Synthesis of novel benzo[h][1,6]naphthyridine derivatives from 4-aminoquinoline and cyclic β-ketoester

Article abstract of DOI:10.1016/j.tet.2010.04.085

This paper describes the synthesis of 2,8-dichloroquinolin-4-amine 4 and 4,5,7-trichloro-3-(2-chlor-oethyl)-2-methylbenzo[h][1,6]naphthyridine 8 as novel class of building blocks. Also describes the regioselective S_NAr reactions of 2,4,8-trichl

Full text of DOI:10.1016/j.tet.2010.04.085

Tetrahedron 66 (2010) 5204e5211
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Tetrahedron
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Synthesis of novel benzo[h][1,6]naphthyridine derivatives from 4-aminoquinoline
and cyclic
b-ketoester
*
Raghunath B. Toche , Balasaheb P. Pagar, Ravindra R. Zoman, Goraksha B. Shinde, Madhukar N. Jachak
Organic Chemistry Research Center, Department of Chemistry, K.R.T. Arts, B.H. Commerce and A.M. Science College, Gangapur Road, Nashik 422002, Maharashtra, India
a r t i c l e i n f o
a b s t r a c t
Article history:
This paper describes the synthesis of 2,8-dichloroquinolin-4-amine 4 and 4,5,7-trichloro-3-(2-chlor-
oethyl)-2-methylbenzo[h][1,6]naphthyridine 8 as novel class of building blocks. Also describes the re-
gioselective SNAr reactions of 2,4,8-trichloroquinoline 2 on C2 and C4 positions with azide, similarly SNAr
reactions of benzo[h][1,6]naphthyridine 8 at C4, C5 positions, and SN2 reactions on C3-(2-chloroethyl) side
chain with nucleophiles such as primary aromatic amines, methoxide/ethoxide, and azide at different
temperatures.
Received 1 December 2009
Received in revised form 30 March 2010
Accepted 21 April 2010
Available online 24 April 2010
Keywords:
Ó 2010 Elsevier Ltd. All rights reserved.
a
-Acetyl g-butyrolactone
Benzo[h][1,6]naphthyridine
2,8-Dichloroquinolin-4-amine
Regioselective
1. Introduction
heteroaromatic nucleus were7,12 synthesized by substituting chlo-
ride in the benzo[h][1,6]naphthyridines with various N-alkyl-4-
Synthesis of azido derivatives of hetarenes1,2 raised question of
regioselectivity during reactions of azide anion with 2,4-dichlor-
oquinoline. 2,4-Dichloroquinolines are known to give nucleophilic
piperidinyl methanolates.13 The benzo[h][1,6]naphthyridines
showed broad spectrum of biological activities,14e18 including high
affinity on 5-HT4 receptors and high selectivity versus other
receptors.19,20
substitution reactions both at
a and g
-positions.3,4 Kinetic studies
of 2,4-dichloroquinoline indicate that the chloro atom at C4 posi-
tion is about two times more reactive toward nucleophiles3,5 and
predominantly an additioneelimination mechanism is observed.6
In order to transform the literature findings for the introduction
of azido groups, we have studied the reaction of 2,4,8-tri-
chloroquinoline 2 at different temperatures. After reduction of
4-azido-2,8-dichloroquinoline 3 with sodium dithionite gives re-
quired 2,8-dichloroquinolin-4-amine 4. Number of electrophiles
failed to react with weakly nucleophilic 4-amino group of the
The acid catalyzed ConradeLimpach reaction21 of 4-amino-
quinoline and acetoacetic ester has been reported and gave high
yields of 2-methylbenzo[h][1,6]naphthyridin-4-ol. Wamhoff and
co-workers22 reported few thermoselective reactions of
a-acetyl
g
-butyrolactone with 2-aminopyridines. Previously, we have car-
ried out regioselective reaction of
b
-ketoesters23e26 with 2-amino/
4-hydroxy quinolones/pyridines. We have designed a new route for
the synthesis of tri/tetracyclic quinoline derivatives from benzo[h]
[1,6]naphthyridine possessing requisite functionalities. Here, we
report regioselective SNAr reactions of 4,5,7-trichloro-3-(2-chlor-
oethyl)-2-methylbenzo[h][1,6]naphthyridine 8 with different nu-
cleophiles such as primary amines, methoxide/ethoxide, and azide
at different temperatures.
4-aminoquinolines.7 The
a-acetyl g-butyrolactone was relatively
strong electrophile for the synthesis of tricyclic and tetracyclic
heteroaromatic compounds. As noted previously8,9 several het-
erocycles with 2-chloroethyl side chain exhibited good in vitro
activity against several cell lines of clinically isolated human tumor.
For further information, the reported SAR studies10 of these type of
compounds and replacement by quinoline nucleus as carrier of
reported substituents were of particular interest because of these
structures in several cytotoxic agents.11 Several antimalarial can-
didates possess usable functional group at C4 position in tricyclic
2. Results and discussion
2,4,8-Trichloroquinoline 2 was synthesized by literature meth-
ods26e28 and reacted with sodium azide (added portion wise within
15 min) in DMF at 55 ꢀC furnished 4-azido-2,8-dichloroquinoline 3
in 85% yield. The same reaction with excess of sodium azide at 80 ꢀC
gave 5-azido-9-chlorotetrazolo[1,5-a]quinoline 5 in 65% yield. It
was observed that if sodium azide was directly poured into reaction
* Corresponding author. Fax: þ91 253 2577341/253 257741; e-mail address:
raghunath_toche@rediffmail.com (R.B. Toche).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.04.085

R.B. Toche et al. / Tetrahedron 66 (2010) 5204e5211
5205
NH2
N
N3
ii
iv
85%
N
81%
Cl
Cl
Cl
Cl
OH
Cl
N
4
3
i
N
H
O
Cl
NH2
N3
Cl
Cl
v
iii
1
2
85%
N
N
N
N
65%
N
N
Cl
Cl
N
N
6
5
Scheme 1. Reagents and conditions: (i) POCl3, reflux; (ii) NaN3, DMF, 55 ꢀC, 2 h; (iii) NaN3, DMF, 80 ꢀC, 3.5 h; (iv) Na2S2O4, methanol, reflux, 3.5 h; (v) Na2S2O4, methanol, reflux,
3.5 h.
mixture at 0 ꢀC or at higher temperature produced green colored
mixture of decomposition products. Generally, azido derivatives
were reduced by triphenylphosphine via Staudinger reaction leads
to iminophosphoranes, which on hydrolysis with 80% aqueous
acetic acid furnished aminoquinolones.29e31 We have successfully
reduced 4-azido 2,8-dichloroquinoline 3 and 5-azido-9-chlorote-
trazolo[1,5-a]quinoline 5 in one step using sodium dithionite32 in
methanol to afford amines 4 and 6 in 80e85% yields (Scheme 1).
Further, we have explored the chemistry of 2,8-dichlor-
at 1575 cmꢁ1 The lowering of lactone carbonyl was due to intra-
molecular H-bonding between CO and NH, which also supports the
Z-configuration of furanone intermediate 7. The 1H NMR spectrum
of 7 in CDCl3 showed the resonance at 2.32 ppm for methyl protons,
two triplets were observed at 3.00 and 4.43 ppm with J¼7.5 Hz
were assignable for CH2CH2O. The down field NH resonance
showed sharp singlet at
d 11.03 (D2O exchangeable), and the
remaining aromatic protons resonance at expected chemical shifts
and splitting pattern. The EIMS of 7 showed Mþ, Mþ2, and Mþ4 at
322, 324, and 326 m/z, respectively, indicating the presence of two
chlorines.
oquinolin-4-amine 4 by reacting with a-acetyl g-butyrolactone in
toluene and catalytic amount of PTSA at 120 ꢀC, furnished ther-
modynamically stable intermediate (Z)-2-aminoethylidene heter-
odihydrofuranone 7 in 77% yield. The weak acid PTSA selectively
protonates keto carbonyl in preference to lactone carbonyl and the
subsequent attack of amino moiety gave dihydrofuranone 7. Use of
other acids such as sulfuric, hydrochloric or acetic acid catalyst
furnished compound 7 in low yield.
Intermediate dihydrofuranone 7 was refluxed in POCl3 fur-
nished mixture of compounds 8 and 9 in 40% and 15% yields, re-
spectively, while direct one pot reaction of 2,8-dichloroquinolin-4-
amine 4 and a-acetyl g
-butyrolactone in POCl3 at 115 ꢀC furnished
compounds 8 and 9 in 20% and 10% yields. Mixture of compounds 8
and 9 was separated by column chromatography eluting with tol-
uene and structures were established by spectral and analytical
data. Both compounds 8 and 9 showed absence of carbonyl and NH
stretching frequency in IR. The 1H NMR spectra of compound 8 in
The structure of compound 7 was assigned using spectroscopic
and analytical methods. For instance IR of 7 showed lactone car-
bonyl (C]O) stretching at 1689 cmꢁ1, NH at 3122 cmꢁ1, and (C]C)
CH3
HN
O
i
O
N
Cl
Cl
(77%)
7
CH3
NH2
N
O
POCl3
+
Cl
O
O
CH3
CH3
Cl
CH3
Cl
N
N
N
4
ii
O
O
iii
Cl
+
Cl
N
NHAr
N
N
Cl
Cl
Cl
Cl
(15%)
9
(80-84%)
(40%)
10a-b
8
Ar ; 10a = CH2C6H5,
10b = o-ClC6H4
Scheme 2. Reagents and conditions: (i) PTSA, toluene, 120 ꢀC, 72 h; (ii) POCl3, 115 ꢀC, 5 h; (iii) ArNH2, 150 ꢀC, 15 min.

5206
R.B. Toche et al. / Tetrahedron 66 (2010) 5204e5211
CH3
CH3
CH3
Cl
Cl
N
N
N
N
Cl
v
Cl
vi
Ar
N
Cl
O
N
H
O
N
H
Cl
Cl
Cl
8
15
16
Ar = C6H5
(83 %)
(93 %)
iii
ii
iv
i
CH3
CH3
CH3
CH3
Cl
N3
Cl
N
N
N
N
N
N
Ar
NHAr
N3
OR
Cl
N
Cl
N
N
Cl
NHAr
Cl
Cl
Cl
Cl
14
(84 %)
12a-h
(80-85 %)
11a-e
(70-75 %)
13a-b
(70-75 %)
11; Ar= CH2C6H5, C6H5,
m-OMeC6H4,
12; Ar= CH2C6H5, C6H5,
13; R= CH3, CH2CH3
m-OMeC6H5,
m-ClC6H4,
m-MeC6H4
p-OMeC6H4, m-ClC6H4,
o-ClC6H4, p-MeC6H4,
p-BrC6H4
Scheme 3. Reagents and conditions: (i) ArNH2, 110 ꢀC, 15 min; (ii) ArNH2, 150 ꢀC, 30 min; (iii) CH3ONa/C2H5ONa, toluene, 120 ꢀC, 24 h; (iv) NaN3, DMF, 30 ꢀC, 10 h; (v) AcOH, reflux,
15 min; (vi) ArNH2, 160 ꢀC, 1 min.
CDCl3 showed resonance at 2.93 ppm singlet for methyl protons,
two triplets at 3.53 and 3.81 ppm, J¼7.2 Hz were assignable to
CH2CH2Cl. The 1H NMR spectra of 9 showed singlet at 2.59 ppm
assignable to methyl protons and slightly more deshielded triplets
observed at 3.24 and 4.84 ppm with J¼8.7 Hz were assignable to
four protons of pyrrole ring. The resonance of aromatic protons in
both compounds 8 and 9 was observed between 7.53 and 8.95 ppm.
The EIMS of 8 showed Mþ, Mþ2, Mþ4, Mþ6, and Mþ8 at 360, 362,
364, 366, and 368 m/z, respectively, due to the presence of four
chlorines and compound 9 showed Mþ, Mþ2 and Mþ4 at 304, 306,
and 308 m/z due to presence of two chlorines. Further elemental
analysis was in agreement with the molecular formula of 4,5,7-
dichloro-3-(2-chloroethyl)-2-methylbenzo[h][1,6]naphthyridine 8
Compound 8 on reaction with sodium methoxide/ethoxide at
120 ꢀC in toluene afforded C4-OR substitution products 13a,b in
70e75% yields. Where as reaction of compound 8 with sodium
azide in DMF at 30 ꢀC gave C4 and C3-(2-chloroethyl) substitution
product 4-azido-3-(2-azidoethyl)-5,7-dichloro-2-methylbenzo[h]
[1,6]naphthyridine 14 in 84% yield. Compounds 13a,b and 14 were
characterized by IR, 1H NMR, elemental analysis, and mass spec-
troscopic methods (Scheme 3).
The iminechloride (eN]CeCl) moiety in compound 8 was
converted to secondary amide by refluxing in glacial acetic acid
furnished
4,7-dichloro-3-(2-chloroethyl)-2-methylbenzo[h][1,6]
naphthyridin-5(6H)-one 15 in 93% yield. The SNAr reaction of
compound 15 with primary aromatic amine at 160 ꢀC furnished
9-chloro-2,3-dihydro-4-methylbenzo-[h][1,6]naphthyridin-1-phe-
nyl-1H-pyrrolo[3,2-c]-11(10H)-one 16 with 83% yield. The forma-
tion of compounds 10a,b,12a,b, and 16 occurred at relatively higher
temperature, while compounds 11aee, 13a,b, and 14 formed at
relatively lower temperature. All these observations proved that C4
position in compound 8 is more reactive than C5 position toward
nucleophilic substitution reactions.
and
9,11-dichloro-4-methyl-2,3-dihydrofuro[3,2-c]benzo[h][1,6]
naphthyridine 9 (Scheme 2).
The
9,11-dichloro-4-methyl-2,3-dihydrofuro[3,2-c]benzo[h]
[1,6]naphthyridine 9 on reaction with primary aromatic amines at
150 ꢀC gave C11 substitution products 10a,b in 80e84% yields. Both
10a,b were characterized by spectral and analytical data (Scheme 2).
The SNAr and SN2 reactions with different nucleophiles at var-
ied temperatures were used to study the relative reactivities at C4,
C5, C7, and C3-(2-chloroethyl) side chain in compound 8. Com-
pound 8 with excess primary aromatic amines at 110 ꢀC gave C4
substitution product 4-chloro-3-(2-chloroethyl)-2-methyl-N-
phenylbenzo[h][1,6]naphthyridin-4-amines 11aee, in 70e75%
yields. While at 150 ꢀC SNAr reaction occurs at both C4 and C5
position along with cyclization at C3-(2-chloroethyl) side chain
furnished 2,3-dihydro-4-methyl-N,1-diphenyl-1H-pyrrolo[3,2-c]
benzo[h][1,6]naphthyridin-11-amines 12aeh in 80e85% yields.
Compounds 11aee and 12aeh were characterized by spectro-
scopic methods (given in Experimental section).
3. Conclusion
In summary, we have disclosed the convenient synthesis of
4-aminoquinoline as useful tools in development of 4,5,7-trichloro-
3-(2-chloroethyl)-2-methylbenzo[h][1,6]naphthyridine 8 by using
a-acetyl g-butyrolactone. Our main interest was concerned with
regioselective synthesis of substituted benzo[h][1,6]naphthyridine
with nucleophiles at different temperature and also the synthesis of
tetracyclic furano[3,2-c] and pyrrolo[3,2-c]benzo[h][1,6]naphthyr-
idine derivatives.

R.B. Toche et al. / Tetrahedron 66 (2010) 5204e5211
5207
4. Experimental
4.1. General
4.2.3. 5-Azido-9-chlorotetrazolo[1,5-a]quinoline (5). A solution of
2,4,8-trichloroquinoline 2 (1.16 g, 0.005 mol) and sodium azide
(0.650 g, 0.01 mol) in DMF (10 mL) was stirred at 80 ꢀC for 10 h. The
progress of the reaction was monitored by TLC till tri-
chloroquinoline was consumed. After completion, the reaction
mixture was stirred into cold water (2 L). The formed crude
product was filtered off, dried, and further purified by column
chromatography using silica gel eluting with toluene gave title
compound 5 (0.796 g, 65%) as yellow colored needles; Rf (10%
Common reagents grade chemicals are either commercially
available and were used without further purification or prepared by
standard literature procedures. The melting points were measured
on Barnstead Electro Thermal melting point apparatus Mod. No.
IA-9200 in open capillary tubes and are uncorrected. Elemental
analyses were determined using Thermo Quest Model No. flash EA
1112-Elemental Analyzer. The IR spectra of compounds were
recorded on Shimadzu IR-408 instrument in potassium bromide
pellets. All mass spectra were recorded on Mat 112 Varian Mat
Bremen mass spectrometer. Routine 1H NMR (300 MHz) and 13C
NMR (75 MHz) spectra were recorded on VARIAN XL-300 in-
strument at 25 ꢀC. The measurements were done using protiated
solventsdCDCl3 and DMSO-d6, with TMS as an internal standard
reference. Coupling constants (J) are quoted to the nearest 0.1 Hz
toluene/ethyl acetate) 0.64, mp 159 ꢀC; IR (KBr):
n 3042, 2922,
2146 (N3), 1616, 1553, 1401, 1250, 854 cmꢁ1 1H NMR (CDCl3):
;
d
6.90 (s, 1H, C4H), 7.43 (t, J¼7.2 Hz, 1H, C7H), 7.77 (d, J¼7.2 Hz,
1H, C8H), 8.54 (d, J¼7.2 Hz, 1H, C6H); MS: m/z (%): 247 (Mþ2, 10),
245 (M, 100), 203 (50), 161 (30). Anal. Calcd for C9H4ClN7
(245.63): C, 44.01; H, 1.64; N, 39.92. Found: C, 44.10; H, 1.50; N,
39.92.
4.2.4. 9-Chlorotetrazolo[1,5-a]quinolin-5-amine (6). A mixture of
5-azido-9-chlorotetrazolo[1,5-a]quinoline 5 (0.956 g, 0.004 mol)
and sodium dithionite (0.86 g, 0.005 mol) in methanol (10 mL) was
heated to reflux for 3.5 h (TLC checked, toluene). The solvent
was evaporated in vacuo and residue poured into ice water
(200 mL). The formed crude product was filtered off, washed
with water, and purified by dissolving it in 1:1 HCl (100 mL) at
50 ꢀC, stirred by adding activated charcoal (0.50 g). After filtering
out charcoal, the resulting solution was neutralized with 2 N
NaOH. The precipitate solid was filtered off, washed with water,
and chemical shift (d-scale) are quoted in parts per million (ppm)
and following abbreviations are used: s¼singlet, d¼doublet,
t¼triplet, q¼quartet, m¼multiplet, br¼broad. Column chromatog-
raphy was performed using silica gel with particle size (60e120
mesh, Merck). All reactions were monitored by TLC carried out
0.2 mm silica gel 60 F254 (Merck) plates using 254 and 366 nm UV
light for detection.
4.2. Synthetic procedures
and recrystallized from ethanol to give title compound
(0.740 g, 85%) as colorless prisms; Rf (20% toluene/ethyl acetate)
0.48, mp 230 ꢀC; IR (KBr):
3390, 3348 (NH2), 3234, 2923, 1642,
1431, 976 cmꢁ1 1H NMR (DMSO-d6):
6.30 (br s, 2H, NH2, D2O
exchangeable), 7.20 (t, J¼8.3 Hz, 1H, C7H), 7.51 (d, J¼8.3 Hz, 1H,
C8H), 7.90 (s, 1H, C4H), 8.81 (d, J¼8.3 Hz, 1H, C6H); MS: m/z (%):
221 (Mþ2, 20), 219 (M, 100), 177 (40), 161 (30), 77 (10). Anal.
Calcd for C9H6ClN5 (219.63): C, 49.22; H, 2.75; N, 31.89. Found:
C, 49.14; H, 2.79; N, 13.92.
6
4.2.1. 4-Azido-2,8-dichloroquinoline (3). To a vigorously stirred so-
lution of 2,4,8-trichloroquinoline 2 (11.55 g, 0.05 mol) in DMF
(100 mL) at 55 ꢀC, sodium azide (3.90 g, 0.06 mol) was added
slowly within 15 min. The resulting red colored solution was kept
stirring for 2 h. The progress of the reaction was monitored by TLC
till the trichloroquinoline was consumed. After completion, the
reaction mixture was poured in cold water (2 L). The obtained solid
was filtered, washed with water, dried, and recrystallized from
ethanol to give title compound 3 (10.11 g, 85%) as a colorless nee-
n
;
d
4.2.5. (Z)-3-(1-(2,8-Dichloroquinolin-4-ylamino)ethylidene)-dihy-
drofuran-2(3H)-one (7). The solution of 2,8-dichloroquinolin-
4-amine 4 (10.65 g, 0.05 mol), a-acetyl-g-butyrolactone (8.96 mL,
dles; Rf (toluene) 0.62, mp 105 ꢀC; IR (KBr):
n
3051, 2922, 2219, 2133
6.50
(N3), 1516, 1500, 1307, 1105, 906, 767 cmꢁ1; 1H NMR (CDCl3):
d
(s, 1H, C3H), 7.10 (t, J¼7.4 Hz, 1H, C6H), 7.73 (d, J¼7.4 Hz, 1H, C7H),
8.30 (d, J¼7.4 Hz, 1H, C5H); MS: m/z (%): 243 (Mþ4, 10), 241 (Mþ2,
50), 239 (M, 100), 197 (70), 77 (20). Anal. Calcd for C9H4Cl2N4
(239.06): C, 45.22; H, 1.69; N, 23.44. Found: C, 45.18; H, 1.73; N,
23.31.
0.07 mol), and catalytic amount of PTSA in toluene (500 mL) was
heated to reflux for 72 h. Azeotropic water separation was done
by using Dean Stark apparatus to monitor the reaction by col-
lecting equivalent amount of water. The solvent was evaporated
in vacuo and the red colored oily residue obtained was poured
into ethanol (200 mL). The solid separated was collected by
suction filtration, dried, and recrystallized from ethanol/DMF
(9:1) to furnish title compound 7 (12.43 g, 77%) as pale yellow
colored prisms; Rf (10% toluene/ethyl acetate) 0.41, mp 208 ꢀC; IR
4.2.2. 2,8-Dichloroquinolin-4-amine (4). A mixture of 4-azido-2,8-
dichloroquinoline 3 (11.95 g, 0.05 mol) and sodium dithionite
(10.44 g, 0.06 mol) in methanol (150 mL) was heated to reflux
for 3.5 h (TLC checked, toluene). The solvent was evaporated in
vacuo and residue was stirred into ice water (1 L). The
obtained solid was filtered, washed with water (10 mL). The
product was further purified by dissolving in 1:1 hydrochloric
acid (500 mL) at 50 ꢀC, stirred by adding activated charcoal
(5 g). After filtering out charcoal, the resulting solution was
neutralized with 2 N NaOH. The precipitated solid was filtered,
washed with water, and recrystallized from ethanol to give
title compound 4 (7.90 g, 85%) as colorless prisms; Rf (10%
(KBr):
n
3122 (NH), 1689 (C]Olactone), 1662, 1575, 1477, 1334,
1240, 1134, 968, 773 cmꢁ1
;
1H NMR (CDCl3):
d
2.32 (s, 3H, CH3),
3.00 (t, J¼7.5 Hz, 2H, CH2CH2O), 4.43 (t, J¼7.5 Hz, 2H, CH2CH2O),
6.98 (s, 1H, C3H), 7.43 (t, J¼7.2 Hz, 1H, C6H), 7.78 (d, J¼7.2 Hz, 1H,
C7H), 7.96 (d, J¼7.2 Hz, 1H, C5H), 11.03 (s, 1H, NH, D2O ex-
changeable); 13C NMR (CDCl3):
d 14.11, 60.82, 61.34, 105.32, 119.17,
119.38, 130.80, 132.03, 133.22, 143.76, 148.67, 151.33, 164.48,
168.57; MS: m/z (%): 326 (Mþ4, 10), 324 (Mþ2, 20), 322 (M, 70),
274 (40), 198 (50), 147 (40), 129 (20), 44 (40). Anal. Calcd for
C15H12Cl2N2O2 (323.17): C, 55.75; H, 3.74; N, 8.67. Found: C,
55.65; H, 3.81; N, 8.57.
toluene/ethyl acetate) 0.31, mp 235 ꢀC; IR (KBr):
(NH2), 3197, 1645, 1575, 1355, 1116, 759 cmꢁ1 1H NMR (DMSO-
d6): 4.90 (br s, 2H, NH2, D2O exchangeable), 6.59 (s, 1H, C3H),
n 3462, 3319
;
d
7.56 (t, J¼7.5 Hz, 1H, C6H), 7.59 (d, J¼7.5 Hz, 1H, C7H), 8.93 (d,
J¼7.5 Hz, 1H, C5H); MS: m/z (%): 216 (Mþ4, 40), 214 (Mþ2, 50),
212 (M, 90), 173 (20), 141 (20), 127 (30), 77 (10), 44 (31). Anal.
Calcd for C9H6Cl2N2 (213.06): C, 50.73; H, 2.84; N, 13.15.
Found: C, 50.65; H, 2.79; N, 13.21.
4.2.6. 4,5,7-Trichloro-3-(2-chloroethyl)-2-methylbenzo[h][1,6]naph-
thyridine (8) and 9,11-dichloro-4-methyl-2,3-dihydrofuro[3,2-c]
benzo[h][1,6]naphthyridine (9). Method A. The solution of (Z)-3-(1-
(2,8-dichloroquinolin-4-ylamino)ethylidine)-dihydrofuran-2(3H)-
one 7 (9.69 g, 0.03 mol) in phosphorous oxychloride (80 mL) was

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R.B. Toche et al. / Tetrahedron 66 (2010) 5204e5211
heated to reflux for 4 h. After completion of reaction, excess POCl3
was evaporated in vacuo. The red colored residue obtained was
poured into ice water (1 L) and solution was neutralized with solid
sodium carbonate (10 g). The separated solid product was collected
by suction filtration. The TLC analysis in toluene showed two
products. The mixture of crude product was separated by column
chromatography on silica gel eluting with toluene, yields title
compounds 8 (4.32 g, 40%) and 9 (1.36 g, 15%).
4.2.7.2. 9-Chloro-2,3-dihydro-4-methyl-N-(2-chloropenyl)furo
[3,2-c]-benzo[h][1,6]naphthyridin-11-amine (10b). Recrystallized
from ethanol to afford colorless prisms; yield (0.332 g, 84%); Rf (20%
toluene/ethyl acetate) 0.37, mp 237 ꢀC; IR (KBr):
3415, 3060, 1627,
1597, 1534, 1033, 742 cmꢁ1 1H NMR (CDCl3):
2.39 (s, 3H, CH3),
2.94 (t, J¼7.2 Hz, 2H, CH2CH2O), 3.41 (t, J¼7.2 Hz, 2H, CH2CH2O),
6.57 (t, J¼6.7 Hz, 1H, ArH), 6.72 (d, J¼6.7 Hz, 1H, ArH), 7.12 (m, 2H,
ArH), 7.41 (t, J¼7.2 Hz, 1H, C7H), 7.65 (d, J¼7.2 Hz, 1H, C8H), 8.3 (s,
1H, NH, D2O exchangeable), 8.87 (d, J¼7.2 Hz,1H, C6H); MS: m/z (%):
400 (Mþ4, 10), 398 (Mþ2, 50), 396 (M, 100), 276 (20), 176 (20), 130
(20), 99 (15). Anal. Calcd for C21H15Cl2N3O (396.27): C, 63.65; H,
3.82; N, 10.60. Found: C, 63.70; H, 3.76; N, 10.65.
n
;
d
Method B. The mixture of 2,8-dichloroquinolin-4-amine
4
(6.39 g, 0.03 mol) and -acetyl -butyrolactone (5.12 mL, 0.04 mol)
a
g
in POCl3 (80 mL) was heated to reflux for 3 h. After completion of
reaction, the workup was carried out as described in method A. The
TLC analysis in toluene showed two products. The mixtures of
crude product were separated by column chromatography on silica
gel eluting with toluene. The solvent was evaporated in vacuo to
give title compounds 8 (2.16 g, 20%) and 9 (0.90 g, 10%).
4.2.8. 5,7-Dichloro-3-(2-chloroethyl)-2-methyl-N-phenylbenzo[h]
[1,6]naphthyridin-4-amines (11aee). A mixture of 4,5,7-trichloro-
3-(2-chloroethyl)-2-methylbenzo[h][1,6]naphthyridine 8 (0.360 g,
0.001 mol) and primary aromatic amine (0.01 mL) was heated at
110 ꢀC for about 15e25 min. After cooling down to room temper-
ature, methanol (100 mL) was added, the crude product separated
was collected by suction filtration, dried, and recrystallized from
the suitable solvent to furnish compounds 11aee in good yields.
4.2.6.1. 4,5,7-Trichloro-3-(2-chloroethyl)-2-methylbenzo[h][1,6]
naphthyridine (8). Recrystallized from ethanol to afford yellow
prisms; Rf (toluene) 0.64, mp 151 ꢀC; IR (KBr):
n
2958, 2922, 2854,
1568, 1545, 1433, 1329, 1122, 941, 844, 785 cmꢁ1; 1H NMR (CDCl3):
2.93 (s, 3H, CH3), 3.53 (t, J¼7.2 Hz, 2H, CH2CH2Cl), 3.81 (t, J¼7.2 Hz,
d
2H, CH2CH2Cl), 7.56 (t, J¼7.5 Hz, 1H, C9H), 7.83 (d, J¼7.5 Hz, 1H,
4.2.8.1. N-Benzyl-5,7-dichloro-3-(2-chloroethyl)-2-methylbenzo
[h][1,6]naphthyridin-4-amine (11a). Recrystallized from ethanol/
DMF (8:2) to afford colorless prisms; yield (0.301 g, 70%); Rf (tolu-
C8H), 8.93 (d, J¼7.5 Hz, 1H, C10H); 13C NMR (CDCl3):
d 25.13, 33.85,
41.08, 123.38, 126.01, 127.65, 127.81, 131.41, 132.32, 132.54, 140.69,
142.21, 147.42, 149.80, 163.11; MS: m/z (%): 368 (Mþ8, 10), 366
(Mþ6, 20), 364 (Mþ4, 50), 362 (Mþ2, 90), 360 (M, 90), 323 (08), 311
(100), 287 (07), 274 (20), 239 (10), 198 (20), 116 (12), 99 (10), 49
(15). Anal. Calcd for C15H10Cl4N2 (360.07): C, 50.04; H, 2.80; N, 7.78.
Found: C, 49.93; H, 2.85; N, 7.69.
ene) 0.62, mp 190 ꢀC; IR (KBr):
n
3481 (NH), 3077, 2922, 1563, 1525,
1306, 1187, 1028, 827, 736, 697, 648 cmꢁ1
;
1H NMR (CDCl3):
d
2.86
(s, 3H, CH3), 3.45 (t, J¼7.1 Hz, 2H, CH2CH2Cl), 3.74 (t, J¼7.1 Hz, 2H,
CH2CH2Cl), 5.00 (d, J¼4.5 Hz, 2H, CH2NH), 7.28e7.38 (m, 5H, ArH),
7.53 (t, J¼7.2 Hz, 1H, C9H), 7.68 (d, J¼7.2 Hz, 1H, C8H), 8.72 (t,
J¼4.5 Hz, 1H, CH2NH, D2O exchangeable), 8.74 (d, J¼7.2 Hz, 1H,
4.2.6.2. 9,11-Dichloro-4-methyl-2,3-dihydrofuro[3,2-c]benzo[h]
C10H); 13C NMR (CDCl3):
d 24.63, 33.54, 40.99, 46.39, 110.57, 122.16,
[1,6]naphthyridine (9). Recrystallized from ethanol to afford yellow
122.34, 123.20, 127.32, 128.34, 128.58, 129.50, 129.71, 130.83, 139.07,
140.11, 142.37, 150.33, 151.36, 160.94; MS: m/z (%): 436 (Mþ6, 20),
434 (Mþ4, 25), 432 (Mþ2, 50), 430 (M, 90), 405 (50), 390 (60), 377
(15), 345 (20), 307 (20), 141 (30), 127 (30), 77 (20), 44 (50). Anal.
Calcd for C22H18Cl3N3 (430.76): C, 61.34; H, 4.21; N, 9.75. Found: C,
61.27; H, 4.49; N, 9.68.
prisms; Rf (toluene) 0.14, mp 231 ꢀC; IR (KBr):
n
2972, 2918, 1604,
1573, 1428, 1314, 1187, 945, 777 cmꢁ1
;
1H NMR (CDCl3):
d
2.59 (s,
3H, CH3), 3.24 (t, J¼8.7 Hz, 2H, CH2CH2O), 4.84 (t, J¼8.7 Hz, 2H,
CH2CH2O), 7.54 (t, J¼7.5 Hz, 1H, C7H), 7.82 (d, J¼7.5 Hz, 1H, C8H),
8.95 (d, J¼7.5 Hz, 1H, C6H); 13C NMR (CDCl3):
d 26.10, 32.96, 33.56,
124.40, 124.75, 127.31, 130.69, 131.25, 132.60, 139.50, 141.10, 146.23,
149.21, 150.33, 161.37; MS: m/z (%): 308 (Mþ4, 40), 306 (Mþ2, 70),
304 (M, 100), 269 (20), 263 (20), 227 (10), 164 (10). Anal. Calcd for
C15H10Cl2N2O (305.16): C, 59.04; H, 3.30; N, 9.18. Found: C, 59.01; H,
3.23; N, 9.15.
4.2.8.2. 5,7-Dichloro-3-(2-chloroethyl)-2-methyl-N-phenylbenzo
[h][1,6]naphthyridin-4-amine 11b. Recrystallized from ethanol/
DMF (8:2) to afford pale yellow prisms; yield (0.304 g, 73%); Rf
(toluene) 0.64, mp 186 ꢀC; IR (KBr):
n
3430 (NH), 2835, 1572, 1534,
1456, 1205, 1157, 1051, 769, 787 cmꢁ1
;
1H NMR (CDCl3):
d
2.91 (s,
4.2.7. 9-Chloro-2,3-dihydro-4-methyl-N-substitutedfuro[3,2-
c]-benzo[h][1,6]-naphthyridine-11-amines (10a,b). A mixture of
9,11-dichloro-4-methyl-2,3-dihydrofuro[3,2-c]benzo[h][1,6]naph-
thyridine 9 (0.304 g, 0.001 mol) and primary aromatic amine
(0.01 mol) was heated at 110 ꢀC for 15 min. After cooled down to
room temperature, methanol (10 mL) was added. The crude
product separated was collected by suction filtration give title
compounds 10a,b.
3H, CH3), 3.46 (t, J¼7.1 Hz, 2H, CH2CH2Cl), 3.74 (t, J¼7.1 Hz, 2H,
CH2CH2Cl), 7.26e7.33 (m, 5H, ArH), 7.55 (t, J¼7.2 Hz, 1H, C9H), 7.75
(d, J¼7.2 Hz,1H, C8H), 8.79 (d, J¼7.2 Hz,1H, C10H), 9.0 (s, 1H, CH2NH,
D2O exchangeable); 13C NMR (CDCl3):
d 24.66, 33.71, 40.94, 110.48,
120.07, 122.86, 123.06, 123.17, 123.26, 128.84, 130.05, 130.16, 130.84,
139.30, 139.51, 141.70, 148.08, 150.23, 161.37; MS: m/z (%): 422
(Mþ6, 10), 420 (Mþ4, 20), 418 (Mþ2, 70), 416 (M, 100), 415 (100),
410 (80), 347 (20), 317 (20), 173 (20), 141 (40), 127 (30), 77 (20).
Anal. Calcd for C21H16Cl3N3 (416.73): C, 60.52; H, 3.87; N, 10.08.
Found: C, 60.67; H, 3.79; N, 10.11.
4.2.7.1. 9-Chloro-2,3-dihydro-4-methyl-N-benzylfuro[3,2-c]-
benzo[h][1,6]naphthyridine-11-amine (10a). Recrystallized from
ethanol to afford colorless prisms; yield (0.295 g, 80%); Rf (20%
4.2.8.3. 5,7-Dichloro-3-(2-chloroethyl)-N-(3-methoxyphenyl)-2-
toluene/ethyl acetate) 0.53, mp 227 ꢀC; IR (KBr):
n
3417 (NH), 2922,
methylbenzo[h][1,6]naphthyridine-4-amine
from ethanol/DMF (8:2) to afford yellow prisms; yield (0.308 g,
69%); Rf (toluene) 0.48, mp 176 ꢀC; IR (KBr):
3425 (NH), 2833,
1575, 1536, 1457, 1313, 1159, 1051, 767, 787 cmꢁ1; 1H NMR (CDCl3):
(11c). Recrystallized
1616, 1591, 1594, 1199, 950 cmꢁ1
;
1H NMR (CDCl3):
d
2.59 (s, 3H,
CH3), 3.24 (t, J¼8.7 Hz, 2H, CH2CH2O), 4.84 (t, J¼8.7 Hz, 2H,
CH2CH2O), 4.97 (d, J¼5.1 Hz, 2H, CH2NH), 7.09 (t, J¼7 Hz, 2H, ArH),
7.12 (d, J¼7 Hz, 2H, ArH), 7.32 (t, J¼7 Hz, 1H, ArH), 7.58 (t, J¼7.5 Hz,
1H, C7H), 7.68 (d, J¼7.5 Hz, 1H, C8H), 8.10 (d, J¼5.1 Hz, 1H, CH2NH,
D2O exchangeable), 8.72 (d, J¼7.5 Hz, 1H, C6H); MS: m/z (%): 377
(Mþ2, 30), 375 (M, 100), 227 (20), 177 (30), 113 (30), 99 (10). Anal.
Calcd for C22H18ClN3O (375.85): C, 70.30; H, 4.83; N, 11.18. Found: C,
70.35; H, 4.76; N, 11.12.
n
d
2.92 (s, 3H, CH3), 3.49 (t, J¼7.1 Hz, 2H, CH2CH2Cl), 3.76 (t, J¼7.1 Hz,
2H, CH2CH2Cl), 3.92 (s, 3H, OCH3), 6.73 (d, J¼7.5 Hz, 1H, ArH), 7.29
(s, 1H, ArH), 7.30e7.35 (m, 2H, ArH), 7.36 (t, J¼7.5 Hz, 1H, C9H), 7.75
(d, J¼7.5 Hz, 1H, C8H), 8.1 (s, 1H, NH, D2O exchangeable), 8.81 (d,
J¼7.5 Hz, 1H, C10H); MS: m/z (%): 452 (Mþ6,10), 450 (Mþ4, 20), 448
(Mþ2, 70), 446 (M, 100), 410 (90), 395 (10), 347 (20), 317 (20), 223

R.B. Toche et al. / Tetrahedron 66 (2010) 5204e5211
5209
(15), 173 (20), 141 (40), 127 (30), 77 (20). Anal. Calcd for
C22H18Cl3N3O (446.76): C, 59.15; H, 4.06; N, 9.41. Found: C, 59.23; H,
4.09; N, 9.37.
AreH), 7.34 (t, J¼7.5 Hz, 1H, C7H), 7.73 (d, J¼7.5 Hz, 1H, C8H), 8.40 (s,
1H, NH, D2O exchangeable), 8.84 (d, J¼7.5 Hz, 1H, C6H); 13C NMR
(CDCl3):
d 22.89, 26.72, 59.05, 104.59, 118.97, 119.47, 122.17, 122.75,
123.06,123.78,124.57,127.94,128.42,129.64,130.03, 130.25,139.65,
142.44, 148.11, 148.76, 150.46, 150.76, 157.80; MS: m/z (%): 438
(Mþ2, 30), 436 (M, 100), 354 (20), 254 (20), 232 (30), 216 (10), 106
(15), 91 (40). Anal. Calcd for C27H21ClN4 (436.94): C, 74.22; H, 4.84;
N, 12.82. Found: C, 74.33; H, 4.49; N, 11.91.
4.2.8.4. 5,7-Dichloro-3-(2-chloroethyl)-N-(3-chlorophenyl)-2-
methylbenzo[h][1,6]naphthyridin-4-amine
from ethanol/DMF (8:2) to afford yellow prisms; yield (0.347 g,
77%); Rf (toluene) 0.64, mp 163 ꢀC; IR (KBr):
3436 (NH), 2966,
1600, 1568, 1538, 1425, 1335, 1166, 886, 767 cmꢁ1; 1H NMR (CDCl3):
2.93 (s, 3H, CH3), 3.46 (t, J¼7.5 Hz, 2H, CH2CH2Cl), 3.75 (t, J¼7.5 Hz,
(11d). Recrystallized
n
d
4.2.9.3. 9-Chloro-N,1-(di-3-methoxyphenyl)-2,3-dihydro-4-
2H, CH2CH2Cl), 7.12 (d, J¼7.5 Hz, 1H, ArH), 7.23 (s, 1H, ArH),
7.25e7.34 (m, 2H, ArH), 7.39 (t, J¼7.8 Hz, 1H, C9H), 7.76 (d, J¼7.8 Hz,
1H, C8H), 8.1 (s, 1H, NH, D2O exchangeable), 8.81 (d, J¼7.8 Hz, 1H,
C10H); MS: m/z (%): 459 (Mþ8, 15), 457 (Mþ6, 20), 455 (Mþ4, 40),
453 (Mþ2, 70), 451 (M, 100), 449 (42), 430 (20), 378 (10), 317 (23),
245 (20), 170 (45), 123 (25), 77 (20). Anal. Calcd for C21H15Cl4N3
(451.18): C, 55.90; H, 3.35; N, 9.31. Found: C, 55.33; H, 3.31; N, 9.23.
methyl-1H-pyrrolo[3,2-c]benzo
[h][1,6]naphthyridin-11-amine
(12c). Recrystallized from ethanol/DMF (5:5) to afford yellow
prisms; yield (0.402 g, 81%); Rf (10% toluene/ethyl acetate) 0.33, mp
185 ꢀC; IR (KBr):
n
3353 (NH), 2933, 2870, 1554, 1542, 1433, 1254,
1110, 1067, 1020, 768, 749, 663 cmꢁ1; 1H NMR (CDCl3):
d
2.67 (s, 3H,
CH3), 3.26 (t, J¼7.5 Hz, 2H, CH2CH2N), 3.61 (t, J¼7.5 Hz, 2H,
CH2CH2N), 3.85 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 6.45e6.6 (m, 6H,
ArH), 7.00e7.20 (m, 2H, ArH), 7.29 (t, J¼7.2 Hz, 1H, C7H), 7.6 (d,
J¼7.2 Hz, 1H, C8H), 7.8 (s, 1H, NH, D2O exchangeable), 8.98 (d,
J¼7.2 Hz, 1H, C6H); MS: m/z (%): 498 (Mþ2, 70), 496 (M, 100), 481
(40), 374 (70), 331 (20), 248 (30), 92 (40). Anal. Calcd for
C29H25ClN4O2 (496.99): C, 70.08; H, 5.07; N, 11.27. Found: C, 69.96;
H, 4.99; N, 11.21.
4.2.8.5. 4,7-Dichloro-3-(2-chloroethyl)-2-methyl-N-m-tolylbenzo
[h][1,6]naphthyridin-5-amine (11e). Recrystallized from ethanol/
DMF (8:2) to afford yellow prisms; yield (0.301 g, 70%); Rf (toluene)
0.48, mp 164 ꢀC; IR (KBr):
n
3431 (NH), 2960, 1611, 1561, 1537, 1435,
1345, 1163, 883, 767 cmꢁ1
;
1H NMR (CDCl3):
d
2.45 (s, 3H, ArCH3),
2.89 (s, 3H, CH3), 3.51 (t, J¼7.5 Hz, 2H, CH2CH2Cl), 3.79 (t, J¼7.5 Hz,
2H, CH2CH2Cl), 6.74 (d, J¼7.8 Hz, 1H, ArH), 6.93 (s, 1H, ArH),
7.15e7.27 (m, 2H, ArH), 7.30 (t, J¼7.5 Hz, 1H, C9H), 7.74 (d, J¼7.5 Hz,
1H, C8H), 8.81 (s, 1H, NH, D2O exchangeable), 8.78 (d, J¼7.5 Hz, 1H,
C10H); MS: m/z (%): 436 (Mþ6, 19), 434 (Mþ4, 20), 432 (Mþ2, 50),
430 (M, 70), 402 (20), 365 (10), 317 (23), 245 (20),170 (47),123 (25),
77 (22). Anal. Calcd for C22H18Cl3N3 (430.76): C, 61.34; H, 4.21; N,
9.75. Found: C, 61.24; H, 4.49; N, 9.68.
4.2.9.4. 9-Chloro-N,1-(di-4-methoxyphenyl)-2,3-dihydro-4-
methyl-1H-pyrrolo[3,2-c]benzo[h][1,6]naphthyridin-11-amine
(12d). Recrystallized from ethanol/DMF (5:5) to afford yellow
prisms, yield (0.362 g, 73%); Rf (10% toluene/ethyl acetate) 0.29, mp
205 ꢀC; IR (KBr):
n
3360 (NH), 2919, 1580, 1525, 1323, 1045,
2.62 (s, 3H, CH3), 3.09 (t, J¼7.2 Hz, 2H,
746 cmꢁ1; 1H NMR (CDCl3):
d
CH2CH2N), 3.45 (t, J¼7.2 Hz, 2H, CH2CH2N), 3.67 (s, 3H, OCH3), 3.81
(s, 3H, OCH3), 6.67e7.00 (m, 8H, ArH), 7.63 (t, J¼7.8 Hz, 1H, C7H),
7.82 (d, J¼7.8 Hz, 1H, C8H), 8.61 (s, 1H, NH, D2O exchangeable), 8.89
(d, J¼7.8 Hz, 1H, C6H); MS: m/z (%): 498 (Mþ2, 80), 496 (M, 90), 481
(40), 409 (30), 318 (20), 248 (30), 77 (50). Anal. Calcd for
C29H25ClN4O2 (496.99): C, 70.08; H, 5.07; N, 11.27. Found. C, 69.76;
H, 4.91; N, 11.31.
4.2.9. 9-Chloro-N,1-dibenzyl-2,3-dihydro-4-methyl-1H-pyrrolo[3,2-
c]benzo[h][1,6]naphthyridin-11-amine (12aeh). A mixture of 4,5,7-
trichloro-3-(2-chloroethyl)-2-methylbenzo[h][1,6]naphthyridine 8
(0.360 g, 0.001 mol) and primary aromatic amine (0.01 mol) was
heated at 150 ꢀC for about 30 min. After cooling down to room
temperature, methanol (100 mL) was added, the crude product
obtained was collected by suction filtration, washed with metha-
nol, dried, and recrystallized from suitable solvent to furnish
compounds 12aeh in good yields.
4.2.9.5. 9-Chloro-N,1-(di-3-chlorophenyl)-2,3-dihydro-4-methyl-
1H-pyrrolo[3,2-c]benzo[h][1,6]naphthyridin-11-amine
Recrystallized from DMF to afford yellow prisms, yield (0.421 g,
85%); Rf (10% toluene/ethyl acetate) 0.44, mp 288 ꢀC; IR (KBr):
3365 (NH), 2823, 1565, 1532, 1470, 1332, 1168, 1054, 925 cmꢁ1 1H
NMR (DMSO-d6):
2.71 (s, 3H, CH3), 3.01 (t, J¼8.1 Hz, 2H,
(12e).
n
4.2.9.1. 9-Chloro-N,1-dibenzyl-2,3-dihydro-4-methyl-1H-pyrrolo
;
[3,2-c]benzo[h][1,6]naphthyridin-11-amine
from ethanol/DMF (5:5) to afford colorless prisms; yield (0.385 g,
83%); Rf (10% toluene/ethyl acetate) 0.40, mp 189 ꢀC; IR (KBr):
3372 (NH), 3053, 2929, 1590, 1535, 1356, 1194, 779, 744 cmꢁ1 1H
NMR (CDCl3):
(12a). Recrystallized
d
CH2CH2N), 3.99 (t, J¼8.1 Hz, 2H, CH2CH2N), 6.89e7.22 (m, 8H, ArH),
7.74 (t, J¼7.6 Hz,1H, C7H), 7.86 (d, J¼7.6 Hz,1H, C8H), 8.31 (s,1H, NH,
D2O exchangeable), 8.88 (d, J¼7.6 Hz, 1H, C6H); MS: m/z (%): 511
(Mþ6, 20), 509 (Mþ4, 50), 507 (Mþ2, 100), 505 (M, 100), 469 (20),
378 (80), 330 (20), 235 (50), 216 (20), 164 (15), 75 (80), 63 (20).
Anal. Calcd for C27H19Cl3N4 (505.83): C, 64.11; H, 3.79; N, 11.08.
Found: C, 64.21; H, 4.08; N, 11.02.
n
;
d
2.56 (s, 3H, CH3), 2.89 (t, J¼8.5 Hz, 2H, CH2CH2N),
3.60 (t, J¼8.5 Hz, 2H, CH2CH2N), 4.33 (s, 2H, CH2), 4.69 (d, J¼4.8 Hz,
2H, CH2), 7.06e7.22 (m, 10H, AreH), 7.33 (t, J¼7.2 Hz, 1H, C7H), 7.75
(d, J¼7.2 Hz, 1H, C8H), 8.79 (d, J¼4.8 Hz, 1H, NH, D2O exchangeable),
8.85 (d, J¼7.2 Hz, 1H, C6H); 13C NMR (CDCl3):
d 22.96, 26.81, 45.29,
53.52, 60.54, 103.68, 121.59, 122.91, 123.44, 126.81, 127.04, 127.38,
127.44,128.29,128.69,128.78,129.65,129.93, 136.99,139.15,142.95,
150.72, 152.46, 156.97, 157.87; MS: m/z (%): 466 (Mþ2, 10), 464 (M,
10), 372 (80), 373 (100), 295 (10), 268 (20), 217 (10), 106 (15), 91
(70). Anal. Calcd for C29H25ClN4 (464.99): C, 74.91; H, 5.42; N, 12.05.
Found. C, 73.01; H, 5.33; N, 12.13.
4.2.9.6. 9-Chloro-N,1-(di-2-chlorophenyl)-2,3-dihydro-4-methyl-
1H-pyrrolo[3,2-c]benzo[h][1,6]naphthyridin-11-amine (12f). Recrys-
tallized from ethanol/DMF (5:5) to afford yellow prisms; yield
(0.398 g, 79%); Rf (10% toluene/ethyl acetate) 0.58, mp 293 ꢀC; IR
(KBr):
n
3353 (NH), 2918, 2848, 1579, 1521, 1473, 1328, 1197, 1054,
2.71 (s, 3H, CH3), 3.01
925, 775, 746, 688 cmꢁ1; 1H NMR (CDCl3):
d
(t, J¼8.1 Hz, 2H, CH2CH2N), 3.99 (t, J¼8.1 Hz, 2H, CH2CH2N),
6.89e7.22 (m, 8H, ArH), 7.67 (t, J¼7.2 Hz, 1H, C7H), 7.79 (d, J¼7.2 Hz,
1H, C8H), 8.25 (s, 1H, NH, D2O exchangeable), 8.85 (d, J¼7.2 Hz, 1H,
C6H); MS: m/z (%): 511 (Mþ6, 20), 509 (Mþ4, 50), 507 (Mþ2, 100),
505 (M, 100), 469 (20), 378 (80), 330 (20), 253 (20), 235 (50), 216
(20), 164 (15), 111 (50), 75 (80), 63 (20), 44 (30). Anal. Calcd for
C27H19Cl3N4 (505.83): C, 64.11; H, 3.79; N, 11.08. Found: C, 64.23; H,
3.76; N, 11.23.
4.2.9.2. 9-Chloro-N,1-diphenyl-2,3-dihydro-4-methyl-1H-pyrrolo
[3,2-c]benzo[h][1,6]naphthyridin-11-amine
from ethanol/DMF (5:5) to afford yellow prisms; yield (0.358 g,
82%); Rf (20% toluene/ethyl acetate) 0.31, mp 272 ꢀC; IR (KBr):
3322 (NH), 2934, 2880, 1576, 1532, 1467, 1233, 1150, 1054, 765,
767 cmꢁ1; 1H NMR (CDCl3):
2.68 (s, 3H, CH3), 3.17 (t, J¼8.2 Hz, 2H,
CH2CH2N), 4.44 (t, J¼8.2 Hz, 2H, CH2CH2N), 6.93e7.26 (m, 10H,
(12b). Recrystallized
n
d

5210
R.B. Toche et al. / Tetrahedron 66 (2010) 5204e5211
4.2.9.7. 9-Chloro-N,1-(di-4-methylphenyl)-2,3-dihydro-4-methyl-
1H-pyrrolo[3,2-c]benzo[h][1,6]naphthyridin-11-amine (12g).
room temperature for 10 h. The progress of reaction was monitored
by TLC. After completion, the reaction mixture was slowly added
over cold water (200 mL). The obtained solid was filtered off and
recrystallized from ethanol to give title compound 14 (0.313 g, 84%)
as colorless prisms; Rf (10% toluene/ethyl acetate) 0.60, mp 191 ꢀC;
Recrystallized from ethanol/DMF (5:5) to afford yellow prisms;
yield (0.375 g, 81%); Rf (10% toluene/ethyl acetate) 0.38, mp 249 ꢀC;
IR (KBr):
n
3427 (NH), 2914, 3087, 1585, 1529, 1409, 1269, 1080, 975,
750, 688 cmꢁ1
;
1H NMR (CDCl3):
d
2.13 (s, 3H, ArCH3), 2.27 (s, 3H,
IR (KBr):
n ;
2964, 2147 (N3), 1594, 1544, 1383, 1234, 1077, 785 cmꢁ1
ArCH3), 2.65 (s, 3H, CH3), 3.14 (t, J¼8.4 Hz, 2H, CH2CH2N), 4.35 (t,
J¼8.4 Hz, 2H, CH2CH2N), 6.87e7.00 (m, 8H, ArH), 7.63 (t, J¼7.2 Hz,
1H, C7H), 7.69 (d, J¼7.2 Hz, 1H, C8H), 8.33 (s, 1H, NH, D2O ex-
changeable), 8.87 (d, J¼j7.2 Hz, 1H, C6H); MS: m/z (%): 466 (Mþ2,
60), 464 (M,90), 373 (50), 282 (60), 246 (10), 192 (10), 104 (20), 93
(100), 77 (50). Anal. Calcd for C29H25ClN4 (464.99): C, 74.91; H, 5.42;
N, 12.05. Found: C, 74.33; H, 5.49; N, 11.91.
1H NMR (CDCl3):
d
2.90 (s, 3H, CH3), 3.50 (t, J¼7.2 Hz, 2H,
CH2CH2N3), 3.86 (t, J¼7.2 Hz, 2H, CH2CH2N3), 7.68 (t, J¼7.8 Hz, 1H,
C9H), 7.98 (d, J¼7.8 Hz, 1H, C8H), 9.16 (d, J¼7.8 Hz, 1H, C10H); 13C
NMR (CDCl3):
d 24.29, 31.16, 42.36, 124.07, 125.41, 125.91, 127.01,
128.20, 131.11, 134.69, 140.23, 142.69, 146.06, 148.21, 163.37; MS: m/
z (%): 376 (Mþ4, 10), 374 (Mþ2, 10), 372 (M, 20), 323 (20), 308 (60),
279 (100), 245 (100), 140 (90), 91 (90). Anal. Calcd for C15H10Cl2N8
(373.2): C, 48.27; H, 2.70; N, 30.03. Found: C, 48.39; H, 2.50; N,
30.17.
4.2.9.8. 9-Chloro-N,1-(di-4-bromophenyl)-2,3-dihydro-4-methyl-
1H-pyrrolo[3,2-c]benzo[h][1,6]naphthyridin-11-amine
(12h).
Recrystallized from ethanol/DMF (5:5) to afford yellow prisms;
4.2.12. 4,7-Dichloro-3-(2-chloroethyl)-2-methylbenzo[h][1,6]naph-
thyridin-5(6H)-one (15). A mixture of 4,5,7-trichloro-3-(2-chlor-
oethyl)-2-methylbenzo[h][1,6]naphthyridine 8 (1.08 g, 0.003 mol)
in glacial acetic acid (10 mL) was heated to reflux for 15 min. After
cooling down to room temperature, methanol (50 mL) was added,
the crude product obtained was collected by suction filtration,
dried, and recrystallized from ethanol/DMF (9:1) to give title
compound 15 (0.317 g, 93%) as pink colored prisms; Rf (10% tolu-
yield (0.433 g, 73%); Rf (10% toluene/ethyl acetate) 0.33, mp 315 ꢀC;
IR (KBr):
n
3353 (NH), 2960, 2698, 2663,1587,1153,1497,1328,1142,
927, 831, 775, 744, 626 cmꢁ1
;
1H NMR (DMSO-d6):
d
2.79 (s, 3H,
CH3), 2.98 (t, J¼8.5 Hz, 2H, CH2CH2N), 3.90 (t, J¼8.5 Hz, 2H,
CH2CH2N), 6.89e7.34 (m, 8H, ArH), 7.37 (t, J¼7.5 Hz, 1H, C7H), 7.78
(d, J¼7.5 Hz, 1H, C8H), 8.90 (d, J¼7.5 Hz, 1H, C6H), 9.01 (s, 1H, NH,
D2O exchangeable); MS: m/z (%): 600 (Mþ6, 10), 598 (Mþ4, 10), 596
(Mþ2, 10), 594 (M, 20), 513 (10), 410 (10), 342 (10), 281 (10), 207
(20), 149 (20), 135 (80), 108 (90), 81 (50), 66 (50), 44 (100). Anal.
Calcd for C27H19Br2ClN4 (594.73): C, 54.53; H, 3.22; N, 9.42. Found:
C, 54.60; H, 3.27; N, 9.32.
ene/ethyl acetate) 0.51, mp 254 ꢀC; IR (KBr):
n
3339 (NH), 3186,
2.91 (s,
3143, 1676 (C]Olactum), 1249, 734 cmꢁ1; 1H NMR (CDCl3):
d
3H, CH3), 3.57 (t, J¼7.1 Hz, 2H, CH2CH2Cl), 3.83 (t, J¼7.1 Hz, 2H,
CH2CH2Cl), 7.59 (t, J¼7.5 Hz, 1H, C9H), 7.77 (d, J¼7.5 Hz, 1H, C8H), 8.1
(s, 1H, NH, D2O exchangeable), 8.97 (d, J¼7.5 Hz,1H, C10H); 13C NMR
4.2.10. 5,7-Dichloro-3-(2-chloroethyl)-4-alkoxy-2-ethylbenzo[h][1,6]
naphthyridines (13a,b). A mixture of 4,5,7-trichloro-3-(2-chlor-
oethyl)-2-methylbenzo[h][1,6]naphthyridine 8 (0.360 g, 0.001 mL)
and sodium alkoxide (0.002 mol) in toluene was heated to reflux
for 24 h. (TLC checked, Toluene) The solvent was evaporated in
vacuo, the residue obtained was stirred into methanol. The formed
crude product was collected by suction filtration washed with
methanol, dried, and recrystallized from suitable solvent.
(CDCl3): d 23.26, 30.95, 42.65, 119.40, 121.72, 122.14, 126.75, 128.00,
128.20, 128.63, 128.74, 136.66, 142.23, 161.54, 170.61; MS: m/z (%):
347 (Mþ6, 10), 345 (Mþ4, 30), 343 (Mþ2, 50), 341 (M, 100), 274
(20), 198 (20), 99 (10). Anal. Calcd for C15H11Cl3N2O (341.62): C,
52.74; H, 3.25; N, 8.20. Found: C, 52.47; H, 3.31; N, 8.29.
4.2.13. 9-Chloro-2,3-dihydro-4-methylbenzo[h][1,6]naphthyridin-1-
phenyl-1H-pyrrolo[3,2-c]-11(10H)-one (16). A mixture of 4,7-
dichloro-3-(2-chloroethyl)-2-methylbenzo[h][1,6]naphthyridine-5
(6H)-one 15 (0.360 g, 0.001 mol) and primary aromatic amine
(0.01 mol) was heated to 160 ꢀC for 30 min. After reaction had
completed, the reaction mixture was cooled to room temperature,
methanol (10 mL) was added, and resulting solid formed was col-
lected by suction filtration, dried, and recrystallized from ethanol to
give title compound 16 (0.299 g, 83%) as yellow prisms; Rf (10%
4.2.10.1. 5,7-Dichloro-3-(2-chloroethyl)-4-methoxy-2-methyl-
benzo[h][1,6]naphthyridine (13a). Recrystallized from ethanol to
afford colorless prisms; yield (0.298 g, 84%); Rf (toluene) 0.81, mp
180 ꢀC; IR (KBr):
n
2962, 2837, 1583, 1425, 1321, 1162, 1033,
2.89 (s, 3H, CH3), 3.44 (t, J¼7.6 Hz, 2H,
776 cmꢁ1; 1H NMR (CDCl3):
d
CH2CH2Cl), 3.92 (t, J¼7.6 Hz, 2H, CH2CH2Cl), 4.19 (s, 3H, OCH3), 7.54
(t, J¼7.5 Hz, 1H, C9H), 7.94 (d, J¼7.5 Hz, 1H, C8H), 8.83 (d, J¼7.5 Hz,
1H, C10H); MS: m/z (%): 360 (Mþ6, 50), 358 (Mþ4, 60), 356 (Mþ2,
80), 354 (M, 100), 325 (100), 319 (60), 275 (70), 198 (20), 138 (50),
49 (70). Anal. Calcd for C16H13Cl3N2O (355.65): C, 54.03; H, 3.68; N,
7.88. Found: C, 54.22; H, 3.57; N, 7.81.
toluene/ethyl acetate) 0.40, mp 272 ꢀC; IR (KBr):
n
3339 (NH), 3186,
2.70 (s,
3143, 1676 (C]Olactum), 1249, 734 cmꢁ1; 1H NMR (CDCl3):
d
3H, CH3), 3.23 (t, J¼7.8 Hz, 2H, CH2CH2N), 4.43 (t, J¼7.8 Hz, 2H,
CH2CH2N), 7.00e7.30 (m, 5H, ArH), 7.46 (t, J¼7.2 Hz,1H, C7H), 7.70 (d,
J¼7.2 Hz, 1H, C8H), 8.10 (s, 1H, NH, D2O exchangeable), 8.89 (d,
J¼7.2 Hz, 1H, C6H); MS: m/z (%): 363 (Mþ2, 30), 361 (M, 100), 254
(20), 221 (10), 91 (50). Anal. Calcd for C21H16ClN3O (361.82): C, 69.71;
H, 4.46; N, 11.61. Found: C, 69.70; H, 4.49; N, 11.67.
4.2.10.2. 5,7-Dichloro-3-(2-chloroethyl)-4-ethoxy-2-methylbenzo
[h][1,6]naphthyridine (13b). Recrystallized from ethanol to afford
yellow prisms; yield (0.258 g, 70%); Rf (toluene) 0.81, mp 197 ꢀC; IR
(KBr):
(CDCl3):
n ;
2976, 2893, 1583, 1315, 1190, 1035, 750 cmꢁ1 1H NMR
Acknowledgements
d
1.58 (t, J¼7.5 Hz, 3H, OCH2CH3), 2.89 (s, 3H, CH3), 3.51 (t,
J¼7.8 Hz, 2H, CH2CH2Cl), 3.80 (t, J¼7.8 Hz, 2H, CH2CH2Cl), 4.75 (q,
J¼7.5 Hz, 2H, OCH2CH3), 7.39 (t, J¼7.8 Hz, 1H, C9H), 7.76 (d, J¼7.8 Hz,
1H, C8H), 8.85 (d, J¼7.8 Hz, 1H, C10H); MS: m/z (%): 375 (Mþ6, 50),
373 (Mþ4, 60), 371 (Mþ2, 80), 369 (M, 100), 325 (100), 319 (60),
275 (70), 198 (20), 138 (50), 49 (70). Anal. Calcd for C17H15Cl3N2O
(369.67): C, 55.23; H, 4.09; N, 7.58. Found: C, 55.22; H, 4.11; N, 7.53.
The authors thank to UGC New Delhi and BCUD University of
Pune, India for financial support to this research project. Authors
also thanks to Department of Chemistry University of Pune, IIT-
Powai Mumbai and Principal KTHM College Nashik, for spectral and
analytical facilites.
4.2.11. 4-Azido-3-(2-azidoethyl)-5,7-dichloro-2-methylbenzo[h][1,6]
naphthyridine (14). A mixture of 4,5,7-trichloro-3-(2-chloroethyl)-
2-methylbenzo[h][1,6]naphthyridine 8 (0.360 g, 0.001 mol) and
sodium azide (0.195 g 0.003 mol) in DMF (15 mL) was stirred at
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2010.04.085.

R.B. Toche et al. / Tetrahedron 66 (2010) 5204e5211
5211
15. Gorlitzer, K.; Bode, M.; Jones, P. G.; Jomaa, H. Pharmazie 2005, 60, 172e174.
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