A one-pot synthesis of substituted pyrido[2,3-b]indolizines

Article abstract of DOI:10.1016/j.tet.2010.12.047

An efficient and novel approach to the synthesis of substituted pyrido[2,3-b]indolizine-10-carbonitriles was developed. These structures are practically unavailable through previously described methods. The cascade transformation involves the reaction of

Full text of DOI:10.1016/j.tet.2010.12.047

Tetrahedron 67 (2011) 1071e1075
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Tetrahedron
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A one-pot synthesis of substituted pyrido[2,3-b]indolizines
*
Fernanda Proenc¸ a , Marta Costa
Department of Chemistry, University of Minho, Campos de Gualtar 4710-057 Braga, Portugal
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient and novel approach to the synthesis of substituted pyrido[2,3-b]indolizine-10-carbonitriles
Received 8 November 2010
Received in revised form 10 December 2010
Accepted 15 December 2010
Available online 21 December 2010
was developed. These structures are practically unavailable through previously described methods. The
cascade transformation involves the reaction of a,b-unsaturated carbonyl compounds with a stable dimer
prepared from 1-(cyanomethyl)pyridinium chloride. The reaction was performed under reflux conditions
in ethanol/water and in the presence of sodium acetate. This procedure represents a eco-friendly
regioselective approach to the pyrido[2,3-b]indolizine core structure.
Keywords:
1-(Cyanomethyl)pyridinium chloride
Acetylacetone
Ó 2010 Elsevier Ltd. All rights reserved.
a,b-unsaturated carbonyl compounds
Pyrido[2,3-b]indolizine
One-pot synthesis
1. Introduction
The present work reports the synthesis of substituted pyrido
[2,3-b]indolizine-10-carbonitriles from the reaction of the dipyr-
The indolizine nucleus is present in a diversity of biologically
active compounds and can be considered an important scaffold for
the preparation of new pharmaceuticals. In fact, many natural and
synthetic derivatives have been identified as anticancer,1 antiviral,2
anti-inflamatory,3 anti-tuberculosis,4 analgesic,5 and antioxidant6
agents. As a result, different approaches have been reported in
the literature for their synthesis.7
Fused tricyclic structures combining the indolizine and pyridine
moieties are rather uncommon. To our knowledge, the only syn-
thesis of pyrido[2,3-b]indolizines reported in the literature uses the
reaction of 2-amino-3-(arylcarbonyl)indolizine-1-carbonitrile with
substituted acetophenones.8 Poor yields of the product (5e20%)
have been reported when the reaction was performed in DMF, at
80 ꢀC and in the presence of potassium tert-butoxide. The yield was
improved (29e65%) when the reaction was carried out at room
temperature, with no solvent and using a large excess of aceto-
phenone (34e86 M equiv).
idinium dichloride 3 with a,b-unsaturated carbonyl compounds, in
ethanol and water, using sodium acetate as catalyst.
2. Results and discussion
A recent study on the synthesis of 1-(cyanomethyl) pyridinium
chlorides11 from substituted pyridines and chloroacetonitrile,
revealed the competitive formation of compound 3 when the reflux
in acetonitrile was extended for 1 day. After 4 days under reflux
conditions, the dipyridinium salt 3 was isolated as a cream solid in
57% yield. The formation of this product can be rationalized by
nucleophilic attack of the methylene carbon atom of a pyridinium
salt molecule to the cyano group of another molecule, followed by
tautomerization (Scheme 1).
In recent years, the need to use eco-friendly synthetic method-
ologies has emerged, especially in the pharmaceutical industry. The
use of polar aprotic solvents, such as DMF is problematic for the
environment and has human reproductive risks. The search for
solvents with reduced environmental impact is one of the major
goals recently identified by pharmaceutical manufacturers.9 In our
research group, this concernprompted us touse greensolvents, such
as water and ethanol, to improve safety of the synthetic processes.10
Scheme 1. Proposed reaction mechanism for the dimerization of 1-(cyanomethyl)
pyridinium chloride 1.
Compound 3 proved to be stable at room temperature for at
least 6 months and no special requirements were necessary for
storage. In the infrared spectrum of this compound, multiple bands
in the 3500e1800 cmꢁ1 region were associated with different
* Corresponding author. Tel.: þ351 253604379; fax: þ351 253 604383; e-mail
address: fproenca@quimica.uminho.pt (F. Proenc¸ a).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.12.047

1072
F. Proenc¸ a, M. Costa / Tetrahedron 67 (2011) 1071e1075
Table 2
CeH/NeH stretching vibrations of the dipyridinium salt. The cyano
group leads to a clear, medium intensity band at 2195 cmꢁ1. In the
1H NMR spectrum, the amino group generates two broad singlets
Optimization of the reaction conditions for the synthesis of pyrido[2,3-b]indolizine-
10-carbonitrile 4b
centered at
d 8.5 and d 9.0 ppm, reflecting a hindered rotation
barrier across the CeN bond.
The formation of the pyrido[2,3-b]indolizine core was initially
detected in the reaction of the dipyridinium dichloride 3 with
acetylacetone. The reagents were combined in a 1:2 M ratio, in
aqueous sodium carbonate solution and a small amount of solid
material, identified as 4a, was isolated after 3 h at 60 ꢀC (Table 1,
entry 1).
Entry
Equiv
3:6b
Reaction conditions
Product,
yield (%)
Table 1
Experimental conditions used in the reaction of dipyridinium dichloride 3 and
acetylacetone
1
2
1:1
1:1
H2O, Na2CO3 (1.2 equiv), reflux (8 h)
EtOH, N-methylpiperazine (2 equiv),
reflux (15 h)
EtOH, H2O, NaOAc (5 equiv), reflux (4 days)
H2O, Na2CO3 (1.2 equiv), reflux (8 h)
4b, 67%
4b, 38%
O
Cl
O
O
N
3
4
1.4:1
1:1
4b, 91%
4b, 67%
N
NC
N
and/or
H2N
N
+
NH
CN
N
CN
Cl
Table 3
Synthesis of pyrido[2,3-b]indolizine-10-carbonitrile 4
4a
3
5
Entry
Reaction conditions
Product, Yield
1
2
3
4
Na2CO3 aq (0.05 M), 60 ꢀC (3 h)
H2O, Na2CO3 (1 equiv), reflux (60 min)
H2O, reflux (18 h)
4a, 3%
4a, 30%
da
EtOH, N-methylpiperazine (2 equiv), reflux (21 h)
4a, 35%
5, 12%
a
No reaction, by TLC.
Compd 4
R1
R2
Equiv
3:6
Time
(days)
Yield
(%)
4a
4b
CH3
Ph
CH3
1:2a
4
4
79
The use of reflux conditions (entry 2) led to an improved yield of
the product (30%). The reaction only proceeds in the presence of
base, considering that no evolution was detected by TLC after 18 h
under reflux in aqueous media (entry 3). Reflux in ethanol and
N-methylpiperazine resulted in the isolation of 4a (35%) and a
compound identified as 5 (12%) was collected from the mother
liquor (entry 4). Indolizine 5 partiallyevolved to 4awhen a DMSO-d6
solution of this compound and N-methylpiperazine (1.2 M equiv)
was kept at 60 ꢀC for 19 h.
The reaction of the dipyridinium dichloride 3 with 1-phenyl-
butane-1,3-dione in aqueous Na2CO3 (1.1 M equiv), led to a complex
mixture after 19 h under reflux conditions. A major product could
not be isolated from this reaction and the difficulty was partially
associated with the poor selectivity of the nucleophilic attack to the
1.4:1
91
OCH3
OCH3
4c
Ph
1.1:1
4
77
OCH3
4d
4e
4f
Ph
Ph
Ph
1.2:1
1.3:1
1.3:1
4
4
3
63
77
90
CH3
OH
OH
OH
carbonyl group. To overcome this problem, a,b-unsaturated dicar-
4g
4h
Ph
Ph
1.2:1
1.2:1
4
4
85
90
F
bonyl compounds were reacted with the dipyridinium dichloride 3.
The experimental conditions were selected from a study using
3-(4-methoxyphenyl)-1-phenylprop-2-en-1-one 4b, summarized
in Table 2.
Cl
The use of aqueous sodium carbonate solution (entry 1) led to
an isolated yield of 67% of product 4b after refluxing for 8 h. The
low solubility of compound 6b in water was considered a problem
and ethanol was selected as an alternative solvent, using N-meth-
ylpiperazine as base (entry 2). After refluxing the solution for 15 h,
a complex mixture was formed and the pure product 4b was iso-
lated in only 38% yield. A mixture of ethanol and water was used, in
combination with a base soluble in both these solvents (sodium
acetate). The pure product 4b was isolated in 91% yield after
refluxing the solution for 4 days (entry 3).
This combination of solvents and base was selected for all the
reactions between compounds 6 and the dimer 3. The isolated yield
of the products 4bei is summarized in Table 3. The reaction of
compound 3 with acetylacetone was also performed under these
optimized experimental conditions, leading to the product 4a in
79% yield.
4i
Ph
1:1.1
7
75
NO2
a
Acetylacetone was used in this case.
All the compounds were fully characterized by the usual spec-
troscopic techniques and the preparation of a crystal of 4b from
dichloromethane provided the X-ray for this structure (Fig. 1). The
data collected confirms the structure of the isolated products and
indicates that, in compound 4b, the three fused rings are co-planar,
with the phenyl ring twisted out of this plane by 25.2ꢀ and the aryl
ring by 66.1 . The bond length for C3eC19 (1.508 A) further sup-
ports the poor conjugation between the aryl and the pyridine rings.
The bond length for C5eC6 (1.331 A) and for C7eC8 (1.321 A) is
similar to the value reported in the literature for the C]C bond in
ꢀ
ꢀ
ꢀ
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F. Proenc¸ a, M. Costa / Tetrahedron 67 (2011) 1071e1075
1073
Table 4
Experimental conditions used for the intramolecular cyclization of compound 3
Entry
Reaction conditions
Product
1
2
3
EtOH, NaOAc (4.5 equiv), reflux (25 h)
Na2CO3 aq (0.05 M), rt (7 h)
EtOH, N-methylpiperazine (2.2 equiv),
reflux (23 h)
MeOH, NaOCH3 (1.1 M, 1.3 equiv), rt (1 h)
Acetonitrile, DBU, reflux (2 days)
Complex mixturea
No reactionb
Complex mixturea
4
5
Complex mixturea
3, 29%c
a
By 1H NMR.
By TLC.
b
c
Mother liquor was a complex mixture, by 1H NMR.
efficient synthesis of the tricyclic product 4. In this case, the 1H
NMR spectrum of the reaction mixture was analyzed after 25 h of
reflux and showed no evidence for the formation of indolizine 11.
Different bases (sodium carbonate or N-methylpiperazine) and
solvents (water, methanol or acetonitrile) were also used, leading
usually to complex reaction mixtures (Table 4, entries 2e5). This
observation may indicate that pathway A is favored or, alterna-
tively, that indolizine 11 is unstable and can only be isolated when
a substituent is incorporated in the amino group. The fact that
compound 5 was identified in the reaction of 3 with acetylacetone
supports this assumption.
Fig. 1. Crystal structure for pyrido[2,3-b]indolizine-10-carbonitrile 4b.
12
ꢀ
ꢀ
cyclohexadiene (1.332 A). The bond length for C4eN2 (1.376 A)
also reflects the single bond character of this linkage.12
The formation of the pyrido[2,3-b]indolizine-10-carbonitriles
4bei is probably the result of nucleophilic attack of the active
methylene group in dimer 3 to the beta carbon of 6 and of the
amino group of 3 to the carbonyl carbon atom of 6 (Scheme 2,
pathway A). Intramolecular cyclization in the intermediate species
7 leads directly to the final structure 4 after elimination of HCl and
pyridinium chloride.
3. Conclusion
A new and simple one-pot procedure was developed for the
synthesis of substituted pyrido[2,3-b]indolizine-10-carbonitriles
from easily available
a,b-unsaturated carbonyl compounds and
a stable dimer generated from 1-(cyanomethyl)pyridinium chlo-
ride. The reaction proceeded in a combination of water and ethanol,
with sodium acetate catalysis. The products were isolated by simple
filtration in a high purity form and in yields ranging from 63 to 91%.
(A)
Cl
CN
CN
N
O
H
Cl
Cl
R2
(A)
-H2O
N
N
N
+
Ph
R2
H
H
NH2
N
Cl
(B)
4. Experimental section
4.1. General
(A)
6
7
Ph
3
-HCl
(B)
All compounds were fully characterized by elemental analysis
and spectroscopic data. The NMR spectra were recorded on
a Varian Unity Plus at 300 MHz for 1H and 75 MHz for 13C or on
a Bruker Avance 3400 at 400 MHz for 1H and 100 MHz for 13C,
including the 1He13C correlation spectra (HMQC and HMBC).
Deuterated DMSO was used as solvent. The chemical shifts are
Cl
Cl
H
N
NC
N
NH
H
NH2
H
N
N
R2
Cl
NC
NC
H
H
H
N
N
N
H
Ph
8
10
9
expressed in
d (ppm) and the coupling constants (J) in Hertz (Hz).
H
N
Cl
The peak patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; m, multiplet, and br, broad. IR spectra were recorded on an
FT-IR Bomem MB using Nujol mulls and NaCl cells. The reactions
were monitored by thin layer chromatography (TLC) using silica
gel 60 F254 (Merck). The melting points were determined on
a Stuart SMP3 melting point apparatus. Elemental analysis was
performed on a LECO CHNS-932 instrument. Crystallographic
information files of compound 4b were obtained from the
C.A.C.T.I. e Universidade de Vigo.
-
H
O
H
N
Cl
-
R2
Ph
Ph
H
N
R2
H2N
H
CN
CN
N
N
N
-H2
-H2O
R2
H
Ph
N
CN
4
11
12
Scheme 2. Proposed mechanism for the synthesis of pyrido[2,3-b]indolizine-10-car-
bonitrile 4bei.
4.2. Synthesis of 1,10-[2-amino-1-cyanoprop-1-ene-1,3-diyl]
dipyridinium dichloride 3
Analternative pathway is equally plausible (Scheme 2, pathway B)
starting with intramolecular cyclization of compound 3 to generate
a substituted indolizine 11 after tautomerization and elimination of
1-(Cyanomethyl)pyridinium chloride
1
(4.79 mmol) was
pyridinium chloride. Reaction of 11 with the a,b-unsaturated com-
refluxed in CH3CN (80 mL) for 4 days. The off-white solid was fil-
tered and washed with CH3CN, leading to the pure product 3
(1.36 mmol). Mp 245e246 ꢀC; IR (Nujol mull) 3500e1800 (broad,
pound 6 through nucleophilic attack by the enamine moiety leads to
the isolated product 4 after dehydration followed by oxidation.
In order to understand the feasibility of pathway B, the dimer 3
was combined with sodium acetate and refluxed in ethanol
(Table 4, entry 1). These conditions were previously selected for the
fringed), 2195, 1667, 1662, 1598, 1461 cmꢁ1 1H NMR (300 MHz,
;
DMSO-d6)
d
5.90 (s, 2H), 8.27 (t, J¼6.9 Hz, 2H), 8.34 (t, J¼6.9 Hz, 2H),
8.40e8.58 (br s, 1H), 8.70e8.80 (m, 2H), 8.92e9.12 (br s, 1H), 9.36

1074
F. Proenc¸ a, M. Costa / Tetrahedron 67 (2011) 1071e1075
(d, J¼6.9 Hz, 2H), 9.44 (d, J¼5.7 Hz, 2H); 13C NMR (75 MHz, DMSO-
2.0 Hz, 2H), 7.44e7.55 (m, 6H), 7.70 (s, 1H), 7.84 (dt, J¼8.8, 1.2 Hz,
1H), 8.06 (dd, J¼6.6, 1.2 Hz, 1H), 8.24 (dd, J¼7.6, 1.6 Hz, 2H), 9.97 (s,
d6)
d 58.6, 88.1, 116.6, 128.2, 130.0, 145.9, 146.9, 148.4, 148.0, 153.3.
Anal. Calcd for C14H14N4Cl2$0.8H2O: C, 51.95; H, 4.82; N, 17.32.
1H); 13C NMR (100 MHz, DMSO-d6)
d 74.9, 112.2, 115.5, 116.1 (2C),
Found: C, 51.91; H, 4.88; N, 17.71.
116.2, 117.2, 119.8, 125.8, 127.2 (2C), 128.1, 128.8 (2C), 129.3, 129.6,
130.1 (2C), 138.0, 138.5, 143.4, 146.0, 154.6, 158.4. Anal. Calcd for
C24H15N3O: C, 79.78; H, 4.16; N, 11.63. Found: C, 79.71; H, 4.20; N,
11.54.
4.3. General procedure for the synthesis of pyrido[2,3-b]
indolizine-10-carbonitrile 4aei
a
,
b
-Unsaturated dicarbonyl compound (0.21 mmol) was added
4.3.6. 4-(3,4-Dihydroxyphenyl)-2-phenylpyrido[2,3-b]indolizine-10-
carbonitrile (4f). Green solid isolated after reflux for 3 days (0.10 g,
90%). Mp higher than 300 ꢀC. 1H NMR (400 MHz, DMSO-d6)
to a solution of 1,10-[2-amino-1-cyanoprop-1-ene-1,3-diyl]dipyr-
idinium dichloride 3 (0.29 mmol) and sodium acetate (1.10 mmol)
in EtOH (6 mL) and water (1 mL). The yellow solution was refluxed
for 3e7 days and then concentrated in the rotary evaporator. After
cooling in an ice-bath, the solid started to precipitate. The solid was
filtered and washed with water, leading to the pure product 4.
d
6.88e6.93 (m, 2H), 6.97e7.00 (m, 2H), 7.44e7.50 (m, 4H), 7.69 (s,
1H), 7.84 (dd, J¼8.6, 0.8 Hz, 1H), 8.10 (d, J¼7.2 Hz, 1H), 8.24 (dd,
J¼7.8, 1.2 Hz, 2H), 9.45 (s, 2H); 13C NMR (100 MHz, DMSO-d6)
d 74.9,
112.2, 115.5, 115.8, 116.1, 116.3, 117.2, 119.7, 119.8, 126.3, 127.2 (2C),
128.2, 128.8 (2C), 129.3, 129.6, 138.2, 138.5, 143.4, 146.0, 146.7, 154.6.
4.3.1. 2,4-Dimethylpyrido[2,3-b]indolizine-10-carbonitrile (4a).
IR (Nujol mull) n 3600e3000 (broad), 2196, 1634, 1599, 1558, 1511,
Brown solid. Mp 270e272 ꢀC; IR (Nujol mull)
n
2197, 1636, 1595,
1461 cmꢁ1. Anal. Calcd for C24H15N3O2$0.8H2O: C, 73.58; H, 4.24; N,
1571, 1519, 1462 cmꢁ1; 1H NMR (400 MHz, DMSO-d6)
d
2.60 (s, 3H),
10.73. Found: C, 73.52; H, 4.22; N, 11.09.
2.88 (s, 3H), 7.05 (td, J¼7.0, 1.2 Hz, 1H), 7.10 (s, 1H), 7.56 (td, J¼6.8,
0.8 Hz, 1H), 7.82 (dt, J¼7.6, 1.2 Hz, 1H), 9.01 (d, J¼7.2 Hz, 1H); 13C
4.3.7. 4-(4-Fluorophenyl)-2-phenylpyrido[2,3-b]indolizine-10-car-
NMR (100 MHz, DMSO-d6)
d
19.3, 24.1, 73.9,112.3,115.7,116.8,119.6,
bonitrile (4g). Yellow solid. Mp higher than 300 ꢀC; IR (Nujol mull)
n
120.9, 128.9, 130.2, 134.2, 142.2, 145.2, 157.0. Anal. Calcd for
C14H11N3$0.2H2O: C, 74.80; H, 5.08; N, 18.70. Found: C, 74.72; H,
4.87; N, 18.91.
2208, 1638, 1609, 1593, 1568, 1533, 1509, 1464 cmꢁ1
(300 MHz, DMSO-d6)
;
1H NMR
6.87 (td, J¼7.2, 1.2 Hz, 1H), 7.44e7.58 (m,
d
6H), 7.70e7.79 (m, 3H), 7.85 (dt, J¼9.0, 1.2 Hz, 1H), 7.90 (dt, J¼6.9,
1.2 Hz, 1H), 8.26 (dd, J¼8.2, 1.2 Hz, 2H); 13C NMR (75 MHz, DMSO-
4.3.2. 4-(4-Methoxyphenyl)-2-phenylpyrido[2,3-b]indolizine-10-
carbonitrile (4b). Greenish-yellow solid. Mp higher than 300 ꢀC;
d6)
d
75.0, 112.1, 114.9, 115.97, 116.0 (d, J¼21.4 Hz, 2C), 117.0, 119.3,
127.0 (2C), 127.9, 128.5, 129.0 (2C), 129.4 (2C), 130.8 (d, J¼8.2 Hz,
2C), 131.8 (d, J¼3.2 Hz), 136.4, 138.2, 143.3, 145.8, 154.6, 162.5 (d,
J¼245.4 Hz). Anal. Calcd for C24H14N3F$0.09H2O: C, 78.99; H, 3.89;
N, 11.52. Found: C, 79.22; H, 3.98; N, 11.53.
IR (Nujol mull)
n ;
2205, 1638, 1609, 1578, 1557, 1513, 1461 cmꢁ1
1H NMR (400 MHz, DMSO-d6)
d
3.88 (s, 3H), 6.89 (td, J¼6.8,
1.2 Hz, 1H), 7.20 (dd, J¼6.8, 2.0 Hz, 2H), 7.45e7.57 (m, 4H), 7.62
(dd, J¼6.8, 2.4 Hz, 2H), 7.73 (s, 1H), 7.86 (dt, J¼8.8, 1.2 Hz, 1H),
8.02 (dt, J¼7.6, 0.8 Hz, 1H), 8.26 (dd, J¼8.4, 1.2 Hz, 2H); 13C NMR
4.3.8. 4-(4-Chlorophenyl)-2-phenylpyrido[2,3-b]indolizine-10-car-
(100 MHz, DMSO-d6)
d
55.4, 74.9, 112.3, 114.7 (2C), 115.5, 116.3,
bonitrile (4h). Greenish-yellow solid. Mp 272e275 ꢀC; IR (Nujol
117.3, 119.7, 127.2 (2C), 127.6, 128.1, 128.8 (2C), 129.3, 129.7, 130.2
(2C), 137.6, 138.4, 143.5, 146.1, 154.7, 160.1. Anal. Calcd for
C25H17N3O.0.5H2O: C, 78.12; H, 4.69; N, 10.94. Found: C, 78.16; H,
4.54; N, 10.81.
mull)
(400 MHz, DMSO-d6)
n
2211, 1636, 1599, 1573, 1555, 1534, 1514, 1461 cmꢁ1; 1H NMR
d
6.90 (t, J¼6.4 Hz, 1H), 7.46e7.57 (m, 4H),
7.69e7.75 (m, 4H), 7.76 (s, 1H), 7.86 (d, J¼8.8 Hz, 1H), 7.93 (d,
J¼7.2 Hz, 1H), 8.25 (d, J¼7.2 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
d
75.0, 112.5, 115.4, 116.1, 117.3, 119.3, 127.2 (2C), 128.3, 128.8 (2C),
4.3.3. 4-(3,4-Dimethoxyphenyl)-2-phenylpyrido[2,3-b]indolizine-10-
129.3 (2C), 129.4, 129.8, 130.8 (2C), 134.3, 134.5, 136.4, 138.3, 143.5,
146.0, 154.6. Anal. Calcd for C24H14N3Cl$0.2H2O: C, 75.18; H, 3.76; N,
10.96. Found: C, 75.15; H, 3.97; N, 11.03.
carbonitrile (4c). Green solid. Mp 262e264 ꢀC; IR (Nujol mull)
n
2207, 1634, 1606, 1588, 1558, 1508, 1465 cmꢁ1; 1H NMR (400 MHz,
DMSO-d6)
d
3.79 (s, 3H), 3.88 (s, 3H), 6.91 (td, J¼7.2, 1.2 Hz, 1H), 7.21
(s, 2H), 7.30 (s, 1H), 7.45e7.58 (m, 4H), 7.77 (s, 1H), 7.87 (dd, J¼8.4,
4.3.9. 4-(3-Nitrophenyl)-2-phenylpyrido[2,3-b]indolizine-10-car-
0.8 Hz, 1H), 8.08 (d, J¼7.2 Hz, 1H), 8.27 (d, J¼7.8, 1.2 Hz, 2H); 13C
bonitrile (4i). Greenish solid. Mp higher than 300 ꢀC; IR (Nujol
NMR (100 MHz, DMSO-d6)
d
55.6, 55.7, 74.9, 112.2, 112.27, 112.33,
mull)
(400 MHz, DMSO-d6)
n
2206, 1637, 1578, 1561, 1530, 1515, 1501, 1460 cmꢁ1; 1H NMR
115.5, 116.3, 117.2, 119.7, 121.1, 127.2 (2C), 127.7, 128.4, 128.8 (2C),
129.3, 129.8, 137.8, 138.5, 143.5, 146.1, 149.2, 149.6, 154.6. Anal. Calcd
for C26H19N3O2: C, 77.04; H, 4.69; N, 10.37. Found: C, 77.36; H, 4.69;
N, 10.31.
d
6.85 (dt, J¼6.6, 1.2 Hz, 1H), 7.46e7.58 (m,
4H), 7.86e7.96 (m, 4H), 8.16 (dt, J¼8.2, 1.6 Hz, 1H), 8.29 (dd, J¼8.4,
1.2 Hz, 2H), 8.49 (dq, J¼8.4, 1.2 Hz, 1H), 8.60 (t, J¼1.6 Hz, 1H); 13C
NMR (100 MHz, DMSO-d6)
d 75.0, 112.6, 115.4, 116.2, 117.2, 119.3,
123.9, 124.2, 127.2 (2C), 128.6, 128.8, 129.5 (2C), 129.9, 130.8, 135.3,
135.6, 137.2, 138.2, 143.6, 146.1, 148.2, 154.7. Anal. Calcd for
C24H14N4O2$0.6H2O: C, 71.86; H, 3.79; N, 13.97. Found: C, 71.78; H,
3.86; N, 13.98.
4.3.4. 4-(4-Methylphenyl)-2-phenylpyrido[2,3-b]indolizine-10-car-
bonitrile (4d). After Green solid. Mp 229e231 ꢀC; IR (Nujol mull)
n
2204, 1635, 1578, 1557, 1513, 1463 cmꢁ1; 1H NMR (400 MHz, DMSO-
d6)
2.46 (s, 3H), 6.87 (td, J¼6.8, 1.6 Hz, 1H), 7.44e7.58 (m, 8H), 7.72
d
(s, 1H), 7.85 (dt, J¼8.8, 1.2 Hz, 1H), 7.95 (dd, J¼7.2, 1.6 Hz, 1H), 8.24
4.4. Synthesis of 2-{[4-oxopent-2-en-2-yl]amino}indolizine-
1-carbonitrile 5
(dd, J¼7.2, 1.6 Hz, 2H); 13C NMR (100 MHz, DMSO-d6)
d 21.0, 75.0,
112.3, 115.4, 116.1, 117.3, 119.5, 127.2 (2C), 128.0, 128.6 (2C), 128.8
(2C), 129.3, 129.7, 129.8 (2C), 132.7, 137.7, 138.4, 139.0, 143.4, 146.0,
154.6. Anal. Calcd for C25H17N3: C, 83.56; H, 4.74; N, 11.70. Found: C,
83.62; H, 4.71; N, 11.64.
Compound 5 was isolated from the mother liquor, in the syn-
thesis of compound 4a under the conditions referred in Table 1,
entry 4. Green solid. Mp 165e167 ꢀC; IR (Nujol mull)
n
3136, 2191,
1H NMR (400 MHz,
d 2.04 (s, 3H), 2.22 (s, 3H), 5.40 (s, 1H), 6.61 (s, 1H), 6.94
1633, 1614, 1594, 1546, 1524, 1460 cmꢁ1
DMSO-d6)
;
4.3.5. 4-(4-Hydroxyphenyl)-2-phenylpyrido[2,3-b]indolizine-10-car-
bonitrile (4e). Green solid. Mp higher than 300 ꢀC; IR (Nujol mull)
n
(td, J¼7.0, 1.2 Hz, 1H), 7.16 (td, J¼7.8, 1.2 Hz, 1H), 7.56 (dt, J¼8.8,
3328, 2194, 1637, 1616, 1588, 1571, 1513, 1462 cmꢁ1
;
1H NMR
1.2 Hz, 1H), 8.34 (dd, J¼6.8, 0.8 Hz, 1H), 12.89 (s, 1H); 13C NMR
(400 MHz, DMSO-d6)
d
6.89 (td, J¼6.8, 1.6 Hz, 1H), 7.01 (dd, J¼6.8,
(100 MHz, DMSO-d6) d 20.0, 29.1, 87.0, 94.1, 99.4, 112.6, 113.4,

F. Proenc¸ a, M. Costa / Tetrahedron 67 (2011) 1071e1075
1075
102, 515e533; (c) Asano, N.; Nash, R.; Molyneux, R.; Fleet, G. Tetrahedron:
Asymmetry 2000, 11, 1645e1680.
118.4, 123.8, 125.7, 135.7, 136.8, 158.4, 196.5. Anal. Calcd for
C14H13N3O$0.1H2O: C, 69.77; H, 5.48; N, 17.44. Found: C, 69.63; H,
5.39; N, 17.67.
2. Bolle, L.; Andrei, G.; Snoeck, R.; Zhang, Y.; Lommel, A.; Otto, M.; Bousseau, A.;
Roy, C.; Clercq, E.; Naesens, L. Biochem. Pharmacol. 2004, 67, 325e336.
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241e243; (b) Kitadokoro, K.; Hagishita, S.; Sato, T.; Ohtani, M.; Miki, K.
J. Biochem. 1998, 123, 619e623.
Acknowledgements
4. Gundersen, L.; Charnock, C.; Negussie, A.; Risea, F.; Teklu, S. Eur. J. Pharm. Sci.
2007, 30, 26e35.
~
We gratefully acknowledge the financial support from Fundac¸ ao
ˇ
5. Campagna, F.; Carotti, A.; Casini, G.; Macripo, M. Heterocycles 1990, 31, 97e107.
6. (a) Ostby, O.; Dalhus, B.; Gundersen, L.; Rise, F.; Bast, A.; Haenen, G. Eur. J. Org.
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Pergamon: Oxford, 1996; Vol. 8, pp 237e248.
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para a Ciencia e a Tecnologia through a Ph.D. grant awarded to
Marta Costa (SFRH/BD/31531/2006).
Supplementary data
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.12.047.
References and notes
10. Proenc¸ a, F.; Costa, M. Green Chem. 2008, 10, 995e998.
11. Proenc¸ a, F.; Costa, M. Tetrahedron 2010, 66, 4542e4550.
12. Lide, D. CRC Handbook of Chemistry and Physics, 76th ed.; CRC Press: Boca Raton,
FL, 1995, Chapter 9, pp 1e13.
1. (a) Shen, Y.; Lv, P.; Chen, W.; Liu, P.; Zhang, M.; Zhu, H. Eur. J. Med. Chem. 2010,
45, 3184e3190; (b) Bols, M.; Lillelund, V.; Jensen, H.; Liang, X. Chem. Rev. 2002,