Copper-free Sonogashira coupling of 2-chloroquinolines with phenyl acetylene and quick annulation to benzo[b][1,6]naphthyridine derivatives in aqueous ammonia

Article abstract of DOI:10.1016/j.tet.2008.10.010

An efficient copper-free Sonogashira coupling of 2-chloroquinolines with phenyl acetylene to 2-ethynylquinolines is described. We further discussed the one pot facile annulation of 2-alkynylquinoline-3-carboxaldehydes to 3-phenylbenzo[b][1,6]naphthyridines in aqueous ammonia in excellent yield.

Full text of DOI:10.1016/j.tet.2008.10.010

Tetrahedron 64 (2008) 11680–11685
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Copper-free Sonogashira coupling of 2-chloroquinolines with phenyl acetylene
and quick annulation to benzo[b][1,6]naphthyridine derivatives in aqueous
ammonia
*
Atish Chandra, Bhawana Singh, Shraddha Upadhyay, Radhey M. Singh
Department of Chemistry, Banaras Hindu University, Varanasi 221 005, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 13 August 2008
Received in revised form 6 October 2008
Accepted 7 October 2008
Available online 14 October 2008
An efficient copper-free Sonogashira coupling of 2-chloroquinolines with phenyl acetylene to 2-ethy-
nylquinolines is described. We further discussed the one pot facile annulation of 2-alkynylquinoline-3-
carboxaldehydes to 3-phenylbenzo[b][1,6]naphthyridines in aqueous ammonia in excellent yield.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Sonogashira coupling
Copper-free
Naphthyridine
2-Chloroquinoline-3-carboxaldehyde
1. Introduction
of olefinic bond from their 3-homoallylalcohol analogues.10 We
further anticipated that their 2-alkynyl analogues could also serve
Among the variety of transition-metal catalyzed coupling re-
actions, Sonogashira coupling reaction of aryl halides with terminal
acetylene, provides an effective route for C–C bond formation, has
become useful method for the preparation of arylalkynes and
conjugated enynes,1 and has been widely applied as a key step in
natural product synthesis and molecular organic materials.2,3 Ini-
tially, the most common catalytic system for the Sonogashira
reaction was palladium–phosphine complexes with CuI as the co-
catalyst in excess of amines.1a–c,4 In recent years significant prog-
ress has been made in this reaction and an efficient copper-free
catalyst systems has been developed, which avoided the homo-
coupling.4f,5 However, the copper-free Sonogashira reaction has
been intensively investigated with aryl/heteroaryl iodide and bro-
mide derivatives6 and only few examples with aryl chloride are
known.4d,7 Recently, Plenio and co-workers have reported the
copper-free coupling reaction of pyridyl chlorides with terminal
alkynes in aqueous/organic solvents, but it required bulky phe-
nylphosphine ligand.8 The 3-cyano-/3-formyl-2-chloroquinolines,
easily accessible precursors are in our hand in connection with the
studies of new routes for the synthesis of carbo-/hetero-annula-
tedquinolines.9 Recently, we have reported the synthesis of cyclo-
penta-/pyrano-annulatedquinolines via intramolecular cyclization
as other new route towards annulations. Therefore, with this view
our effort is to develop the condition of Sonogashira coupling for
the synthesis of 2-alkynylquinolines from 2-chloroquinolines. Thus,
in this paper we describe copper-free, palladium-catalyst for the
Sonogashira coupling of 3-cyano/formyl-2-quinolinyl chlorides
with phenyl acetylene under mild condition.
2. Results and discussion
Initially, we chose 2-chloroquinoline-3-carboxaldehyde (1a)
with phenyl acetylene as model reaction to investigate the copper-
free Sonogashira reaction and optimization of the reaction condi-
tions. Thus, the reaction of 1a (0.25 mmol) with phenyl acetylene
(0.26 mmol) was carried out in the presence of PdCl2 (4 mol %),
triphenylphosphine (8 mol %) and triethylamine (2 equiv) in CH3CN
as a solvent at 80 ꢀC under an inert atmosphere for 4 h, the iso-
lated product was characterized as 2-alkynylquinoline-3-carbox-
aldehyde (2a) in 87% yield (Scheme 1, Table 2, entry 1).
Ph
CHO
CHO
Cl
PdCl2 / PPh3 / TEA
CH3CN, 80 °C
N
2a
N
1a
R
R
Ph
R = H
* Corresponding author.
Scheme 1.
E-mail address: rmohan@bhu.ac.in (R.M. Singh).
0040-4020/$ – see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2008.10.010

A. Chandra et al. / Tetrahedron 64 (2008) 11680–11685
11681
Table 1
Table 2 (continued)
Optimization of reaction conditions on Sonogashira coupling
Entry
Substrate
Product
CN
Time (h) Yield (%)
Entry
Catalyst
Base
Solvent
Ligand
Time (h)
Yield (%)
CN
Cl
1
2
3
4
5
6
7
PdCl2
Pd(OAc)2
PdCl2
PdCl2
PdCl2
Et3N
Et3N
K2CO3
DABCO
Cs2CO3
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMF
PPh3
PPh3
PPh3
PPh3
PPh3
Bu4NBr
PPh3
4
5
12
8
87
78
45
52
Trace
77
70
12
4
3
6
76
83
89
N
N
Ph
Ph
Ph
Ph
2l
1l
d
CN
Cl
CN
CHO
CN
PdCl2
PdCl2/CuI
2
15
Et3N
13
14
N
1m
N
2m
Next, we turned our attention towards the effect of various
parameters on the copper-free Sonogashira coupling reaction. The
results are reported in Table 1. It was found that amongst four bases
such as Et3N, Cs2CO3, K2CO3 and DABCO tested, Et3N was the best
Ph
Ph
Ph
CHO
Cl
N
N
N
1n
2n
Table 2
Ph
CN
Cl
Copper-free Sonogashira reaction of heteroaryl chloride with phenyl acetylene
15
1.5
92
Entry
1
Substrate
CHO
Cl
Product
CHO
Time (h) Yield (%)
N
1o
2o
4
87
85
85
N
2a
N
1a
Ph
CHO
(Table 1, entries 1–5). However, Bu4NBr was found fast in accom-
plishing the reaction, but yield was poor (Table 1, entry 6). As can be
seen from Table 1, PdCl2/PPh3/TEA was found most effective catalyst
for the aforesaid reaction as shorter reaction time and better yield
of product (Table 1, entry 1). It is noteworthy that the same coupling
reaction was also tried with CuI in longer time with moderate yield
of the desired product (Table 1, entry 7).
After optimizing the reaction conditions, we applied the reaction
on a series of heteroaryl chlorides (1a–o), which afforded the cor-
responding products 2a–o, respectively, in a good yield (Table 2).
Annulationprocesses have provenpowerful methodology for the
synthesis of complicated heterocycles. In recent years, synthesis
of pyridine-annulated ring system intensively investigated from
CHO
2
3
3.5
3
N
N
Cl
2b
1b
Ph
CHO
CHO
Cl
N
2c
N
1c
Ph
CHO
CHO
4
5
6
7
3
88
80
78
83
MeO
N
MeO
N
Cl
Ph
1d
2d
b-chloroacrolein moiety involving condensation with N-t-butyl-
CHO
Cl
CHO
amine followed by palladium-catalyzed cyclization with internal
alkynes,11 as well as three-step sequences involving the Sonogashira
coupling of terminal alkynes and subsequent condensation to aldi-
mines followed by annulation in the presence of either electrophile
or transition metals have been developed.12 Similarly, analogous
synthesis has been reported for naphthyridines but annulation oc-
curred with alcoholic ammonia in a sealed tube.13 This encouraged
us to examine the similar reactions on our substrates 2a–g. In con-
trast to expensive and foul smelling amines, anhydrous solvents,
inert conditions and catalysts, we were delighted to observe that the
analogous annulation reaction of substrates 2a–g was occurred, in
the absence of catalyst, with aqueous ammonia within 15 min.
Thus, the reaction of 2-alkynylquinoline-3-carboxaldehyde (2a)
(0.5 mmol) and K2CO3 (0.75 mmol) in ethanol is refluxed with
excess amount of aqueous ammonia. The product was isolated in
excellent yield and characterized as 3-phenylbenzo[b][1,6]-
naphthyridine (3a) from spectral data (Scheme 2).
4
N
1e
N
Ph
Ph
2e
CHO
Cl
CHO
4
N
1f
N
2f
MeO
CHO
MeO
CHO
Cl
3.5
N
2g
N
1g
Ph
CN
CN
Cl
8
2
88
80
82
N
N
1h
2h
Ph
CN
CN
9
2
N
2i
N
1i
Cl
CHO
Aq. NH3 / K2CO3
Ph
N
EtOH, Δ , 15 min
CN
CN
Cl
N
Ph
N
R
R
10
3.5
Ph
N
3
2
N
2j
N
-H+
H
Ph
H
1j
N+
N
-EtO-
N
Ph
R
R
CN
CN
Cl
Ph
EtO
A
B
11
4
84
MeO
N
MeO
N
R = H, Me, OMe, Et.
Ph
1k
2k
Scheme 2.

11682
A. Chandra et al. / Tetrahedron 64 (2008) 11680–11685
Table 3
Table 4
Representative base mediated annulation of 2-alkynecarbaldehydes
Representative base mediated annulation of oxime
Entry
Alkyne aldehyde
R
Product
Yield (%)
Entry
Oxime
R
Product
Yield (%)
1
2
3
4
5
6
2a
2b
2c
2d
2e
2f
H
3a
3b
3c
3d
3e
3f
89
88
86
81
91
93
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
H
5a
5b
5c
5d
5e
5f
91
94
90
89
94
96
6-Me
7-Me
7-OMe
8-Me
8-Et
6-Me
7-Me
7-OMe
8-Me
8-Et
line (77.0 ppm) of CDCl3 (for 13C). Mass spectra were recorded from
SAIF, CDRI, Lucknow and SAIF, Panjab University, Chandigadh. High-
resolution mass spectra were recorded using Micromass Q-TOF
micro mass spectrometer equipped with a Harvard syringe pump
apparatus using electron spray ionization mode at the SAIF, IIT
Madras, Chennai. Elemental analyses were carried out using EXTER,
CE-440 elemental analyzer at the Department of Chemistry, Faculty
of Science, Banaras Hindu University, Varanasi. Thin-layer chro-
matographies (TLC) were performed on glass plates (7.5ꢁ2.5 and
7.5ꢁ5.0 cm) coated with Loba Chemie’s silica gel GF 254 and vari-
ous combinations of ethyl acetate and hexane were used as eluent.
Visualization of spots was accomplished by exposure to UV light.
Qualigen’s silica gel (60–120 mesh) was used for column chroma-
tography (approximately 15–20 g per 1 g of the crude product).
Thus, after optimizing the reaction conditions of annulation on
2a, the reaction with other substrates 2a–f afforded corresponding
benzo[b][1,6]naphthyridines (3a–f) in excellent yield (Table 3).
Further, the cyclization reaction was attempted with 3-cyano-
quinoline derivatives with the view to synthesize 1-amino-3-phe-
nylbenzonaphthyridine. Thus, when 3-cyanoquinoline derivative
(2h) was treated with aqueous ammonia under similar reaction
condition and also by adding more ammonia solution and in-
creasing temperature ranging from 80 to 120 ꢀC, the corresponding
desired product could not be isolated at all, starting cyanoquinoline
was being recovered. From this observation we speculate that the
aldimine A initially formed from 2 would be, of short lived, im-
mediately cyclized to naphthyridine derivatives 3 (Scheme 2).
The cyclization reaction was further investigated with their
corresponding oximes 4a–f under identical reaction conditions
with a view that the base would activate the nucleophilicity of
aldoxime nitrogen atom via generating N-oxide anion of aldoxime,
which accelerate the cyclization to the desired products 5a–f. Thus,
when oximes 4a–f (0.5 mmol), prepared by conventional pro-
cedure, were refluxed with K2CO3 and excess of aqueous ammonia
in ethanol, reactions were completed in 5 min and products were
characterized as benzo[b][1,6]naphthyridine-2-oxides (5a–f) in
excellent yields, which support our speculation (Scheme 3, Table 4).
4.2. General procedure for Copper-free Sonogashira coupling
A mixture of heteroaryl chloride 1 (0.25 mmol), phenyl acetyl-
ene (0.26 mmol), PdCl2 (4 mol %), PPh3 (8 mol %), CH3CN (4 mL) and
TEA (0.5 mmol) was stirred under N2 at 80 ꢀC for time ranging
between 1.5 and 6 h (as monitored by TLC). The reaction mixture
was concentrated in vacuo and residue was purified by column
chromatography on silica gel using EtOAc/hexane as eluent in dif-
ferent polarity.
3. Conclusions
4.2.1. 2-Phenylethynyl-quinoline-3-carbaldehyde (2a)
In summary, we optimized copper-free Sonogashira coupling on
less explored chlorine of 2-chloroquinoline and 2-chloropyridine
derivatives with phenyl acetylene and described their annulations
to desired benzo[b][1,6]naphthyridines was even more facile in
aqueous ammonia. This class of compounds also exhibited, beside
biological activity,14,15 photophysical and photochemical behav-
iours.16 Further, the resulting Sonogashira coupling products, 2-
ethynequinolines, could be used as key intermediate in area of
synthetic organic chemistry.
White solid; yield: 87%; mp 118 ꢀC; Rf (11% EtOAc–hexane) 0.54;
IR (KBr): 2208, 1693 cmꢂ1 1H NMR (300 MHz, CDCl3):
; d 7.43 (3H,
m), 7.62–7.72 (3H, m), 7.88 (1H, t, J 7.5 Hz), 7.98 (1H, d, J 8.1 Hz), 8.20
(1H, d, J 5.7 Hz), 8.76 (1H, s), 10.81 (1H, s); 13C NMR (75 MHz,
CDCl3):
d 85.6, 95.5, 121.4, 126.4, 128.2, 128.6, 128.9, 129.4, 129.7,
129.9, 132.3, 133.0, 137.2, 147.9, 150.2, 190.8. Anal. Calcd for
C18H11NO: C, 84.03; H, 4.31; N, 5.44. Found: C, 83.37; H, 4.43; N,
5.23.
4.2.2. 6-Methyl-2-phenylethynyl-quinoline-3-carbaldehyde (2b)
White solid; yield: 85%; mp 132 ꢀC; Rf (11% EtOAc–hexane) 0.61;
4. Experimental section
4.1. General
IR (KBr): 2210, 1691 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
2.58 (3H, s),
7.43 (3H, m), 7.70 (4H, m), 8.08 (1H, d, J 8.4 Hz), 8.67 (1H, s), 10.80
(1H, s); 13C NMR (75 MHz, CDCl3):
21.6, 85.6, 95.0, 121.4, 126.4,
d
Melting points are measured using Buchi Melting-point appa-
ratus in an open capillary tubes and are uncorrected. IR spectra
were recorded on VARIAN 3300 FTIR spectrophotometers. 1H
(300 MHz) and 13C (75 MHz) NMR spectra were recorded on JEOL
128.2, 128.5, 128.8, 128.9, 129.7, 132.2, 135.4, 136.2, 138.5, 143.0,
148.8, 190.8. Anal. Calcd for C19H13NO: C, 84.11; H, 4.83; N, 5.16.
Found: C, 83.65; H, 4.98; N, 5.39.
AL 300 MHz spectrometer. The chemical shifts (
pling constants (Hz) are reported in the standard fashion with
reference to either internal tetramethylsilane (for 1H) or the central
d
ppm) and cou-
4.2.3. 7-Methyl-2-phenylethynyl-quinoline-3-carbaldehyde (2c)
Colourless needle; yield: 85%; mp 125 ꢀC; Rf (11% EtOAc–hex-
ane) 0.39; IR (KBr): 2208, 1689 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
OH
CH
N
O-
CHO
N+
NH2OH.HCl
K2CO3
NaOAc / MeOH
Δ
5 min
EtOH,
,
N
N
N
Ph
R
R
R
Ph
Ph
R = H, Me, OMe, Et.
4
2
5
Scheme 3.

A. Chandra et al. / Tetrahedron 64 (2008) 11680–11685
11683
d
2.62 (3H, s), 7.45 (4H, m), 7.78 (2H, m), 7.83 (1H, d, J 9.0 Hz), 8.01
NMR (75 MHz, CDCl3):
d
22.3, 86.4, 95.4, 108.8, 116.7, 121.2, 123.2,
(1H, s), 8.81 (1H, s), 10.82 (1H, s); 13C NMR (75 MHz, CDCl3):
d
22.3,
127.6, 128.5, 128.6, 130.0, 131.0, 132.7, 141.6, 143.0, 144.4. 148.9. Anal.
Calcd for C19H12N2: C, 85.05; H, 4.51; N, 10.44. Found: C, 84.41; H,
4.82; N, 10.28.
85.7, 95.4, 121.5, 124.6, 128.3, 128.4, 128.6, 129.3, 129.8, 130.6, 132.3,
136.7, 144.0, 144.3, 150.4, 190.8; MS: m/z¼272 (MþH)þ. HRMS Calcd
for C19H14NO [MþH]þ 272.1075; found 272.1082.
4.2.11. 7-Methoxy-2-phenylethynyl-quinoline-3-carbonitrile (2k)
White solid; yield: 84%; mp 122 ꢀC; Rf (11% EtOAc–hexane) 0.38;
4.2.4. 7-Methoxy-2-phenylethynyl-quinoline-3-carbaldehyde (2d)
White solid; yield: 88%; mp 195 ꢀC; Rf (11% EtOAc–hexane) 0.40;
IR (KBr): 2218 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
3.99 (3H, s), 7.40–
7.46 (4H, m), 7.73 (4H, m), 8.42 (1H, s); 13C NMR (75 MHz, CDCl3):
55.8, 86.3, 95.3, 107.2, 107.4, 116.7, 120.4, 121.2, 122.1, 128.5, 129.0,
IR (KBr): 2212,1687 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
3.99 (3H, s),
7.29 (1H, s), 7.41–7.49 (4H, m), 7.69 (2H, m), 7.85 (1H, d, J 9.0 Hz),
8.66 (1H, s), 10.76 (1H, s); 13C NMR (75 MHz, CDCl3):
55.8, 85.6,
d
d
129.9, 132.6, 141.1, 143.5, 150.8, 163.6. Anal. Calcd for C19H12N2O: C,
80.27; H, 4.25; N, 9.85. Found: C, 79.65; H, 4.16; N, 9.63.
95.3, 107.1, 121.4, 121.8, 127.3, 128.5, 129.7, 130.7, 132.3, 132.7, 136.4,
144.5, 152.3, 163.7, 190.6. Anal. Calcd for C19H13NO2: C, 79.43; H,
4.56; N, 4.87. Found: C, 79.98; H, 4.41; N, 4.95.
4.2.12. 8-Methyl-2-phenylethynyl-quinoline-3-carbonitrile (2l)
Light yellow crystal; yield: 76%; mp 93 ꢀC; Rf (5% EtOAc–hexane)
4.2.5. 8-Methyl-2-phenylethynyl-quinoline-3-carbaldehyde (2e)
Light yellow crystal; yield: 80%; mp 148–150 ꢀC; Rf (11% EtOAc–
0.38; IR (KBr): 2211 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
2.84 (3H, s),
7.41 (3H, m), 7.55 (1H, t, J 7.8 Hz), 7.68–7.77 (4H, m), 8.49 (1H, s); 13C
NMR (75 MHz, CDCl3): 17.9, 86.8, 95.0, 109.5, 116.7, 121.4, 125.0,
hexane) 0.54; IR (KBr): 2208, 1689 cmꢂ1
;
1H NMR (300 MHz,
d
CDCl3):
d
2.87 (3H, s), 7.42–7.54 (4H, m), 7.72 (3H, m), 7.80 (1H, d, J
18.0,
125.9, 128.4, 128.5, 129.8, 132.6, 133.2, 137.9, 141.7, 142.1, 147.7. Anal.
Calcd for C19H12N2: C, 85.05; H, 4.51; N, 10.44. Found: C, 84.63; H,
4.32; N, 10.54.
8.1 Hz), 8.71 (1H, s), 10.82 (1H, s); 13C NMR (75 MHz, CDCl3):
d
86.0, 94.8, 121.5, 126.4, 127.5, 127.9, 128.5, 129.6, 132.2, 132.4, 133.0,
137.0, 137.5, 142.6, 149.2, 191.1. Anal. Calcd for C19H13NO: C, 84.11; H,
4.83; N, 5.16. Found: C, 83.67; H, 5.00; N, 5.31.
4.2.13. 8-Ethyl-2-phenylethynyl-quinoline-3-carbonitrile (2m)
Colourless solid; yield: 83%; mp 85 ꢀC; Rf (5% EtOAc–hexane)
4.2.6. 8-Ethyl-2-phenylethynyl-quinoline-3-carbaldehyde (2f)
Colourless solid; yield: 78%; mp 88 ꢀC; Rf (5% EtOAc–hexane)
0.40; IR (KBr): 2223 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
1.39 (3H, t, J
7.5 Hz), 1.34 (2H, q, J 7.5 Hz), 7.42 (3H, m), 7.59 (1H, t, J 7.2 Hz), 7.68–
7.77 (4H, m), 8.50 (1H, s); 13C NMR (75 MHz, CDCl3):
14.8, 24.1,
0.43; IR (KBr): 2205, 1688 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
1.41
d
(3H, t, J 7.5 Hz), 3.90 (2H, q, J 7.5 Hz), 7.44 (3H, m), 7.56 (1H, t, J
7.8 Hz), 7.71 (3H, m), 7.80 (1H, d, J 7.8 Hz), 8.71 (1H, s), 10.82 (1H, s);
86.8, 94.7, 109.4, 116.7, 121.4, 125.0, 125.7, 128.4, 128.5, 129.8, 131.5,
132.6, 141.6, 142.1, 143.6, 147.1. Anal. Calcd for C20H14N2: C, 85.08; H,
5.00; N, 9.92. Found: C, 84.70; H, 5.12; N, 9.83.
13C NMR (75 MHz, CDCl3):
d 14.8, 24.2, 86.2, 94.6,125.6,126.5,127.5,
128.1, 128.5, 128.6, 128.9, 129.6, 131.3, 132.2, 137.2, 142.7, 143.4,
191.2. Anal. Calcd for C20H15NO: C, 84.19; H, 5.30; N, 4.91. Found: C,
83.75; H, 5.49; N, 4.73.
4.2.14. 5-Phenyl-2-phenylethynyl-pyridine-3-carbaldehyde (2n)
Colourless solid; yield: 89%; mp 91 ꢀC; Rf (7% EtOAc–hexane)
0.43; IR (KBr): 2209, 1695 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
7.41–
7.69 (10H, m), 8.41 (1H, s), 9.07 (1H, s), 10.73 (1H, s); 13C NMR
(75 MHz, CDCl3): 84.8, 96.5, 121.4, 127.1, 128.6, 129.0, 129.4, 129.8,
4.2.7. 6-Methoxy-2-phenylethynyl-quinoline-3-carbaldehyde (2g)
Light yellow solid; yield: 83%; mp 154 ꢀC; Rf (11% EtOAc–hexane)
d
0.40; IR (KBr): 2206, 1693 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
3.97
131.6, 132.2, 132.5, 135.9, 136.2, 144.5, 152.8, 190.9. Anal. Calcd for
C20H13NO: C, 84.78; H, 4.62; N, 4.94. Found: C, 84.31; H, 4.74; N,
5.16.
(3H, s), 7.18 (1H, d, J 2.7 Hz), 7.42–7.53 (4H, m), 7.67–7.70 (2H, m),
8.05 (1H, d, J 9.3 Hz), 8.63 (1H, s), 10.79 (1H, s); 13C NMR (75 MHz,
CDCl3):
d 55.8, 85.5, 94.7, 106.2, 121.5, 126.3, 127.7, 128.5, 129.0,
129.6, 130.7, 132.2, 135.3, 141.4, 146.6, 159.0, 191.0. Anal. Calcd for
C19H13NO2: C, 79.43; H, 4.56; N, 4.87. Found: C, 79.08; H, 4.25; N,
4.96.
4.2.15. 5-Phenyl-2-phenylethynyl-pyridine-3-carbonitrile (2o)
White solid; yield: 92%; mp 121 ꢀC; Rf (7% EtOAc–hexane) 0.42;
IR (KBr): 2213 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
7.40–7.61 (8H,
m), 7.70 (2H, m), 8.14 (1H, s), 9.00 (1H, s); 13C NMR (75 MHz, CDCl3):
85.7, 96.6, 112.9, 116.1, 121.1, 127.0, 128.5, 129.4, 129.5, 130.0, 132.5,
4.2.8. 2-Phenylethynyl-quinoline-3-carbonitrile (2h)
d
Colourless needle; yield: 88%; mp 165–166 ꢀC; Rf (11% EtOAc–
135.0, 135.3,137.7, 144.2,151.3. Anal. Calcd for C20H12N2: C, 85.69; H,
4.31; N, 9.99. Found: C, 85.78; H, 4.45; N, 9.72.
hexane) 0.47; IR (KBr): 2215, 2106 cmꢂ1 1H NMR (300 MHz,
;
CDCl3):
d
7.44 (3H, m), 7.68–7.90 (5H, m), 8.16 (1H, d, J 8.1 Hz), 8.56
86.2, 95.6, 109.7, 116.4, 121.1,
(1H, s); 13C NMR (75 MHz, CDCl3):
d
4.3. Transformation of aldehydes (2a–f) to benzo[b]-
125.0, 128.0, 128.5, 129.6, 130.0, 132.6, 133.2, 135.0, 142.0, 142.9,
148.6; MS: m/z¼255 (MþH)þ. HRMS Calcd for C18H11N2 [MþH]þ
255.0922; found 255.0919.
[1,6]naphthyridines (3a–f)
To a solution of 2 (0.5 mmol) in EtOH (7 mL) were added K2CO3
(0.75 mmol) and saturated with aq NH3. The reaction mixture was
stirred at refluxed temperature. The reaction completed after
15 min (as monitored by TLC). The reaction mixture allowed to pour
in chilled water (7 mL) and precipitate filtered out and dried.
4.2.9. 6-Methyl-2-phenylethynyl-quinoline-3-carbonitrile (2i)
White solid; yield: 80%; mp 118–119 ꢀC; Rf (11% EtOAc–hexane)
0.53; IR (KBr): 2212 cmꢂ1; 1H NMR (300 MHz, CDCl3):
d
2.58 (3H, s),
7.41 (3H, m), 7.63 (1H, s), 7.70–7.76 (3H, m), 8.05 (1H, d, J 8.4 Hz),
8.45 (1H, s); 13C NMR (75 MHz, CDCl3):
21.7, 86.3, 95.1,109.6,116.5,
d
4.3.1. 3-Phenylbenzo[b][1,6]naphthyridine (3a)
121.2, 125.0, 126.7, 128.5, 129.2, 129.9, 132.6, 135.4, 139.2, 141.2,
142.0, 147.3; MS: m/z¼269 (MþH)þ. HRMS Calcd for C19H13N2
[MþH]þ 269.1079; found 269.1076.
Light green solid; yield: 89%; mp 172 ꢀC; Rf (20% EtOAc–hexane)
0.49; IR (KBr): 3052, 1613, 1441 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
7.46–7.63 (4H, m), 7.90 (1H, t, J 7.2 Hz), 8.02 (1H, d, J 8.4 Hz), 8.24
(3H, m), 8.45 (1H, s), 8.98 (1H, s), 9.61 (1H, s); 13C NMR (75 MHz,
4.2.10. 7-Methyl-2-phenylethynyl-quinoline-3-carbonitrile (2j)
Light yellow crystal; yield: 82%; mp 88 ꢀC; Rf (11% EtOAc–hex-
CDCl3): d 116.6, 121.1, 126.3, 127.0, 127.2, 128.9, 129.0, 129.2, 129.4,
132.6, 137.2, 138.8, 150.4, 152.1, 153.8, 154.7; MS: m/z¼257 (MþH)þ.
Anal. Calcd for C18H12N2: C, 84.35; H, 4.72; N,10.93. Found: C, 84.71;
H, 4.49; N, 10.74.
ane) 0.53; IR (KBr): 2217 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
2.61
(3H, s), 7.41–7.51 (4H, m), 7.75 (3H, m), 7.94 (1H, s), 8.49 (1H, s); 13C

11684
A. Chandra et al. / Tetrahedron 64 (2008) 11680–11685
4.3.2. 8-Methyl-3-phenylbenzo[b][1,6]naphthyridine (3b)
4.5.1. 3-Phenylbenzo[b][1,6]naphthyridine-2-oxide (5a)
Light green solid; yield: 88%; mp 112 ꢀC; Rf (11% EtOAc–hexane)
Light yellow solid; yield: 91%; mp 175 ꢀC; Rf (60% EtOAc–hexane)
0.33; IR (KBr): 2922, 1618, 1404 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
0.36;IR (KBr): 3054,1620,1434,1284,1189 cmꢂ1; 1HNMR (300 MHz,
d
2.61 (3H, s), 7.45–7.54 (3H, m), 7.75 (1H, d, J 9.0 Hz), 7.82 (1H, s),
8.15 (1H, d, J 9.0 Hz), 8.41 (2H, m), 8.42 (1H, s), 8.84 (1H, s), 9.58 (1H,
s); 13C NMR (75 MHz, CDCl3):
21.7, 116.6, 121.2, 126.9, 127.1, 128.8,
CDCl3):
d
7.53–7.62 (4H, m), 7.87–8.02 (4H, m), 8.17 (2H, m), 8.62 (1H,
122.2,125.7,127.6,127.7,
s), 9.06 (1H, s); 13C NMR (75 MHz, CDCl3):
d
d
128.2,128.3,129.6,129.8,129.9,131.9,132.1,132.2,136.0,144.0,150.3,
150.9; MS: m/z¼273 (MþH)þ. Anal. Calcd for C18H12N2O: C, 79.40; H,
4.44; N, 10.29. Found: C, 79.18; H, 4.32; N, 10.55.
128.9, 129.0, 135.5, 135.9, 136.3, 138.9, 149.8, 150.9, 151.0, 153.4,
154.5; MS: m/z¼271 (MþH)þ. Anal. Calcd for C19H14N2: C, 84.42; H,
5.22; N, 10.36. Found: C, 84.08; H, 5.13; N, 10.17.
4.5.2. 8-Methyl-3-benzo[b][1,6]naphthyridine-2-oxide (5b)
4.3.3. 7-Methyl-3-phenylbenzo[b][1,6]naphthyridine (3c)
Light yellow solid; yield: 94%; mp 190 ꢀC; Rf (60% EtOAc–hex-
Light green solid; yield: 86%; mp 197 ꢀC; Rf (20% EtOAc–hexane)
ane) 0.39; IR (KBr): 2922, 1630, 1414, 1284, 1172 cmꢂ1 1H NMR
;
0.52; IR (KBr): 2923, 1605, 1436 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3):
8.07 (1H, d, J 8.4 Hz), 8.14 (1H, s), 8.50 (1H, s), 9.03 (1H, s); 13C NMR
(75 MHz, CDCl3): 21.8, 122.3, 125.7, 126.4, 127.8, 128.1, 129.3, 129.7,
d 2.60 (3H, s), 7.52 (3H, m), 7.67–7.80 (4H, m),
d
2.65 (3H, s), 7.43–7.57 (4H, m), 7.99 (2H, m), 8.25 (2H, m), 8.42
(1H, s), 8.90 (1H, s), 9.56 (1H, s); 13C NMR (75 MHz, CDCl3):
d
22.5,
d
116.6, 120.9, 125.5, 127.2, 127.7, 128.6, 128.9, 129.1, 129.2, 136.8,
139.0, 143.6, 150.5, 152.4, 153.8, 154.6. Anal. Calcd for C19H14N2: C,
84.42; H, 5.22; N, 10.36. Found: C, 84.03; H, 5.39; N, 10.15.
129.8, 130.8, 132.3, 134.8, 136.0, 137.8, 143.5, 149.3, 150.5; MS:
m/z¼287 (MþH)þ. Anal. Calcd for C19H14N2O: C, 79.70; H, 4.93; N,
9.78. Found: C, 79.93; H, 5.16; N, 9.52.
4.3.4. 7-Methoxy-3-phenylbenzo[b][1,6]naphthyridine (3d)
4.5.3. 7-Methyl-3-phenylbenzo[b][1,6]naphthyridine-2-oxide (5c)
Light yellow solid; yield: 90%; mp 185 ꢀC; Rf (60% EtOAc–hexane)
0.36; IR (KBr): 2922,1625,1447,1277,1191 cmꢂ1; 1H NMR (300 MHz,
Light green solid; yield: 88%; mp 220 ꢀC; Rf (25% EtOAc–hexane)
0.48; IR (KBr): 2925, 1614, 1470 cmꢂ1 1H NMR (300 MHz, CDCl3):
;
d
4.04 (3H, s), 7.45–7.60 (5H, m), 7.92 (1H, d, J 9.3 Hz), 8.24 (2H, m),
8.36 (1H, s), 8.83 (1H, s), 9.52 (1H, s); 13C NMR (75 MHz, CDCl3):
55.8,105.1,116.2,120.2,121.9,123.4,127.2,128.9,129.0,130.1,136.6,
CDCl3):
d
2.63 (3H, s), 7.51 (4H, m), 7.88–7.95 (4H, m), 8.13 (1H, s),
22.4, 121.8,
8.56 (1H, s), 9.03 (1H, s); 13C NMR (75 MHz, CDCl3):
d
d
125.6,126.1,127.9,128.0,128.2,129.8,130.5,131.7,132.3,136.1,142.9,
144.1,146.8,150.6,150.7. Anal. Calcd for C19H14N2O: C, 79.70; H, 4.93;
N, 9.78. Found: C, 79.39; H, 5.16; N, 9.65.
139.0, 150.7, 154.0, 154.1, 154.3, 163.3. Anal. Calcd for C19H14N2O: C,
79.70; H, 4.93; N, 9.78. Found: C, 79.48; H, 5.15; N, 9.53.
4.3.5. 6-Methyl-3-phenylbenzo[b][1,6]naphthyridine (3e)
4.5.4. 7-Methoxy-3-phenylbenzo[b][1,6]naphthyridine-2-oxide (5d)
Light yellow solid; yield: 89%; mp 188 ꢀC; Rf (60% EtOAc–hex-
Light green solid; yield: 91%; mp 201 ꢀC; Rf (11% EtOAc–hexane)
0.53; IR (KBr): 2922, 1614, 1443 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
ane) 0.41; IR (KBr): 2922, 1619, 1459, 1251, 1173 cmꢂ1 1H NMR
;
d
2.96 (3H, s), 7.45–7.55 (4H, m), 7.72 (1H, d, J 7.5 Hz), 7.92 (1H, d, J
8.1 Hz), 8.26 (2H, m), 8.50 (1H, s), 8.91 (1H, s), 9.59 (1H, s); 13C NMR
(75 MHz, CDCl3): 18.5, 117.3, 121.0, 126.2, 127.0, 127.1, 127.2, 128.9,
(300 MHz, CDCl3):
d 4.03 (3H, s), 7.40 (1H, s), 7.52 (4H, m), 7.85 (3H,
m), 8.08 (1H, s), 8.51 (1H, s), 9.02 (1H, s); 13C NMR (75 MHz, CDCl3):
d
d 55.8, 105.4, 121.0, 123.1, 124.1, 125.1, 128.2, 129.5, 129.8, 129.9,
129.0, 131.7, 137.0, 137.4, 139.1, 149.7, 151.7, 153.5, 154.5. Anal. Calcd
for C19H14N2: C, 84.42; H, 5.22; N, 10.36. Found: C, 83.95; H, 5.39; N,
10.51.
131.9, 132.4, 136.4, 144.3, 150.8, 152.4, 162.8; MS: m/z¼303 (MþH)þ.
Anal. Calcd for C19H14N2O2: C, 75.48; H, 4.67; N, 9.27. Found: C,
74.87; H, 4.51; N, 9.45.
4.3.6. 6-Ethyl-3-phenylbenzo[b][1,6]naphthyridine (3f)
4.5.5. 6-Methyl-3-phenylbenzo[b][1,6]naphthyridine-
2-oxide (5e)
Light green solid; yield: 93%; mp 130 ꢀC; Rf (11% EtOAc–hexane)
0.60; IR (KBr): 1610, 1430 cmꢂ1
;
1H NMR (300 MHz, CDCl3):
d
1.48
Light yellow solid; yield: 94%; mp 119 ꢀC; Rf (60% EtOAc–hexane)
(3H, t), 3.48 (2H, q, J 7.5 Hz), 7.45–7.55 (4H, m), 7.72 (1H, d, J 6.3 Hz),
7.92 (1H, d, J 8.4 Hz), 8.26 (2H, m), 8.48 (1H, s), 8.91 (1H, s), 9.58 (1H,
0.62; IR (KBr): 2921,1625,1437,1286,1170 cmꢂ1; 1H NMR (300 MHz,
CDCl3):
8.22 (1H, s), 8.57 (1H, s), 9.05 (1H, s); 13C NMR (75 MHz, CDCl3):
18.2,121.8,126.3,127.4,127.7,128.2,129.2,129.7,131.2,132.2,132.3,
d 2.89 (3H, s), 7.51 (4H, m), 7.66 (1H, d, J 6.6 Hz), 7.86 (3H, m),
s); 13C NMR (75 MHz, CDCl3):
d 14.6, 24.7, 117.4, 121.0, 126.3, 126.9,
127.1, 127.2, 128.8, 129.0, 129.9, 137.0, 139.1, 143.1, 149.7, 151.0, 153.4,
154.5; MS: m/z¼285 (MþH)þ. Anal. Calcd for C20H16N2: C, 84.48; H,
5.67; N, 9.85. Found: C, 83.75; H, 5.46; N, 9.73.
d
132.4, 136.1, 137.6, 143.2, 149.8, 150.4. Anal. Calcd for C19H14N2O: C,
79.70; H, 4.93; N, 9.78. Found: C, 80.11; H, 5.14; N, 9.71.
4.4. Transformation of aldehydes (2a–f) to corresponding
oximes (4a–f)
4.5.6. 6-Ethyl-3-phenylbenzo[b][1,6]naphthyridine-2-oxide (5f)
Light yellow solid; yield: 96%; mp 122 ꢀC; Rf (60% EtOAc–hex-
ane) 0.65; IR (KBr): 2962, 2926, 1436, 1283, 1184 cmꢂ1 1H NMR
;
To a solution of 2a–f (1 mmol) in methanol (5 mL) were added
sodium acetate (1.5 mmol) and hydroxylamine hydrochloride
(1.2 mmol), the solution allowed to stirred for 5 min, a white pre-
cipitate observed. After vacuum evaporation of solvent, reaction
mixture poured in water (10 mL), and filtered out. These oximes
were pure enough for further use.
(300 MHz, CDCl3):
7.68 (5H, m), 7.82–7.86 (3H, m), 8.20 (1H, s), 8.57 (1H, s), 9.05 (1H,
s); 13C NMR (75 MHz, CDCl3):
14.7, 24.6, 121.8, 126.2, 126.4, 127.5,
127.8, 128.2, 129.5, 129.7, 129.8, 132.1, 132.4, 136.0, 143.2, 143.4,
149.2, 150.4; MS: m/z¼301 (MþH)þ. Anal. Calcd for C20H16N2O: C,
79.98; H, 5.37; N, 9.33. Found: C, 79.68; H, 5.21; N, 9.25.
d 1.43 (3H, t, J 7.2 Hz), 3.40 (2H, q, J 7.2 Hz), 7.51–
d
4.5. Transformation of oximes (4a–f) to benzo[b][1,6]-
Acknowledgements
naphthyridines-2-oxide analogues (5a–f)
The authors acknowledge CSIR New Delhi and UGC New Delhi for
financial support. A.C. and B.S. is thankful to CSIR for Senior Research
Fellowship. Authors also thank Head, Department of Chemistry,
Faculty of Science, Banaras Hindu University, Varanasi for providing
spectral and analytical facility and to Prof. S. Baskaran, IIT Madras,
Chennai, India for providing HRMS of compounds 2c, 2h and 2i.
To a solution of 4 (0.5 mmol) in EtOH (7 mL) was added K2CO3
(0.75 mmol) and the solution was stirred at reflux temperature. The
reaction completed after 5 min (as monitored by TLC/green solu-
tion appeared). The reaction mixture allowed to pour in chilled
water (7 mL) and precipitate filtered out and dried.

A. Chandra et al. / Tetrahedron 64 (2008) 11680–11685
11685
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