Preparation of new nitrogen-bridged heterocycles. 64. A smooth formation of 2,4-diarylpyrido[2,3-b]indolizine-10-carbonitrile derivatives

Article abstract of DOI:10.3987/COM-08-S(F)44

The syntheses of the title compounds from the reactions of 2-amino-3-(arylcarbonyl)indolizine-1-carbonitriles with various acetophenones in the presence of strong base were investigated. When the reactions were carried out between 2-aminoindolizines and 1

Full text of DOI:10.3987/COM-08-S(F)44

HETEROCYCLES, Vol. 77, No. 1, 2009
471
HETEROCYCLES, Vol. 77, No. 1, 2009, pp. 471 - 481. © The Japan Institute of Heterocyclic Chemistry
Received, 11th July, 2008, Accepted, 22nd August, 2008, Published online, 25th August, 2008.
DOI: 10.3987/COM-08-S(F)44
PREPARATION OF NEW NITROGEN-BRIDGED HETEROCYCLES. 64.1
A SMOOTH FORMATION OF 2,4-DIARYLPYRIDO[2,3-b]INDOLIZINE-
10-CARBONITRILE DERIVATIVES
Akikazu Kakehi, * Hiroyuki Suga, and Shuichi Sato
Department of Chemistry and Material Engineering, Faculty of Engineering,
Shinshu University, Wakasato, Nagano 380-8553, Japan
E-Mail: akakehi@shinshu-u.ac.jp
Abstract – The syntheses of the title compounds from the reactions of
2-amino-3-(arylcarbonyl)indolizine-1-carbonitriles with various acetophenones in
the presence of strong base were investigated. When the reactions were carried
out between 2-aminoindolizines and 1.2-equimolar amounts of acetophenones, the
yields for the target molecules were low or very low. However, when a large
excess of acetophenones were used without any solvent or in as small as amount
of solvent as possible, their yields were considerably improved. The smooth
hydrolysis of the 10-cyano group to the carbamoyl one was also observed.
Previously we reported a first construction method for pyrido[2,3-b]indolizine ring system starting from
some 3-acetyl-2-(alkylamino)indolizine derivatives.2 We particularly noticed during the reaction that, in
contrast with the 2-thiol group,3 the 2-alkylamino group on the indolizine ring was scarcely reactive to
various electrophiles even under more drastic conditions. The extremely lowered reactivity of the
2-alkylamino group is maybe due to the severe steric congestion caused by the shorter carbon-nitrogen
bond and to the tight hydrogen-bonding between the 2-alkylamino proton and the 3-acyl carbonyl group.
Hence, the only group which we could introduce at that time was the smallest functional group, formyl,
and the intramolecular dehydration reaction between the resulting 2-formamide and the 3-acetyl group on
the indolizine ring afforded the corresponding 1,4-dihydropyrido[2,3-b]indolizin-4-one derivative.
Recently two groups have reported the formation of pyrido[2,3-b]indolizines and pyrimido[4,5-b]-
indolizines in the reactions of 2-(N-unsubstituted amino)indolizines with some electrophiles.4,5 They
have also described that these products have an antimicrobial activity and are selective partial agonists or
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Dedicated to Professor Emeritus Keiichiro Fukumoto on the occasion of his 75th birthday.

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HETEROCYCLES, Vol. 77, No. 1, 2009
antagonists of human CRF1 receptor. In the continuation of our effort for nitrogen-bridged heterocycle
synthesis, we are very interested in the use of 2-(N-unsubstituted amino)indolizines as a starting material
because of their ready availability6,7 and their expected increased reactivity due to the relief of steric
congestion. To the best of my knowledge, pyrido[2,3-b]indolizine derivatives functionalized at the
4-position have been prepared from the alkyl 2-amino-1-arylindolizine-3-carboxylates,4 but those
functionalized at the 10-position are unknown until now. We selected a cyano group as a functional one
at the 10-position in the target molecules because of the less steric hindrance and of the ready
convertibility to other functional groups. In this paper we report the synthesis of the title compounds
from the reaction of the 2-amino-3-(arylcarbonyl)indolizine-3-carbonitriles and some acetophenones in
the presence of a base.
RESULTS AND DISCUSSION
We first examined the N-alkylation of 2-amino-3-benzoylindolizine-1-carbonitriles (1a—c) with
electrophilic agents such as ethyl bromoacetate and phenacyl bromide under various conditions, but no
significant products could be obtained at all. So, we turned our attention to the dehydration between
the 2-amino group on the indolizine ring and the ketone carbonyl one in the acetophenone compound.
When the mixture of 2-amino-3-benzoylindolizine-1-carbonitrile (1a) and a 1.2-equivalent of
acetophenone (2a) was allowed to react in chloroform or ethanol in the presence of a base such as
triethylamine
or
1,8-diazabicyclo[5.4.0]undec-7-ene,
the
direct
formation
of
2,4-diphenylpyrido[2,3-b]indolizine-10-carbonitrile (3a) with very strong fluorescence was observed,
though the yield was very low (<3%). After numerous modifications of the reaction conditions, we
found a little improvement (13%) for the yield of 3a when the N,N-dimethylformamide (DMF) solution
of 1a and 2a was treated with potassium tert-butoxide at 80 oC in a water bath for 6h (Method A). The
results of the reactions of 2-amino-3-benzoyl- (1a), 2-amino-3-(p-chlorobenzoyl)- (1b) or
2-amino-3-(p-bromobenzoyl)indolizine-1-carbonitirile
p-chloroacetophenone (2b), p-methylacetophenone
(1c)
(2c),
with
acetophenone
(2a),
(2d),
p-bromoacetophenone
p-methoxyacetophenone (2e), and methyl 2-naphthyl ketone (2f) under the conditions of Method A are
shown in Scheme 1, but their yields were not be satisfactory (<24%). To improve further these yields
we next examined the amounts of acetophenone and solvent and the reaction temperature which is
employed. The reactions of 2-aminoindolizines 1a—c with a large excess of liquid acetophenones
2a—c (34—86 equivalents) without any solvent in the presence of potassium tert-butoxide at room
temperature (Method B) and similar treatment of 1a—c and solid acetophenones 2d—f (34 equivalents)
dissolved in small amount of DMF as possible (Method C) provided the corresponding
2,4-diarylpyrido[2,3-b]indolizine-10-carbonitrile derivatives 3a—r in 27—68% yields. The decrease of

HETEROCYCLES, Vol. 77, No. 1, 2009
473
the mole number of 2a used gave the decreased yield of product (3a) and the increase did not lead to the
o
improvement in the yield. In addition, the reaction at a higher temperature (80 C) was accompanied
with a small amount of hydrolytic product 4a (see below) together with the expected compound 3a. In
these reactions primary imine intermediates such as 8 (see Scheme 3) were not detected at all. These
results are exhibited in Scheme 1.
CN
CN
9
6
10
8
7
tert-BuOK
N1
+ MeCOAr
NH2
N
5
N
2 Ar
2a—f
O
4
3
Method A: 1.2 eq. 2a—f in DMF (10 mL) at 80 oC for 6h
Method B: 34—86 eq. 2a—c at rt for 6h
Method C: 34 eq. 2d—f in DMF (1 or 1.5 mL) at rt for 6h
R1
3a—r
Yield (%)
R1
1a—c (0.5 mmol)
Yield (%)
C
A
R1 Ar
1
R1
C
B
A
B
3
j
3
a
b
c
d
e
f
R1 Ar
a
b
c
H
Cl p-BrC6H4
Cl p-MeOC6H4
Cl 2-naphthyl
Br Ph
5
-- 61
-- 68
-- 48
55 --
30 --
H
H
H
H
H
H
Ph
13 48 --
20 33 --
17 29 --
16 -- 58
Cl
Br
k
l
6
3
8
8
p-ClC6H4
p-MeC6H4
p-BrC6H4
Ar
2
m
n
o
p
q
r
a
b
c
Ph
Br p-ClC6H4
Br p-MeC6H4
Br p-BrC6H4
p-MeOC6H4 13 -- 34
p-ClC6H4
p-MeC6H4
a) 35 --
-- 65
2-naphthyl 24 -- 46
6
g
h
i
Cl Ph
5
7
5
61 --
29 --
27 --
d
e
f
p-BrC6H4
Br p-MeOC6H4 11 -- 52
Cl p-ClC6H4
Cl p-MeC6H4
p-MeOC6H4
2-naphthyl
Br 2-naphthyl
a) Trace.
5
-- 47
Scheme 1
When pyrido[2,3-b]indolizine-10-carbonitriles 3a,d thus obtained were treated with conc. sulfuric acid at
room temperature for 3h, the corresponding 10-carboxamides 4a,b were obtained in 80 and 83% yields,
respectively (Scheme 2).
O
H
N
CN
H
N
conc.H2SO4
at rt for 3 h
N
N
N
Ar
Ar
4a (Ar=Ph, 80%)
4b (Ar=p-BrC6H4, 83%)
3a,d
Scheme 2

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HETEROCYCLES, Vol. 77, No. 1, 2009
The structural assignments for products 3a—r and 4a,b were performed mainly by elemental and IR and
1H-NMR spectral analyses.
The elemental analyses for 3a—r were in good accord with our proposed
compositions and the IR spectra showed a cyano absorption band in the range of 2205—2213 cm-1 for
3a—r and carbonyl and amino bands at 1647, 3156, and 3366 cm-1 for 4a and at 1642, 3192, and 3382
1
cm-1 for 4b, respectively. In the H-NMR spectra (see Table 1) of 3a—r and 4a,b the chemical shifts
and signal patterns of the pyrido[2,3-b]indolizine ring protons were very similar to each other except for
the 9-H signal. The 9-H signal for 4a,b was shifted considerably to the lower magnetic region by the
deshielding effect of the 10-carbamoyl group. In addition, one of the amide protons resonated at the low
field ( 9.46 for 4a and  9.35 for 4b) attributable to a hydrogen-bonding between it and the nitrogen
atom on the newly constructed pyridine ring. The final structural confirmation of products 3a—r and
4a,b was carried out by X-ray analyses of the compounds (3c and 4b). The ORTEP drawing8 of 3c and
4a is showed in Figure 1.9
N3
N3
O1
Br1
N1
N1
N2
N2
4b
3c
Figure 1. ORTEP drawings of compounds 3c and 4b.
Table 1. 1H-NMR spectral data for the ring protons of 3a—r and 4a,b
Noa) C-3
C-6
C-7
C-8
C-9
Noa) C-3
C-6
C-7
C-8
C-9
3a
3b
3c
3d
3e
3f
3g
3h
3i
7.59 7.84 6.54 7.29 7.78
7.54 7.83 6.55 7.30 7.77
7.54 7.81 6.52 7.26 7.75
7.51 7.81 6.54 7.29 7.74
7.52 7.81 6.52 7.27 7.77
7.75 7.84 6.54 7.30 7.81
7.53 7.86 6.61 7.30 7.79
7.47 7.83 6.60 7.32 7.76
7.52 7.83 6.59 7.39 7.79
7.47 7.83 6.60 7.32 7.76
3k
3l
7.48 7.83 6.59 7.30 7.78
7.67 7.84 6.58 7.29 7.78
3m 7.56 7.86 6.61 7.33 7.82
3n
3o
3p
3q
3r
4a
4b
7.49 7.85 6.62 7.33 7.80
7.54 7.85 6.60 7.31 7.80
7.51 7.85 6.62 7.34 7.81
7.46 7.83 6.59 7.30 7.77
7.70 7.86 6.61 7.32 7.81
7.54 7.81 6.49 7.26 8.78
7.50 7.82 6.51 7.29 8.80
3j
a) J6,7=6.9-7.1 Hz, J6,8=0.9-1.0 Hz, J7,8=6.9-7.1 Hz, J7,9=1.1-1.2 Hz, J8,9=8.9-9.1 Hz.

HETEROCYCLES, Vol. 77, No. 1, 2009
475
Mechanistically, the formation of the title compounds 3a—r may be as shown in Scheme 3. The
deprotonation from the 2-amino group of 1a—c by a strong base followed by the nucleophilic addition of
the resulting amide 5 onto the carbonyl carbon of acetophenones 2a—f may provide the alkoxide ion 6.
The proton abstraction of the alkoxide ion 6 and subsequent dehydration should afford the imine
intermediate 7. The base-catalized dehydration between the active methyl and the 3-acyl carbonyl group
in 7 can lead to the pyrido[2,3-b]indolizine derivatives (3a—r) via the corresponding intermediates 8 and
9 (Path A). There is an alternative route (Path B) in which the nucleophilic addition of the
arylcarbonylmethanide 10, generated from the deprotonation of 2a—f, to the 2-arylcarbonyl carbon
followed by the protonation and dehydration of the adduct 11 may provide
2-amino-3-(2-arylcarbonylvinyl)indolizines 12 and subsequent base catalyzed intramolecular dehydration
should form the same products 3a—r. However, we could not determine whether these reactions
proceed through Path A or Path B, because intermediates such as 7 and 12 could not be detected during
these reactions.
CN
NH
CN
CN
CN
H
2a—f
H+
t-BuOK
-H+
N
N
N
Ar
Ar
O-
Ar
Me
N
N
N
Ar'
N
Path a
-H2O
-
O
O
O
O
CH2
Me
Ar'
Ar'
8
Ar'
7
6
5
-H+
t-BuOK
CN
NH
CN
CN
CN
t-BuOK
NH2
NH2
N
-H+
N
N
N
N
Ar
Ar
Ar
O
O
O
Ar'
Ar'
13
Ar'
12
O-
9
-H2O
Ar'
1a—c
Path b
H+
H+
-H2O
CN
Ar CH2
CN
CN
NH
H+
O
10
NH2
O
N
N
N
N
Ar
-H2O
Ar
-H+
O
t-BuOK
Ar
Ar'
3a—r
Ar'
11
Ar'
14
O
2a—f
Path A
Path B
Scheme 3
EXPERIMENTAL
Melting points were measured with a Yanagimoto micromelting point apparatus and were not corrected.
1
Microanalyses were carried out on a Perkin-Elmer 2400 elemental analyzer.
The H-NMR and
13C-NMR spectra were determined with a JEOL JNM-LA400 (1H: 400 MHz) spectrometer in

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HETEROCYCLES, Vol. 77, No. 1, 2009
deuteriochloroform with tetramethylsilane used as the internal standard; the chemical shifts are expressed
in  values. The IR spectra were taken with JASCO FT/IR-5300 IR spectrophotometers.
Reactions of 2-aminoindolizines (1) with acetophenones (2). General method A. A mixture of
2-amino-3-arylcarbonylindolizine-1-carbonitirile (1, 0.5 mmol), acetophenone derivative (2, 0.6 mmol),
and potassium tert-butoxide (1.1 mmol) was dissolved in DMF (10 mL) and the resulting solution was
o
heated in a water bath (80 C) for 6 h. After the removal of potassium tert-butoxide by filterating the
resulting solution through the thin layer of alumina, the filtrate was concentrated at reduced pressure.
The residue was separated by column chromatography on alumina using hexane, Et2O, and CHCl3 as an
eluent. The fractions involving the desired pyrido[2,3-b]indolizine (3), which has very strong
fluorescence, were combined and concentrated at reduced pressure. The crude product (3) was purified
by recrystallization from CHCl3-hexane. The respective yields for these compounds (3a—r) in method
A are shown in Scheme 1. The changes (temperature, solvents (DMSO, acetic acid, and benzene), and
base (NaH, Et3N, and DBU) ) of the reaction conditions in this method did not provide good results.
General method B. To a solution of 2-amino-3-arylcarbonylindolizine-1-carbonitirile (1, 0.5 mmol)
dissolved in liquid acetophenone derivative (2a—c, 17—43 mmol), potassium tert-butoxide (1.1 mmol)
was added and the resulting mixture was stirred at room temperature for 6h. The reaction mixture was
treated according to the procedure described in method A.
The yields for compounds
(3a—c,g—i,m—o) obtained by this method are shown in Scheme 1, and the amounts of 2a—c used to
dissolve 2-aminoindolizines (1a—c) are shown in each description for products (3a—c,g—i,m—o).
o
When these reactions were performed at a higher temperature (80 C), the improvement in the yields for
pyridoindolizines (3) were not observed and, in addition, the concomitant formation of 10-carboxamide
derivative (4) was confirmed.
General method C. A solution of 2-amino-3-arylcarbonylindolizine-1-carbonitirile (1, 0.5 mmol), solid
acetophenone derivative (2d—f, 17 mmol), potassium tert-butoxide (1.1 mmol), and DMF (1 or 1.5 mL)
was allowed to react at room temperature for 6h. Similar work-ups of the reaction mixtures provided the
corresponding pyrido[2,3-b]indolizines (3d—f,j—l,p—r) in the yields indicated in Scheme 1. The
amount of the DMF used to dissolve 1a—c and 2d—f are indicated in each description for products
(3d—f,j—l,p—r).
The 1H-NMR spectral data for the ring protons of the pyrido[2,3-b]indolizine skeleton are listed in Table
1, and other spectral and analytical data and some reaction conditions are shown below.
2,4-Diphenylpyrido[2,3-b]indolizine-10-carbonitrile (3a): from 1a and 2a (17 mmol for method B),

HETEROCYCLES, Vol. 77, No. 1, 2009
477
o
yellow prisms, mp 246—247 C. IR (KBr): 2207 cm-1. 1H-NMR : 7.40—7.56 (5H, m, Ar-H),
7.59—7.66 (3H, m, Ar-H), 8.19—8.25 (2H, m, Ar-H). 13C-NMR : 111.1, 115.1, 116.0, 117.7, 119.3,
127.2, 127.6, 127.6, 128.3, 128.4, 128.9, 129.1, 135.9, 136.8, 138.5, 143.4, 146.1, 155.4 (two carbon are
overlapping). Anal. Calcd for C24H15N3: C, 83.46; H, 4.38; N, 12.17. Found: C, 83.54; H, 4.33; N,
12.14.
2-(p-Chlorophenyl)-4-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3b): from 1a and 2b (17 mmol for
method B), yellow needles, mp 259—260 oC.
IR (KBr): 2207 cm-1. 1H-NMR : 7.41—7.46 (2H, m,
Ar-H), 7.50—7.55 (2H, m, Ar-H), 7.60—7.65 (3H, m, Ar-H), 8.13—8.18 (2H, m, Ar-H). Anal. Calcd
for C24H14ClN3: C, 75.89; H, 3.72; N, 11.06. Found: C, 76.12; H, 3.53; N, 11.02.
2-(p-Methylphenyl)-4-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3c): from 1a and 2c (17 mmol for
method B), yellow prisms, mp 281—282 oC.
IR (KBr):  2203 cm-1.
1H-NMR : 2.41 (3H, s, Me),
7.25—7.30 (2H, m, Ar-H), 7.50—7.56 (2H, m, Ar-H), 7.58—7.65 (3H, m, Ar-H), 8.08—8.14 (2H, m,
Ar-H). 13C-NMR : 21.4, 111.2, 115.4, 115.9, 117.8, 119.3, 127.2, 127.6, 127.8, 128.5, 129.2, 129.2,
129.3, 135.9, 136.2, 136.9, 139.2, 143.5, 146.3, 155.6 (two carbon are overlapping). Anal. Calcd for
C25H17N3: C, 83.54; H, 4.77; N, 11.69. Found: C, 83.59; H, 4.71; N, 11.70.
2-(p-Bromophenyl)-4-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3d): from 1a and 2d (DMF (1 mL)
o
for method C), yellow needles, mp 281—283 C. IR (KBr):  2207 cm-1. 1H-NMR : 7.52—7.59
(4H, m, Ar-H), 7.60—7.67 (3H, m, Ar-H), 8.03—8.10 (2H, m, Ar-H). Anal. Calcd for C24H14BrN3: C,
67.94; H, 3.33; N, 9.90. Found: C, 68.17; H, 3.13; N, 9.87.
2-(p-Methoxyphenyl)-4-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3e): from 1a and 2e (DMF (1 ml)
o
for method C), yellow needles, mp 291—292 C. IR (KBr) cm-1: 2207.
1H-NMR : 3.88 (3H, s,
OMe), 6.97—7.02 (2H, m, Ar-H), 7.50—7.54 (2H, m, Ar-H), 7.58—7.63 (3H, m, Ar-H), 8.16—8.21 (2H,
m, Ar-H). Anal. Calcd for C25H17N3O: C, 79.98; H, 4.56; N, 11.19. Found: C, 80.00; H, 4.64; N, 11.10.
2-(2-Naphthyl)-4-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3f): from 1a and 2f (DMF (1.5 mL) for
o
method C), yellow needles, mp 296—297 C. IR (KBr) cm-1: 2205.
1H-NMR : 7.48—7.59 (4H,
m, Ar-H), 7.60—7.67 (3H, m, Ar-H), 7.86—7.91 (1H, m, Ar-H), 7.94—8.00 (2H, m, Ar-H), 8.43 (1H, dd,
J=8.8, 2.0 Hz, Ar-H), 8.69 (1H, d, J=2.0 Hz, Ar-H). Anal. Calcd for C28H17N3: C, 85.04; H, 4.33; N,
10.63. Found: C, 85.17; H, 4.22; N, 10.61.
4-(p-Chlorophenyl)-2-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3g): From 1b and 2a (43 mmol for

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HETEROCYCLES, Vol. 77, No. 1, 2009
o
method B), yellow prisms, mp 292 C. IR (KBr) cm-1: 2213. 1H-NMR : 7.41—7.52 (5H, m, Ar-H),
7.74—7.79 (2H, m, Ar-H), 8.17—8.22 (2H, m, Ar-H). 13C-NMR : 111.6, 115.1, 116.1, 118.0, 119.2,
127.4, 127.6, 127.9, 128.6, 129.3, 129.6, 129.9, 134.6, 135.6, 135.7, 138.5, 143.6, 146.4, 155.7 (one
carbon is overlapping). Anal. Calcd for C24H14ClN3: C, 75.89; H, 3.72; N, 11.06. Found: C, 75.74; H,
3.90; N, 11.02.
2,4-Bis(p-chlorophenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3h): From 1b and 2b (33 mmol for
o
method B), yellow prisms, mp >300 C. IR (KBr) cm-1: 2211. 1H-NMR : 7.39—7.44 (2H, m,
Ar-H), 7.47—7.52 (2H, m, Ar-H), 7.58—7.64 (2H, m, Ar-H), 8.10—8.15 (2H, m, Ar-H). 13C-NMR :
111.7, 115.0, 115.7, 118.0, 119.2, 127.6, 128.0, 128.5, 128.7, 129.6, 129.9, 134.4, 135.4, 135.7, 135.9,
136.9, 143.7, 146.3, 154.2 (one carbon is overlapping). Anal. Calcd for C24H13Cl2N3: C, 69.58; H, 3.16;
N, 10.14. Found: C, 69.85; H, 2.98; N, 10.06.
4-(p-Chlorophenyl)-2-(p-methylphenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3i): From 1b and 2c (38
mmol for method B), yellow needles, mp 295—298 oC. IR (KBr) cm-1: 2205. 1H-NMR : 2.42 (3H, s,
Me), 7.27—7.31 (2H, m, Ar-H), 7.45—7.50 (2H, m, Ar-H), 7.57—7.62 (2H, m, Ar-H), 8.08—8.13 (2H,
m, Ar-H). 13C-NMR : 21.4, 111.5, 115.2, 115.8, 117.8, 119.0, 127.1, 127.6, 127.7, 129.3, 129.5, 129.9,
134.6, 135.4, 135.6, 135.6, 139.3, 143.4, 146.2, 155.5 (one carbon is overlapping). Anal. Calcd for
C25H16ClN3: C, 76.24; H, 4.09; N, 10.67. Found: C, 76.45; H, 3.89; N, 10.65.
2-(p-Bromophenyl)-4-(p-chlorophenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3j): From 1b and 2d
o
(DMF (1 mL) for method C), yellow needles, mp >300 C. IR (KBr) cm-1: 2209. 1H-NMR :
7.47—7.52 (2H, m, Ar-H), 7.54—7.64 (4H, m, Ar-H), 8.03—8.07 (2H, m, Ar-H). Anal. Calcd for
C24H13BrClN3: C, 62.84; H, 2.86; N, 9.16. Found: C, 62.94; H, 2.74; N, 9.17.
4-(p-Chlorophenyl)-2-(p-methoxyphenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3k): From 1b and 2e
o
(DMF (1 mL) for method C), yellow needles, mp 290—292 C. IR (KBr) cm-1: 2207. 1H-NMR :
3.88 (3H, s, OMe), 6.98—7.03 (2H, m, Ar-H), 7.45—7.51 (2H, m, Ar-H), 7.57—7.63 (2H, m, Ar-H),
8.14—8.21 (2H, m, Ar-H). Anal. Calcd for C25H16ClN3O: C, 73.26; H, 3.93; N, 10.25. Found: C,
73.52; H, 3.72; N, 10.20.
4-(p-Chlorophenyl)-2-(2-naphthyl)pyrido[2,3-b]indolizine-10-carbonitrile (3l): From 1b and 2f (DMF
o
(1.5 mL) for method C), yellow needles, mp >300 C. IR (KBr) cm-1: 2207. 1H-NMR : 7.47—7.57
(4H, m, Ar-H), 7.60—7.65 (2H, m, Ar-H), 7.84—7.89 (1H, m, Ar-H), 7.90—7.96 (2H, m, Ar-H), 8.38
(1H, dd, J=8.8, 2.0 Hz, Ar-H), 8.62 (1H, d, J=2.0 Hz, Ar-H).
Anal. Calcd for C28H16ClN3: C, 78.23; H,

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479
3.75; N, 9.77. Found: C, 78.38; H, 3.60; N, 9.77.
4-(p-Bromophenyl)-2-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3m): From 1c and 2a (35 mmol for
o
method B), yellow prisms, mp 292—294 C. IR (KBr) cm-1: 2211. 1H-NMR : 7.40—7.54 (5H, m,
Ar-H), 7.74—7.79 (2H, m, Ar-H), 8.19—8.25 (2H, m, Ar-H).
Anal. Calcd for C24H14BrN3: C, 67.94;
H, 3.33; N, 9.90. Found: C, 68.22; H, 3.06; N, 9.89.
4-(p-Bromophenyl)-2-(p-chlorophenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3n): From 1c and 2b (25
mmol for method B), yellow prisms, mp >300 oC. IR (KBr) cm-1: 2211. 1H-NMR : 7.41—7.47 (4H,
m, Ar-H), 7.75—7.79 (2H, m, Ar-H), 8.12— 8.17 (2H, m, Ar-H).
Anal. Calcd for C24H13BrClN3: C,
62.84; H, 2.86; N, 9.16 Found: C, 62.49; H, 3.10; N, 9.27.
4-(p-Bromophenyl)-2-(p-methylphenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3o): From 1c and 2c (33
mmol for method B), yellow prisms, mp >300 oC. IR (KBr) cm-1: 2205. 1H-NMR : 2.42 (3H, s, Me),
7.27—7.31 (2H, m, Ar-H), 7.38—7.44 (2H, m, Ar-H), 7.72—7.77 (2H, m, Ar-H), 8.09—8.14 (2H, m,
Ar-H).
Anal. Calcd for C25H16BrN3: C, 68.50; H, 3.68; N, 9.59. Found: C, 68.74; H, 3.52; N, 9.51.
2,4-Bis(p-bromophenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3p): From 1c and 2d (DMF (1 mL) for
method C), yellow prisms, mp >300 oC. IR (KBr) cm-1: 2209. 1H-NMR : 7.40—7.44 (2H, m, Ar-H),
7.59—7.64 (2H, m, Ar-H), 7.75—7.79 (2H, m, Ar-H), 8.07—8.12 (2H, m, Ar-H).
Anal. Calcd for
C24H13Br2N3: C, 57.29; H, 2.60; N, 8.19. Found: C, 57.63; H, 2.42; N, 8.19.
4-(p-Bromophenyl)-2-(p-methoxyphenyl)pyrido[2,3-b]indolizine-10-carbonitrile (3q): From 1c and 2e
(DMF (1 mL) for method C), yellow prisms, mp 292 oC. IR (KBr) cm-1: 2205. 1H-NMR : 3.88 (3H, s,
OMe), 6.97—7.03 (2H, m, Ar-H), 7.39—7.45 (2H, m, Ar-H), 7.73—7.78 (2H, m, Ar-H), 8.13—8.19 (2H,
m, Ar-H).
9.30.
Anal. Calcd for C25H16BrN3O: C, 66.09; H, 3.55; N, 9.25. Found: C, 65.96; H, 3.63; N,
4-(p-Bromophenyl)-2-(2-naphthyl)pyrido[2,3-b]indolizine-10-carbonitrile (3r): From 1c and 2f (DMF
o
(1.5 mL) for method C), yellow prisms, mp >300 C. IR (KBr) cm-1: 2207. 1H-NMR : 7.44—7.55
(4H, m, Ar-H), 7.75—7.81 (2H, m, Ar-H), 7.85—7.90 (1H, m, Ar-H), 7.92—7.98 (2H, m, Ar-H), 8.39
(1H, dd, J=8.8, 2.0 Hz, Ar-H), 8.65 (1H, d, J=2.0 Hz, Ar-H). Anal. Calcd for C28H16BrN3: C, 70.90; H,
3.40; N, 8.86. Found: C, 71.12; H, 3.25; N, 8.78.
Acid
hydrolyses
of
pyrido[2,3-b]indolizine-10-carbonitiriles.
A
mixture
of
2,4-diarylpyrido[2,3-b]indolizine-10-carbonitirile (3a or 3d, 0.3 mmol) and conc. sulfuric acid (3 g) was

480
HETEROCYCLES, Vol. 77, No. 1, 2009
stirred at rt for 3h. The mixture was poured into cold water (70 mL) and the crystalline products which
were separated were collected by suction. The aqueous filtrate was then neutralized by 1N sodium
hydroxide and the resulting solution was extracted twice with 30 mL of CHCl3. The residue from the
chloroform layers and the crystalline product were combined and separated by column chromatography
on alumina using CHCl3 and CHCl3-EtOH (10:1) as an eluent. The recrystallization form CHCl3
1
afforded the corresponding 10-carboxamide derivative (4a or 4b). The H-NMR spectral data for the
ring protons of the pyrido[2,3-b]indolizine skeleton are listed in Table 1, and other spectral and analytical
data are shown below.
o
2,4-Diphenylpyrido[2,3-b]indolizine-10-carboxamide (4a): From 3a, yellow prisms, mp 284—286 C.
IR (KBr) cm-1: 1647, 3156, 3366. 1H-NMR : 5.69 (1H, br s, NH), 7.41—7.67 (8H, m, Ar-H),
8.07—8.19 (2H, m, Ar-H), 9.46 (1H, br s, NH).
Anal. Calcd for C24H17N3O: C, 79.32; H, 4.72; N,
11.56. Found: C, 79.52; H, 4.64; N, 11.44.
2-(p-Bromophenyl)-4-phenylpyrido[2,3-b]indolizine-10-carboxamide (4b): From 3d, yellow prisms, mp
o
>300 C. IR (KBr) cm-1: 1642, 3192, 3382. 1H-NMR : 5.68 (1H, br s, NH), 7.51—7.56 (2H, m,
Ar-H), 7.59—7.67 (5H, m, Ar-H), 7.98—8.02 (2H, m, Ar-H), 9.35 (1H, br s, NH).
Anal. Calcd for
C24H16BrN3O: C, 65.17; H, 3.65; N, 9.50. Found: C, 65.32; H, 3.80; N, 9.19.
Crystallography of 2-(p-methylphenyl)-4-phenylpyrido[2,3-b]indolizine-10-carbonitrile (3c)
A
yellow prismatic single crystal (0.62x0.38x0.06mm) grown from chloroform was used for the unit-cell
determinations and data was collected using a Rigaku AFC5S four-circle diffractometer with
graphite-monochromated MoKradiation (=0.71069 Å). The crystal data of this compound are as
follows: 3c: C25H17N3; M=352.47; monoclinic, space group P21/n (#14), Z=4 with a=7.293 (9) Å,
b=13.172 (13) Å, c=19.901 (11) Å, =98.18 (8)o,V=1892.5 (30) Å3 and Dcalc.=1.261 g/cm3. All
calculations were performed using CrystalStructure.10 The structure was solved by a direct method
(SIR).11 The non-hydrogen atoms were refined anisotropically, and the hydrogen atoms were attached at
the idealized position and not refined. The final R- and Rw-factors after full-matrix least-squares
refinements were 0.055 and 0.040 respectively for 1898 (I>2.00observed reflections.
Crystallography of 2-(p-Bromophenyl)-4-phenylpyrido[2,3-b]indolizine-10-carboxamide (4b)
A yellow prismatic single crystal (0.58x0.52x0.16mm) grown from CHCl3 was used for the unit-cell
determinations and data was collected using a Rigaku AFC5S four-circle diffractometer with
graphite-monochromated MoKradiation (=0.71069 Å). The crystal data of this compound are as
follows: 3c: C24H16BrN3O-CHCl3; M=561.69; triclinic, space group P-1(#2), Z=2 with a=10.491 (11) Å,

HETEROCYCLES, Vol. 77, No. 1, 2009
481
b=11.856 (15) Å, c=10.30 (2) Å, =110.11 (15)o, =98.18 (8)o, =97.46 (9),V=1159.6 (33) Å3 and
Dcalc.=1.609 g/cm3. All calculations were performed using CrystalStructure.10 The structure was
solved by a direct method (SIR).11 The non-hydrogen atoms were refined anisotropically, and the
hydrogen atoms were attached at the idealized position and not refined. The final R- and Rw-factors after
full-matrix least-squares refinements were 0.083 and 0.062 respectively for 2621 (I>2.00observed
reflections.
REFERENCES
1. For part 63 of this series, see A. Kakehi, H. Suga, A. Izumita, and T. Abe, Heterocycles, 2008, 76,
391.
2. A. Kakehi, S. Ito, S. Hayashi, and T. Fujii, Bull. Chem. Soc. Jpn., 1995, 68, 3573.
3. A. Kakehi, S. Ito, N. Yamada, and K. Yamaguchi, Chem. Pharm. Bull., 1990, 38, 1527.
4. T. Yoon, PCT Int. Appl., 1999, 56.
5. O. I. A. El-Salam, Monat. Chem., 2000, 131, 959.
6. H. Pauls and F. Kroehnke, Chem. Ber., 1977, 110, 1294.
7. G. E. Khoroshilov, Chem. Heterocyl, Comp., 2001, 37, 1141.
8. C. K. Johnson, "ORTEO II, Report ORNL-5138," Oak Ridge National Laboratory, Oak Ridge,
Tennessee, 1976.
9. The chloroform molecule involved in the crystal lattice of compound 4b is omitted.
10. SIR92: A. Altmare, G. Cascarano, C. Giacovazzo, A. Guagliardi, M. Burla, G. Polridori, and M.
Camalli, J. Appl. Cryst., 1994, 27, 435.
11. CrystalStructure 3.8: Crystal Structure Analysis Package, Rigaku and Rigaku/MSC (2000—2006).
9009 New Trails Dr. The Woodlands TX 77381 USA.