p-Cl
o-Br
m-Br
p-Br
o-CH3O
p-CH3O
m-Cl
p-Cl
p-NO2
p-Br
63 (5a)
68 (5b)
52 (5c)
56 (5d)
59 (5e)
82 (5f)
84 (5g)
55 (5h)
56 (5i)
73 (5j)
77 (5k)
51 (5l)
53 (5m)
58 (5n)
9
10
11
12
13
14
p-Br
p-Br
m-Cl
Fig. 2 Molecular structure of 1-cyanoindolizines 2b and 2h.
a
Isolated yield.
The structures of 2b, 2h and 4c are shown in Fig. 2 and 3.27
X-ray crystallographic analysis determined that products 2b, 2h
and 4c possess a cyano, an aroyl and an aryl contiguous
substituent at C(1), C(2), and C(3). On the basis of spectroscopic
evidence the structure of compounds 2a–n, 3a–d and 4a–c was
identified as 3-aryl-2-aroyl-1-cyanoindolizine or 3-aryl-2-aroyl-1-
cyanobenzo indolizine.
possess an aryl, an aroyl and a cyano contiguous substituent at
C(1), C(2), and C(3). On the basis of spectroscopic evidence the
structure of compounds 5a–n was identified as 3-cyano-1-aryl-2-
aroylindolizine.
On the basis of the above experimental results together with
related reports, the reaction mechanism shown in Scheme 2
was proposed. First, under basic conditions, iodine promoted
the form of cyclopropane enolate anion [A]28 and its conjuga-
tion cyclopropyl anion, which was followed by ring opening
reaction on the cyclopropyl anion to generate anion [B]. Then,
1,3-dipolar cycloaddition of anion [B] as a 1,3-dipole to pyridine
gave the enolate anion [C]. Further removal of ethyl formate
formed dihydroindolizine [D].29 Finally, the dehydroaromatiza-
tion of dihydroindolizine [D] resulted in the formation of the
corresponding 1-cyanoindolizidine under air conditions in
the presence of iodine. Similarly, 3-cyanoindolizidine was
obtained because the benzyl anion [B0] was a stable resonance
in pyridine30 (Scheme 2). The a-carbon anion of [B] with two
strongly electrondrawing groups (cyano and ester groups) is a
stable resonance in a weak polar solvent such as toluene. However,
the a-carbon anion of [B] possesses larger space steric hindrances
and is solvated with difficulty by a strong polar solvent (pyridine),
and it is uneasy to obtain a stable structure in pyridine. In contrast,
[B0] with smaller space steric hindrances is solvated easily by
pyridine to form a stable resonance structure.
To test the generality of this new approach for the construction
of the cyanoindolizine, the reactions of pyridine as both a substrate
and a solvent with selected 1-cyanocyclopropane 1-ester were
examined under identical conditions as above (Scheme 1). Inter-
estingly, 3-cyanoindolizine derivatives 5a–n can be prepared in
good yields, respectively (Table 5, entries 1–14), the result of
which suggested that there are different reaction mechanisms
for toluene or pyridine as a solvent.
The structures of 5a and 5b are shown in Fig. 4.27 X-ray
crystallographic analysis determined that products 5a and 5b
In conclusion, direct annulation of pyridine derivatives with
1-cyanocyclopropane 1-ester to form cyanoindolizine derivatives
Fig. 3 Molecular structure of 1-cyanoindolizine 4c.
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Notes and references
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Scheme 2 Possible mechanism in the synthesis of cyanoindolizines.
has been accomplished in a regioselective manner. The reaction
proceeds with easy accessibility for 1-cyanocyclopropane 1-ester
bearing aryl and aroyl groups, and molecular iodine as a
non-expensive catalyst. Due to the described usefulness of
cyanoindolizine derivatives, such simple reaction conditions
and functional group tolerance offer a new attractive method
for access to such structures. It is noteworthy that this is the
first successful example of iodine-catalyzed one-pot cyclization
of a cyanoindolizidine system with 2-aroyl and aryl groups.
Therefore, from these results, it can be envisioned that this
method will find many applications in organic chemistry and
medicinal chemistry.
Financial support of this research from the National Natural
Science Foundation of China (NNSFC 21173181) is gratefully
acknowledged by authors. A Project Funded by the Priority
Academic Program Development of Jiangsu Higher Education
Institutions is acknowledged.
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