Synthesis of benzo[3,4-h][1,6]naphthyridines via Friedlaender condensation with active methylenes

Article abstract of DOI:10.1002/jhet.391

Novel 4-amino-6-chloroquinoline-3-carbaldehyde has been synthesized by synchronous reduction by lithium aluminiumhydride and finally oxidation with MnO₂. Friedlaender condensation of it with reactive methylenes furnished novel benzo[3,4-h][1,6]

Full text of DOI:10.1002/jhet.391

¨
March 2011
Synthesis of Benzo[3,4-h][1,6]naphthyridines via Friedlander
Condensation with Active Methylenes
301
Ramhari V. Rote, Sandeep M. Bagul, Deepak P. Shelar, Sandeep R. Patil,
Raghunath B. Toche, and Madhukar N. Jachak*
Organic Chemistry Research Center, Department of Chemistry, K.R.T. Arts, B.H.Commerce and
A. M. Science College, Nashik, Maharashtra 422 002, India
*E-mail: mnjachak@hotmail.com
Received September 25, 2009
DOI 10.1002/jhet.391
Published online 3 December 2010 in Wiley Online Library (wileyonlinelibrary.com).
Novel 4-amino-6-chloroquinoline-3-carbaldehyde has been synthesized by synchronous reduction by
¨
lithium aluminiumhydride and finally oxidation with MnO2. Friedlander condensation of it with reactive
methylenes furnished novel benzo[3,4-h][1,6]naphthyridine derivatives.
J. Heterocyclic Chem., 48, 301 (2011).
INTRODUCTION
condensation of it with various reactive methylenes.
In this communication we have synthesized ben-
zo[3,4-h][1,6]naphthyridines, which may have potential
biological activities such as antimalarials [32], antago-
nists of 5-HT4 receptor [33], reported earlier.
The construction of ring structures from orthoaminoal-
dehyde as a starting material has wide applicability for
the annulation of heterocyclic systems. This construction
method predominates the direction of ring growth (angu-
lar vs. linear) and generally permits the direct and regio-
specific introduction of functional groups and/or substitu-
ents in the newly formed heterocyclic ring. Among
numerous possibilities for ortho joined functionalities
those containing carbon and nitrogen are of particular in-
terest, because the numerous combinations of their differ-
ent oxidation states and easy accessibility of simple deriv-
atives provide them with exceptional versatility in hetero
annulation reaction. From literature, it was noted that
o-aminobenzaldehyde, the first and best known member
of this class of compounds has been utilized for synthesis
of various heterocycles [1–17]. Annulation reaction of
heterocyclic aminoaldehydes provide a synthetic entry
into heterocyclic systems fused to pyridine [18–21], pyr-
azole [22–25], and quinoline nucleus [26,27]. The func-
tionalized quinolines and their benzo/hetero-fused analo-
gous present in numerous natural products along with the
wide spectrum of physiological activities [28]. In our ear-
lier communication, we have reported the synthetic utility
of heterocyclic o-aminoaldehyde in which annulation of
heterocyclic system on to pyrazole and pyrazolopyridine
nuclei was performed [29–31].
Godard and Queguiner reported synthesis of 4-amino-
quinoline-3-carbaldehyde by following sequence of reac-
tion [34]. In their sequence, the anhydride I was treated
with NH3 to furnish carboxamide II. The alkaline hy-
drolysis of II with KOH yielded aminoacid III, which
was esterified with MeOH/ H2SO4 to yield orthoami-
noester IV. The lithium aluminiumhydride reduction of
IV yielded primary alcohol V and finally oxidation with
MnO2 furnished a orthoaminoaldehyde 1a (Fig. 1).
We have adopted different strategy for synthesis of 4-
amino-6-chloroquinoline-3-carbaldehyde 1b (heterocy-
clic orthoaminoaldehyde). Chloro-ester A was synthe-
sized in the beginning by reported method [35], starting
with p-chloroaniline. Then SN2 displacement of chloro
functionality at position 4 was achieved with NaN3 in
DMF at room temperature to yield B quantitatively. The
synchronous reduction of both azido and ester group in
B by lithium aluminiumhydride in dry THF at 0–5ꢀC
yielded the ortho amino alcohol C in 79% yield. Finally,
oxidation of C with manganese (IV) oxide, without
protecting amino group [34,36], in dichloromethane at
room temperature furnish desire target molecule
4-amino-6-chloroquinoline-3-carbaldehyde 1b in 71%
yield. In this step, expected N-oxide was not formed
as revealed by spectral and analytical data. The
These literature reports and our continuous interest in
this area prompted us to report the novel synthesis of
¨
orthoaminoformylquinoline and study of Friedlander
C
V
2010 HeteroCorporation

302
R. V. Rote, S. M. Bagul, D. P. Shelar, S. R. Patil, R. B. Toche, and M. N. Jachak
Vol 48
Figure 1. Godard method for synthesis of 4-aminoquinoline-3-carbaldehyde.
¨
intermediates B, C, and 1b were characterized by IR,
1H, and 13C NMR, mass spectroscopy and elemental
analysis (Scheme 1).
The Friedlander condensation can be catalyzed by
various reagents [37]. When we extend our synthetic
investigation to CH-acidic compounds such as benzoyla-
cetonitrile 8a–d, b-ketoester 10a, b-ketoamide 10b, and
diethyl malonate 12, we found that already piperidine as
base was sufficient strong to catalyze the condensation
reaction. Thus, cyclocondensation of 1b with 8a–d,
10a–b, and 12, afforded 9-Chloro-2-arylbenzo[h][1,6]-
naphthyridine-3-carbonitriles 9a–d, Ethyl 9-Chloro-
2-methylbenzo[h][1,6]naphthyridine-3-carboxylate 11a,
9-Chloro-2-methyl-N-phenylbenzo[h][1,6]naphthyridine-
3-carboxamide 11b and Ethyl 9-Chloro-1,2-dihydro-2-
oxobenzo[h][1,6]naphthyridine-3-carboxylate 13, res-
pectively, in 75–85% yield (Scheme 3). Compounds 9,
11, and 13 were characterized by IR, 1H, and 13C
NMR, mass spectroscopy and elemental analysis.
In our approach, the yields of intermediates B, C, and
1b are excellent. This method is versatile and scalable.
Compound 1b in hand reacted with alkyl and/or aryl
ketones 2a–k in DMF at reflux using potassium hydroxide
(KOH) as a base to yield benzo[h] naphthyridines 3a–k in
68–80% yield. Analogously 1b when reacted with unsym-
metric dialkyl ketones 4a–b, instead of expected mixture
of two isomer [29], only single isomer 5a–b were obtained
in good yield. However, reaction of 1b with malononitrile
6 under similar reaction condition was unsuccessful. This
condensation was achieved by refluxing a mixture of 1b,
malononitrile and piperidine in ethanol to yield benzo
naphthyridine 7, having nitrile and amino functionality
ortho to each other, in 78% yield (Scheme 2).
In conclusion herein, we report novel and scalable
route towards orthoaminoformylquinoline 1b. A series
of novel benzo[3,4-h][1,6]naphthyridines and benzo[3,4-
1
Compounds 3, 5, and 7 were characterized by IR, H,
and 13C NMR, mass spectroscopy and elemental analysis.
Scheme 1
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
Synthesis of Benzo[3,4-h][1,6]naphthyridines via Friedlander Condensation with
Active Methylenes
March 2011
303
Scheme 2
commercially available and were used without further purifica-
tion or prepared by standard literature procedures.
¨
h][1,6]naphthyridone was synthesized by Friedlander
condensation reaction of 4-amino-6-chloroquinoline-3-
carbaldehyde 1b with reactive methylene compounds.
Ethyl 4-Azido-6-chloroquinoline-3-carboxylate (B). A
mixture of A [35] (0.246 g, 1 mmol) and sodium azide
(0.065 g, 1 mmol) in DMF (2 mL) was stirred at RT for 2 h.
After completion of the reaction (TLC check), the solvent was
distilled out by vacuum distillation. The reaction mass was
quenched in ice cold water (10 mL) and extracted with three
fraction of ethyl acetate (12 mL ꢁ 3). The organic layer was
dried over sodium sulphate and solvent was evaporated under
reduced pressure. The crude solid was washed with methanol,
filtered, and dried to furnish B as colorless solid; (0.182 g,
74%), mp 292–293ꢀC; ir (potassium bromide): 3086(w),
EXPERIMENTAL
Melting points were determined on a Gallenkamp melting
point apparatus, Mod. MFB595 in open capillary tubes and are
uncorrected. 1H (300 MHz) and 13C (75 MHz) NMR spectra
were measured on a Varian XL-300 spectrometer using tetra-
methylsilane as the internal standard. IR spectra were recorded
using a Shimadzu IR-408, a Shimadzu FTIR instrument with
potassium bromide discs. Mass spectrum was recorded on Shi-
madzu GC-MS QP mass spectrometer with an ionization
potential of 70 eV. Elemental analyses were obtained on a
Hosli CH-Analyzer and are within 60.3 of the theoretical
percentage.
1
2920(m), 2134(m), 1770(s), 1563(s) cmꢂ1; H NMR (CDCl3):
d 1.33 (t, J ¼ 6.9 Hz, 3H), 4.45 (q, J ¼ 6.9 Hz, 2H), 7.73 (dd,
J ¼ 8.5, 2.2 Hz, 1H), 7.81 (d, J ¼ 2.2 Hz, 1H), 8.23 (d, J ¼
8.5 Hz, 1H), 8.92 (s, 1H); 13C NMR (CDCl3): d 14.02, 60.3,
124.5, 128.6, 129.4, 131.7, 133.1, 133.9, 138.4, 146.2, 146.9,
166.2; ms: m/z (%) 276 (Mþ,100), 278 (Mþ2, 32); Anal.
Calcd. for C12H9ClN4O2 (276.68): C, 52.09; H, 3.28; N, 20.25.
Found: C, 52.25; H, 3.37; N, 20.43.
All reactions were monitored by thin layer chromatography
on 0.2 mm silica gel F-254 (Merck) plates using UV light
(254 and 366 nm) for detection. Common reagents were either
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

304
R. V. Rote, S. M. Bagul, D. P. Shelar, S. R. Patil, R. B. Toche, and M. N. Jachak
Vol 48
Scheme 3
CHO); 13C NMR (DMSO-d6): d 115.2, 121.5, 123.7, 130.7,
131.8, 133.0, 142.6, 145.3, 159.9, 193.0; ms: m/z (%) 206
(Mþ, 100), 208 (Mþ2, 31); Anal. Calcd. For C10H7ClN2O
(206.63): C, 58.13; H, 3.41; N, 13.56. Found. C, 58.23; H,
3.47; N, 13.62.
General procedure for the synthesis of compounds 3a–
k. A mixture of 1b (0.206 g, 1 mmol) and 2a–k (1 mmol) in
DMF with catalytic amount of KOH was heated under reflux
for 3 h, after completion of the reaction (TLC check), solvent
was evaporated under reduced pressure. The crude solid was
washed with methanol, filtered, dried under high vacuum, and
recrystallized from ethanol: DMF (7:3) to furnish compounds
3a–k in 68–80% yield.
9-Chloro-2-methylbenzo[h][1,6]naphthyridine (3a). Pale
yellow solid; (0.148 g, 72%); mp 282–283ꢀC; ir (potassium
bromide): 3111(w), 3040(w), 2833(m), 2830(m), 2905(m),
1671(s), 1659(w), 1561(w) cmꢂ1 1H NMR (DMSO-d6): d
;
2.47 (s, 3H), 7.73 (d, J ¼ 8.4 Hz, 1H), 7.91 (d, J ¼ 8.4 Hz,
1H), 8.54 (d, J ¼ 8.4 Hz, 1H), 8.75 (d, J ¼ 8.4 Hz, 1H), 9.24
(s, 1H), 9.33 (s, 1H); 13C NMR (DMSO-d6): d 24.2, 119.9,
121.4, 122.7, 125.3, 125.9, 130.1, 130.8, 131.1, 133.8, 135.3,
145.6, 156.2; ms: m/z (%) 228 (Mþ, 100), 230 (Mþ2, 34);
Anal. Calcd. For C13H9ClN2 (228.66): C, 68.28; H, 3.97; N,
12.25. Found. C, 68.34; H, 4.1; N, 12.31.
(4-Amino-6-chloroquinolin-3-yl)methanol (C). A solution
of B (0.276 g, 1 mmol) in tetrahydrofuran (2 mL) was added
slowly into the dispersed lithium aluminium hydride (0.144 g,
4 mmol) in tetrahydrofuran (2 mL) at 0–5ꢀC, after addition,
the reaction mass was allowed to stand at RT and further
stirred for 3 h. After completion of reaction (TLC check), the
reaction mass was quenched in saturated sodium sulphate solu-
tion (2–3 mL) at 0–5ꢀC and extracted in three fraction of ethyl
acetate (5 mL ꢁ 3). The combined organic layer was washed
with water (5 mL ꢁ 3), then dried over anhydrous sodium sul-
phate, filtered, and the solvent was evaporated under reduced
pressure, the crude solid was washed with methanol, filtered,
dried under high vacuum, and recrystallized from ethanol:
DMF (8:2) to give C as colorless solid; (0.218 g, 79%); mp
221–222ꢀC; ir (potassium bromide): 3443(m), 3354(m),
3248(s), 2895(w), 1660(s), 1564(s), 1500(s) cmꢂ1 1H NMR
;
(DMSO-d6): d 4.56 (d, J ¼ 5.4 Hz, 2H, CH2), 5.13 (t, J ¼ 5.4
Hz, 1H, OH), 6.62 (s, 2H, NH2), 7.55 (d, J ¼ 9 Hz, 1H), 7.76
(d, J ¼ 9 Hz, 1H), 8.36 (s, 1H), 8.37 (s, 1H); 13C NMR
(DMSO-d6): d 56.3, 116.7, 119.4, 122.9, 129.7, 130.5, 131.1,
146.4, 149.2, 151.9; ms: m/z (%) 208 (Mþ,100), 210 (Mþ2,
33); Anal. Calcd. For C10H9ClN2O (208.64): C, 57.57; H 4.35;
N, 13.43. Found: C, 57.63; H, 4.46; N, 13.51.
4-Amino-6-chloroquinoline-3-carbaldehyde (1b). To the
solution of C (0.208 g, 1 mmol) in dichloromethane (2 mL),
manganese (IV) dioxide (0.170 g, 2 mmol) was added. The
reaction mixture was stirred at 25ꢀC for 24 h. After comple-
tion of the reaction (TLC check), the reaction mass was fil-
tered through celite and solvent was evaporated under reduced
pressure, the crude solid was washed with methanol, filtered,
dried under high vacuum, and recrystallized from ethanol:
DMF (6:4) to give 1b as pale brown needles; (0.147 g, 71%);
mp 319–320ꢀC; ir (potassium bromide): 3323(m), 3093(m),
9-Chloro-2-phenylbenzo[h][1,6]naphthyridine (3b). Colorless
solid; (0.154 g, 75%); mp 298–299ꢀC; ir (potassium bromide):
3022(w), 2979(m), 1668(m), 1639(w), 1567(m), 1559(m),
1
1518(w) cmꢂ1; H NMR (DMSO-d6): d 7.66 (m, 3H, ArAH),
7.81 (d, J ¼ 8.1 Hz, 1H), 8.13 (d, J ¼ 8.1 Hz, 1H), 8.46 (m, 3H),
8.71 (d, J ¼ 8.4 Hz, 1H), 9.12 (s, 1H), 9.40 (s, 1H); 13C NMR
(DMSO-d6): d 121.2, 123.9, 126.7 (2 C’s), 128.0, 128.1, 128.3,
128.9 (2 C’s), 130.0, 131.6, 132.7, 133.4, 136.1, 136.9, 144.7,
148.2, 154.3; ms: m/z (%) 290 (Mþ, 100), 292 (Mþ2, 35); Anal.
Calcd. For C18H11ClN2 (290.75): C, 74.36; H, 3.81; N, 9.63.
Found. C, 74.48; H, 3.79; N, 9.77.
1
2926(m), 2783(w), 1714(s), 1657(s), 1589(m) cmꢂ1; H NMR
(DMSO-d6): d 7.77 (d, J ¼ 8.7 Hz, 1H), 7.80 (d, J ¼ 8.7 Hz,
1H), 8.67 (s, 1H), 8.73 (s, 1H), 8.91 (s, 2H, NH2), 9.96 (s, 1H,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
Synthesis of Benzo[3,4-h][1,6]naphthyridines via Friedlander Condensation with
Active Methylenes
March 2011
305
9-Chloro-3-methyl-2-phenylbenzo[h][1,6]naphthyridine
(3c). Pale yellow solid; (0.164 g, 80%); mp 294–295ꢀC; ir
(potassium bromide): 3093(w), 2973(w), 1643(s), 1631(m),
9-Chloro-2-(3,4-dimethoxyphenyl)benzo[h][1,6]naphthyri-
dine (3h). Pale yellow solid; (0.154 g, 75%); mp 294–295ꢀC;
ir (potassium bromide): 3018(m), 2963(w), 1683(w), 1669(m)
1
1612(m), 1582(m), 1567(m) cmꢂ1
;
1H NMR (DMSO-d6): d
cmꢂ1; H NMR (DMSO-d6): d 3.67 (s, 6H), 7.06 (d, J ¼ 7.5
2.31 (s, 3H), 7.22–7.56 (m, 5H), 7.84 (d, J ¼ 7.4 Hz, 1H),
8.01 (d, J ¼ 7.4 Hz, 1H), 8.37 (s, 1H), 8.82 (s, 1H), 9.15 (s,
1H); 13C NMR (DMSO-d6): d 14.5, 121.7, 124.0, 126.9,
128.6, 129.1, 129.7, 130.1, 130.3, 132.0, 132.4, 132.9, 133.1,
135.2, 135.3, 137.3, 146.6, 150.1, 160.8; ms: m/z (%) 304
(Mþ, 100), 306 (Mþ2, 32); Anal. Calcd. For C19H13ClN2
(304.77): C, 74.88; H, 4.30; N, 9.19. Found. C, 74.91; H, 4.43;
N, 9.24.
9-Chloro-2-(2-chlorophenyl)benzo[h][1,6]naphthyridine
(3d). Colorless solid; (0.140 g, 68%); mp 276–277ꢀC; ir (po-
tassium bromide): 2985(m), 2822(w), 2818(m), 1691(m),
1637(w), 1583(w), 1501(w) cmꢂ1 1H NMR (DMSO-d6): d
;
7.44 (m, 2H), 7.51 (d, J ¼ 8.2 Hz, 1H), 7.63 (d, J ¼ 8.2 Hz,
1H), 7.93 (d, J ¼ 7.5 Hz, 1H, ), 8.12 (d, J ¼ 7.5 Hz, 1H),
8.24 (d, J ¼ 6.7 Hz, 1H), 8.42 (d, J ¼ 6.7 Hz, 1H), 9.27
(s, 1H), 9.33 (s, 1H); 13C NMR (DMSO-d6): d 120.5, 123.3,
124.9, 126.8, 127.5, 127.9, 128.2, 129.1, 130.3, 131.1, 131.9,
132.4, 132.7, 134.0, 134.7, 145.1, 149.1, 152.7; ms: m/z (%)
324 (Mþ, 100), 326 (Mþ2, 31), 328 (Mþ4, 18); Anal. Calcd.
For C18H10Cl2N2 (325.19): C, 66.48; H, 3.10; N, 8.16. Found.
C, 66.52; H, 3.19; N, 8.27.
Hz, 1H), 7.30 (dd, J ¼ 7.2,2.2 Hz, 1H), 7.35 (d, J ¼ 2.2 Hz,
1H), 8.23 (d, J ¼ 8.4 Hz, 1H), 8.35 (d, J ¼ 7.4 Hz, 1H), 8.50
(d, J ¼ 8.4 Hz, 1H), 8.75 (d, J ¼ 7.4 Hz, 1H), 9.11 (s, 1H),
9.23 (s, 1H); ms: m/z (%) 350 (Mþ, 100), 352 (Mþ2, 34);
Anal. Calcd. For C20H15ClN2O2 (350.80): C, 68.48; H, 4.31;
N, 7.99. Found. C, 68.53; H, 4.42; N, 8.1.
9-Chloro-2-(2,6-dimethoxyphenyl)benzo[h][1,6]naphthyri-
dine (3i). Colorless solid; (0.158 g, 77%); mp 297–298ꢀC; ir
(potassium bromide): 2981(m), 2897(w), 1676(m), 1632(m),
1
1548(w) cmꢂ1; H NMR (DMSO-d6): d 3.79 (s, 6H), 7.43 (m,
3H, ArAH), 8.3 1(d, J ¼ 8.2 Hz, 1H), 8.42 (d, J ¼ 7.8 Hz,
1H), 8.45 (d, J ¼ 8.2 Hz, 1H), 8.73 (d, J ¼ 7.8 Hz, 1H), 9.10
(s, 1H), 9.17 (s, 1H); ms: m/z (%) 350 (Mþ, 100), 352 (Mþ2,
36); Anal. Calcd. For C20H15ClN2O2 (350.80): C, 68.48; H,
4.31; N, 7.99. Found. C, 68.50; H, 4.37; N, 8.2.
9-Chloro-2-p-tolylbenzo[h][1,6]naphthyridine (3j). Colorless
solid; (0.156 g, 76%); mp 297–298ꢀC; ir (potassium bromide):
2981(m), 2978(w), 2896(m), 1635(m), 1618(m), 1512(w)
1
cmꢂ1; H NMR (DMSO-d6): d 2.43 (s, 3H, CH3), 7.37 (d, J ¼
8.4 Hz, 2H), 7.51 (d, J ¼ 8.4 Hz, 2H), 8.10 (d, J ¼ 8.5 Hz,
1H), 8.23 (d, J ¼ 8.2 Hz, 1H), 8.27 (d, J ¼ 8.5 Hz, 1H), 8.44
(d, J ¼ 8.2 Hz, 1H), 8.91 (s, 1H), 9.13 (s, 1H); ms: m/z (%)
304 (Mþ, 100), 306 (Mþ2, 31); Anal. Calcd. For C19H13ClN2
(304.77): C, 74.88; H, 4.30; N, 9.19. Found. C, 74.91; H, 4.33;
N, 9.27.
9-Chloro-2-(4-chlorophenyl)benzo[h][1,6]naphthyridine
(3e). Pale yellow solid; (0.142 g, 69%); mp 269–270ꢀC; ir (po-
tassium bromide): 3012(m), 2921(m), 2817(w), 1658(m), 1649(s),
1
1486(m), 1422(w), 1583(w) cmꢂ1; H NMR (DMSO-d6): d 7.37
(d, J ¼ 7.9 Hz, 2H), 7.91 (d, J ¼ 8.3 Hz, 1H), 8.14 (d, J ¼ 8.3
Hz, 1H), 8.36 (d, J ¼ 7.2 Hz, 1H, ), 8.52 (d, J ¼ 7.9 Hz, 2H),
8.65 (d, J ¼ 7.2 Hz, 1H), 9.00 (s, 1H), 9.24 (s, 1H); 13C NMR
(DMSO-d6): d 118.3, 123.0, 127.2, 127.9, 128.9 (2 C’s) 130.0,
130.7, 130.9, 131.2, 133.3, 134.1, 134.7, 143.8 (2 C’s) 147.2,
154.0, 157.1; ms: m/z (%) 324 (Mþ,100), 326 (Mþ2, 36), 328
(Mþ4, 13); Anal. Calcd. For C18H10Cl2N2 (325.19): C, 66.48; H,
3.10; N, 8.16. Found. C, 66.49; H, 3.21; N, 8.29.
2-(3,5-Bis(trifluoromethyl)phenyl)-9-chlorobenzo[h][1,6]-
naphthyridine (3k). Colorless solid; (0.154 g, 75%); mp 283–
284ꢀC; ir (potassium bromide): 3012(m), 2937(m), 1683(w),
1662(s), 1544(m), 1537(w); 1H NMR (DMSO-d6): d 7.87 (m,
1H), 8.16 (m, 2H), 8.65 (dd, J ¼ 2.7,8.4 Hz, 1H), 8.80 (dd,
J ¼ 2.7,8.4 Hz,1H), 8.93 (s,2H), 9.01 (s, 1H), 9.44 (s, 1H);
ms: m/z (%) 426 (Mþ, 100), 428 (Mþ2, 33); Anal. Calcd. For
C20H9ClF6N2 (426.74): C, 56.33; H, 2.11; N, 6.57. Found. C,
56.31; H, 2.17; N, 6.56.
General procedure for the synthesis of compounds 5a
and b. A mixture of 1b (0.206 g, 1 mmol) and corresponding
ketones 4a–b (1 mmol) in DMF with catalytic amount of
KOH was heated under reflux for 3 h. After completion of the
reaction (TLC check), solvent was evaporated under reduced
pressure, the crude solid was washed with methanol, filtered,
dried under high vacuum, and recrystallized from ethanol:
DMF (6:4) to furnish 5a–b in 76–79% yield.
9-Chloro-2-(4-fluorophenyl)benzo[h][1,6]naphthyridine
(3f). Colorless solid; (0.150 g, 73%); mp 297–298ꢀC; ir (po-
tassium bromide): 2989(m), 2817(w), 1631(m), 1604(m),
1
1588(m), 1563(m) cmꢂ1; H NMR (DMSO-d6): d 7.55 (d, J ¼
8.4 Hz, 2H), 7.71 (d, J ¼ 7.4 Hz, 1H), 7.93 (d, J ¼ 7.4 Hz,
1H), 8.06 (d, J ¼ 7.5 Hz, 1H), 8.19 (d, J ¼ 7.5 Hz, 1H), 8.58
(d, J ¼ 8.4 Hz, 2H), 8.90 (s, 1H), 9.26 (s, 1H ); 13C NMR
(DMSO-d6): d 113.4 (2 C’s), 120.7, 122.9, 125.6, 125.8,
129.1(2 C’s), 129.9, 131.1, 131.9, 132.0, 133.7, 135.1, 144.6,
147.9, 154.1, 159.3; ms: m/z (%) 308 (Mþ, 100), 310 (Mþ2,
33); Anal. Calcd. For C18H10ClFN2 (308.74): C, 70.03; H,
3.26; N, 9.07. Found. C, 70.11; H, 3.37; N, 9.19.
9-Chloro-2,3-dimethylbenzo[h][1,6]naphthyridine (5a). Pale
yellow solid; (0.160 g, 78%); mp 302–303ꢀC; ir (potassium
bromide): 3012(w), 2982(m), 2811(m), 1683(m), 1661(w),
1
2-(4-Bromophenyl)-9-chlorobenzo[h][1,6]naphthyridine
(3g). Pale yellow solid; (0.150 g, 73%); mp 267–268ꢀC; ir
(potassium bromide): 3005(w), 2918(m), 1645(m), 1623(w),
1537(m), 1518(s) cmꢂ1; H NMR (DMSO-d6): d 2.55 (s, 3H),
2.71 (s, 3H), 7.86 (d, J ¼ 6.6 Hz, 1H), 8.10 (d, J ¼ 6.6 Hz,
1H), 8.32 (s, 1H) 8.96 (s, 1H), 9.30 (s, 1H); 13C NMR
(DMSO-d6): d 16.3, 18.1, 120.7, 126.6, 127.8, 130.1, 131.3,
132.6, 133.1, 133.2, 135.0, 145.7, 150.0, 159.1; ms: m/z (%)
242 (Mþ, 100), 244 (Mþ2, 37); Anal. Calcd. For C14H11ClN2
(242.70): C, 69.28; H, 4.57; N, 11.54. Found. C, 69.37; H,
4.58; N, 11.63.
9-Chloro-2-methyl-3-phenylbenzo[h][1,6]naphthyridine
(5b). Pale yellow solid; (0.156 g, 76%); mp 291–292ꢀC; ir
(potassium bromide): 3314(m), 3017(m), 2983(w), 1683(m),
1676(w), 1560(w), 1553(w) cmꢂ1 1H NMR (DMSO-d6): d
;
1
1522(m) cmꢂ1; H NMR (DMSO-d6): d 7.25 (d, J ¼ 7.5 Hz,
2H), 7.81 (d, J ¼ 8.5 Hz, 1H), 8.23 (d, J ¼ 8.5 Hz, 1H), 8.37
(d, J ¼ 7.6 Hz, 1H, ), 8.56 (d, J ¼ 7.5 Hz, 2H), 8.53 (d, J ¼
7.6 Hz, 1H), 9.08 (s, 1H), 9.31 (s, 1H); 13C NMR (DMSO-d6):
d 117.7, 123.5, 126.9, 128.0, 129.0 (2 C’s) 131.0, 131.2,
131.3, 131.4, 134.0, 134.2, 134.6, 144 (2 C’s) 147.0, 154.4,
159.8; ms: m/z (%) 368 (Mþ, 78), 370 (Mþ2, 95), 372 (Mþ4,
19); Anal. Calcd. For C18H10BrClN2 (369.64): C, 58.49; H,
2.73; N, 7.58. Found. C, 58.58; H, 2.75; N, 7.69.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

306
R. V. Rote, S. M. Bagul, D. P. Shelar, S. R. Patil, R. B. Toche, and M. N. Jachak
Vol 48
2.60 (s, 3H), 7.22–7.56 (m, 5H), 8.07 (d, J ¼ 7.4 Hz, 1H),
8.29 (d, J ¼ 7.4 Hz, 1H), 8.45 (s, 1H), 9.03 (s, 1H), 9.25 (s,
1H); ms: m/z (%) 304 (Mþ, 100), 306 (Mþ2, 32); Anal. Calcd.
For C19H13ClN2 (304.77): C, 74.88: H, 4.30; N, 9.19. Found.
C, 74.93; H, 4.48; N, 9.21.
131.1, 132.2 (2 C’s), 132.9 133.0, 134.7, 138.2, 140.1, 144.3,
147.9, 163.8; ms: m/z (%) 451 (Mþ, 100), 453 (Mþ2, 31);
Anal. Calcd. For C21H8ClF6N3 (451.75): C, 55.87; H, 1.77; N,
9.31. Found. C, 55.83; H, 1.90; N, 9.28.
9-Chloro-(2,5-dimethoxyphenyl)benzo[h][1,6]naphthyridine-
3-carbonitrile (9d). Pale yellow solid; (0.175 g, 85%); mp
293–294ꢀC; ir (potassium bromide): 2986(m), 2947(w),
2-Amino-9-chlorobenzo[h][1,6]naphthyridine-3-carboni-
trile (7). A mixture of 1b (0.206 g, 1 mmol) and malononi-
trile 6 (0.066 g, 1 mmol) in ethanol with catalytic amount of
piperidine was heated under reflux for 2 h. After completion
of reaction (TLC check), separated solid was collected by fil-
tration and recrystallized from DMF to furnish compound 7 as
colorless needles; (0.160 g, 78%); mp 279–280ꢀC; ir (potas-
sium bromide): 3406(s), 3315(w), 3084(m), 2962(w), 2744(w),
2218(m), 1683(w), 1669(w), 1527(m) cmꢂ1
;
1H NMR
(DMSO-d6): d 3.65 (s, 6H), 7.01–7.35 (m, 3H, ArAH), 8.01
(d, J ¼ 8.2 Hz, 1H), 8.23 (d, J ¼ 8.2 Hz, 1H), 8.59 (s, 1H),
8.73 (s, 1H), 9.10 (s, 1H); ms: m/z (%) 375 (Mþ, 100), 377
(Mþ2, 33); Anal. Calcd. For C21H14ClN3O2 (375.81): C,
69.12; H, 3.75; N, 11.18. Found. C, 69.17; H, 3.81; N, 11.27.
General procedure for the synthesis of compounds 11a
and b. A mixture of 1b (0.206 g, 1 mmol) and corresponding
diketone 10a–b (1 mmol) in DMF with catalytic amount of pi-
peridine was heated under reflux for 3 h. After completion of
the reaction (TLC check), solvent was evaporated under
reduced pressure. The crude solid was washed with methanol,
filtered, dried under high vacuum, and recrystallized from
ethanol: DMF (6:4) to furnish compound 11a–b in 77–79%
yield.
2218(m), 1660(s), 1599(s), 1489(s) cmꢂ1 1H NMR (DMSO-
;
d6): d 7.86 (d, J ¼ 8.7 Hz, 1H), 7.88 (s, 2H, NH2), 8.02 (d,
J ¼ 8.7 Hz, 1H), 8.75 (s, 1H), 8.89 (s, 1H), 9.05 (s, 1H); 13C
NMR (DMSO-d6): d 95.2, 119.6, 120.5, 127.3, 127.9, 129.1,
131.2, 133.1, 135.9, 142.7, 146.8, 149.6, 163.0; ms: m/z (%)
254 (Mþ, 100), 256 (Mþ2, 35); Anal. Calcd. For C13H7ClN4
(254.67): C, 61.31: H, 2.77; N, 22.00. Found. C, 61.36; H,
2.86; N, 22.09.
General procedure for the synthesis of compounds 9a–
d. A mixture of 1b (0.206 g, 1 mmol) and corresponding ben-
zoylacetonitrile 8a–d (1 mmol) in DMF with catalytic amount
of piperidine was heated under reflux for 2 h. After completion
of the reaction (TLC check), solvent was evaporated under
reduced pressure. The crude solid was washed with methanol,
filtered, dried under high vacuum, and recrystallized from
ethanol: DMF (8:2) to furnish compounds 9a–d in 75–85%
yield.
Ethyl 9-Chloro-2-methylbenzo[h][1,6]naphthyridine-3-car-
boxylate (11a). Colorless solid; (0.158 g, 77%); mp 297–
298ꢀC; ir (potassium bromide): 3161(w), 3073(m), 2981(m),
1
2935(m), 1767(s), 1661(s), 1624(m), 1510(m) cmꢂ1; H NMR
(DMSO-d6): d 1.33 (s, 3H), 3.78 (t, J ¼ 6.9 Hz, 3H), 4.35 (q,
J ¼ 6.9 Hz, 2H, OCH2), 7.92 (d, J ¼ 8.4 Hz, 1H), 8.17 (d,
J ¼ 8.4 Hz, 1H), 8.54 (s, 1H), 8.86 (s, 1H), 9.14 (s, 1H); ms:
m/z (%) 300 (Mþ, 100), 302 (Mþ2, 33); Anal. Calcd. For
C16H13ClN2O2 (300.74): C, 63.90; H, 4.36; N, 9.31. Found. C,
63.97; H, 4.49; N, 9.30.
9-Chloro-2-(4-chlorophenyl)benzo[h][1,6]naphthyridine-3-
carbonitrile (9a). Pale brown solid; (0.170 g, 83%); mp 297–
298ꢀC; ir (potassium bromide): 3002(w), 2987(m), 2811(m),
9-Chloro-2-methyl-N-phenylbenzo[h][1,6]naphthyridine-3-
carboxamide (11b). Pale yellow solid; (0.150 g, 73%); mp
271–272ꢀC; ir (potassium bromide): 3336(s), 3152(m),
1
2217(m), 1678(s), 1657(m), 1583(w), 1559(w) cmꢂ1; H NMR
(DMSO-d6): d 7.62 (d, J ¼ 7.6 Hz, 2H), 7.91 (d, J ¼ 8.2 Hz,
1H), 8.05 (d, J ¼ 7.6 Hz, 2H), 8.23 (d, J ¼ 8.2 Hz, 1H), 8.54
(s, 1H), 8.81 (s, 1H), 9.17 (s, 1H); 13C NMR (DMSO-d6): d
91.9, 117.6, 122.2, 123.8, 126.7, 129.1, 129.3, 129.7, (2 C’s),
130.1, 131.8, 132.6, 133.1, 133.3, 135.5, 140.3, 144.2, 149.1,
164.4; ms: m/z (%) 349 (Mþ, 100), 351 (Mþ2, 36), 353
(Mþ4, 14); Anal. Calcd. For C19H9Cl2N3 (350.20): C, 65.16;
H, 2.59; N, 12.00. Found. C, 65.21; H, 2.66; N, 12.11.
3017(w), 2880(m), 1693(s), 1642(s), 1624(m), 1517(w) cmꢂ1
;
1H NMR (DMSO-d6): d 1.36 (s, 3H, CH3), 7.34 (m, 5H,
ArAH), 8.01 (d, J ¼ 8.2 Hz, 1H), 8.16 (d, J ¼ 8.2 Hz, 1H),
8.34 (s, 1H), 8.80 (s, 1H), 9.14 (s, 1H), 11.80 (s, 1H, NH);
ms: m/z (%) 347 (Mþ, 100), 349 (Mþ2, 35); Anal. Calcd. For
C20H14ClN3O (347.80): C, 69.07; H, 4.06; N, 12.0. Found. C,
69.14; H, 4.01; N, 12.06.
2-(4-Bromophenyl)-9-chlorobenzo[h][1,6]naphthyridine-3-
carbonitrile (9b). Pale brown solid; (0.166 g, 81%); mp 297–
298ꢀC; ir (potassium bromide): 2963(m), 2917(m), 2221(m),
Ethyl 9-Chloro-1,2-dihydro-2-oxobenzo[h][1,6]naphthyri-
dine-3-carboxylate (13). Colorless solid; (0.152 g, 74%); mp
247–248ꢀC; ir (potassium bromide) 3398(w), 3167(m),
3072(m), 2980(s), 1741(m), 1699(s), 1662(s), 1604(s), 1500(w)
1682(w), 1667(m), 1591(m), 1551(w) cmꢂ1
;
1H NMR
1
cmꢂ1; H NMR (DMSO-d6): d 1.33 (t, J ¼ 6.9 Hz, 3H, CH3),
(DMSO-d6): d 7.75 (d, J ¼ 7.5 Hz, 2H), 8.01 (d, J ¼ 8.4 Hz,
1H), 8.15 (d, J ¼ 7.5 Hz, 2H), 8.33 (d, J ¼ 8.4 Hz, 1H), 8.64
(s, 1H), 8.81 (s, 1H), 9.01 (s, 1H); 13C NMR (DMSO-d6): d
90.0, 118.0, 123.2, 126.4, 126.8, 130.2, 130.3, 130.7, (2 C’s),
131.1, 131.7, 132.9, 134.1, 134.3, 135.7, 141.0, 143.2, 150.1,
165.3; ms: m/z (%) 394 (Mþ, 81), 396 (Mþ2, 97), 398 (Mþ4,
22); Anal. Calcd. For C19H9BrClN3 (394.65): C, 57.82; H,
2.30; N, 10.65. Found. C, 57.83; H, 2.41; N, 10.72.
4.34 (q, J ¼ 6.9 Hz, 2H, OCH2), 7.83 (d, J ¼ 7.8 Hz, 1H),
8.02 (d, J ¼ 7.8 Hz, 1H), 8.71 (s, 1H), 9.00 (s, 1H), 9.16 (s,
1H), 12.8 (s, 1H); 13C NMR (DMSO-d6): d 14.1, 60.9, 110.4,
116.9, 122.4, 123.4 131.5, 131.6, 131.8, 142.0, 143.1, 146.2,
151.5, 159.2, 163.6; ms: m/z (%) 302 (Mþ, 100), 304 (Mþ2,
34); Anal. Calcd. For C15H11ClN2O3 (302.71): C, 59.52; H,
3.66; N, 9.25. Found. C, 59.41; H, 3.67; N, 9.19.
2-(3,5-Bis(trifluoromethyl)phenyl)-9-chlorobenzo[h][1,6]-
naphthyridine-3-carbonitrile (9c). Colorless solid; (0.164 g,
80%); mp 291–292ꢀC; ir (potassium bromide): 3012(m),
2969(m), 2219(m), 1673(w), 1656(m), 1569(m), 1533(w)
REFERENCES AND NOTES
1
cmꢂ1; H NMR (DMSO-d6): d 7.76 (s, 1H), 8.03 (s, 2H), 8.14
[1] Fehnel, E. A. J Org Chem 1966, 31, 2899.
(d, J ¼ 7.5 Hz, 1H), 8.18 (d, J ¼ 7.5 Hz, 1H), 8.64 (s, 1H),
8.83 (s, 1H), 9.38 (s, 1H); 13C NMR (DMSO-d6): d 89.5,
105.3, 124.1, 124.3, 124.9, 125.7, 126.8, 128.2, 128.8 (2 C’s),
[2] Kempter, G.; Andratschke, P.; Heilmann, D.; Krausmann,
H.; Mietasch, M. Chem Ber 1964, 97, 16.
[3] Kempter, G.; Hirschberg, S. Chem Ber 1965, 98, 419.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

¨
Synthesis of Benzo[3,4-h][1,6]naphthyridines via Friedlander Condensation with
Active Methylenes
March 2011
307
[4] Nolting, E.; Herzbaum, A. Ber 1911, 44, 2585.
[23] Simay, A.; Takacs, K.; Toth, L. Acta Chim Acad Sci Hung
1982, 109, 175.
[24] Ahluwalia, V. K.; Dahiya, A. Indian J Chem 1996, 35B,
1208.
[25] Ahluwalia, V. K.; Dahiya, A.; Garg, V. K. Indian J Chem
1997, 36B, 88.
[5] Clemo, R.; Felton, D. G. I. J Chem Soc 1952, 1658.
[6] Markgraf, J. H.; Katt, R. J.; Scott, W. L.; Shefrin, R. N.
J Org Chem 1969, 34, 4134.
[7] Liao, T. K.; Nyberg, W. H.; Cheng, C. C. J Heterocycl
Chem 1971, 8, 373.
[8] Zalkow, L. H.; Nabors, J. B.; French, K.; Bisarya, S. C.
J Chem Soc C 1971, 3551.
[26] Godard, A.; Queguiner, G. J Heterocycl Chem 1980, 17,
465.
[9] Borch, R. F.; Grudzinskas, C. V.; Peterson, D. A.; Weber,
L. D. J Org Chem 1972, 37, 1141.
[27] Godard, A.; Queguiner, G. J Heterocycl Chem 1982, 19,
1279.
[28] Michael, J. Nat Prod Rep 1997, 14, 605.
[10] Jacquignon, P.; Croisy, A.; Ricci, A.; Balucani, D. Collect
Czech Chem Commun 1973, 38, 3862.
[29] Jachak, M. N.; Avhale, A. B.; Tantak, C. D.; Toche, R. B.
J Heterocycl Chem 2005, 42, 1.
[11] Croisy, A.; Jacqquignon, P.; Fravolini, A. J Heterocycl
Chem 1974, 11, 113.
[12] Cliff, G. R.; Jones, G.; Woollard, J. McK. J Chem Soc Per-
kin I 1974, 2072.
[30] Jachak, M. N.; Avhale, A. B.; Tantak, C. D.; Toche, R. B.
J Heterocycl Chem 2006, 43, 1169.
[13] Sugasawa, T.; Toyoda, T.; Sasakura, K. Chem Pharm Bull
1974, 22, 771.
[31] Jachak, M. N.; Avhale, A. B.; Toche, R. B.; Sabnis, R. W.
J Heterocycl Chem 2007, 44, 343.
[14] Tang, C. S. F.; Morrow, C. J.; Rapoport, H. J Am Chem
Soc 1975, 97, 159.
[32] Roseman, K.; Gould, M.; Linfield, M.; Edwards, B. J Med
Chem 1970, 13, 230.
[15] Imai, Y.; Johnson, E. F.; Katto, T.; Kurihara, M.; Stille,
J. K. J Polym Sci Polym Chem Ed 1975, 13, 2233.
[16] Eltsov, A. V.; Timpe, H. I.; Rtishchev, N. I. Zh. Org Khim
1975, 11, 398.
[33] Hinschberger, A.; Butt, S.; Lelong, V.; Boulouard, M.;
Dumuis, A.; Dauphin, F.; Bureau, R.; Pfeiffer, B.; Renard, P.; Rault,
S. J Med Chem 2003, 46, 138.
[34] Godard, A.; Queguiner, G. J Heterocycl Chem 1980, 17,
465.
[17] Settimo, A. Da.; Primofiore, G.; Livo, O.; Ferrarini, P. L.;
Spinelli, S. J Heterocycl Chem 1979, 16, 169.
[18] Hawes, E. M.; Wibberley, D. G. J Chem Soc 1966, 315.
[19] Majewicz, T. G.; Caluwe, P. J Org Chem 1975, 3407.
[20] Hawes, E. M.; Wibberley, D. G. J Chem Soc C 1967, 1564.
[21] Hawes, E. M.; Gorecki, D. K. J.; Gedir, R. G. J Med Chem
1977, 20, 838.
[35] Hohn, H.; Janssen, W. J Heterocycl Chem 1972, 9, 235.
[36] Wilfred, C. D. Malays J Chem 2006, 8, 52.
[37] (a) Cheng, C. C.; Yan, S. Y. Org React 1982, 28, 37; (b)
Mundy, B. P.; Ellerd, M. G. Name Reactions and Reagents in Organic
Synthesis; Wiley: New York, 1982;
p 86; (c) Karthikeyan, G.;
[22] Haufel, J.; Breitmaier, E. Angew Chem Int Ed 1977, 13,
604.
Perumal, P. T. J Heterocycl Chem 2004, 41, 1039; (d) Diaz-Ortiz, A.;
Hoz, de la.; Langa, F. Green Chem 2000, 2, 165.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet