Regioselective intramolecular electrophilic substitution reactions involving π-deficient pyridine substrates: a new entry to pyridoquinazolines and benzo[h][1,6]naphthyridines

Article abstract of DOI:10.1016/j.tet.2009.11.115

Regioselective intramolecular electrophilic substitution reactions have been described in π-deficient pyridine substrates tethered at C-2 to the aryl amine. The presence and nature of ring activating groups at C-6 led to the involvement of either N-1 or C-3 of the pyridine ring in the cyclization thereby leading to the regioselective synthesis of pyridoquinazolines and naphthyridines in excellent yields.

Full text of DOI:10.1016/j.tet.2009.11.115

Tetrahedron 66 (2010) 862–870
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Regioselective intramolecular electrophilic substitution reactions involving
p
-deficient pyridine substrates: a new entry to pyridoquinazolines
and benzo[h][1,6]naphthyridinesq
*
Piyush K. Agarwal, Mohammad Saifuddin, Bijoy Kundu
Medicinal Chemistry Division, Central Drug Research Institute, CSIR, Chattar Manjil Palace, Lucknow 226001, UP, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Regioselective intramolecular electrophilic substitution reactions have been described in
p-deficient
Received 6 November 2009
Received in revised form
26 November 2009
Accepted 27 November 2009
Available online 4 December 2009
pyridine substrates tethered at C-2 to the aryl amine. The presence and nature of ring activating groups
at C-6 led to the involvement of either N-1 or C-3 of the pyridine ring in the cyclization thereby leading to
the regioselective synthesis of pyridoquinazolines and naphthyridines in excellent yields.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Naphthyridines
Pyridoquinazolines
Cationic
p-cyclization
Regioselectivity
1. Introduction
above reported strategies generally suffer from certain disadvan-
tages, such as stringent reaction conditions, low yields and poor
1,6-Naphthyridine is an important pharmacophore present in
many natural1 and designed synthetic products of therapeutic
importance. They are associated with a wide spectrum of biological
activities ranging from anticancer,2 antiherpes,3 anti-HIV-1,4 anti-
microbial,5 adrenoceptor blocking6 to sortase A,7 HIV-1 integrase
inhibitors,8 and Spleen Tyrosine Kinase9 inhibitory activities.
Earlier reports for the synthesis of 1,6-naphthyridine skeleton
involved Skraup synthesis10 starting from 4-aminopyridine in 40%
yield and a multiple-step synthesis using Heck coupling11 in 51%
yield. The synthesis of benzo[h][1,6]naphthyridines has been car-
ried out either via rearrangement of Pyrrolobenzodiazepinones
generality and limited diversity.
In continuation of our studies of cationic p-cyclization in p-de-
ficient systems tethered to aryl amines,15 we focused our attention
on pyridines for generating naphthyridine based compounds.
Structurally, naphthyridine nucleus is a combination of two pyri-
dine (privileged structure16) units, which makes it a useful class of
compounds in drug discovery. The presence of a multiply bonded
nitrogen atom in pyridines not only deactivates the ring toward
electrophilic substitution than benzene but also imparts a differen-
tiating effect on the carbons toward electrophilic substitution. The
carbons at
more deactivated than
exposed to electrophilic substitution, the nitrogen remains the most
preferred target by electrophiles, thus preventing C-3 ( -carbon)
a- and
g
-positions to the doubly bonded nitrogen are
12
after heating with POCl3 or via Friedlander condensation of
b
-position.17 However, when pyridine is
4-amino-3-formyl quinolines with either aldehydes or ketones to
furnish benzo[h][1,6]naphthyridines in 40–56% yields.13 Recently,
Walton et al.14 described a multistep synthesis of benzo[h][1,6]-
naphthyridines by irradiating (microwave) oxime ethers of
2-aryl-3-formyl pyridine in 63–68% yield. Photochemical trans-
formation of tertiary amidines has been also used for the synthesis
of benzo[h][1,6]naphthyridines albeit in 15–30% yields. Thus, the
b
electrophilic substitution. Indeed, halogenation, nitration, and sul-
fonation of pyridine not only require drastic conditions; even the
yields of C-3 substituted products are exceptionally low.18 Literature
precedence on the involvement of C-3 of pyridine in cationic
p-
cyclization as nucleophile is scarce.19 However, the method suffers
from limited diversity and involves pyridine substrate tethered to
aliphatic amine with exclusive involvement of C-3 in cyclization. In
this paper, we describe regioselective intramolecular electrophilic
cyclization involving either N-1 or C-3 of the pyridine ring leading to
the synthesis of pyridoquinazolines and naphthyridines.
q
CDRI Communication No. 7910
* Corresponding author. Tel.: þ91 522 2612411 18; fax: þ91 522 2623405.
E-mail addresses: b_kundu@cdri.res.in, bijoy_kundu@yahoo.com (B. Kundu).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.11.115

P.K. Agarwal et al. / Tetrahedron 66 (2010) 862–870
863
2. Results and discussion
cyclization thereby leading to the formation of 6-(4-nitrophenyl)-
5,6-dihydro-8H-pyrido[1,2-c]quinazolin-8-one 6a. Thus, the pres-
ence of OMe group at the 2-position of the pyridine ring could be
playing an important role in facilitating the regioselective nucleo-
philic attack by the lone pair of electrons of pyridyl nitrogen instead
Our studies commenced with the design of pyridine-based
substrates suitable for cationic
pyridine fails to promote cyclization, we decided to incorporate an
electron-donating group at the carbon ortho to the nitrogen and
introduce an aryl amine as a source for electrophilic component
(iminium ion) at the carbon again ortho to the nitrogen so as to
p-cyclization. Since inactivated
of C-3 (as
p-nucleophile) on to the iminium ion, as initially envis-
aged by us.
facilitate
p-cyclization using C-3. Though C-4 (ortho to C-3) also
Table 1
remains an option for introducing an aryl amine, we initially
decided to work with C-2 linked aryl amine due to its synthetic
feasibility. Accordingly, the key pyridine-based intermediate
required for the synthesis of benzo[h][1,6]naphthyridines was
identified as the substrate 2-(6-methoxy-pyridin-2-yl)-phenyl-
amine 4a. The latter was synthesized by the Suzuki reaction of
2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine 3a20
with 2-Bromo-6-methoxy-pyridine 2a21 as shown in Scheme 1. The
intermediate 2a was prepared by selective nucleophilic sub-
stitution of 2,6-dibromopyridine 1.
Optimization of reaction conditions for the conversion of 4a into 6a
Entry
Reaction Conditions
Temp (ꢀC)
Time (h)
Yield of 6a
1
2
3
4
5
6
7
8
2% TFA in DCM
rt
rt
rt
rt
24
24
24
24
24
24
24
16
16
16
16
0
0
0
0
0
1% p-TsOH in ACN
Yb(OTf)3 in CH3CN
1%Triflic acid in DMF
1% p-TsOH in ACN
Yb(OTf)3 in CH3CN
1%Triflic acid in DMF
1% TFA in toluene
1% p-TsOH in ACN
1%Triflic acid in DMF
1% TFA in toluene
80 ꢀ
80 ꢀ
C
C
0
80 ꢀC
28
25
36
42
95
80 ꢀC
9
10
11
110 ꢀC
110 ꢀC
110 ꢀC
3a R1 = H
3b R1 = CH3
O
R1
B
O
R1
NH2
R1
O
N
NH2
(i)
3
R
N
R2
N
H
(ii)
Br
N
Br
NH2
R
N
Br
Pyridoquinazoline 6
R2CHO
1 % TFA,
Toluene,
2a R = OMe,
O
N
1
R2
4a (R = OMe, R1= H)
2b R = N(CH3)2,
2c R = N(CH2CH3)2
4b (R = OMe, R1= CH3)
N
R1
4c (R = N(CH3)2, R1= H)
4d (R = N(CH3)2, R1= CH3)
4e (R = N(CH2CH3)2, R1= H)
4f (R = N(CH2CH3)2, R1= CH3)
110 °C, 16 h.
O
N
4a (R1= H)
4b (R1= CH3)
R1
R2 = 4-NO2-Ph, 4-Cl-Ph, 4-Br-Ph,
4-F-Ph, 3,4-(Cl)2-Ph, 4-(OCH2CH3)-Ph
5
Scheme 1. Reagents and conditions: (i) NaOMe, MeOH, 80 ꢀC, 20 h. (ii) PdCl2(PPh3)2,
Na2CO3, 80 ꢀC, DMF, 1 h.
Scheme 2. Synthesis of 6-phenyl-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-8-one.
Initially, the cationic
p-cyclization reaction of the substrate 4a
with p-nitrobenzaldehyde was investigated using either 1% TFA/
DCM at rt or pTsOH in toluene at 80 ꢀC conditions, however, both
the protocols failed to give the desired product. Next, the reaction
was carried out in the presence of a variety of Bronsted acids
(Table 1) and best result involving complete conversion was
obtained only when reaction was carried out in 1% TFA in toluene at
110 ꢀC. The crude product exhibiting >98% purity on HPLC was
purified using column chromatography furnishing a new product in
95% isolated yield. Surprisingly, the chemical characterization of the
isolated product using NMR showed the formation of a product 6-
(4-nitrophenyl)-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-8-one 6a
(Scheme 2) instead of the desired 2-methoxy-5-(4-nitro-phenyl)-
benzo[h][1,6]naphthyridine 5. The formation of 6a appears to have
occurred by the attack of the lone pair of electrons present on the
pyridyl nitrogen onto the iminium carbon instead of the attack by
R1
R1
O
N
O
N
R2
N
H
R2
N
6
7
Figure 1. Proposed mechanism for the synthesis of 6.
Quinazoline-based compounds are one of the most crucial
heterocyclic skeletons (privileged structure16) as they are part of
a vast range of therapeutically active molecules. Armed with this
observation we set out to explore the application of our strategy
for generating quinazoline-based compounds. A careful survey of
the literature showed two reports for the synthesis of Pyrido[1,2-
c]quinazoline template via multiple-step synthesis.22 However,
the strategies suffered from low yields and poor diversity. We
studied the scope and limitation of our methodology by treating
substrate 4a (R¼OMe; R1¼H) with several aryl aldehydes (Table 2)
containing either electron withdrawing or electron-donating
substituents. Although, reactions of substrate 4 with aldehydes
having electron-withdrawing groups, such as nitro, chloro, flouro,
bromo furnished 6a–d and g in >90% isolated yields (Table 2),
aldehydes with electron-donating group such as N(Me)2 and
the C-3 (as
an intramolecular electrophilic cycloelimination reaction involving
N-1 instead of the envisaged cationic -cyclization involving C-3.
p-nucleophile) of the pyridyl ring. Thus, we encountered
p
Surprisingly, this phenomenon pertaining to the involvement of N-
1 was not observed by Padwa and Brodney19 in their pyridine
substrates when tethered with an aliphatic amine. A plausible
mechanism for the unexpected formation of the product 6a (Fig. 1)
may be attributed to the attack by the lone pair of electron present
on the pyridyl nitrogen onto the iminium carbon in the in-
termediate 7 followed by demethylation and an intramolecular

864
P.K. Agarwal et al. / Tetrahedron 66 (2010) 862–870
–OCH3 either failed or furnished product (entry 8) in <15% iso-
lated yields. Similar observations were also made with substrate
4b (R¼OMe; R1¼CH3), which smoothly underwent cyclo-
elimination reactions when treated with aldehydes having elec-
tron-withdrawing substituents to furnish 6i–l in excellent isolated
yields (Table 2). In general the dihydro derivatives 6 were found to
be stable and attempts to oxidize them using DDQ/KMnO4 were
not successful.
R2
R2
H
NH2
R1
R2CHO
NH
R1
NH
R1
R
N
R
N
1 % TFA,
Toluene,
110 °C, 16 h
R
N
4c (R = N(CH3)2, R1= H)
4d (R = N(CH3)2, R1= CH3)
4e (R = N(CH2CH3)2, R1= H)
4f (R = N(CH2CH3)2, R1= CH3)
R2
R2
Table 2
[O]
N
NH
Synthesis of 8H-Pyrido[1,2-c]quinazolin-8-one
R2
R1
Product
Yield (%)
R
N
R
N
Entry
Substrate
1
2
3
4
5
6
7
8
4a
4a
4a
4a
4a
4a
4a
4a
4b
4b
4b
4b
4-NO2-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
6a
6b
6c
6d
6e
6f
6g
6h
6i
96
92
94
95
NR
NR
90
15
95
93
90
89
R2= 4-Cl-Ph, 4-NO2-Ph, 4-Br-Ph, 4-F-Ph, 4-
N(Me)2-Ph, 4-OCH2CH3-Ph, 2-OH-Ph
R1
R1
8
4-F-C6H4-
4-(CH3)2N-C6H4-
3,4-(OCH3)2-C6H4-
3,4-(Cl)2-C6H4-
4-(OCH2CH3)-C6H4-
4-NO2-C6H4-
4-Cl-C6H4-
Scheme 3. Synthesis of benzo[h][1,6]naphthyridine 8.
Table 3
Synthesis of benzo[h][1,6]naphthyridine 8
9
10
11
12
6j
6k
6l
4-Br-C6H4-
4-F-C6H4-
Entry
Substrate
R2
R1
Product
Yield (%)
1
2
3
4
5
6
7
8
4c
4c
4c
4c
4c
4c
4d
4d
4d
4d
4d
4d
4d
4e
4e
4e
4e
4e
4e
4e
4f
4-NO2-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
4-OH- C6H4-
4-(CH3)2N-C6H4-
3,4-(O CH3)2-C6H4-
4-NO2-C6H4-
4-Cl-C6H4-
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
H
H
H
H
H
H
H
H
CH3
CH3
CH3
CH3
CH3
8a
8b
8c
8d
8e
8f
8g
8h
8i
8j
8k
8l
8m
8n
8o
8p
8q
8r
97
93
95
90
91
90
94
92
93
90
91
90
88
95
93
94
91
86
88
90
86
90
95
93
89
NR¼No reaction.
Next, in an attempt to synthesize compounds based on naph-
thyridines via cationic -cyclization, we decided to block the attack
p
of pyridyl nitrogen onto the iminium ion by replacing the OMe
group with a poorly labile but with ring activating properties such
as N,N-dimethyl group to afford substrate 4c (Scheme 3). We en-
visaged that due to the resistant nature of N–C bond to cleavage in
N(CH3)2 group, the attack by the lone pair of electron of the
nitrogen of pyridine onto the iminium ion would not be fruitful
thereby leaving C-3 as the only option to effect the desired regio-
selective cationic p-cyclization. Synthesis of 4c was carried out by
treating 1 with dimethylamine to give 2b, which was then sub-
jected to Suzuki coupling with boronate 3a. Compound 4c was then
9
4-Br-C6H4-
4-F-C6H4-
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
4-(CH3)2N-C6H4-
3,4-(OCH3)2-C6H4-
4-(OCH2CH3)-C6H4-
4-NO2-C6H4-
4-Cl-C6H4-
4-Br-C6H4-
4-F-C6H4-
4-OH- C6H4-
4-(CH3)2N-C6H4-
4-(OCH2CH3)-C6H4-
4-(CH3)2N-C6H4
4-Br-C6H4-
4-NO2-C6H4-
4-Cl-C6H4
4-(OCH2CH3)-C6H4-
8s
8t
subjected to cationic
p-cyclization by treating with p-nitro-
benzaldehyde in the presence of 1% TFA in toluene at 110 ꢀC, which
effected complete conversion of 4c and afforded a new product
>99% purity based on HPLC. The crude product obtained after
workup was purified by silica gel column chromatography using
EtOAc/hexane as an eluent furnishing 8a in 97% isolated yield. The
latter was characterized using 1D and 2D NMR and ESMS. As
8u
8v
8w
8x
8y
4f
4f
4f
4f
reported earlier by us15, the cationic
p-cyclization occurred via
3. Conclusion
protonation of the azomethine bond followed by regioselective
intramolecular nucleophilic attack (Pictet–Spengler type) by the
pyridyl carbon C-3 to afford an unstable intermediate, which then
underwent spontaneous oxidation to N,N-dimethyl-5-(4-nitro-
phenyl)benzo[h][1,6]naphthyridin-2-amine 8a. This is in contrast
to the formation of dihydropyridoquinazolinones 6 via cyclo-
elimination wherein phenomenon of spontaneous oxidation was
not observed. This may be attributed to the high order stability of 6,
which in turn makes it adamant toward oxidation. The scope and
limitation of our strategy was then examined by treating substrates
4c and its derivatives 4d, 4e, and 4f with aryl aldehydes having both
electron withdrawing and donating substituents (Table 3). Pleas-
ingly, neither aldehydes (R2) having electron-donating as well as
electron-withdrawing group nor substitutions on aryl amine (R1)
and pyridine (R) had any adverse effect on the rate of cyclization
and benzo[h][1,6]naphthyridines 8 in general were obtained in
excellent (85–97%) isolated yields. Indeed, aliphatic aldehydes and
In conclusion, we have developed mild and efficient protocol for
the regioselective synthesis of benzo[h][1,6]naphthyridines and
6-phenyl-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-8-one via either
intramolecular electrophilic or cationic
appropriately substituted -deficient pyridine substrates. The ob-
served regioselectivity, demonstrates the efficacy and versatility of
p-cyclization routes using
p
using such electrophilic cyclizations involving
for the synthesis of novel chemprobes.
p-deficient systems
4. Experimental
4.1. General
All solvents were commercially available and used without
purification. All products were characterized by 1H NMR, 13C NMR,
ESMS, IR, and HPLC. Analytical TLC was performed using 2.5ꢁ5 cm
plated coated with a 0.25 mm thickness of silica gel. 60F-254 Merck
and visualization was accomplished with UV light and iodine.
ketones failed to undergo cationic
p-cyclization, which may be
attributed to the poor electrophilic nature of the resulting corre-
sponding iminium ions.

P.K. Agarwal et al. / Tetrahedron 66 (2010) 862–870
865
Column chromatography was performed using silica gel 60 Thomas
Baker (100–200 mesh). 1H NMR spectra (200/300 MHz) are repor-
ted as follows: chemical shifts in ppm downfield from TMS as in-
CDCl3)
d
¼7.22–7.16 (1H, m, ArH), 6.60 (1H, d, J¼7.4 Hz, ArH), 6.34
(1H, d, J¼8.4, ArH), 3.47 (4H, q, J¼7.0 Hz, CH2), 1.16 (6H, t, J¼7.0 Hz,
CH3); 13C NMR (50 MHz, CDCl3)
d
¼158.1, 140.6, 139.2, 113.3, 104.2,
ternal standard
(d
scale), multiplicity [br¼broad, s¼singlet,
42.8,13.2; mass (ESþ) m/z 229.2 (Mþþ1); Anal. Calcd for C9H13BrN2:
d¼doublet, t¼triplet, q¼quartet, m¼multiplet, o¼overlapped, in-
tegration and coupling constant (Hz)]. All 13C NMR spectra (50/
75 MHz) were recorded at 25 ꢀC with complete proton decoupling
and reported in ppm. Elemental analyses were performed on
a Carlo Erba 1108 microanalyzer or Elementar’s Vario EL III micro-
analyzer in the SAIF division of our institute. Analytical HPLC were
performed on C-18 reverse-phase column (150 mmꢁ4.8 mm).
Mass spectra were recorded on a Merck MS-8000 spectrometer and
HR/EI Mass spectra were done on JEOL-600H at 70 eV. Melting
points reported were uncorrected.
C, 47.18; H, 5.72; N, 12.23. Found: C, 47.15; H, 5.74; N, 12.21.
4.5. General procedure for the synthesis of 2-(4,4,5,5-
tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenylamine (3)
The solution of 2-bromoaniline (2.0 g, 11.62 mmol), bis[pina-
clolato]diboron (3.24 g, 12.78 mmol), potassium acetate (1.7 g,
17.43 mmol), and tricyclohexyl phosphine (0.39 g, 1.39 mmol) in
dry dioxane (15 ml) was purged with nitrogen for 15 min followed
by the addition of tris[dibenzylideneacetone]dipalladium(0)
(0.53 g, 0.58 mmol). The reaction mixture was heated at 80 ꢀC for
16 h, filtered through Celite, washed with ethyl acetate and con-
centrated to get the product, which was used without further
purification.
4.2. Procedure for the synthesis of 2-bromo-6-
methoxypyridine (2a)
A mixture of 2,6-dibromopyridine 1 (1.0 g, 4.20 mmol) and so-
dium methoxide (0.39 g, 7.25 mmol) in methanol was heated at
80 ꢀC for 24 h. After completion of the reaction as evident by TLC
analysis, methanol was distilled off, water (20 mL) was added and
compound was extracted with ethyl acetate (15 mLꢁ3). The organic
layer washed with brine, dried over Na2SO4 and then concentrated
in vacuo. The reaction mixture was then subjected to column
chromatography (100–200 silica gel) using ethyl acetate:hexane
(98:2, v/v) as eluent. Yield¼0.65 g (81%), colorless oil, Rf¼0.50
4.6. General procedure for the synthesis of 2-pyridin-2-
ylaniline (4a–e)
The solution of 2-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-
phenylamine 3a (0.87 g, 4.0 mmol) and 2-bromo-6-methoxypyr-
idine 2a (0.5 g, 2.67 mmol) in DMF (5 mL) was degassed with
nitrogen for 15 min followed by addition of Na2CO3 (5.0 mL, 2 M)
under continuous flow of nitrogen. PdCl2 (PPh3)2 (0.30 g,
0.26 mmol) were added to the reaction mixture under a nitrogen
atmosphere. The reaction mixture was stirred at 80 ꢀC for 2 h. The
solution was diluted with H2O (5 mL), and then the product was
extracted three times with EtOAc (10 mL). The combined organic
layer was dried over Na2SO4 and the solvent was removed in vacuo.
The crude product was purified on a silica gel column using hex-
ane:ethyl acetate (90:10, v/v) as eluent to afford 2-(6-methox-
ypyridin-2-yl)aniline 4a.
(Hexane), IR (Neat) nmax 2972, 1590, 1464, 1409 cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
d
¼7.44–7.38 (1H, m, ArH), 7.05 (1H, d, J¼7.4 Hz,
ArH), 6.69 (1H, d, J¼8.2 Hz, ArH), 3.93 (3H, s, OCH3); 13C NMR
(75 MHz, CDCl3)
d
¼163.8, 140.4, 138.7, 120.3, 109.9, 54.1; mass (ESþ)
m/z 187.9 (Mþþ1); Anal. Calcd for C6H6BrNO: C, 38.33; H, 3.22; N,
7.45. Found: C, 38.28; H, 3.25; N, 7.39.
4.3. Procedure for the synthesis of 6-bromo-N,N-
dimethylpyridin-2-amine (2b)
To a solution of 2,6-dibromopyridine 1 (1.0 g, 4.20 mmol) and
dimethylamine (5.6 M) in ethanol (1.5 mL) was heated at 80 ꢀC in
a sealed tube for 16 h. Reaction mixture was allowed to come to
room temperature, ethanol was distilled off, water (20 mL) was
added and compound was extracted with ethyl acetate (15 mLꢁ3).
The organic layer washed with brine, dried over Na2SO4 and then
concentrated in vacuo. The crude mixture was then subjected to
column chromatography (100–200 silica gel) using ethyl acetate:-
hexane (95:5, v/v) as eluent. Yield¼0.73 g (85%), colorless oil,
Rf¼0.50 (1:9 EtOAc:Hexane), IR (Neat) nmax 3305, 2906, 1598,
4.6.1. 2-(6-Methoxypyridin-2-yl)aniline (4a). Yield¼0.43 g (80%),
yellow solid, mp 42–44 ꢀC, Rf¼0.50 (1:9 EtOAc:Hexane), IR (KBr)
nmax 3344, 3039, 2938, 1256 cmꢂ1 1H NMR (300 MHz, CDCl3)
;
d
¼7.66 (1H, t, J¼7.9 Hz, ArH), 7.50 (1H, dd, J¼1.3, 7.7 Hz, ArH), 7.24–
7.14 (2H, m, ArH), 6.81–6.74 (2H, m, ArH), 6.66 (1H, d, J¼8.2 Hz,
ArH), 5.56 (2H, br s, NH2), 3.95 (3H, s, OCH3); 13C NMR (50 MHz,
CDCl3)
d
¼162.7, 157.0, 146.3, 139.5, 129.8, 129.6, 122.6, 117.9, 117.3,
115.1, 108.1, 53.4; mass (ESþ) m/z 201.2 (Mþþ1); Anal. Calcd for
C12H12N2O: C, 71.98; H, 6.04; N, 13.99. Found: C, 71.95; H, 6.07; N,
13.97.
1174 cmꢂ1
;
1H NMR (200 MHz, CDCl3)
d¼7.28–7.20 (1H, m, ArH),
6.66 (1H, d, J¼11.1 Hz, ArH), 6.37 (1H, d, J¼12.5 Hz, ArH), 3.06 (6H, s,
4 . 6 . 2 . 2 - ( 6 - M e t h o x y p y r i d i n - 2 - y l ) - 4 - m e t h y l a n i l i n e
(4b). Yield¼0.66 g (82%), yellow oil, Rf¼0.30 (2:8 EtOAc:Hexane), IR
(Neat) nmax 3310, 3007, 2929,1257 cmꢂ1; 1H NMR (300 MHz, CDCl3)
N(CH3)2); 13C NMR (50 MHz, CDCl3)
d
¼159.3, 140.2, 139.1, 114.2,
103.9, 37.9; mass (ESþ) m/z 201.2 (Mþþ1); Anal. Calcd for C7H9BrN2:
C, 41.82; H, 4.51; N, 13.93. Found: C, 41.80; H, 4.54; N, 13.91.
d
¼7.64 (1H, t, J¼7.9 Hz, ArH), 7.3 (1H, s, ArH), 7.22 (1H, t, J¼8.0 Hz,
ArH), 6.98 (1H, d, J¼8.0 Hz, ArH), 6.69–6.63 (2H, m, ArH), 5.36 (2H,
4.4. Procedure for the synthesis of 6-bromo-N,N-
s, NH2), 3.94 (3H, s, OCH3), 2.28 (3H, s, CH3); 13C NMR (50 MHz,
diethylpyridin-2-amine (2c)
CDCl3)
d
¼162.7, 157.1, 143.7, 139.5, 130.6, 130.1, 127.0, 122.9, 117.4,
115.8, 108.1, 53.4, 20.6; mass (ESþ) m/z 215.3 (Mþþ1); Anal. Calcd
for C13H14N2O: C, 72.87; H, 6.59; N, 13.07. Found: C, 72.85; H, 6.61;
N, 13.08.
To a solution of 2,6-dibromopyridine 1 (1.0 g, 4.20 mmol) in
DMF (5 ml) was added diethylamine (0.45 ml, 4.20 mmol) in
a sealed tube and heated to 100 ꢀC for 12 h. The reaction mixture
was allowed to cool, water (25 ml) was added and compound was
extracted with ethyl acetate (15 mLꢁ3). The organic layer was
washed with brine, dried over Na2SO4 and then concentrated in
vacuo. The crude mixture was then subjected to column chroma-
tography (100–200 silica gel) using ethyl acetate:hexane (95:5, v/v)
as eluent. Yield¼0.72 g (75%), yellow oil, Rf¼0.50 (Hexane), IR
4.6.3. 6-(2-Aminophenyl)-N,N-dimethylpyridin-2-amine
(4c). Yield¼0.89 g (85%), yellow oil, Rf¼0.50 (1:1 EtOAc:Hexane), IR
(Neat) nmax 3305, 2923,1600,1369 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼7.56–748 (2H, m, ArH), 7.16–7.10 (1H, m, ArH), 6.90 (1H, d,
J¼7.5 Hz, ArH), 6.78–6.72 (2H, m, ArH), 6.42 (1H, d, J¼8.5 Hz, ArH),
5.70 (2H, br s, NH2), 3.10 (6H, s, N(CH3)2); 13C NMR (50 MHz, CDCl3)
(Neat) nmax 2969, 1583, 1493, 1450, 1115 cmꢂ1
;
1H NMR (300 MHz,
d¼158.2, 157.6, 146.4, 138.2, 129.6, 129.4, 123.7, 117.7, 117.1, 110.3,

866
P.K. Agarwal et al. / Tetrahedron 66 (2010) 862–870
103.5, 38.4; mass (ESþ) m/z 214.3 (Mþþ1); Anal. Calcd for C13H15N3:
J¼8.1 Hz, ArH), 7.38 (1H, s, CH), 7.27–7.23 (1H, m, ArH), 7.15 (4H, m,
C, 73.21; H, 7.09; N, 19.70. Found: C, 73.25; H, 7.03; N, 19.69.
ArH), 6.92–6.83 (2H, m, ArH), 6.64–6.60 (2H, m, ArH), 5.12 (1H, br s,
NH); 13C NMR (75 MHz, CDCl3)
d¼141.4, 141.2, 139.9, 137.7, 134.0,
4.6.4. 6-(2-Amino-5-methylphenyl)-N,N
dimethylpyridin-2-amine
131.9, 128.7, 127.9, 124.6, 120.9, 118.2, 117.8, 117.7, 102.0, 61.8; mass
(ESþ) m/z 309.2 (Mþþ1); Anal. Calcd for C18H13ClN2O: C, 70.02; H,
4.24; N, 9.07. Found: C, 70.00; H, 4.27; N, 9.04.
(4d). Yield¼1.32 g (78%), yellow oil, Rf¼0.37 (2:8 EtOAc:Hexane), IR
(Neat) nmax 3305, 2919, 1604, 1595, 1181 cmꢂ1; 1H NMR (300 MHz,
CDCl3)
d
¼7.56–7.50 (1H, m, ArH), 7.30 (1H, d, J¼1.2 Hz, ArH), 6.97–
6.94 (1H, m, ArH), 6.89 (1H, d, J¼7.5 Hz, ArH), 6.66 (1H, d, J¼8.1 Hz,
4.7.3. 6-(4-Bromophenyl)-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-
8-one (6c). Yield¼0.24 g (94%), yellow solid, mp 187–188 ꢀC,
Rf¼0.50 (2:8 EtOAc:Hexane), IR (KBr) nmax 3386, 3025, 2990,
ArH), 6.42 (1H, d, J¼8.5 Hz, ArH), 5.29 (2H, br s, NH2), 3.10 (6H, s,
N(CH3)2), 2.28 (3H, s, CH3); 13C NMR (50 MHz, CDCl3)
d¼158.3,
157.7, 143.9, 138.2, 130.1, 126.9, 124.0, 117.3, 110.4, 103.5, 38.5, 20.7;
mass (ESþ) m/z 228.3 (Mþþ1); Anal. Calcd for C14H17N3: C, 73.98; H,
7.54; N, 18.49. Found: C, 73.96; H, 7.58; N, 18.47.
1532 cmꢂ1; 1H NMR (300 MHz, DMSO-d6)
d
¼7.77 (1H, d, J¼3.7 Hz,
NH), 7.68 (1H, d, J¼7.7 Hz, ArH), 7.60–7.55 (1H, m, ArH), 7.46 (2H,
d, J¼8.52 Hz, ArH), 7.24–7.19 (1H, m, ArH), 7.13 (1H, d, J¼3.7 Hz,
CH), 7.06 (2H, d, J¼8.52 Hz, ArH), 6.89 (1H, d, J¼7.6 Hz, ArH), 6.83
(1H, d, J¼7.0 Hz, ArH), 6.78–6.73 (1H, m, ArH), 6.46 (1H, d,
4.6.5. 6-(2-Aminophenyl)-N,N-diethylpyridin-2-amine
(4e). Yield¼0.88 g (84%), yellow oil, Rf¼0.50 (2:8 EtOAc:Hexane), IR
(Neat) nmax 3305, 2977, 1598, 1454, 1263 cmꢂ1; 1H NMR (200 MHz,
J¼9.5 Hz, ArH); 13C NMR (75 MHz, DMSO-d6)
¼160.3, 142.5, 141.1,
d
140.2, 139.1, 131.8, 131.3, 128.3, 124.7, 121.1, 119.3, 116.7, 116.5, 116.4,
116.3, 100.9, 60.7; mass (ESþ) m/z 353.2 (Mþþ1); Anal. Calcd for
C18H13BrN2O: C, 61.21; H, 3.71; N, 7.93; Found: C, 61.15; H, 3.75; N,
7.92.
CDCl3)
d
¼7.58–7.45 (2H, m, ArH), 7.16–7.08 (1H, m, ArH), 6.84 (1H,
d, J¼11.3 Hz, ArH), 6.78–6.70 (2H, m, ArH), 6.37 (1H, d, J¼12.8 Hz,
ArH), 5.67 (2H, br s, NH2), 3.52 (4H, q, J¼10.6 Hz, CH2), 1.19 (6H, t,
J¼10.6 Hz, CH3); 13C NMR (75 MHz, CDCl3)
¼166.4, 162.6, 158.1,
d
149.3, 131.1, 128.9, 116.9, 116.6, 115.2, 105.9; mass (ESþ) m/z 242.3
(Mþþ1); Anal. Calcd for C15H19N3: C, 74.65; H, 7.94; N, 17.41. Found:
C, 74.63; H, 7.95; N, 17.42.
4.7.4. 6-(4-Fluorophenyl)-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-
8-one (6d). Yield¼0.20 g (95%), yellow solid, mp 150–152 ꢀC,
Rf¼0.38 (2:8 EtOAc:Hexane), IR (KBr) nmax 3280, 2937, 1647,
1541 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼7.58 (1H, d, J¼7.5 Hz,
4.6.6. 6-(2-Amino-5-methylphenyl)-N,N-diethyl pyridin-2-amine
ArH), 7.48–7.43 (1H, m, ArH), 7.38 (1H, d, J¼3.9 Hz, CH), 7.28–7.18
(3H, m, ArH), 6.91–6.82 (4H, m, ArH), 6.62 (2H, t, J¼7.6 Hz, ArH)
(4f). Yield¼ 2.80 g (84%), yellow oil, Rf¼0.50 (2:8 EtOAc:Hexane),
IR (Neat) nmax 3294, 2969, 1540 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
5.08 (1H, br s, NH); 13C NMR (75 MHz, CDCl3)
d
¼160.3, 142.6, 141.1,
d
¼7.51–7.45 (1H, m, ArH), 7.29 (1H, s, ArH), 6.96–6.93 (1H, m, ArH),
140.2,135.9,135.8,131.8,128.2,128.1,124.7,119.3,116.6 (d, J¼69 Hz),
116.3, 115.3, 115.0, 100.9, 60.7; mass (ESþ) m/z 293.3 (Mþþ1); Anal.
Calcd for C18H13FN2O: C, 73.96; H, 4.48; N, 9.58. Found: C, 73.95; H,
4.45; N, 9.55.
6.82 (1H, d, J¼7.5 Hz, ArH), 6.64 (1H, d, J¼8.0 Hz, ArH), 6.36 (1H, d,
J¼8.5 Hz, ArH), 3.52 (4H, q, J¼7.1 Hz, CH2), 2.7 (3H, s, CH3), 1.18 (6H,
t, J¼7.1 Hz, CH3); 13C NMR (50 MHz, CDCl3)
¼158.2, 156.6, 144.1,
d
138.4, 130.4, 130.3, 127.1, 124.6, 117.5, 110.2, 103.5, 42.9, 21.0, 13.5;
mass (ESþ) m/z 256.3 (Mþþ1); Anal. Calcd for C16H21N3: C, 75.26; H,
8.29; N, 16.46. Found: C, 75.24; H, 8.30; N, 16.47.
4.7.5. 6-(3,4-Dichlorophenyl)-5,6-dihydro-8H-pyrido[1,2-c]quinazo-
lin-8-one (6g). Yield¼0.16 g (90%), yellow solid, mp 80–82 ꢀC,
Rf¼0.38 (2:8 EtOAc:Hexane), IR (KBr) nmax 3266, 2938, 1645,
4.7. General procedure for the synthesis of pyrido[1,2-c]
quinazolin-8-one 6 and benzo[1,6]naphthyridine 8 via
1536 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼7.58 (1H, dd, J¼1.0, 7.9 Hz,
ArH), 7.50–7.45 (1H, m, ArH), 7.36–7.30 (2H, m, ArH, CH), 7.28–7.22
(2H, m, ArH), 6.05–6.02 (1H, m, ArH), 6.95–6.87 (2H, m, ArH), 6.65–
6.60 (2H, m, ArH), 5.07 (1H, br s, NH); 13C NMR (50 MHz, CDCl3)
cationic
p cyclization from substrates (4a–f)
A mixture of 4a–f (1.0 mmol) and aldehyde (1.1 mmol) in tolu-
ene (5 mL) was treated with TFA (0.1 mmol) at 110 ꢀC for 8 h. The
completion of reaction was monitored by TLC. After that the solvent
was evaporated, and the residue so obtained was triturated with aq
NaHCO3 (10 mL). It was then extracted with EtOAc (20 mL), washed
with brine (10 mL), and dried over Na2SO4. EtOAc was evaporated
to dryness under reduced pressure and the crude product was
purified by column chromatography using hexane:ethyl acetate as
eluent.
d
¼161.7, 141.1, 140.9, 140.1, 139.6, 132.9, 132.5, 132.1, 130.6, 128.8,
125.9, 124.8, 121.4, 118.6, 118.1, 118.0, 102.2, 61.5; mass (ESþ) m/z
243.2 (Mþþ1); Anal. Calcd for C18H12Cl2N2O: C, 62.99; H, 3.52; N,
8.16. Found: C, 62.95; H, 3.53; N, 8.13.
4.7.6. 6-(4-Ethoxyphenyl)-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-
8-one (6h). Yield¼0.04 g (15%), yellow solid, mp 163 ꢀC, Rf¼0.40
(2:8 EtOAc:Hexane), IR (KBr) nmax 3258, 2985, 1641, 1536 cmꢂ1; 1H
NMR (300 MHz, DMSO-d6)
d
¼7.71 (1H, d, J¼3.7 Hz, NH), 7.68 (1H, d,
J¼8.0 Hz, ArH), 7.58–7.53 (1H, m, ArH), 7.23–7.17 (1H, m, ArH), 7.08
(1H, d, J¼3.6, CH), 7.01 (2H, d, J¼8.6 Hz, ArH), 6.86 (1H, d, J¼7.3 Hz,
ArH), 6.81–6.71 (4H, m, ArH), 6.44 (1H, dd, J¼0.8, 9.0 Hz, ArH), 3.91
(2H, q, J¼7.0 Hz, CH2), 1.24 (3H, t, J¼7.0 Hz, CH3); 13C NMR (50 MHz,
4.7.1. 6-(4-Nitrophenyl)-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-8-
one (6a). Yield¼0.20 g (96%), yellow solid, mp 135–136 ꢀC, Rf¼0.30
(2:8 EtOAc:Hexane), IR (KBr) nmax 3289, 2969, 1532, 1341 cmꢂ1; 1H
NMR (200 MHz, DMSO-d6)
d
¼8.11 (2H, d, J¼13.2 Hz, ArH), 7.88 (1H,
CDCl3)
d¼160.3, 158.1, 142.8, 141.3, 139.9, 131.6, 131.4, 127.2, 124.6,
d, J¼5.8 Hz, NH), 7.70–7.56 (2H, m, ArH), 7.35 (2H, d, J¼13.0 Hz,
ArH), 7.25–7.21 (2H, m, ArH), 6.91–6.85 (2H, m, ArH, CH), 6.79–6.73
(1H, m, ArH), 6.50 (1H, dd, J¼13.5 Hz, ArH); 13C NMR (75 MHz,
118.9, 116.6, 116.5, 116.2, 114.1, 100.7, 62.9, 60.8, 14.6; mass (ESþ) m/z
319.2 (Mþþ1); Anal. Calcd for C20H18N2O2: C, 75.45; H, 5.70; N, 8.80.
Found: C, 75.53; H, 5.65; N, 8.78.
DMSO-d6)
d
¼160.8, 147.6, 142.7, 141.4, 140.9, 132.3, 127.9, 125.3,
124.0, 120.1, 117.3, 116.9, 101.6, 61.3; mass (ESþ) m/z 320.2 (Mþþ1);
Anal. Calcd for C18H13N3O3: C, 67.71; H, 4.10; N, 13.16. Found: C,
67.69; H, 4.13; N, 13.18.
4.7.7. 2-Methyl-6-(4-nitrophenyl)-5,6-dihydro-8H-pyrido[1,2-c]qui-
nazolin-8-one (6i). Yield¼0.24 g (95%), yellow oil, Rf¼0.80 (3:7
EtOAc:Hexane), IR (KBr) nmax 3282, 2930, 1533, 1343 cmꢂ1; 1H NMR
(300 MHz, CDCl3)
d
¼8.02 (2H, d, J¼8.8 Hz, ArH), 7.52–7.37 (5H, m,
4.7.2. 6-(4-Chlorophenyl)-5,6-dihydro-8H-pyrido[1,2-c]quinazolin-
ArH), 7.01 (1H, d, J¼8.0 Hz, ArH), 6.85 (1H, d, J¼8.1 Hz, ArH), 6.65
(2H, d, J¼8.2 Hz, ArH), 4.94 (1H, d, J¼4.9 Hz, NH), 2.28 (3H, s, CH3);
8-one (6b). Yield¼0.21 g (92%), yellow oil, Rf¼0.40 (2:8 EtOA-
c:Hexane), IR (Neat) nmax 3020, 2928, 1650, 1490, 1216 cmꢂ1
;
1H
13C NMR (75 MHz, CDCl3)
d¼161.72, 147.5, 146.5, 141.1, 140.2, 138.4,
NMR (300 MHz, CDCl3)
d¼7.57 (1H, d, J¼7.9 Hz, ArH), 7.46 (1H, t,
133.1,127.6,124.7,123.6,118.6,117.6,102.2, 61.9, 20.9; mass (ESþ) m/z

P.K. Agarwal et al. / Tetrahedron 66 (2010) 862–870
867
334.3 (Mþþ1); Anal. Calcd for C19H15N3O3: C, 68.46; H, 4.54; N,
(2:8 EtOAc:Hexane), IR (KBr) nmax 3055, 2922, 1598, 1380 cmꢂ1; 1H
NMR (300 MHz, CDCl3)
12.61. Found: C, 68.41; H, 4.49; N, 12.57.
d
¼9.00 (1H, dd, J¼1.2, 8.1 Hz, ArH), 8.11 (1H,
dd, J¼0.7, 8.2 Hz, ArH), 7.99 (1H, d, J¼9.3 Hz, ArH), 7.77–7.68 (1H, m,
ArH), 7.68–7.63 (2H, m, ArH), 7.62–7.56 (3H, m, ArH), 6.82 (1H, d,
J¼9.3 Hz, ArH), 3.34 (6H, s, N(CH3)2); 13C NMR (75 MHz, CDCl3)
4.7.8. 6-(4-Chlorophenyl)-2-methyl-5,6-dihydro-8H-pyrido[1,2-
c]quinazolin-8-one (6j). Yield¼0.22 g (93%), yellow solid, mp 157–
180 ꢀC, Rf¼0.56 (3:7 EtOAc:Hexane), IR (KBr) nmax 3320, 2922, 1643,
d
¼159.0, 158.8, 150.0, 146.7, 138.6, 136.8, 131.7, 131.5, 130.0, 129.2,
1536 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼7.47–7.42 (1H, m, ArH),
126.1, 124.9, 123.9, 123.1, 112.6, 107.9, 38.1; mass (ESþ) m/z 378.4
(Mþþ1); Anal. Calcd for C20H16BrN3: C, 63.50; H, 4.26; N, 11.11.
Found: C, 63.48; H, 4.29; N, 11.09.
7.36 (2H, s, ArH), 7.1 (4H, s, ArH), 7.06 (1H, d, J¼7.9 Hz, ArH), 6.78
(1H, d, J¼8.1 Hz, ArH), 6.62–6.58 (2H, m, ArH), 4.94 (1H, d, J¼3.6 Hz,
NH), 2.27 (3H, s, CH3); 13C NMR (50 MHz, CDCl3)
d
¼141.2, 139.8,
138.9, 137.7, 133.8, 132.9, 130.3, 128.5, 128.4, 127.9, 126.3, 124.6,
118.4, 118.1, 117.5, 101.9, 61.9, 20.8; mass (ESþ) m/z 323.3 (Mþþ1);
Anal. Calcd for C19H15ClN2O: C, 70.70; H, 4.68; N, 8.68. Found: C,
70.67; H, 4.70; N, 8.69.
4.7.14. 4-[2-(Dimethylamino)benzo[h][1,6]naphthyridin-5-yl]phenol
(8d). Yield¼0.26 g (90%), white solid, mp >250 ꢀC, Rf¼0.20 (2:8
EtOAc:Hexane), IR (KBr) nmax 2925, 1601, 1526, 1213 cmꢂ1; 1H NMR
(300 MHz, CDCl3)
d
¼9.82 (1H, s, OH), 8.89 (1H, d, J¼7.1 Hz, ArH),
8.09 (1H, d, J¼7.8 Hz, ArH), 7.96 (1H, d, J¼7.9 Hz, ArH), 7.78–7.72
(1H, m, ArH), 7.63–7.58 (1H, m, ArH), 7.53 (2H, d, J¼8.5 Hz, ArH),
7.09 (1H, d, J¼9.4 Hz, ArH), 6.95 (2H, d, J¼8.5 Hz, ArH), 3.33 (6H, s,
4.7.9. 6-(4-Bromophenyl)-2-methyl-5,6-dihydro-8H-pyrido[1,2-
c]quinazolin-8-one (6k). Yield¼0.25 g (90%), yellow solid, mp 151–
153 ꢀC, Rf¼0.60 (3:7 EtOAc:Hexane), IR (KBr) nmax 3330, 2930, 1644,
N(CH3)2); 13C NMR (50 MHz, CDCl3)
d¼161.2, 160.1, 158.8, 156.2,
1532 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼7.42 (1H, t, J¼8.1 Hz, ArH),
152.0, 138.1, 136.4, 132.7, 132.6, 127.9, 124.3, 123.3, 120.6, 120.3,
116.0, 111.5, 110.8, 38.3; mass (ESþ) m/z 316.3 (Mþþ1); Anal. Calcd
for C20H17N3O: C, 76.17; H, 5.43; N, 13.32. Found: C, 76.15; H, 5.44;
N, 13.29.
7.32 (1H, d, J¼4.5 Hz, CH), 7.30 (1H, s, ArH), 7.20 (2H, d, J¼8.4 Hz,
ArH), 7.04 (2H, d, J¼8.4 Hz, ArH), 6.99 (1H, d, J¼8.1 Hz, ArH), 6.72 (1H,
d, J¼8.1 Hz, ArH), 6.58 (2H, d, J¼8.7 Hz, ArH), 5.76 (1H, s, NH), 2.22
(3H, s, CH3); 13C NMR (50 MHz, CDCl3)
d¼161.7, 141.3, 139.8, 138.9,
138.2, 131.4, 130.2, 128.2, 124.6, 122.0, 118.3, 118.1, 117.4, 101.9, 61.9,
20.8; mass (ESþ) m/z 367.2 (Mþþ1); Anal. Calcd for C19H15BrN2O: C,
62.14; H, 4.12; N, 7.63; O, 4.36. Found: C, 62.16; H, 4.10; N, 7.67.
4 . 7 . 15 . 5 - [ 4 - ( D i m e t h y l a m i n o ) p h e n y l ] - N , N - d i m e -
thylbenzo[h][1,6]naphthyridin-2-amine (8e). Yield¼0.29 g (91%),
yellow solid, mp 205 ꢀC, Rf¼0.25 (2:8 EtOAc:Hexane), IR (KBr) nmax
3438, 2892, 1607, 1355 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d¼8.98
4.7.10. 6-(4-Fluorophenyl)-2-methyl-5,6-dihydro-8H-pyrido[1,2-
c]quinazolin-8-one (6l). Yield¼0.20 g (89%), yellow solid, mp 179–
180 ꢀC, Rf¼0.65 (3:7 EtOAc:Hexane), IR (KBr) nmax 3294, 2922, 1647,
(1H, dd, J¼1.0, 8.1 Hz, ArH), 8.20 (1H, d, J¼9.3 Hz, ArH), 8.12 (1H, d,
J¼8.2 Hz, ArH), 7.74–7.69 (1H, m, ArH), 7.64 (2H, d, J¼8.8 Hz, ArH),
7.59–7.54 (1H, m, ArH), 6.86 (2H, d, J¼8.8 Hz, ArH), 6.82 (1H, d,
J¼9.3 Hz, ArH), 3.34 (6H, s, N(CH3)2), 3.04 (6H, s, N(CH3)2); 13C NMR
1540 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼7.46–7.43 (1H, m, ArH),
7.37 (2H, s, ArH), 7.21–7.17 (2H, m, ArH), 7.08 (1H, dd, J¼1.3, 9.4 Hz,
ArH), 6.90–6.82 (2H, m, ArH), 6.78 (1H, d, J¼8.1 Hz, ArH), 6.83 (2H, t,
J¼7.2 Hz, ArH), 4.84 (1H, d, J¼3.9 Hz, NH), 2.28(3H, s, CH3); 13C NMR
(75 MHz, CDCl3)
d
¼160.3, 158.9, 151.0, 150.1, 147.1, 137.8, 131.1, 129.7,
129.1, 127.9, 125.4, 124.7, 123.9, 113.1, 112.3, 109.8, 107.5, 40.7, 38.1;
mass (ESþ) m/z 343.4 (Mþþ1), MS (HR EI) m/z calcd for [Mþ]
342.1844 found 342.1821; Anal. Calcd for C22H22N4: C, 77.16; H,
6.48; N, 16.36. Found: C, 77.11; H, 6.49; N, 16.40.
(50 MHz, CDCl3)
d
¼161.8, 141.3, 139.8, 138.9, 135.0, 134.9, 132.9,
130.6, 128.4, 128.2, 124.7, 118.7, 118.3, 117.8, 115.6, 115.1, 101.8, 62.0,
20.9; mass (ESþ) m/z 307.3 (Mþþ1); Anal. Calcd for C19H15FN2O: C,
74.50; H, 4.94; N, 9.14. Found: C, 74.53; H, 4.91; N, 9.16.
4.7.16. 5-(3,4-Dimethoxyphenyl)-N,N-dimethylbenzo[h][1,6]naph-
thyridin-2-amine (8f). Yield¼0.30 g (90%), yellow solid, mp 180–
181 ꢀC, Rf¼0.30 (2:8 EtOAc:Hexane), IR (KBr) nmax 2932, 1604, 1519,
4.7.11. N,N-Dimethyl-5-(4-nitrophenyl)benzo[h][1,6]naphthyridin-2-
amine (8a). Yield¼0.31 g (97%), yellow solid, mp 197 ꢀC, Rf¼0.35
(2:8 EtOAc:Hexane), IR (KBr) nmax 3618, 2930, 1610, 1520 cmꢂ1; 1H
1259 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼9.00 (1H, dd, J¼1.5, 8.1 Hz,
ArH), 8.13–8.10 (2H, m, ArH), 7.77–7.71 (1H, m, ArH), 7.63–7.57 (1H,
m, ArH), 7.31–7.21 (2H, m, ArH), 7.02 (1H, d, J¼8.2 Hz, ArH), 6.83
(1H, d, J¼9.3 Hz, ArH), 3.97 (6H, s, (OCH3)2), 3.35 (6H, s, N(CH3)2);
NMR (300 MHz, CDCl3)
d
¼9.02 (1H, dd, J¼1.1, 8.1 Hz, ArH), 8.40 (2H,
dd, J¼1.9, 6.9 Hz, ArH), 8.12 (1H, dd, J¼0.6, 8.2 Hz, ArH), 7.94–7.87
(3H, m, ArH), 7.80–7.75 (1H, m, ArH), 7.68–7.63 (1H, m, ArH), 6.86
(1H, d, J¼9.3 Hz, ArH), 3.36 (6H, s, N(CH3)2); 13C NMR (75 MHz,
13C NMR (50 MHz, CDCl3)
d
¼159.8, 159.0, 150.0, 149.7, 149.2, 146.9,
137.4,132.6,129.8,129.2,125.8,124.8,123.9,122.7,113.0,113.0,111.0,
107.7, 56.2, 56.2, 38.1; mass (ESþ) m/z 360.3 (Mþþ1); Anal. Calcd for
C22H21N3O2: C, 73.52; H, 5.89; N, 11.69. Found: C, 73.55; H, 5.87; N,
11.73.
CDCl3)
d
¼159.0, 157.4, 150.0, 148.0, 146.6, 146.2, 136.2, 130.9, 130.2,
129.3, 126.6, 125.0, 124.1, 123.7, 112.3, 108.2, 38.1; mass (ESþ) m/z
345.2 (Mþþ1), MS (HR EI) m/z calcd for [Mþ] 344.1273 found
344.1291; Anal. Calcd for C20H16N4O2: C, 69.76; H, 4.68; N, 16.27.
Found: C, 69.79; H, 4.69; N, 16.23.
4.7.17. N,N,9-Trimethyl-5-(4-nitrophenyl)benzo[h][1,6]naphthyridin-
2-amine (8g). Yield¼0.29 g (94%), yellow solid, mp >250 ꢀC,
Rf¼0.45 (2:8 EtOAc:Hexane), IR (KBr) nmax 2927, 1604, 1515,
4.7.12. 5-(4-Chlorophenyl)-N,N-dimethylbenzo[h][1,6]naphthyridin-
2-amine (8b). Yield¼0.29 g (93%), yellow solid, mp 195 ꢀC, Rf¼0.50
1343 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼8.78 (1H, s, ArH), 8.38
(2:8 EtOAc:Hexane), IR (KBr) nmax 2930, 1602, 1376, 1131 cmꢂ1
;
1H
(2H, d, J¼8.3 Hz, ArH), 8.01 (1H, d, J¼8.4 Hz, ArH), 7.93–7.87 (3H, m,
ArH), 7.60 (1H, d, J¼8.3 Hz, ArH), 6.85 (1H, d, J¼9.3 Hz, ArH), 3.37
(6H, s, N(CH3)2), 2.64 (3H, s, CH3); 13C NMR (50 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d
¼9.00 (1H, dd, J¼1.2, 8.1 Hz, ArH), 8.11 (1H,
d, J¼8.2 Hz, ArH), 8.0 (1H, d, J¼9.3 Hz, ArH), 7.78–7.73 (1H, m, ArH),
7.66–7.60 (3H, m, ArH), 7.53–7.50 (2H, m, ArH), 6.83 (1H, d,
J¼9.3 Hz, ArH), 3.35 (6H, s, N(CH3)2); 13C NMR (50 MHz, CDCl3)
d
¼159.0, 156.5, 149.8, 147.9, 146.3, 145.1, 136.7, 136.2, 132.1, 130.9,
129.2, 124.8, 123.8, 123.3, 112.4, 108.2, 38.2, 22.1; mass (ESþ) m/z
359.3 (Mþþ1), MS (HR EI) m/z calcd for [Mþ] 358.1430 found
358.1411; Anal. Calcd for C21H18N4O2: C, 70.38; H, 5.06; N, 15.63.
Found: C, 70.35; H, 5.04; N, 15.66.
d
¼159.0, 158.8, 150.0, 146.8, 138.3, 136.8, 134.8, 131.2, 129.9, 129.3,
128.7, 126.1, 124.9, 124.0, 112.7, 107.9, 38.0; mass (ESþ) m/z 334.4
(Mþþ1); Anal. Calcd for C20H16ClN3: C, 71.96; H, 4.83; N, 12.59.
Found: C, 71.99; H, 4.81; N, 12.58.
4.7.18. 5-(4-Chlorophenyl)-N,N,9-trimethylbenzo[h][1,6]naphthyr-
idin-2-amine (8h). Yield¼0.28 g (92%), white solid, mp 206–208 ꢀC,
Rf¼0.46 (2:8 EtOAc:Hexane), IR (KBr) nmax 3422, 19.13, 1606,
4.7.13. 5-(4-Bromophenyl)-N,N-dimethylbenzo[h][1,6]naphthyridin-
2-amine (8c). Yield¼0.34 g (95%), yellow solid, mp 190 ꢀC, Rf¼0.45

868
P.K. Agarwal et al. / Tetrahedron 66 (2010) 862–870
1379 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼8.76 (1H, s, ArH), 8.01–
J¼8.6 Hz, ArH), 7.55 (1H, dd, J¼1.9, 8.4 Hz, ArH), 7.04 (2H, d,
J¼8.6 Hz, ArH), 6.80 (1H, d, J¼9.3 Hz, ArH), 4.12 (2H, q, J¼7.0 Hz,
CH2), 3.34 (6H, s, N(CH3)2), 2.62 (3H, s, CH3), 1.34 (3H, t, J¼7.0 Hz,
7.96 (2H, m, ArH), 7.64 (2H, d, J¼8.4 Hz, ArH), 7.57 (1H, dd, J¼2.0,
8.4 Hz, ArH), 7.50 (2H, d, J¼8.4 Hz, ArH), 6.80 (1H, d, J¼9.3 Hz, ArH),
3.35 (6H, s, N(CH3)2), 2.63 (3H, s, CH3); 13C NMR (50 MHz, CDCl3)
CH3); 13C NMR (50 MHz, CDCl3)
d
¼159.4, 158.8, 149.8, 145.2, 137.2,
d
¼158.8, 157.7, 149.5, 145.0, 138.2, 136.7, 135.9, 134.6, 131.7, 131.2,
135.4, 132.3, 131.5, 128.9, 124.5, 123.1, 114.4, 112.9, 107.4, 63.6, 37.9,
21.9, 14.9; mass (ESþ) m/z 358.3 (Mþþ1); Anal. Calcd for
C23H23N3O: C, 77.28; H, 6.49; N, 11.76. Found: C, 77.25; H, 6.51; N,
11.73.
128.9, 128.6, 124.6, 123.1, 112.6, 107.7, 37.9, 21.9; mass (ESþ) m/z
348.4 (Mþþ1); Anal. Calcd for C21H18ClN3: C, 72.51; H, 5.22; N,
12.08. Found: C, 72.48; H, 5.24; N, 12.06.
4.7.19. 5-(4-Bromophenyl)-N,N,9-trimethylbenzo[h][1,6]naphthyr-
idin-2-amine (8i). Yield¼0.32 g (93%), yellow solid, mp 188–200 ꢀC,
Rf¼0.42 (2:8 EtOAc:Hexane), IR (KBr) nmax 2932, 1610, 1419,
4.7.24. N,N-Diethyl-5-(4-nitrophenyl)benzo[h][1,6]naphthyridin-2-
amine (8n). Yield¼0.29 g (95%), yellow solid, mp 161 ꢀC, Rf¼0.35
(2:8 EtOAc:Hexane), IR (KBr) nmax 3063, 2953, 1610, 1341 cmꢂ1; 1H
1119 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼8.72 (1H, s, ArH), 8.35 (1H,
NMR (300 MHz, CDCl3)
d
¼9.00 (1H, dd, J¼1.2, 8.1 Hz, ArH), 8.40
d, J¼8.5 Hz, ArH), 7.98 (1H, d, J¼9.5 Hz, ArH), 7.74–7.69 (3H, m,
ArH), 7.63 (2H, d, J¼8.3 Hz, ArH), 6.98 (1H, d, J¼9.5 Hz, ArH), 3.45
(6H, s, N(CH3)2), 2.65 (3H, s, CH3); 13C NMR (50 MHz, CDCl3)
(2H, dd, J¼1.9, 7.0 Hz, ArH), 8.10 (1H, d, J¼8.2 Hz, ArH), 7.91–7.88
(3H, m, ArH), 7.80–7.74 (1H, m, ArH), 7.67–7.62 (1H, m, ArH), 6.80
(1H, d, J¼9.4 Hz, ArH), 3.78 (4H, q, J¼7.1 Hz, CH2), 1.35 (6H, t,
d
¼160.3, 154.8, 152.3, 138.8, 137.8, 136.5, 134.4, 132.3, 132.0, 129.8,
J¼7.1 Hz, CH3); 13C NMR (75 MHz, CDCl3)
¼157.7, 157.4, 150.4,
d
126.5, 124.4, 123.7, 122.2, 111.2, 110.4, 38.53, 22.1; mass (ESþ) m/z
392.3 (Mþþ1); Anal. Calcd for C21H18BrN3: C, 64.30; H, 4.62; N,
10.71. Found: C, 64.28; H, 4.63; N, 10.73.
148.0, 146.7, 146.3, 136.2, 130.9, 130.1, 129.3, 126.5, 125.2, 124.1,
123.7, 112.3, 108.3, 43.3, 13.1; mass (ESþ) m/z 373.3 (Mþþ1); Anal.
Calcd for C22H20N4O2: C, 70.95; H, 5.41; N, 15.04. Found: C, 70.91; H,
5.43; N, 15.01.
4.7.20. 5-(4-Fluorophenyl)-N,N,9-trimethylbenzo[h][1,6]naphthyr-
idin-2-amine (8j). Yield¼0.26 g (90%), white solid, mp 209–
211 ꢀC, Rf¼0.37 (2:8 EtOAc:Hexane), IR (KBr) nmax 2914, 1607,
4.7.25. N-[5-(4-Chlorophenyl)benzo[h][1,6]naphthyridin-2-yl]-N,N-
diethylamine (8o). Yield¼0.28 g (93%), yellow solid, mp 130 ꢀC,
Rf¼0.50 (2:8 EtOAc:Hexane), IR (KBr) nmax 3071, 2977, 2930, 1598,
1517, 1380 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼8.76 (1H, s, ArH),
8.02–7.97 (2H, m, ArH), 7.70–7.65 (2H, m, ArH), 7.57 (1H,, dd,
J¼1.8, 8.4 Hz, ArH), 7.25–7.18 (2H, m, ArH), 6.80 (1H, d, J¼9.3 Hz,
ArH), 3.35 (6H, s, N(CH3)2), 2.63 (3H, s, CH3); 13C NMR (50 MHz,
1345 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d
¼8.98 (1H, dd, J¼1.4, 8.1 Hz,
ArH), 8.10 (1H, d, J¼8.1 Hz, ArH), 7.97 (1H, d, J¼9.3 Hz, ArH), 7.77–
7.71 (1H, m, ArH), 7.66–7.58 (3H, m, ArH), 7.53–7.46 (2H, m, ArH),
6.78 (1H, d, J¼9.3 Hz, ArH), 3.76 (4H, q, J¼7.0 Hz, CH2), 1.34 (6H, t,
CDCl3)
d
¼165.6, 160.6, 158.9, 157.9, 149.6, 145.1, 136.8, 135.9 (d,
J¼12 Hz), 135.8, 131.7, 131.5, 128.9, 124.6, 123.1, 115.6, 115.2, 112.8,
107.7, 38.0, 21.9; mass (ESþ) m/z 332.4 (Mþþ1), MS (HR EI) m/z
calcd for [Mþ] 332.15630 found 332.15616; Anal. Calcd for
C21H18FN3: C, 76.11; H, 5.47; N, 12.68. Found: C, 76.13; H, 5.58; N,
12.67.
J¼7.0 Hz, CH3); 13C NMR (75 MHz, CDCl3)
¼158.7, 157.5, 150.3,
d
146.8, 138.3, 136.8, 134.8, 131.2, 129.9, 129.2, 129.1, 128.7, 126.0,
125.0, 123.9, 112.6, 107.9, 43.2, 13.1; mass (ESþ) m/z 362.4
(Mþþ1),MS (HR EI) m/z calcd for [Mþ] 361.1346 found 361.1340;
Anal. Calcd for C22H20ClN3: C, 73.02; H, 5.57; N, 11.61. Found: C,
73.07; H, 5.58; N, 11.57.
4 . 7 . 2 1. N , N , 9 -T r i m e t h y l - 5 - ( 4 - N , N - d i m e t h y l p h e -
nyl)benzo[h][1,6]naphthyridin-2-amine (8k). Yield¼0.28 g (91%),
yellow solid, mp 214–215 ꢀC, Rf¼0.75 (2:8 EtOAc:Hexane), IR (KBr)
4.7.26. 5-(4-Bromophenyl)-N,N-diethylbenzo[h][1,6]naphthyridin-2-
amine (8p). Yield¼0.32 g (94%), yellow oil, Rf¼0.50 (2:8 EtOA-
nmax 2919, 1603, 1366, 1194 cmꢂ1; 1H NMR (300 MHz, CDCl3)
d¼8.6
c:Hexane), IR (Neat) nmax 2930, 1661, 1606, 1361 cmꢂ1 1H NMR
;
(1H, s, ArH), 8.37 (1H, d, J¼8.3 Hz, ArH), 8.16 (1H, d, J¼9.5 Hz, ArH),
7.69–7.62 (3H, m, ArH), 6.89 (1H, d, J¼9.5 Hz ArH), 6.80 (2H, d,
J¼8.8 Hz, ArH), 3.39 (6H, s, N(CH3)2), 3.07 (6H, s, N(CH3)2), 2.62
(200 MHz, CDCl3)
d
¼9.00 (1H, dd, J¼2.4, 12.1 Hz, ArH), 8.12–8.07
(1H, m, ArH), 7.94 (1H, d, J¼13.9 Hz, ArH), 7.69–7.62 (3H, m,
ArH), 7.60–7.53 (3H, m, ArH), 6.74 (1H, d, J¼13.9 Hz, ArH), 3.74
(4H, q, J¼10.6 Hz, CH2), 1.31 (6H, t, J¼10.6 Hz, CH3); 13C NMR
(3H, s, CH3); 13C NMR (50 MHz, DMSO-d6)
d
¼159.5, 156.0, 152.0,
150.9, 137.9, 136.8, 133.4, 131.8, 123.2, 123.1, 121.9, 111.6, 110.6,
110.3, 38.3, 37.8, 21.4; mass (ESþ) m/z 357.4 (Mþþ1); Anal. Calcd
for C23H24N4: C, 77.50; H, 6.79; N, 15.72. Found: C, 77.52; H, 6.80;
N, 15.69.
(50 MHz, CDCl3)
d
¼158.7, 157.5, 150.3, 146.7, 138.7, 136.7, 132.8,
131.6, 131.5, 131.0, 129.9, 129.1, 126.0, 124.9, 123.9, 123.0, 112.5,
107.9, 43.2, 13.1; mass (ESþ) m/z 406.3 (Mþþ1); Anal. Calcd for
C22H20BrN3: C, 65.03; H, 4.96; N, 10.34. Found: C, 65.01; H, 4.93;
N, 10.37.
4.7.22. N,N,9-Trimethyl-5-(3,4-dimethoxyphenyl)benzo[h][1,6]naph-
thyridin-2-amine (8l). Yield¼0.29 g (90%), yellow solid, mp
218–219 ꢀC, Rf¼0.82 (2:8 EtOAc:Hexane), IR (KBr) nmax 2931, 1607,
4.7.27. N,N-Diethyl-5-(4-fluorophenyl)benzo[h][1,6]naphthyridin-2-
amine (8q). Yield¼0.26 g (91%), yellow solid, mp 118 ꢀC, Rf¼0.40
(2:8 EtOAc:Hexane), IR (KBr) nmax 2971, 2922, 1600, 1351 cmꢂ1; 1H
1390, 1266 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d¼8.72 (1H, s, ArH),
8.36 (1H, d, J¼4.8 Hz, ArH), 8.13 (1H, d, J¼9.3 Hz, ArH), 7.67 (1H, d,
J¼6.7 Hz, ArH), 7.40 (1H, s, ArH), 7.26(1H, s, ArH), 7.02 (1H, d,
J¼7.2 Hz, ArH), 6.94 (1H, d, J¼9.4 Hz, ArH), 3.97 (6H, s, (OCH3)2),
3.43 (6H, s, N(CH3)2), 2.64 (3H, s, CH3); 13C NMR (50 MHz, CDCl3)
NMR (300 MHz, CDCl3)
d
¼8.98 (1H, dd, J¼1.2, 8.1 Hz, ArH), 8.10 (1H,
d, J¼7.6 Hz, ArH), 7.98 (1H, d, J¼9.3 Hz, ArH), 7.77–7.58 (4H, m,
ArH), 7.26–7.19 (2H, m, ArH), 6.78 (1H, d, J¼9.3 Hz, ArH), 3.76 (4H, q,
J¼7.1 Hz, CH2), 1.33 (6H, t, J¼7.1 Hz, CH3); 13C NMR (75 MHz, CDCl3)
d
¼160.1, 156.2, 152.0, 151.8, 149.5, 138.5, 138.0, 134.0, 124.3, 124.2,
d¼164.8, 161.8, 158.9, 157.5, 150.3, 146.8, 136.9, 135.9, 129.9, 129.2,
123.5, 113.5, 111.6, 111.1, 109.7, 56.4, 56.2, 38.4, 22.1; mass (ESþ) m/z
374.4.3 (Mþþ1); Anal. Calcd for C23H23N3O2: C, 73.97; H, 6.21; N,
11.25. Found: C, 73.99; H, 6.22; N, 11.23.
125.9, 125.0, 123.9, 115.7, 115.4, 112.8, 107.9, 43.3, 13.1; mass (ESþ)
m/z 346.4 (Mþþ1); Anal. Calcd for C22H20FN3: C, 76.50; H, 5.84; N,
12.17. Found: C, 76.45; H, 5.86; N, 12.21.
4.7.23. 5-(4-Ethoxyphenyl)-N,N,9-trimethylbenzo[h][1,6]naphthyr-
idin-2-amine (8m). Yield¼0.27 g (88%), white solid, mp 183–
185 ꢀC, Rf¼0.44 (2:8 EtOAc:Hexane), IR (KBr) nmax 2922, 1601, 1376,
4.7.28. 4-[2-(Diethylamino)benzo[h][1,6]naphthyridin-5-yl]phenol
(8r). Yield¼0.24 g (86%), yellow solid, mp >250 ꢀC, Rf¼0.20 (2:8
EtOAc:Hexane), IR (KBr) nmax 2985, 2922, 1606, 1353 cmꢂ1; 1H NMR
12539 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼8.75 (1H, s, ArH), 8.07
(300 MHz, DMSO-d6)
d
¼9.81 (1H, s, OH), 8.45 (1H, dd, J¼1.1, 8.1 Hz,
(1H, d, J¼9.3 Hz, ArH), 8.01 (1H, d, J¼8.4 Hz, ArH), 7.63 (2H, d,
ArH), 8.06 (1H, d, J¼9.3 Hz, ArH), 7.95 (1H, d, J¼7.6 Hz, ArH),

P.K. Agarwal et al. / Tetrahedron 66 (2010) 862–870
869
7.77–7.72 (1H, m, ArH), 7.64–7.52 (1H, m, ArH), 7.54 (2H, d,
J¼8.5 Hz, ArH), 7.06 (1H, d, J¼9.3 Hz, ArH), 6.95 (2H, d, J¼8.5 Hz,
ArH), 3.74 (4H, q, J¼6.9 Hz, CH2), 1.25 (6H, t, J¼6.9 Hz, CH3); 13C
ArH), 7.58 (1H, dd, J¼2.0, 8.5 Hz, ArH), 6.80 (1H, d, J¼9.3 Hz, ArH),
3.78 (4H, q, J¼7.0 Hz, CH2), 2.64 (3H, s, CH3), 1.34 (6H, t, J¼7.0 Hz,
CH3); 13C NMR (50 MHz, CDCl3)
d
¼157.5, 156.4, 150.0, 147.8, 146.3,
NMR (75 MHz, DMSO-d6)
d
¼159.0, 157.9, 157.0, 149.2, 146.3, 136.8,
145.0, 136.4, 136.0, 131.9, 130.8, 129.0, 124.9, 123.6, 123.2, 112.3,
108.1, 43.2, 22.0, 13.1; mass (ESþ) m/z 387.2 (Mþþ1); Anal. Calcd for
C23H22N4O2: C, 71.48; H, 5.74; N, 14.50. Found: C, 71.46; H, 5.76; N,
14.51.
131.0, 129.9, 129.5, 128.6, 125.4, 123.9, 123.3, 114.9, 111.9, 108.5, 42.4,
12.8; mass (ESþ) m/z 344.4 (Mþþ1); Anal. Calcd for C22H21N3O: C,
76.94; H, 6.16; N, 12.24. Found: C, 76.93; H, 6.18; N, 12.21.
4.7.29. N,N-Diethyl-5-(4-N,N-dimethylphenyl)benzo[h][1,6]naph-
4.7.34. N-[5-(4-Chlorophenyl)-9-methylbenzo[h][1,6]naphthyridin-
2-yl]-N,N-diethylamine (8x). Yield¼0.27 g (90%), white solid, mp
158–160 ꢀC, Rf¼0.52 (2:8 EtOAc:Hexane), IR (KBr) nmax 3287, 2922,
thyridin-2-amine (8s). Yield¼0.27 g (88%), yellow oil, Rf¼0.30 (2:8
EtOAc:Hexane), IR (Neat) nmax 3422, 2922, 1604, 1355 cmꢂ1 1H
;
NMR (300 MHz, CDCl3)
d
¼8.96 (1H, dd, J¼1.2, 8.1 Hz, ArH), 8.17 (1H,
1603, 1509 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d¼8.72 (1H, s, ArH),
d, J¼9.3 Hz, ArH), 8.10 (1H, d, J¼8.1 Hz, ArH), 7.73–7.68 (1H, m, ArH),
7.65–7.63 (2H, m, ArH), 7.60–7.53 (1H, m, ArH), 6.86 (2H, d,
J¼8.8 Hz, ArH), 6.76 (1H, d, J¼9.3 Hz, ArH) 3.76 (4H, q, J¼7.0 Hz,
CH2), 3.04 (6H, s, N(CH3)2), 1.33 (6H, t, J¼7.0 Hz, CH3); 13C NMR
8.01–7.93 (2H, m, ArH), 7.65–7.62 (2H, m, ArH), 7.56 (1H, dd, J¼1.9,
8.3 Hz, ArH), 7.51–7.48 (2H, m, ArH), 6.76 (1H, d, J¼9.3 Hz, ArH),
3.78 (4H, q, J¼6.9 Hz, CH2), 2.62 (3H, s, CH3), 1.33 (6H, t, J¼6.9 Hz,
CH3); 13C NMR (50 MHz, CDCl3)
d
¼157.7, 157.4, 149.9, 145.1, 138.3,
(75 MHz, CDCl3)
d
¼160.2, 157.4, 150.9, 150.4, 147.1, 137.7, 131.0,
136.7, 135.8, 134.6, 131.7, 131.2, 128.9, 128.6, 124.7, 123.1, 112.6, 107.8,
43.1, 22.0, 13.1; mass (ESþ) m/z 376.3 (Mþþ1), MS (HR EI) m/z calcd
for [Mþ] 375.1502 found 375.1520; Anal. Calcd for C23H22ClN3: C,
73.49; H, 5.90; N, 11.18. Found: C, 72.49; H, 5.93; N, 11.19.
129.6, 129.0, 127.9, 125.3, 123.9, 113.0, 112.2, 107.5, 43.2, 13.2; mass
(ESþ) m/z 371.4 (Mþþ1); Anal. Calcd for C24H26N4: C, 77.80; H, 7.07;
N, 15.12. Found: C, 77.77; H, 7.08; N, 15.14.
4.7.30. N,N-Diethyl-5-(4-ethoxyphenyl) benzo[h][1,6 ]naphthyridin-
4.7.35. N-[5-(4-Ethoxyphenyl)-9-methyl benzo [h][1,6]naphthyridin-
2-yl]-N,N-diethylamine (8y). Yield¼0.27 g (89%), yellow oil, Rf¼0.30
(2:8 EtOAc:Hexane), IR (Neat) nmax 3294, 2922, 1605, 1520 cmꢂ1; 1H
2-amine (8t). Yield¼0.28 g (90%), yellow oil, Rf¼0.38 (2:8 EtOA-
c:Hexane), IR (Neat) nmax 3415, 2974, 1604, 1245 cmꢂ1 1H NMR
;
(300 MHz, CDCl3)
d
¼8.97 (1H, dd, J¼2.2, 12.1 Hz, ArH), 8.10 (1H, dd,
NMR (300 MHz, CDCl3)
d
¼8.71 (1H, s, ArH), 8.04–7.99 (2H, m, ArH),
J¼1.6, 12.5 Hz, ArH), 8.05 (1H, d, J¼13.9 Hz, ArH), 7.76–7.53 (4H, m,
ArH), 7.07–6.99 (2H, m, ArH), 6.76 (1H, d, J¼13.9 Hz, ArH), 4.10 (2H,
q, J¼10.4 Hz, CH2), 3.73 (4H, q, J¼10.5 Hz, CH2), 1.45 (3H, t,
J¼10.4 Hz, CH3), 1.34 (6H, t, J¼10.5 Hz, CH3); 13C NMR (75 MHz,
7.62 (2H, d, J¼8.7 Hz, ArH), 7.53 (1H, dd, J¼1.9, 8.4 Hz, ArH), 7.04–
6.99 (2H, m, ArH), 6.70 (1H, d, J¼9.3 Hz, ArH), 4.08 (2H, q, J¼7.0 Hz,
CH2), 3.71 (4H, q, J¼7.0 Hz, CH2), 2.60 (3H, s, CH3), 1.43 (3H, t,
J¼7.0 Hz, CH3), 1.29 (6H, t, J¼7.0 Hz, CH3); 13C NMR (50 MHz, CDCl3)
CDCl3)
d
¼159.7, 159.4, 157.3, 150.2, 146.8, 137.2, 132.0, 131.1, 129.6,
d
¼159.1, 158.8, 157.3, 149.9, 145.2, 137.2, 135.2, 132.2, 131.4, 131.1,
128.9, 125.5, 124.8, 123.8, 114.4, 112.8, 107.6, 63.5, 43.1, 14.9, 13.0;
mass (ESþ) m/z 372.4 (Mþþ1); Anal. Calcd for C24H25N3O: C, 77.60;
H, 6.78; N, 11.31. Found: C, 77.57; H, 6.83; N, 11.3.
128.8, 124.6, 123.0, 114.3, 112.9, 107.5, 63.6, 43.0, 21.9, 14.9, 13.0;
mass (ESþ) m/z 386.3 (Mþþ1); Anal. Calcd for C25H27N3O: C, 77.89;
H, 7.06; N, 10.90. Found: C, 77.93; H, 7.03; N, 10.92.
4.7.31. N-[5-(4-Dimethylaminophenyl)-9-methylbenzo[h][1,6]naph-
thyridin-2-yl]-N,N-diethylamine (8u). Yield¼0.26 g (86%), yellow
oil, Rf¼0.25 (3:7 EtOAc:Hexane), IR (Neat) nmax 3294, 2922, 1601,
Acknowledgements
PKA and MS are thankful to CSIR, New Delhi, India for
fellowships.
1517 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d¼8.70 (1H, s, ArH), 8.12
(1H, d, J¼9.3 Hz, ArH), 8.00 (1H, d, J¼8.3 Hz, ArH), 7.62 (2H, d,
J¼8.7 Hz, ArH), 7.52 (1H, dd, J¼1.8, 8.3 Hz, ArH), 6.83 (2H, d,
J¼8.7 Hz, ArH), 6.71 (1H, d, J¼9.3 Hz, ArH), 3.72 (4H, q, J¼7.0 Hz,
CH2), 2.99 (6H, s, N(CH3)2), 2.60 (3H, s, CH3), 1.29 (6H, t, J¼7.0 Hz,
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.11.115.
CH3); 13C NMR (50 MHz, CDCl3)
d
¼159.2, 157.2, 150.7, 149.9, 145.2,
137.5, 134.8, 131.3, 130.9, 128.7, 127.7, 124.4, 122.9, 112.9, 112.1,
107.3, 42.9, 40.5, 21.9, 13.1; mass (ESþ) m/z 385.4 (Mþþ1); Anal.
Calcd for C25H28N4: C, 78.09; H, 7.34; N, 14.57. Found: C, 78.07; H,
7.35; N, 14.58.
References and notes
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4.7.32. N-[5-(4-Bromophenyl)-9-methylbenzo[h][1,6]naphthyridin-
2-yl]-N,N-diethylamine (8v). Yield¼0.29 g (90%), white solid, mp
151–152 ꢀC, Rf¼0.49 (2:8 EtOAc:Hexane), IR (KBr) nmax 3298, 2922,
1602, 1350 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d¼8.72 (1H, s, ArH),
8.00–7.93 (2H, m, ArH), 7.67–7.63 (2H, m, ArH), 7.58–7.54 (3H, m,
ArH), 6.76 (1H, d, J¼9.3 Hz, ArH), 3.76 (4H, q, J¼7.1 Hz, CH2), 2.62
(3H, s, CH3), 1.33 (6H, t, J¼7.1 Hz, CH3); 13C NMR (50 MHz, CDCl3)
d
¼157.8, 157.4, 149.9, 145.1, 138.8, 136.7, 135.8, 131.7, 131.6, 131.5,
128.9,124.7, 123.1,122.8,112.6,107.8, 43.1, 22.0, 13.1; mass (ESþ) m/z
420.3 (Mþþ1), MS (HR EI) m/z calcd for [Mþ] 420.10753 found
420.10416; Anal. Calcd for C23H22BrN3: C, 65.72; H, 5.28; N, 10.00.
Found: C, 65.70; H, 5.29; N, 10.02.
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Moyer, G.; Schleif, W. A.; Gabryelski, L. J.; Jin, L.; Chen, I.-W.; Ellis, J. D.; Wong, B. K.;
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4.7.33. N-[5-(4-Nitrophenyl)-9-methylbenzo[h][1,6]naphthyridin-2-
yl]-N,N-diethylamine (8w). Yield¼0.29 g (95%), yellow solid, mp
189–190 ꢀC, Rf¼0.45 (2:8 EtOAc:Hexane), IR (KBr) nmax 3284, 2969,
1601, 1507 cmꢂ1
;
1H NMR (300 MHz, CDCl3)
d
¼8.74 (1H, s, ArH),
8.48 (2H, d, J¼8.8 Hz, ArH), 7.99 (1H, d, J¼8.3 Hz, ArH), 7.88 (3H, m,

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