Three-step synthesis of ethyl canthinone-3-carboxylates from ethyl 4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate via a Pd-catalyzed Suzuki-Miyaura coupling and a Cu-catalyzed amidation reaction

Article abstract of DOI:10.1021/jo200824b

Ethyl canthin-6-one-1-carboxylate (1b) and nine analogues 1c-k were prepared from readily prepared ethyl 4-bromo-6-methoxy-1,5-naphthyridine-3- carboxylate (2b) via a three-step non-classical approach that focused on construction of the central pyrrole (r

Full text of DOI:10.1021/jo200824b

ARTICLE
pubs.acs.org/joc
Three-Step Synthesis of Ethyl Canthinone-3-carboxylates from Ethyl
4-Bromo-6-methoxy-1,5-naphthyridine-3-carboxylate via a
Pd-Catalyzed SuzukiꢀMiyaura Coupling and a Cu-Catalyzed
Amidation Reaction
Heraklidia A. Ioannidou,† Aaron Martin,†,‡ Andreas Gollner,†,‡ and Panayiotis A. Koutentis*,†
†Department of Chemistry, University of Cyprus, P.O. Box 20537, 1678 Nicosia, Cyprus
‡Cyano Research Corporation Ltd., P.O. Box 28670, 2081 Nicosia, Cyprus
S Supporting Information
b
ABSTRACT: Ethyl canthin-6-one-1-carboxylate (1b) and nine
analogues 1cꢀk were prepared from readily prepared ethyl
4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (2b) via
a three-step non-classical approach that focused on construc-
tion of the central pyrrole (ring B) using Pd-catalyzed Suzukiꢀ
Miyaura coupling followed by Cu-catalyzed CꢀN coupling.
Furthermore, treatment of the ethyl canthinone-1-carboxylate
1b with NaOH in DCM/MeOH (9:1) gave the canthin-6-one-
1-carboxylic acid (6) in high yield. All compounds are fully characterized.
1. INTRODUCTION
Canthin-6-one (1, Figure 1) (6H-indolo[3,2,1-de][1,5]naph-
thyridin-6-one), first isolated in 1952 by Haynes,1 is the parent of
the >120-member canthinone alkaloid family, which includes over
40 naturally occurring analogues.2 Selected canthin-6-one alka-
loids have interesting biological properties including antiparasitic
activity against Trypanosoma cruzi (Chagas disease)3 and Plasmo-
dium falciparum (malaria),4 antibacterial,5 and antifungal6 proper-
ties. Furthermore, some canthinones are cytotoxic against several
Figure 1. Structure and chemical numbering of canthin-6-one.
strains of cancer cells4a,b,7 and act as vasodilators since they can
inhibit cAMP phosphodiesterase,8 and 1-methoxycanthinone is a
(3a) (R1 = H), and 2-haloarylboronic acids.13 The synthesis
involved construction of ring B via transition-metal-catalyzed
intermolecular CꢀC and intramolecular CꢀN bond formation.
By varying the 2-haloarylboronic acids the construction of analo-
gues bearing substitution on ring A was achieved (Scheme 1).
Here we disclose our successes related to the preparation of
10 new canthinone-1-carboxylates including the first examples of
aza-canthinone analogues startingfromethyl 4-bromo-6-methoxy-
1,5-naphthyridine-3-carboxylate 2b (R1 = CO2Et) via the step-
wise protocol.
potent anti-HIV agent.7f
Owing to this broad range of biological activity there is
continued demand for syntheses that provide functionalized
canthinones efficiently. Canthinones bearing carboxylate groups
are of particular value since modification of the carboxylate group
can lead to a wide variety of other functionalities. We note
that there are several reports on the preparation of canthinone-2-
carboxylates,9 but only two reports on canthinone-5-carboxylates10
and one report each on canthinone-1,2-dicarboxylates11 and
1,2,5-tricarboxylates.9c No specific routes to canthinone-1-carbox-
ylates have been reported, and we therefore considered preparing
a series of this class of canthinones.
2. RESULTS AND DISCUSSION
The “classical” approach to synthesize canthinones relies on the
sequential construction of rings C and D starting from indoles or
construction of the D ringstarting fromβ-carbolines.9bꢀd,g,10a,11,12
Recently, we demonstrated both a rapid one-pot and stepwise
non-classical convergentsynthesisof canthinones 1a (R1 = H) that
required access to available 4-bromo-6-methoxy-1,5-naphthyri-
dine (2a) (R1 = H), 4-bromo-5,6-dihydro-1,5-naphthyrid-6-one
The stepwise synthesis of the desired ethyl canthinone-1-
carboxylate 1b (R1 = CO2Et) (ethyl 6-oxo-6H-indolo[3,2,1-de]-
[1,5]naphthyridine-1-carboxylate) required the known ethyl
4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate (2b), which
Received: April 21, 2011
Published: May 12, 2011
r
2011 American Chemical Society
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Scheme 1. One-Pot and Stepwise Routes to Canthinones via Naphthyridines and Naphthyridones
can be prepared in multigram quantities (3ꢀ5 g) in three steps
Table 1. Reaction of Bromonaphthyridine 2b (1.2 mmol)
with ArB(OH)2 (1.8 equiv) in the Presence of K2CO3 (2 equiv),
from commercially available 6-methoxypyridin-3-amine.14 At-
tempts to access the one-pot procedure required access to the
unknown ethyl 4-bromo-6-oxo-5,6-dihydro-1,5-naphthyridine-
3-carboxylate (3b); however, this route could not be realized
because a clean demethylation of the bromonaphthyridine 2b
using either TMSCl/NaI in MeCN, aq HBr in dioxane at reflux,
or BBr3 in DCM 0 to ca. 20 °C failed.
Pd(dppf)CI2 DCM (5 mol %) in Dioxane/H2O (3:1) Heated
3
at Reflux for 2 h
2.1. SuzukiꢀMiyaura Coupling Reactions of the Bromo-
naphthyridines 2b. With ethyl 4-bromo-6-methoxy-1,5-naph-
thyridine-3-carboxylate (2b) in hand the stepwise synthetic
protocol was followed. As such, the SuzukiꢀMiyaura coupling
of a variety 2-haloarylboronic acids (1.8 equiv) with the bromo-
entry
ArB(OH)2
yield of 4 (%)
naphthyridine 2b using Pd(dppf)Cl2 DCM (5 mol %) as catalyst
3
1
2-BrC6H4B(OH)2
4a (98)
4b (90)
4c (99)
4d (86)
4e (92)
4f (84)
4g (90)
4h (89)
4i (92)
and K2CO3 (2 equiv) as base in aqueous dioxane/H2O (3:1)
heated to reflux for ca. 2 h gave 8-(2-haloaryl)-2-methoxy-
naphthyridines 4aꢀl in high yields (Table 1).
2
2-ClC6H4B(OH)2
3
2,3-Cl2C6H3B(OH)2
2,4-Cl2C6H3B(OH)2
2-Cl-4-F3CC6H3B(OH)2
2-Cl-4-MeC6H3B(OH)2)
2-Cl-4-MeOC6H3B(OH)2
2-Cl-4-FC6H3B(OH)2
2,5-Cl2C6H3B(OH)2
2-Cl-5-F3CC6H3B(OH)2
2-Cl-6-FC6H3B(OH)2
2-Cl-6-MeOC6H3B(OH)2
2-Cl-Pyrid-3-ylB(OH)2
Typically the reactions came to completion with only a
minimal quantity of biphenyl byproduct present (by TLC).
The ethyl 4-(2-haloaryl)-6-methoxy-1,5-naphthyridine-3-
carboxylates 4aꢀl were isolated by dry flash chromatography
(hexane/t-BuOMe, 4:1) as viscous yellow oils that were in nearly
all cases crystallized from pentane. Furthermore, electron impact
(EI) mass spectrometry of these naphthyridines indicated only
very weak or nonvisible parent ions owing to a very facile
fragmentation of the 2-halogen on the 4-aryl substituent, leading
to the m/z (Mþ ꢀ Hal) ion as the base peak.
4
5
6
7
8
9
10
11
12
13
14
4j (92)
a
a
The SuzukiꢀMiyaura coupling also tolerated the use of the
heterocyclic 2-chloropyrid-3-ylboronic acid (entry 13) and
3-chloropyrid-4-ylboronic acid pinacol ester (entry 14), which
afforded the corresponding pyridylnaphthyridines 4k and 4l in
64% and 62% yields, respectively, with no sign of bipyridyl
byproducts. Sterically demanding 2,6-disubstituted arylboronic
acids, however, led to the quantitative recovery of the starting
bromonaphthyridine 2b (entries 11 and 12).
4k (64)
4l (62)
b
3-Cl-Pyrid-4-ylB(OR)2
a No reaction; starting bromonaphthyridine 2b recovered. b 3-Cl-Pyrid-
4-ylB(OR)2 = pinacol ester.
were isolated using dry flash chromatography (t-BuOMe, 100%)
and recrystallized from the same solvent. 1H NMR spectroscopy
of the products showed the absence of the naphthyridine
methoxy signals (ca. 3.7 ppm) and the formation of a broad
exchangeable signal at 8.0ꢀ8.6 ppm attributed to the naphthy-
ridone amide NH. The presence of the amide was also supported
by FTIR spectroscopy, which showed new amide carbonyl
stretching frequencies ν(NH-CdO) 1659ꢀ1697 cmꢀ1. With
the naphthyridones 5aꢀl accessible, formation of the central B
ring could be pursued via a copper-catalyzed Buchwald cyclization.
2.3. Synthesis of Ethyl Canthinone-1-carboxylate 1b and
Its Analogues. Treating ethyl 4-(2-bromophenyl)-6-oxo-5,
6-dihydro-1,5-naphthyridine-3-carboxylate (5a) with our typical
Buchwald conditions [CuI (5 mol %), DMEDA (10 mol %),
2.2. Demethylation of 4-Aryl-6-methoxy-1,5-naphthyri-
dines 4. Demethylation of the ethyl 4-(2-haloaryl)-6-methoxy-
1,5-naphthyridine-3-carboxylates 4aꢀl to afford the desired
ethyl 4-(2-haloaryl)-6-oxo-5,6-dihydro-1,5-naphthyridine-3-car-
boxylates 5aꢀl was achieved using TMSCl/NaI15 in MeCN
heated to reflux for about 1ꢀ2 h (Table 2).
Earlier attempted demethylations using aqueous HCl in
dioxane at reflux that had previously worked well for the nonester
analogues,13 and BBr3 resulted in complex reaction mixtures
(TLC). Interestingly, the TMSCl/NaI demethylation conditions
were selective and differentiated between the naphthyridine and
anisidine methoxy groups (entry 7). The naphthyridones 5aꢀl
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ARTICLE
Table 2. Demethylation of Naphthyridines 4 (0.5 mmol) with
TMSCI (5 equiv) and Nal (3 equiv) in MeCN (1 mL) at Reflux
for 1ꢀ2 h To Give Naphthyridones 5
Table 3. Cyclization of Naphthyridones 5 (0.13 mmol) with
Cul, Ligand, Cs2CO3 (2 equiv), and Water (2 equiv) in Reflux-
ing Dioxane (2 mL) To Give Canthin-6-ones 1
entry
Hal
R
yield of 5 (%)
entry Hal Cul (mol %) ligand (mol %) time (h) R2 yield of 1 (%)
1
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
H
H
5a (70)
5b (81)
5c (92)
5d (83)
5e (80)
5f (74)
5g (89)
5h (98)
5i (97)
5j (92)
5k (83)
51 (67)
1
2
3
4
5
6
7
8
9
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
5
5
DMEDA (10)
DMEDA (10)
DMEDA (60)
DMEDA (60)
DMCDA (60)
DMCDA (60)
1
24
18
9
H
1b (85)
2
a
H
3
3-Cl
30
10
10
10
30
10
10
10
10
20
10
20
10
10
10
20
10
20
H
1b (48)
1b (84)
4
4-Cl
H
5
4-F3C
4-Me
4-MeO
4-F
2
H
1b (74)
b
6
24
8-Cl
8-Cl
9-Cl
9-F3C
9-Me
9-MeO
9-MeO
9-F
7
b
DMCDA (180) 24
8
DMCDA (60)
DMCDA (60)
DMCDA (60)
DMCDA (60)
4
1
1c (85)
1d (90)
9
5-Cl
10
11
12
5-F3C
3-aza
4-aza
10 Cl
11 Cl
12 Cl
13 Cl
14 Cl
15 Cl
16 Cl
17 Cl
18 Cl
19 Cl
20 Cl
12
24
1e (80)
a
DMCDA (120) 24
DMCDA (60) 24
DMCDA (120) 24
1f (73)
a
Cs2CO3 (2 equiv), water (2 equiv) in refluxing dioxane, 1 h]13
gave the ethyl canthinone-1-carboxylate 1b in 85% yield
(Table 3, entry 1). However, these conditions were not success-
ful with the 2-chlorophenyl analogue 5b that gave only traces of
product even after 24 h (entry 2). The reaction could, however,
be driven to completion when additional CuI/DMEDA (a total
of 30 mol % with respect to CuI) was added to the reaction
mixture, affording after 18 h the canthinone 1b in moderate yield
(48%) (entry 3). By premixing various ratios of CuI and
DMEDA in dioxane/H2O (1 mL), we found that a ratio of
CuI (10 mol %)/DMEDA (60 mol %) added to the reaction
mixture of starting material and base in dioxane/H2O (1 mL)
significantly improved the product yield and shortened the
reaction time, affording the desired canthinone 1b in 84% yield
in only 9 h (entry 4). Further increases in the ratio of CuI/
DMEDA, 1:8 and 1:10, did not improve the yields but did
shorten the reaction times further, 82%/3.5 h and 83%/3 h,
respectively. Keeping the ratio of CuI/DMEDA at 1:6 and
reducing the quantity of CuI (5 mol %) led to a very slow
reaction that gave only traces of product after 24 h (TLC). In a
further attempt to improve the cyclization, DMEDA was re-
placed with the ligand trans-N,N0-dimethyl-1,2-cyclohexanedia-
mine (DMCDA), which was known to be particularly effective
for CꢀN coupling of chloro-substituted substrates.16 As such,
when a dioxane/H2O (1 mL) solution of the 2-chlorophenyl
analogue 5b (R1 = H) and Cs2CO3 (2 equiv) was treated with a
premix of CuI (10 mol %)/DMCDA (60 mol %) and heated
to reflux for 2 h, the cyclization was completed, affording
the canthinone 1b in 74% yield (entry 5). These conditions
also worked well for most of the remaining 2-chlorophenyl
derivatives (entries 8ꢀ10, 15, and 16). The exceptions were
the 2,3-dichlorophenyl analogue 5c (R1 = 3-Cl) (entries 6 and 7),
which gave no reaction even with 30 mol % CuI, and the
2-chloro-4-methoxyphenyl, 2-chloro-4-fluorophenyl, 2-chloro-
pyrid-3-yl, and 3-chloropyrid-4-yl analogues, 5g (R1 = 4-MeO),
9-F
1g (70)
1h (89)
DMCDA (60)
DMCDA (60)
DMCDA (60)
DMCDA (120)
DMCDA (60)
DMCDA (120)
1.5 10-Cl
4.3 10-F3C
1i (95)
a
24
8-aza
8-aza
9-aza
9-aza
4
24
4
1j (69)
a
1k (56)
a Incomplete reaction. b No reaction; starting material recovered even
after 24 h.
Scheme 2. Hydrolysis of Ethyl Canthinone-1-carboxylate 1b
5h (R1 = 4-F), 5k (R1 = 3-aza), and 5l(R1 = 4-aza), which required
a CuI catalyst loading of at least 20 mol % to reach completion
(entries 11ꢀ14 and 17ꢀ20) (Table 3). Worthy of note was the
cyclization of the two pyridyl analogues 5k and 5l that afforded, to
the best of our knowledge, the first azacanthinones 1j and 1k in
69% and 56% yields, respectively (entries 18 and 20). The failure
to cyclize the 2,3-dichlorophenyl analogue 5c was surprising since
the analogous non-ester-substituted canthinone was readily
prepared.13 This anomaly is now under further investigation.
Having demonstrated a route to the ethyl canthinone-1-
carboxylates 1bꢀk, we showed that the ester group of the ethyl
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ARTICLE
canthinone-1-carboxylate 1b could be readily hydrolyzed
(Scheme 2). Treating a DCM/MeOH (9:1) solution of the
ethyl canthinone-1-carboxylate 1b with NaOH (4 equiv) at ca.
20 °C for 24 h17 afforded a precipitate assumed to be the sodium
carboxylate. Acidification of the reaction mixture using 10% HCl
followed by extraction with EtOAc afforded the orange canthi-
none-1-carboxylic acid 6 (6-oxo-6H-indolo[3,2,1-de][1,5]naph-
thyrid-ine-1-carboxylic acid) in excellent yield.
80ꢀ81 °C (DCM/pentane), Rf 0.60 (hexane/t-BuOMe, 8:2); (found:
C, 55.7; H, 3.8; N, 7.3. C18H15BrN2O3 requires C, 55.8; H, 3.9; N, 7.2);
λmax (DCM)/nm 231 (log ε 4.01), 264 (3.14), 333 (3.36); νmax/cmꢀ1
1703s, 1612 m, 1498 m, 1402 m, 1338 m, 1255 m, 1110 m, 840 m, 748s;
δH (500 MHz; CD2Cl2) 9.28 (1H, s, Ar H), 8.27 (1H, d, J = 9.0, Ar H),
7.69 (1H, d, J = 7.9, Ar H), 7.40 (1H, ddd, J = 7.4, 7.4, 1.3, Ar H), 7.30
(1H, ddd, J = 8.5, 7.6, 1.7, Ar H), 7.21 (1H, dd, J = 7.6, 1.6, Ar H), 7.17
(1H, d, J = 9.2, Ar H), 4.15 (2H, q, J = 7.1, OCH2), 3.70 (3H, s, OCH3),
1.05 (3H, t, J = 7.1, CH3); δC (125 MHz; CD2Cl2) 166.0 (s), 162.7 (s),
148.5 (d), 147.3 (s), 144.3 (s), 140.4 (d), 140.0 (s), 138.5 (s), 132.2 (d),
130.9 (d), 129.4 (d), 126.9 (d), 126.3 (s), 123.2 (s), 118.3 (d), 61.8
(OCH2), 54.0 (OCH3), 13.9 (CH3); m/z (EI) 307 (Mþ ꢀ Br, 100%),
279 (75), 247 (8), 236 (12), 191 (14), 164 (12).
4.2.1. 4-(2-Chlorophenyl)-6-methoxy-1,5-naphthyridine-3-carbox-
ylate (4b). (307 mg, 90%) as colorless plates, mp 67ꢀ69 °C (pentane),
Rf 0.60 (hexane/t-BuOMe, 8:2); (found: C, 63.2; H, 4.4; N, 8.1.
C18H15ClN2O3 requires C, 63.1; H, 4.4; N, 8.2); λmax (DCM)/nm
236 (log ε 4.03), 261 (3.63), 270 (3.61), 282 inf (3.49), 327 (3.49), 339
(3.46); νmax/cmꢀ1 2992w, 2941w, 1705s (CdO), 1612 m, 1562w, 1501
m, 1479w, 1464w, 1433w, 1402s, 1366 m, 1339s, 1321s, 1290 m, 1261s,
1256 m, 1223 m, 1206 m, 1180w, 1134 m, 1113 m, 1059w, 1034s, 1018
m, 999w, 932w, 868w, 843s, 812w, 775 m, 760 m; δH (500 MHz;
CD2Cl2) 9.28 (1H, s, Ar H), 8.27 (1H, d, J = 9.0, Ar H), 7.50 (1H, dd, J =
7.7, 1.4, Ar H), 7.39 (1H, ddd, J = 7.5, 7.5, 1.8, Ar H), 7.36 (1H, ddd, J =
7.5, 7.5, 1.5, Ar H), 7.24 (1H, dd, J = 7.3, 1.9, Ar H), 7.17 (1H, d, J = 9.2,
Ar H), 4.15 (2H, q, J = 7.1, OCH2), 3.70 (3H, s, OCH3), 1.05 (3H, t, J =
7.2, CH3); δC (125 MHz; CD2Cl2) 166.1 (s), 162.8 (s), 148.5 (d), 145.8
(s), 144.2 (s), 140.4 (d), 140.1 (s), 136.3 (s), 133.3 (s), 131.1 (d), 129.4
(d), 129.1 (d), 126.6 (s), 126.3 (d), 118.3 (d), 61.8 (OCH2), 54.0
(OCH3), 13.9 (CH3); m/z (EI) 308 (MHþ ꢀ Cl, 20%), 307 (Mþ ꢀ Cl,
100), 280 (14), 279 (68), 264 (17), 247 (12), 236 (8), 226 (7), 219 (8),
201 (5), 191 (10), 165 (5), 164 (11), 113 (5).
3. CONCLUSION
Starting from the known ethyl 4-bromo-6-methoxy-1,5-naph-
thyridine-3-carboxylate (2b), a series of eight ethyl canthinone-1-
carboxylates 1bꢀi were prepared bearing various substituents on
the A ring, together with the 8-aza and 9-aza analogues 1j and 1k
that constitute two members of previously unknown ring systems.
The synthetic route that was used involved three key steps: first
the SuzukiꢀMiyaura arylation of the 4-bromonaphthyridine 2b
to afford the ethyl 4-(2-haloaryl)-6-methoxy-1,5-naphthyridine-
3-carboxylates 4aꢀl, then the TMSCl/NaI mediated demethy-
lation to afford the ethyl 4-(2-haloaryl)-6-oxo-5,6-dihydro-1,
5-naphthyridine-3-carboxylates 5aꢀl, and finally the copper-
catalyzed Buchwald cyclization to afford the target ethyl can-
thinone-1-carboxylates 1bꢀk. The biological properties of these
compounds are now being studied.
4. EXPERIMENTAL SECTION
4.1. General Procedures. DCM was freshly distilled from CaH2
under argon. Reactions were protected from atmospheric moisture by
CaCl2 drying tubes. Anhydrous Na2SO4 was used for drying organic
extracts, and all volatiles were removed under reduced pressure. All
reaction mixtures and column eluents were monitored by TLC using
commercial glass backed thin layer chromatography (TLC) plates
(Kieselgel 60 F254). The plates were observed under UV light at 254
and 365 nm. The technique of dry flash chromatography18 was used
throughout for all non-TLC scale chromatographic separations using
silica gel 60 (less than 0.063 mm). Melting points were determined using
a hotstage microscope apparatus. Solvents used for recrystallization are
indicated after the melting point. UV spectra were obtained using a
UVꢀvis spectrophotometer and inflections are identified by the abbre-
viation “inf”. IR spectra were recorded on a FTIR-NIR spectrometer
with a Ge ATR accessory and strong, medium, and weak peaks are
represented by s, m, and w, respectively. 1H and 13C NMR spectra were
recorded either at 300 and 75 MHz, respectively or at 500 and 125 MHz,
respectively. DEPT 135 or APT NMR studies identified quaternary and
tertiary carbons, which are indicated by (s) and (d) notations, respec-
tively. Deuterated solvents were used for homonuclear lock, and the
signals are referenced to the deuterated solvent peaks. Low resolution
(EI) mass spectra were recorded on a GCꢀMS with direct inlet
probe. Ethyl 4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate
(2b) was prepared according to literature procedures.14
4.2.2. Ethyl 4-(2,3-Dichlorophenyl)-6-methoxy-1,5-naphthyridine-
3-carboxylate (4c). (373 mg, 99%) as colorless cubes, mp 107ꢀ108 °C
(pentane), Rf 0.30 (hexane/t-BuOMe, 8:2); (found: C, 57.5; H, 3.9; N,
7.3. C18H14Cl2N2O3 requires C, 57.3; H, 3.7; N, 7.4); λmax (DCM)/nm
232 (log ε 3.94), 261 (3.32), 269 (3.28), 327 (3.27), 339 (3.25); νmax
/
cmꢀ1 3046w (Ar CH), 2990w, 2941w, 1713s (CdO), 1612 m, 1499s,
1479w, 1450w, 1402 m, 1371w, 1339 m, 1323s, 1277 m, 1261 m, 1225
m, 1180w, 1144 m, 1117 m, 1038 m, 1018 m, 991w, 941w, 848 m, 816 m,
789 m, 773w; δH (300 MHz; CD2Cl2) 9.30 (1H, s, Ar H), 8.27 (1H, d,
J = 9.3, Ar H), 7.57 (1H, dd, J = 7.8, 1.8, Ar H), 7.31 (1H, dd, J = 7.8, 7.8,
Ar H), 7.18 (1H, d, J = 9.0, Ar H), 7.14 (1H, dd, J = 7.5, 1.5, Ar H), 4.16
(2H, q, J = 7.0, OCH2), 3.69 (3H, s, OCH3), 1.07 (3H, t, J = 7.1, CH3);
δC (75 MHz; CD2Cl2) 165.7 (s), 162.9 (s), 148.6 (d), 145.4 (s), 144.4
(s), 140.4 (d), 139.9 (s), 138.8 (s), 132.8 (s), 131.7 (s), 129.9 (d), 129.2
(d), 127.1 (d), 126.0 (s), 118.6 (d), 61.9 (OCH2), 54.0 (OCH3), 13.9
(CH3); m/z (EI) 378 (Mþ þ 2, 0.2%), 376 (Mþ, 0.2), 343 [(Mþ þ 2) ꢀ
Cl, 36], 341 (Mþ ꢀ Cl, 100), 333 (2), 331 (4), 315 (17), 313 (61), 298
(10), 278 (7), 270 (11), 254 (7), 225 (7), 198 (8), 189 (4), 162 (8), 126
(5), 99 (5), 63 (9).
4.2.3. Ethyl 4-(2,4-Dichlorophenyl)-6-methoxy-1,5-naphthyridine-
3-carboxylate (4d). (323 mg, 86%) as colorless cubes, mp 82ꢀ83 °C
(pentane), Rf 0.29 (hexane/t-BuOMe, 8:2); (found: C, 57.5; H, 3.7; N,
7.4. C18H14Cl2N2O3 requires C, 57.3; H, 3.7; N, 7.4); λmax (DCM)/nm
232 (log ε 3.66), 261 inf (2.87), 270 inf (2.76), 329 (2.95), 339 (2.93);
νmax/cmꢀ1 2986w, 2941w, 1712s (CdO), 1612 m, 1595w, 1570w,
1557w, 1501s, 1464 m, 1435w, 1404s, 1366 m, 1340 m, 1321s, 1281s,
1267s, 1248 m, 1225 m, 1207 m, 1180w, 1138s, 1115 m, 1099 m, 1057
m, 1034 m, 1016 m, 1001w, 932w, 866 m, 845s, 833s, 814 m, 791 m, 775
m; δH (300 MHz; CD2Cl2) 9.30 (1H, s, Ar H), 8.26 (1H, d, J = 9.0, Ar
H), 7.55 (1H, d, J = 2.1, Ar H), 7.37 (1H, dd, J = 8.3, 2.1, Ar H),
7.25ꢀ7.20 (2H, m, Ar and Ar H), 4.19 (2H, q, J = 7.2, OCH2), 3.72 (3H,
s, OCH3), 1.11 (3H, t, J = 7.1, CH3); δC (75 MHz; CD2Cl2) 165.8 (s),
4.2. Ethyl 4-(2-Bromophenyl)-6-methoxy-1,5-naphthy-
ridine-3-carboxylate (4a) (Typical Procedure; See Table 1,
Entry 1). Ethyl 4-bromo-6-methoxy-1,5-naphthyridine-3-carboxylate
(2b) (310 mg, 1 mmol), K2CO3 (279 mg, 2 equiv), Pd(dppf)Cl2 DCM
3
(41 mg, 0.05 mmol), and 2-bromophenylboronic acid (264 mg, 1.8
mmol) were dissolved in dioxane/H2O (3:1) (2 mL). The stirred
mixture was heated to reflux (preheated oil bath) and refluxed for 2 h
until the reaction was finished (TLC), before it was allowed to cool to ca.
20 °C. It was diluted (DCM, 20 mL), dried (Na2SO4), filtered, and
adsorbed onto silica gel. Dry flash chromatography (hexane/t-BuOMe,
4:1) gave the title compound 4a (378 mg, 98%) as colorless cubes, mp
5116
dx.doi.org/10.1021/jo200824b |J. Org. Chem. 2011, 76, 5113–5122

The Journal of Organic Chemistry
ARTICLE
162.9 (s), 148.4 (d), 144.8 (s), 144.2 (s), 140.3 (d), 139.9 (s), 135.1 (s),
134.3 (s), 134.1 (s), 132.0 (d), 129.0 (d), 126.7 (d), 126.3 (s), 118.6 (d),
62.0 (OCH2), 54.1 (OCH3), 14.0 (CH3); m/z (EI) 343 [(Mþ þ 2) ꢀ
Cl, 33%], 341 (Mþ ꢀ Cl, 100), 333 (3), 331 (5), 315 (19), 313 (63), 298
(14), 278 (5), 270 (7), 253 (7), 225 (9), 198 (11), 190 (4), 163 (3), 147
(5), 124 (3), 99 (4), 80 (5).
(pentane), Rf 0.35 (hexane/t-BuOMe, 8:2); (found: C, 60.1; H, 3.9; N,
7.8. C18H14ClFN2O3 requires C, 59.9; H, 3.9; N, 7.8); λmax (DCM)/nm
233 (log ε 3.88), 261 (3.32), 271 (3.29), 325 (3.20), 339 (3.14); νmax
/
cmꢀ1 3048w, 2986w, 1730s (CdO), 1611 m, 1572w, 1495s, 1470w,
1435w, 1402 m, 1369w, 1339 m, 1273s, 1234 m, 1213 m, 1200 m,
1182w, 1144w, 1113w, 1036w, 1016 m, 991w, 945w, 899 m, 853s, 820w,
804w, 774 m; δH (300 MHz; CD2Cl2) 9.28 (1H, s, Ar H), 8.26 (1H, d,
J = 9.0, Ar H), 7.30ꢀ7.11 (4H, m, Ar H), 4.18 (2H, q, J = 7.1, OCH2),
3.72 (3H, s, OCH3), 1.10 (3H, t, J = 9.0, CH3); δC (75 MHz; CD2Cl2)
165.9 (s), 164.2 (s), 161.9 (d, 1JCF 249.2, FC), 148.5 (d), 144.9 (s), 144.3
(s), 140.4 (d), 140.1 (s), 134.1 (d, 3JCF 10.6, FCCHCCl), 132.1 (d, 4JCF
3.8, FCCHCHCq), 132.4 (d, 3JCF 9.1, FCCHCH), 126.6 (s), 118.5 (d),
116.5 (d, 2JCF 25.7, FCCH), 113.7 (d, 2JCF 21.9, FCCH), 61.9 (OCH2),
54.0 (OCH3), 14.0 (CH3); m/z (EI) 325 (Mþ ꢀ Cl, 100%), 315 (5),
297 (55), 282 (13), 265 (7), 254 (7), 244 (7), 237 (6), 223 (3), 209 (8),
182 (11), 156 (3), 131 (5), 80 (3).
4.2.4. Ethyl 4-[2-Chloro-4-(trifluoromethyl)phenyl]-6-methoxy-1,5-
naphthyridine-3-carboxylate (4e). (377 mg, 92%) as colorless prisms,
mp 90ꢀ91 °C (pentane), Rf 0.29 (hexane/t-BuOMe, 8:2); (found: C,
55.6; H, 3.3; N, 6.6. C19H14ClF3N2O3 requires C, 55.6; H, 3.4; N, 6.8);
λmax (DCM)/nm 233 (log ε 3.71), 272 (2.83), 325 (2.97), 340 (2.89);
νmax/cmꢀ1 2986w, 2945w, 1713 m (CdO), 1612 m, 1499 m, 1472w,
1406w, 1391w, 1368w, 1343w, 1323s, 1288w, 1271 m, 1254w, 1227w,
1209w, 1177s, 1138s, 1117w, 1082 m, 1063w, 1036w, 1015w, 1003w,
934w, 897w, 868w, 843 m, 814w; δH (300 MHz; CD2Cl2) 9.33 (1H, s,
Ar H), 8.28 (1H, d, J = 9.0, Ar H), 7.80 (1H, s, Ar H), 7.64 (1H, d, J = 8.1,
Ar H), 7.39 (1H, d, J = 8.1, Ar H), 7.20 (1H, d, J = 9.0, Ar H), 4.17 (2H, q,
J = 7.1, OCH2), 3.68 (3H, s, OCH3), 1.06 (3H, t, J = 7.1, CH3); δC (75
MHz; CD2Cl2) 165.6 (s), 163.0 (s), 148.6 (d), 144.5 (s), 144.4 (s),
140.7 (s), 140.4 (d), 139.7 (s), 134.1 (s), 131.6 (d), 131.2 (q, 2JCF 33.2,
F3CC), 125.9 (q, 3JCF 3.8, F3CCqCH), 122.3 (q, 3JCF 3.8, F3CCqCH),
123.1 (q, 1JCF 269.8, F3C), 118.8 (d), 62.0 (OCH2), 54.1 (OCH3), 13.8
(CH3); m/z (EI) 411 (Mþ þ H, 0.5%), 409 (Mþ ꢀ H, 1), 376 (MHþ ꢀ
Cl, 22), 375 (Mþ ꢀ Cl, 100), 365 (4), 347 (70), 332, (10), 315 (4), 304
(6), 294 (5), 287 (4), 259 (5), 232 (6), 80 (4), 64 (2).
4.2.5. Ethyl 4-(2-Chloro-4-methylphenyl)-6-methoxy-1,5-naphthy-
ridine-3-carboxylate (4f). (299 mg, 84%) as colorless cubes, mp
69ꢀ71 °C (pentane), Rf 0.35 (hexane/t-BuOMe, 8:2); (found: C,
64.1; H, 4.7; N, 7.7. C19H17ClN2O3 requires C, 64.0; H, 4.8; N, 7.9);
λmax (DCM)/nm 237 (log ε 4.18), 250 inf (3.90), 258 inf (3.78), 267 inf
(3.67), 329 (3.77); νmax/cmꢀ1 2982w, 2943w, 2853w, 1726s (CdO),
1609 m, 1574w, 1493s, 1468w, 1433w, 1402 m, 1368 m, 1341 m, 1283
m, 1259s, 1223s, 1207 m, 1140 m, 1138 m, 1111 m, 1059w, 1038w, 1024
m, 993w, 943w, 878w, 851 m, 829 m, 818w, 772 m; δH (500 MHz;
CD2Cl2) 9.25 (1H, s, Ar H), 8.26 (1H, d, J = 9.0, Ar H), 7.33 (1H, s, Ar
H), 7.17 (1H, d, J = 9.0, Ar H), 7.13ꢀ7.11 (2H, m, Ar H), 4.17 (2H, q, J =
7.2, OCH2), 3.73 (3H, s, OCH3), 2.43 (3H, s, CH3), 1.09 (3H, t, J = 7.2,
CH3); δC (125 MHz; CD2Cl2) 166.2 (s), 162.7 (s), 148.4 (d), 145.9 (s),
144.2 (s), 140.9 (d), 140.3 (s), 139.8 (s), 133.0 (s), 132.9 (Cq), 130.9
(d), 129.6 (d), 127.1 (d), 126.9 (s), 118.2 (d), 61.8 (OCH2), 54.0
(OCH3), 21.3 (CH3), 14.0 (CH3); m/z (EI) 322 (MHþ ꢀ Cl, 19%),
321 (Mþ ꢀ Cl, 100), 311 (4), 293 (53), 278 (11), 261 (4), 250 (6), 240
(4), 233 (6), 205 (6), 178 (3), 151 (3), 138 (3), 127 (2).
4.2.6. Ethyl 4-(2-Chloro-4-methoxyphenyl)-6-methoxy-1,5-naphthy-
ridine-3-carboxylate (4g). (335 mg, 90%) as colorless cubes, mp
97ꢀ99 °C (pentane), Rf 0.23 (hexane/t-BuOMe, 8:2); (found: C,
61.1; H, 4.6; N, 7.4. C19H17ClN2O4 requires C, 61.2; H, 4.6; N, 7.5);
λmax (DCM)/nm 234 (log ε 4.11), 248 inf (3.77), 259 inf (3.67), 269 inf
(3.55), 288 (3.39), 326 (3.55); νmax/cmꢀ1 2984w, 2943w, 2907w,
2832w, 1726s (CdO), 1609s, 1572w, 1506w, 1491s, 1464w, 1427 m,
1402 m, 1368w, 1339 m, 1310w, 1277 m, 1260s, 1236s, 1217s, 1206s,
1182w, 1136 m, 1109 m, 1043 m, 1036 m, 1018 m, 991w, 943w, 889 m,
878w, 851s, 831s, 772 m; δH (300 MHz; CD2Cl2) 9.23 (1H, s, Ar H),
8.25 (1H, d, J = 9.0, Ar H), 7.17 (2H, d, J = 8.4, Ar H), 7.07 (1H, d, J = 3.9,
Ar H), 6.92 (1H, dd, J = 8.4, 3.6, Ar H), 4.18 (2H, q, J = 7.0, OCH2), 3.87
(3H, s, OCH3), 3.75 (3H, s, OCH3), 1.11 (3H, t, J = 7.2, CH3); δC (75
MHz; CD2Cl2) 166.2 (s), 162.7 (s), 160.3 (s), 148.2 (d), 145.7 (s),
144.0 (s), 140.4 (s), 140.2 (d), 133.9 (s), 131.9 (d), 128.0 (s), 127.1 (s),
118.3 (d), 114.4 (d), 112.4 (d), 61.8 (OCH2), 56.0 (OCH3), 54.0
(OCH3), 14.0 (CH3); m/z (EI) 338 (MHþ ꢀ Cl, 25%), 337 (Mþ ꢀ Cl,
100), 327 (5), 309 (42), 294 (13), 277 (3), 265 (4), 251 (8), 241 (3),
221 (3), 213 (3), 178 (3), 151 (4), 99 (3).
4.2.8. Ethyl 4-(2,5-Dichlorophenyl)-6-methoxy-1,5-naphthyridine-
3-carboxylate (4i). (345 mg, 92%) as colorless cubes, mp 85ꢀ86 °C
(pentane), Rf 0.35 (hexane/t-BuOMe, 8:2); (found: C, 57.3; H, 3.7; N,
7.5. C18H14Cl2N2O3 requires C, 57.3; H, 3.7; N, 7.4); λmax (DCM)/nm
232 (log ε 3.74), 261 inf (2.93), 268 inf (2.84), 328 inf (3.01), 340 inf
(2.99); νmax/cmꢀ1 2990w, 2957w, 2905w, 1711s (CdO), 1612 m,
1558w, 1497s, 1456 m, 1431w, 1402s, 1379w, 1368 m, 1339 m, 1317s,
1275 m, 1263 m, 1252 m, 1225 m, 1207 m, 1177w, 1140 m, 1128 m,
1113 m, 1094 m, 1055 m, 1032 m, 1011w, 988w, 883w, 870w, 849s, 824
m, 814 m; δH (500 MHz; CD2Cl2) 9.31 (1H, s, Ar H), 8.27 (1H, d, J =
9.0, Ar H), 7.45 (1H, d, J = 8.7, Ar H), 7.38 (1H, d, J = 8.4, Ar H), 7.27
(1H, s, Ar H), 7.19 (1H, d, J = 9.0, Ar H), 4.20 (2H, q, J = 6.7, OCH2),
3.73 (3H, s, OCH3), 1.11 (3H, t, J = 7.1, CH3); δC (125 MHz; CD2Cl2)
165.7 (s), 162.9 (s), 148.5 (d), 144.5 (s), 144.4 (s), 140.4 (d), 139.8 (s),
138.0 (s), 132.1 (s), 131.9 (s), 130.9 (d), 130.3 (d), 129.3 (d), 126.1 (s),
118.7 (d), 62.0 (OCH2), 54.1 (OCH3), 14.0 (CH3); m/z (EI) 343 [(Mþ
þ 2) ꢀ Cl, 40%], 341 (Mþ ꢀ Cl, 100), 333 (2), 331 (4), 315 (24), 313
(60), 298 (17), 278 (5), 270 (12), 253 (6), 225 (8), 198 (9), 147 (4), 99
(3), 80 (4).
4.2.9. Ethyl 4-[2-Chloro-5-(trifluoromethyl)phenyl]-6-methoxy-1,5-
naphthyridine-3-carboxylate (4j). (377 mg, 92%) as colorless cubes,
mp 89ꢀ90 °C (pentane), Rf 0.47 (hexane/t-BuOMe, 8:2); (found: C,
55.6; H, 3.1; N, 6.8. C19H14ClF3N2O3 requires C, 55.6; H, 3.4; N, 6.8);
λmax (DCM)/nm 232 (log ε 3.70), 262 (3.02), 271 (2.98), 329 (3.00),
341 (2.99); νmax/cmꢀ1 2990w, 2947w, 1724 m (CdO), 1611 m, 1574w,
1495 m, 1437w, 1400 m, 1371w, 1344 m, 1325 m, 1300w, 1287 m,
1263s, 1219 m, 1206w, 1167 m, 1148 m, 1125s, 1113 m, 1080s, 1040w,
1018 m, 989w, 928w, 876w, 845 m, 833 m, 816w, 793w; δH (300 MHz;
CD2Cl2) 9.34 (1H, s, Ar H), 8.29 (1H, d, J = 9.0, Ar H), 7.66 (2H, s, Ar
H), 7.56 (1H, s, Ar H), 7.20 (1H, d, J = 9.0, Ar H), 4.17 (2H, q, J = 7.5,
OCH2), 3.68 (3H, s, OCH3), 1.06 (3H, t, J = 7.4, CH3); δC (75 MHz;
CD2Cl2) 165.6 (s), 163.0 (s), 148.6 (d), 144.5 (s), 144.1 (s), 140.4 (d),
2
139.8 (s), 137.4 (s), 129.8 (d), 127.9 (q, JCF 33.0, F3CC), 128.9 (s),
128.4 (q, 3JCF 3.7, F3CCCH), 126.3 (q, 3JCF 3.7, F3CCCH), 126.0 (q,
1JCF 246.0, F3C), 122.7 (s), 118.7 (d), 62.0 (OCH2), 54.0 (OCH3), 13.9
(CH3); m/z (EI) 376 (MHþ ꢀ Cl, 22%), 375 (Mþ ꢀ Cl, 100), 365 (4),
347 (70), 332 (11), 315 (4), 304 (6), 294 (5), 287 (4), 259 (5), 232 (6),
80 (4).
4.2.10. Ethyl 3-(2-Chloropyrid-3-yl)-6-methoxy-1,5-naphthyridine-
3-carboxylate (4k). (220 mg, 64%) as colorless cubes, mp 120ꢀ122 °C
(pentane), Rf 0.77 (t-BuOMe); (found: C, 59.4; H, 4.1; N, 12.3.
C17H14ClN3O3 requires C, 59.4; H, 4.1; N, 12.2); λmax (DCM)/nm
232 (log ε 3.69), 263 (3.07), 328 (3.01), 338 (3.00); νmax/cmꢀ1 3044w,
2986w, 2945w, 2907w, 1722s (CdO), 1611 m, 1572w, 1557w, 1495s,
1479w, 1449w, 1429w, 1395s, 1371w, 1341 m, 1281 m, 1261 m, 1234s,
1215 m, 1179w, 1146w, 1115 m, 1074w, 1015 m, 974w, 851 m, 810 m,
773 m; δH (500 MHz; CD2Cl2) 9.38 (1H, s, Ar H), 8.50 (1H, br s, Ar H),
8.32 (1H, d, J = 9.0, Ar H), 7.66 (1H, d, J = 7.4 Ar H), 7.43ꢀ7.41 (1H, m,
4.2.7. Ethyl 4-(2-Chloro-4-fluorophenyl)-6-methoxy-1,5-naphthyri-
dine-3-carboxylate (4h). (320 mg, 89%) as colorless cubes, mp 75ꢀ77 °C
5117
dx.doi.org/10.1021/jo200824b |J. Org. Chem. 2011, 76, 5113–5122

The Journal of Organic Chemistry
ARTICLE
Ar H), 7.24 (1H, d, J = 9.2, Ar H), 4.24ꢀ4.22 (2H, m, OCH2), 3.74 (3H,
s, OCH3), 1.13 (3H, t, J = 7.0, CH3); δC (125 MHz; CD2Cl2); 165.6 (s),
162.9 (s), 149.8 (s), 149.0 (d), 148.6 (d), 144.5 (s), 143.9 (s), 140.4 (d),
139.8 (s), 139.7 (d), 133.1 (s), 125.9 (s), 122.0 (d), 118.8 (d), 62.0
(OCH2), 54.1 (OCH3), 14.0 (CH3); m/z (EI) 309 (MHþ ꢀ Cl, 19%),
308 (Mþ ꢀ Cl, 100), 298 (3), 280 (69), 252 (7), 237 (4), 227 (4), 220
(3), 206 (4), 192 (5), 165 (6), 138 (3), 126 (2), 114 (2), 100 (2), 87 (2).
4.2.11. Ethyl 4-(3-Chloropyrid-4-yl)-6-methoxy-1,5-naphthyridine-
3-carboxylate (4l). (213 mg, 62%) as colorless needles, mp 95ꢀ97 °C
(pentane), Rf 0.77 (t-BuOMe); (found: C, 59.5; H, 4.3; N, 12.2.
C17H14ClN3O3 requires C, 59.4; H, 4.1; N, 12.2); λmax (DCM)/nm
229 (log ε 3.31), 249 (2.82), 261 inf (2.85), 267 (2.87), 318 (2.97), 327
(2.97); νmax/cmꢀ1 2982w, 2922w, 1726 m (CdO), 1612w, 1587w,
1566w, 1499 m, 1464w, 1433w, 1402 m, 1371w, 1339 m, 1288 m, 1263
m, 1225 m, 1207w, 1180w, 1138w, 1121 m, 1096s, 1024 m, 980w, 932s,
901s, 854 m, 818w, 770w; δH (500 MHz; CD2Cl2) 9.35 (1H, s, Ar H),
8.70 (1H, s, Ar H), 8.56 (1H, s, Ar H), 8.28 (1H, d, J = 9.0, Ar H),
7.21ꢀ7.19 (2H, m, Ar H), 4.19 (3H, q, J = 6.6, OCH2), 3.69 (3H, s,
OCH3), 1.09 (3H, t, J = 7.0, CH3); δC (125 MHz; CD2Cl2); 165.3 (s),
163.0 (s), 149.2 (d), 148.6 (d), 147.3 (d), 144.8 (s), 144.5 (s), 143.0 (s),
140.4 (d), 139.3 (s), 131.3 (s), 125.5 (s), 125.3 (d), 118.9 (d), 62.1
(OCH2), 54.1 (OCH3), 13.8 (CH3); m/z (EI) 309 (MHþ ꢀ Cl, 19%),
308 (Mþ ꢀ Cl, 100), 298 (3), 280 (65), 252 (7), 237 (4), 227 (4), 206
(4), 192 (5), 165 (5), 138 (2), 114 (2).
4.3. Ethyl 4-(2-Bromophenyl)-6-oxo-5,6-dihydro-1,5-naph-
thyridine-3-carboxylate (5a) (Typical Procedure, Table 2). To
a stirred solution of ethyl 4-(2-bromophenyl)-6-methoxy-1,5-naph-
thyridine-3-carboxylate (4a) (187 mg, 0.5 mmol) and NaI (255 mg,
1.5 mmol) in MeCN (1 mL) was added dropwise TMSCl (314 μL, 2.5
mmol). An orange suspension was formed in the reaction mixture, which
was then refluxed for 1ꢀ2 h until the reaction was finished (TLC). The
reaction was diluted with H2O (10 mL), and Na2S2O2 (25 mg) was
added. The mixture was extracted (DCM, 15 mL), dried (Na2SO4),
filtered, and adsorbed onto silica gel. Dry flash chromatography (t-
BuOMe) gave the title compound 5a (130 mg, 70%) as colorless plates,
mp 201ꢀ203 °C (t-BuOMe), Rf 0.36 (t-BuOMe, 8:2); (found: C, 54.5;
H, 3.9; N, 7.3. C17H13BrN2O3 requires C, 54.7; H, 3.5; N, 7.5); λmax
(DCM)/nm 233 (log ε 3.10), 349 (2.68); νmax/cmꢀ1 1718 m (CdO),
1666s (NHCdO), 1317 m, 1213 m, 1141 m, 1028w, 900w, 852 m, 758
m; δH (500 MHz; CD2Cl2) 9.08 (1H, s, Ar H), 8.33 (1H, br s, NH), 8.01
(1H, d, J = 9.8, Ar H), 7.77 (1H, dd, J = 7.9, 1.1, Ar H), 7.50 (1H, ddd, J =
7.5, 7.6, 1.1, Ar H), 7.43 (1H, ddd, J 8.0, 7.6, 1.7, Ar H), 7.23 (1H, dd, J =
7.6, 1.6, Ar H), 6.84 (1H, d, J = 9.8, Ar H), 4.11 (2H, q, J = 7.1, OCH2),
1.03 (3H, t, J = 7.1, CH3); δC (125 MHz; CD2Cl2) 165.0 (s), 161.6 (s),
146.4 (d), 142.0 (d), 140.4 (s), 135.5 (s), 133.9 (d), 133.8 (s), 132.7 (s),
131.5 (d), 130.8 (d), 128.8 (d), 128.1 (d), 126.3 (s), 123.5 (s), 62.0
(CH2), 13.9 (CH3); m/z (EI) 373 (Mþ þ 1, 1%), 372 (Mþ, 2), 293
(Mþ ꢀ Br, 35), 266 (11), 220 (5), 192 (9).
(CH3); m/z (EI) 330 (Mþ þ 2, 3%), 328 (Mþ, 6), 293 (Mþ ꢀ Cl, 69),
265 (100), 247 (7), 219 (8), 192 (11), 164 (6), 139 (3), 113 (6), 63 (3).
4.3.2. Ethyl 4-(2,3-Dichlorophenyl)-6-oxo-5,6-dihydro-1,5-naphthy-
ridine-3-carboxylate (5c). (166 mg, 92%) as colorless plates, mp
171.5ꢀ172.5 °C (t-BuOMe), Rf 0.38 (t-BuOMe); (found: C, 56.4; H,
3.3; N, 7.6. C17H12Cl2N2O3 requires C, 56.2; H, 3.3; N, 7.7); λmax
(DCM)/nm 232 (log ε 3.59), 250 inf (3.01), 259 inf (2.88), 268 inf
(2.75), 337 inf (3.03), 349 (3.15), 362 (3.04); νmax/cmꢀ1 2978w,
2932w, 1724 m (CdO), 1665s (NHCdO), 1607w, 1578w, 1487w,
1450w, 1418w, 1395w, 1379w, 1325w, 1304 m, 1281w, 1217 m, 1144 m,
1117 m, 1098w, 1047w, 1026w, 972w, 928w, 851 m, 783 m; δH (500
MHz; CD2Cl2) 9.10 (1H, s, Ar H), 8.59 (1H, br s, NH), 8.02 (1H, d, J =
9.8, Ar H), 7.67 (1H, d, J = 8.0, Ar H), 7.41 (1H, dd, J = 7.8, 7.8, Ar H),
7.15 (1H, d, J = 7.6, Ar H), 6.84 (1H, d, J = 9.8, Ar H), 4.13 (2H, m,
OCH2), 1.05 (3H, t, J = 7.1, CH3); δC (125 MHz; CD2Cl2) 164.8 (s),
161.7 (s), 146.5 (d), 142.0 (d), 140.6 (s), 134.7 (s), 134.1 (s), 133.6 (s),
132.7 (s), 132.5 (s), 132.0 (d), 129.0 (d), 128.9 (d), 128.2 (d), 126.1 (s),
62.1 (OCH2), 13.9 (CH3); m/z (EI) 364 (Mþ þ 2, 3%), 362 (Mþ, 5),
329 (20), 327 (Mþ ꢀ Cl, 63), 317 (5), 301 (36), 299 (100), 281 (6), 264
(20), 253 (7), 226 (13), 207 (7), 198 (4), 191 (6), 173 (5), 164 (8), 147
(8), 138 (6), 127 (4), 113 (7), 99 (6), 64 (5), 57 (7).
4.3.3. Ethyl 4-(2,4-Dichlorophenyl)-6-oxo-5,6-dihydro-1,5-naphthy-
ridine-3-carboxylate (5d). (150 mg, 83%) as colorless plates, mp
155ꢀ156.5 °C (t-BuOMe), Rf 0.38 (t-BuOMe); (found: C, 56.4; H,
3.3; N, 7.8. C17H12Cl2N2O3 requires C, 56.2; H, 3.3; N, 7.7); λmax
(DCM)/nm 233 (log ε 3.61), 259 inf (2.99), 268 inf (2.90), 338 inf
(3.04), 349 (3.15), 362 (3.04); νmax/cmꢀ1 3090w, 3032w, 2941w, 1732
m (CdO), 1707 m, 1659s (NHCdO), 1603w, 1557w, 1481w, 1447w,
1379w, 1368w, 1327 m, 1310w, 1296 m, 1206w, 1144 m, 1130 m,
1115w, 1099w, 1059w, 1030w, 1016w, 997w, 856 m, 835w, 822w, 773w,
760w; δH (500 MHz; CD2Cl2) 9.09 (1H, s, Ar H), 8.82 (1H, br s, NH),
8.02 (1H, d, J = 9.9, Ar H), 7.62 (1H, s, Ar H), 7.45 (1H, d, J = 8.2, Ar H),
7.19 (1H, d, J = 8.1, Ar H), 6.83 (1H, d, J = 9.8, Ar H), 4.15 (2H, q, J = 7.0,
OCH2), 1.10 (3H, t, J = 7.1, CH3); δC (125 MHz; CD2Cl2) 164.9 (s),
161.9 (s), 146.4 (d), 142.1 (d), 140.5 (s), 136.7 (s), 134.8 (s), 133.0 (s),
132.9 (s), 131.7 (d), 130.6 (d), 130.5 (s), 128.6 (d), 128.2 (d), 126.4 (s),
62.2 (OCH2), 14.0 (CH3); m/z (EI) 364 (Mþ þ 2, 8%), 362 (Mþ, 12),
329 (29), 327 (Mþ ꢀ Cl, 82), 319 (5), 317 (7), 301 (40), 299 (100), 283
(3), 281 (8), 264 (18), 253 (10), 236 (4), 225 (18), 207 (5), 200 (4),
191 (8), 179 (3), 164 (10), 147 (11), 138 (7), 113 (8), 99 (5), 87 (4),
63 (6).
4.3.4. Ethyl 4-[2-Chloro-4-(trifluoromethyl)phenyl]-6-oxo-5,6-di-
hydro-1,5-naphthyridine-3-carboxylate (5e). (158 mg, 80%) as color-
less cubes, mp 189ꢀ191 °C (t-BuOMe), Rf 0.51 (t-BuOMe); (found: C,
54.5; H, 3.0; N, 7.0. C18H12ClF3N2O3 requires C, 54.5; H, 3.1; N, 7.1);
λmax (DCM)/nm 234 (log ε 4.06), 263 (3.57), 269 (3.53), 339 inf
(3.56), 349 (3.66), 362 (3.54); νmax/cmꢀ1 3019w, 2986w, 2941w,
2851w, 1724 m (CdO), 1665s (NHCdO), 1605 m, 1487w, 1450w,
1395 m, 1368w, 1321s, 1287w, 1204 m, 1171 m, 1134s, 1080 m, 1065 m,
1020w, 883 m, 864 m, 839 m, 800w, 775w; δH (300 MHz; CD2Cl2) 9.13
(1H, s, Ar H), 8.61 (1H, br s, NH), 8.04 (1H, d, J = 9.8, Ar H), 7.88 (1H,
br s, Ar H), 7.73 (1H, d, J = 7.9, Ar H), 7.41 (1H, d, J = 7.9, Ar H), 6.84
(1H, d, J = 9.8, Ar H), 4.12 (2H, q, J = 7.1, OCH2), 1.05 (3H, t, J = 7.1,
CH3); δC (75 MHz; CD2Cl2) 164.7 (s), 162.1 (s), 146.4 (d), 142.0 (d),
4.3.1. Ethyl 4-(2-Chlorophenyl)-6-oxo-5,6-dihydro-1,5-naphthyri-
dine-3-carboxylate (5b). (150 mg, 81%) as colorless needles, mp
130ꢀ132 °C (t-BuOMe), Rf 0.35 (t-BuOMe); (found: C, 62.2; H,
4.0; N, 8.6. C17H13ClN2O3 requires C, 62.1; H, 4.0; N, 8.5); λmax
(DCM)/nm 235 (log ε 3.89), 262 (3.51), 271 (3.50), 338 inf (3.37), 348
(3.48), 363 (3.36); νmax/cmꢀ1 3036w, 2990w, 2953w, 2926w, 1715 m
(CdO), 1661s (NHCdO), 1605 m, 1580w, 1487w, 1450w, 1431w,
1366 m, 1325 m, 1314 m, 1250w, 1234w, 1207 m, 1138 m, 1109 m,
1059w, 1022w, 930w, 856w, 826w, 768 m; δH (500 MHz; CD2Cl2) 9.07
(1H, s, Ar H), 8.45 (1H, br s, NH), 8.01 (1H, d, J = 9.8, Ar H), 7.59 (1H,
dd, J = 8.1, 1.0, Ar H), 7.51 (1H, ddd, J = 7.6, 7.9, 1.8, Ar H), 7.46 (1H,
ddd, J = 7.5, 7.6, 1.2, Ar H), 7.24 (1H, dd, J = 7.6, 1.6, Ar H), 6.84 (1H, d,
J = 9.8, Ar H), 4.80 (2H, dq, J = 7.2, 1.6, OCH2), 1.03 (3H, t, J = 7.2,
CH3); δC (125 MHz; CD2Cl2) 165.1 (s), 161.6 (s), 146.3 (d), 142.0
(d), 140.3 (s), 134.0 (s), 133.8 (s), 132.9 (s), 131.7 (s), 131.5 (d), 130.7
(d), 130.6 (d), 128.2 (d), 128.1 (d), 126.6 (s), 62.0 (OCH2), 13.9
2
140.6 (s), 136.1 (s), 134.9 (s), 133.4 (q, JCF 33.5, F3CC), 133.0 (s),
132.7 (s), 131.6 (d), 128.2 (d), 127.6 (q, 3JCF 3.8, F3CCCH), 126.1 (s),
123.7 (q, 1JCF 272.8, F3C), 124.9 (q, 3JCF 3.5, F3CCCH), 62.3 (OCH2),
13.8 (CH3); m/z (EI) 398 (Mþ þ 2, 3%), 396 (Mþ, 8), 361 (Mþ ꢀ Cl,
50), 351 (5), 333 (100), 315 (7), 287 (7), 260 (9), 241 (4), 232 (4), 207
(4), 192 (3), 181 (3).
4.3.5. Ethyl 4-(2-Chloro-4-methylphenyl)-6-oxo-5,6-dihydro-1,5-naph-
thyridine-3-carboxylate (5f). (127 mg, 74%) as colorless cubes, mp
164ꢀ166 °C (t-BuOMe), Rf 0.40 (t-BuOMe); (found: C, 63.3; H, 4.4; N,
8.1. C18H15ClN2O3 requires C, 63.1; H, 4.4; N, 8.2); λmax (DCM)/nm
5118
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ARTICLE
234 (log ε 3.83), 261 (3.30), 268 (3.25), 339 inf (3.27), 349 (3.37), 360
(3.25); νmax/cmꢀ1 2941w, 2870w, 1732 m (CdO), 1717 m, 1665s
(NHCdO), 1605w, 1558w, 1541w, 1506w, 1485w, 1447w, 1395w,
1381w, 1366w, 1327w, 1310w, 1204 m, 1113 m, 1061w, 1028w, 982w,
966w, 934w, 883w, 849 m, 818 m, 802w; δH (300 MHz; CD2Cl2) 9.06
(1H, s, Ar H), 8.18 (1H, br s, NH), 8.01 (1H, d, J = 9.9, Ar H), 7.42 (1H,
s, Ar H), 7.27 (1H, dd, J = 7.8, 0.6, Ar H), 7.12 (1H, d, J = 7.8, Ar H), 6.86
(1H, d, J = 9.9, Ar H), 4.12 (2H, q, J = 7.1, OCH2), 2.45 (3H, s, CH3),
1.06 (3H, t, J = 7.1, CH3); δC (75 MHz; CD2Cl2) 165.1 (s), 161.6 (s),
146.3 (d), 142.3 (s), 142.1 (d), 140.3 (s), 134.2 (s), 133.4 (s), 133.0 (s),
131.2 (d), 130.4 (d), 129.0 (d), 128.4 (s), 128.0 (d), 126.8 (s), 62.1
(OCH2), 21.3 (CH3), 13.9 (CH3); m/z (EI) 344 (Mþ þ 2, 4%), 342
(Mþ, 7), 307 (Mþ ꢀ Cl, 79), 297 (6), 279 (100), 261 (7), 251 (3), 233
(9), 205 (12), 192 (3), 179 (3), 152 (4), 139 (3), 126 (9), 103 (4), 89
(3), 77 (3), 63 (3).
4.3.6. Ethyl 4-(2-Chloro-4-methoxyphenyl)-6-oxo-5,6-dihydro-1,5-
naphthyridine-3-carboxylate (5g). (159 mg, 89%) as colorless plates,
mp 169ꢀ171 °C (t-BuOMe), Rf 0.23 (t-BuOMe); (found: C, 60.1; H,
4.1; N, 7.8. C18H15ClN2O4 requires C, 60.3; H, 4.2; N, 7.8); λmax
(DCM)/nm 240 (log ε 4.22), 259 inf (3.95), 268 inf (3.80), 286 (3.60),
341 inf (3.99), 348 (4.05), 358 inf (3.97); νmax/cmꢀ1 2970w, 1736 m
(CdO), 1713 m (CdO), 1662s (NHCdO), 1605 m, 1560w, 1497w,
1485w, 1450w, 1367 m, 1329 m, 1310w, 1290 m, 1227s, 1204 m, 1142
m, 1119w, 1051 m, 1038 m, 1018w, 862 m, 853 m, 812w, 775w, 764w;
δH (300 MHz; CD2Cl2) 9.05 (1H, s, Ar H), 8.32 (1H, br s, NH), 8.01
(1H, d, J = 9.9, Ar H), 7.15ꢀ7.12 (2H, m, Ar H), 7.01 (1H, dd, J = 8.4,
2.4, Ar H), 6.84 (1H, d, J = 9.9, Ar H), 4.14 (2H, q, J = 7.1, OCH2), 3.89
(3H, s, OCH3), 1.08 (3H, t, J = 7.2, CH3); δC (75 MHz; CD2Cl2) 165.2
(s), 161.8 (s), 161.6 (s), 146.3 (d), 142.0 (d), 140.2 (s), 134.5 (s), 133.9
(s), 133.3 (s), 131.4 (d), 128.0 (d), 127.1 (s), 123.2 (s), 116.1 (d), 114.3
(d), 62.0 (OCH2), 56.3 (OCH3), 14.0 (CH3); m/z (EI) 360 (Mþ þ 2,
3%), 358 (Mþ, 8), 323 (Mþ ꢀ Cl, 80), 315 (2), 313 (6), 295 (100), 280
(6), 252 (9), 242 (6), 236 (6), 224 (4), 207 (6), 179 (9), 152 (4), 125
(5), 99 (5), 75 (4), 63 (3).
7.55ꢀ7.49 (2H, m, Ar H), 7.26 (1H, s, Ar H), 6.86 (1H, d, J = 9.9, Ar H),
4.16 (2H, q, J = 7.0, OCH2), 1.09 (3H, t, J = 7.1, CH3); δC (125 MHz;
CD2Cl2) 164.7 (s), 161.7 (s), 146.5 (d), 142.0 (d), 140.6 (s), 134.0 (s),
133.5 (s), 132.7 (s), 132.6 (s), 132.4 (s), 131.9 (d), 131.5 (d), 130.7 (d),
128.3 (d), 126.1 (s), 62.2 (OCH2), 13.9 (CH3); m/z (EI) 364 (Mþ þ 2,
6%), 362 (Mþ, 10%), 329 (42), 327 (Mþ ꢀ Cl, 87), 319 (5), 317 (9),
301 (54), 299 (100), 283 (3), 281 (7), 264 (26), 255 (9), 226 (17), 207
(4), 198 (3), 191 (6), 164 (4), 147 (4), 138 (2), 113 (2).
4.3.9. Ethyl 4-[2-Chloro-5-(trifluoromethyl)phenyl]-6-oxo-5,6-di-
hydro-1,5-naphthyridine-3-carboxylate (5j). (182 mg, 92%) as color-
less plates, mp 201ꢀ203.5 °C (t-BuOMe), Rf 0.57 (t-BuOMe); (found:
C, 54.5; H, 3.0; N, 6.9. C18H12ClF3N2O3 requires C, 54.5; H, 3.1; N,
7.1); λmax (DCM)/nm 232 (log ε 3.56), 263 (3.22), 270 (3.21), 283 inf
(3.09), 338 inf (3.03), 348 (3.13), 362 (3.01); νmax/cmꢀ1 3036w,
2967w, 1724 m (CdO), 1668s (NHCdO), 1609 m, 1578w, 1487w,
1381 m, 1327s, 1296s, 1209 m, 1169s, 1123s, 1084s, 1057w, 1034 m,
972w, 934w, 872w, 845 m, 837 m; δH (300 MHz; CD2Cl2) 9.13 (1H, s,
Ar H), 8.70 (1H, br s, NH), 8.02 (1H, d, J = 9.9, Ar H), 7.80ꢀ7.75 (2H,
m, Ar H), 7.53 (1H, d, J = 0.6, Ar H), 6.82 (1H, d, J = 9.6, Ar H), 4.12
(2H, dq, J = 7.2, 1.5, OCH2), 1.03 (3H, t, J = 7.2, CH3); δC (75 MHz;
CD2Cl2) one quarternary carbon peak missing 164.7 (s), 162.0 (s),
146.6 (d), 142.1 (d), 140.7 (s), 138.1 (s), 132.8 (s), 132.6 (s), 131.3
2
3
(d), 130.4 (q, JCF 33.5, F3CC), 128.2 (d), 128.2 (q, JCF 3.7,
3
1
F3CCCH), 128.0 (q, JCF 3.8, F3CCCH), 127.6 (q, JCF 272.8,
F3C), 126.2 (s), 62.2 (OCH2), 13.8 (CH3); m/z (EI) 398 (Mþ þ 2,
8%), 396 (Mþ, 22), 361 (Mþ ꢀ Cl, 84), 353 (3), 351 (9), 333 (100),
315 (9), 313 (8), 287 (10), 264 (3), 260 (12), 241 (7), 232 (4), 226
(3), 207 (4), 192 (4), 181 (3).
4.3.10. Ethyl 4-(2-Chloropyrid-3-yl)-6-oxo-5,6-dihydro-1,5-naphthy-
ridine-3-carboxylate (5k). (137 mg, 83%) as colorless cubes, mp
194ꢀ196 °C (t-BuOMe), Rf 0.09 (t-BuOMe); (found: C, 58.4; H,
3.7; N, 12.7. C16H12ClN3O3 requires C, 58.3; H, 3.7; N, 12.7); λmax
(DCM)/nm 217 (log ε 4.15), 348 (3.30); νmax/cmꢀ1 1724 m (CdO),
1697s (NHCdO), 1602 m, 1556w, 1402w, 1384 m, 1305w, 1220 m,
1141 m, 1076 m, 1026 m, 856w; δH (500 MHz; CD2Cl2) 9.96 (1H, br s,
NH), 9.14 (1H, s, Ar H), 8.62 (1H, d, 2.0, Ar H), 8.06 (1H, d, J = 9.8, Ar
H), 7.62 (1H, d, J = 7.4, Ar H), 7.47 (1H, d, J = 6.2, Ar H), 6.79 (1H, d, J =
9.8, Ar H), 4.17 (2H, q, J = 6.8, OCH2), 1.11 (3H, t, J = 7.2, CH3); δC
(125 MHz; CD2Cl2) 164.8 (s), 162.6 (s), 150.8 (d), 150.5 (s), 146.6 (d),
142.1 (d), 140.7 (s), 139.8 (d), 133.0 (s), 132.5 (s), 129.1 (s), 128.1 (d),
126.1 (s), 123.4 (d), 62.2 (OCH2), 14.0 (CH3); m/z (EI) 329 (Mþ,
11%), 294 (Mþ ꢀ Cl, 95), 284 (7), 266 (100), 256 (4), 248 (6), 238 (9),
221 (10), 193 (15), 167 (11), 140 (7), 114 (8), 100 (3), 96 (4), 87 (7),
62 (6).
4.3.11. Ethyl 4-(3-Chloropyrid-4-yl)-6-oxo-5,6-dihydro-1,5-naphthy-
ridine-3-carboxylate (5l). (110 mg, 67%) as colorless needles, mp
161ꢀ163 °C (t-BuOMe); Rf 0.09 (t-BuOMe); (found: C, 58.2; H,
3.6; N, 12.7, C16H12ClN3O3 requires C, 58.3; H, 3.7; N, 12.7); λmax
(DCM)/nm 216 (log ε 4.16), 336 (3.47); νmax/cmꢀ1 1714 m (CdO),
1660s (NHCdO), 1602w, 1557w, 1371w, 1327 m, 1215 m, 1141 m,
1091w, 1018 m, 854 m; δH (500 MHz; CD2Cl2) 9.56 (1H, br s, NH),
9.12 (1H, s, Ar H), 8.77 (1H, s, Ar H), 8.63 (1H, br s, Ar H), 8.02 (1H, d,
J = 9.8, Ar H), 7.19 (1H, d, J = 2.1, Ar H), 6.77 (1H, d, J = 9.9, Ar H), 4.14
(2H, q, J = 6.8, OCH2), 1.07 (3H, t, J = 7.1, CH3); δC (125 MHz;
CD2Cl2) 164.6 (s), 162.4 (s), 150.6 (d), 148.8 (d), 146.5 (d), 142.1 (d),
140.8 (s), 140.4 (s), 132.3 (s), 131.7 (s), 131.5 (s), 128.3 (d), 125.6 (s),
125.1 (d), 62.4 (OCH2), 13.8 (CH3); m/z (EI) 329 (Mþ, 13%), 294
(Mþ ꢀ Cl, 77), 266 (100), 233 (9), 220 (3), 193 (9), 114 (10), 100 (5).
4.4. Ethyl 6-Oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-
1-carboxylate (1b), (Table 3, entry 1). To a stirred solution of
ethyl 4-(2-bromophenyl)-6-oxo-5,6-dihydro-1,5-naphthyridine-3-car-
boxylate (5a) (48 mg, 0.13 mmol), Cs2CO3 (85 mg, 0.26 mmol), CuI
(2.5 mg, 0.013 mmol) in dioxane (1 mL) were added DMEDA (2.9 μL,
0.026 mmol) and H2O (4.5 μL, 0.26 mmol). The stirred reaction
4.3.7. Ethyl 4-(2-Chloro-4-fluorophenyl)-6-oxo-5,6-dihydro-1,5-naph-
thyridine-3-carboxylate (5h). (170 mg, 98%) as colorless cubes, mp
169ꢀ170 °C (t-BuOMe), Rf 0.38 (t-BuOMe); (found: C, 59.0; H, 3.4;
N, 8.0. C17H12ClFN2O3 requires C, 58.9; H, 3.5; N, 8.1); λmax (DCM)/
nm 234 (log ε 3.55), 251 inf (2.99), 259 inf (2.88), 267 inf (2.76), 339 inf
(3.03), 348 (3.13), 362 (3.01); νmax/cmꢀ1 3173w, 3103w, 3032w (Ar
CH), 2990w, 2941w, 1715 m (CdO), 1667s (NHCdO), 1605 m,
1555w, 1493 m, 1452w, 1391 m, 1369 m, 1328 m, 1312 m, 1263w, 1217
m, 1198 m, 1134 m, 1105w, 1049w, 1024 m, 899 m, 851 m, 824w, 760 m;
δH (500 MHz; CD2Cl2) 9.08 (1H, s, Ar H), 8.67 (1H, br s, NH), 8.02
(1H, d, J = 9.8, Ar H), 7.36 (1H, d, J = 8.5, Ar H), 7.23ꢀ7.20 (2H, m, Ar
H), 6.82 (1H, d, J = 9.9, Ar H), 4.14 (2H, q, J = 6.9, OCH2), 1.09 (3H, t,
J = 7.1, CH3); δC (125 MHz; CD2Cl2) one quaternary peak missing
1
165.0 (s), 163.8 (d, JC3F 251.0, FC), 161.8 (s), 146.4 (d), 142.1 (d),
4
140.5 (s), 135.1 (d, JCF 10.8, FCCHCCl), 133.1 (d, JCF 5.4,
3
FCCHCHCq), 132.1 (d, JCF 9.0, FCCHCH), 128.1 (d), 128.0 (s),
126.7 (s), 118.2 (d, 2JCF 25.3, FCCH), 115.7 (d, 2JCF 21.7, FCCH), 62.2
(OCH2), 14.0 (CH3); m/z (EI) 348 (Mþ þ 2, 4%), 346 (Mþ, 11), 311
(Mþ ꢀ Cl, 71), 301 (6), 283 (100), 265 (14), 237 (14), 210 (21), 191
(5), 182 (10), 157 (5), 131 (10), 105 (3), 81 (3).
4.3.8. Ethyl 4-(2,5-Dichlorophenyl)-6-oxo-5,6-dihydro-1,5-naphthy-
ridine-3-carboxylate (5i). (176 mg, 97%) as colorless cubes, mp
160ꢀ161.5 °C (t-BuOMe), Rf 0.57 (t-BuOMe); (found: C, 56.1; H,
3.3; N, 7.8. C17H12Cl2N2O3 requires C, 56.2; H, 3.3; N, 7.7); λmax
(DCM)/nm 232 (log ε 3.70), 259 inf (2.95), 268 inf (2.82), 339 inf
(3.10), 348 (3.20), 362 (3.08); νmax/cmꢀ1 2959w, 2924w, 2851w, 1726
m (CdO), 1667s (NHCdO), 1607w, 1578w, 1557w, 1489w, 1470w,
1454w, 1406w, 1381 m, 1325 m, 1292w, 1207 m, 1136 m, 1103 m,
1057w, 1034w, 972w, 872w, 947 m, 818 m; δH (500 MHz; CD2Cl2)
9.11 (1H, s, Ar H), 8.51 (1H, br s, NH), 8.02 (1H, d, J = 9.8, Ar H),
5119
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mixture was refluxed (preheated oil bath) until the reaction was
complete (TLC, 1 h) and then allowed to cool to ca. 20 °C. The
mixture was diluted (DCM), dried (Na2SO4), filtered, and adsorbed
onto silica gel. Dry flash chromatography (t-BuOMe) gave the title
compound 1b (32 mg, 85%) as light yellow needles, mp 158ꢀ160 °C
(EtOH), Rf 0.35 (t-BuOMe); (found: C, 70.0; H, 4.1; N, 9.5.
C17H12N2O3 requires C, 69.9; H, 4.1; N, 9.6); λmax (DCM)/nm 232
inf (log ε 3.25), 244 (3.29), 250 inf (3.28), 263 inf (3.13), 269 inf (2.99),
1246w, 1221w, 1213w, 1175s, 1150s, 1126s, 1109s, 1053s, 1007w, 989w,
935w, 914w, 897 m, 878w, 837s, 814w, 807w; δH (500 MHz; CD2Cl2)
9.38 (1H, s, Ar H), 9.13 (1H, d, J = 8.4, Ar H), 8.94 (1H, s, Ar H), 8.03
(1H, d, J = 9.8, Ar H), 7.78 (1H, d, J = 8.4, Ar H), 7.03 (1H, d, J = 9.8, Ar
H), 4.59 (2H, q, J = 7.1, OCH2), 1.53 (3H, t, J = 7.1, CH3); δC (125
MHz; CD2Cl2) 165.4 (s), 159.5 (s), 148.4 (d), 140.0 (s), 139.9 (d),
139.6 (s), 138.8 (s), 133.2 (q, 2JCF 32.5, F3CC), 131.0 (d), 129.2 (d),
129.0 (s), 126.9 (s), 124.4 (q, JCF 271.3, F3C), 122.9 (q, JCF 3.6,
F3CCCH), 122.1 (s), 114.1 (q, 3JCF 3.9, F3CCCH), 62.7 (OCH2), 14.6
(CH3); m/z (EI) 361 (Mþþ1, 21%), 360 (Mþ, 100), 345 (10), 332
(48), 315 (65), 304 (14), 287 (38), 259 (32), 247 (5), 232 (19), 209 (5),
180 (5), 157 (5), 144 (9), 130 (6), 87 (5), 57 (7).
1
3
305 (3.07), 314 (3.06), 363 inf (2.94), 378 (3.10), 398 (3.05); νmax
/
cmꢀ1 2957w, 2922 br m, 2853w, 1722 m (CdO), 1692s (CdO), 1665
m, 1622w, 1601w, 1582w, 1555w, 1483w, 1468w, 1441w, 1416 m, 1391
m, 1366w, 1342w, 1329w, 1294s, 1250 m, 1217 m, 1136s, 1109 m, 1094
m, 1055 m, 1016w, 930w, 910w, 893w, 874w, 854w, 839 m, 804w; δH
(500 MHz; CD2Cl2) 9.32 (1H, s, Ar H), 8.95 (1H, d, J = 7.9, Ar H), 8.64
(1H, d, J = 8.2, Ar H), 7.98 (1H, d, J = 9.8, Ar H), 7.70ꢀ7.74 (1H, m, Ar
H), 7.51ꢀ7.54 (1H, m, Ar H), 6.98 (1H, d, J = 9.8, Ar H), 4.58 (2H, q, J =
7.2, OCH2), 1.53 (3H, t, J = 7.2, CH3); δC (75 MHz; CDCl3) 165.3 (s),
159.3 (s), 147.8 (d), 140.2 (s), 139.2 (d), 138.5 (s), 132.2 (s), 132.0 (d),
130.6 (d), 130.4 (s), 128.3 (d), 126.0 (d), 123.5 (s), 121.2 (s), 116.7 (d),
62.1 (OCH2), 14.5 (CH3); m/z (EI) 293 (Mþþ1, 20%), 292 (Mþ, 100),
277 (7), 264 (36), 247 (60), 236 (21), 219 (26), 191 (25), 164 (22), 138
(7), 113 (4), 110 (7), 96 (8), 86 (5), 63 (4). The title compound could
also be obtained microanytically pure without the use of chromatography,
by filtering the dried solution through a short pad of silica, evaporation,
and recrystallization.
4.5.2. Ethyl 9-Methyl-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-
1-carboxylate (1e). (32 mg, 80%) as beige needles, mp 173.5ꢀ174.5 °C
(EtOH), Rf 0.50 (t-BuOMe); (found: C, 70.6; H, 4.5; N, 9.1.
C18H14N2O3 requires C, 70.6; H, 4.6; N, 9.2); λmax (DCM)/nm 232
(log ε 3.31), 246 inf (3.37), 256 (3.41), 263 inf (3.39), 273 (3.24), 309
(3.21), 318 (3.22), 350 inf (3.01), 365 inf (3.15), 380 (3.29), 400 (3.21);
νmax/cmꢀ1 3078w, 2980w, 2932w, 1707s (OꢀCdO), 1670s
(NꢀCdO), 1665s (CdO), 1626 m, 1605w, 1585w, 1557w, 1468w,
1429 m, 1416 m, 1395w, 1362w, 1335 m, 1287s, 1250 m, 1231 m, 1150s,
1109s, 1099 m, 1053 m, 1022w, 955w, 881w, 849 m, 837s, 802 m; δH
(500 MHz; CD2Cl2) 9.28 (1H, s, Ar H), 8.77 (1H, d, J = 8.2, Ar H), 8.45
(1H, s, Ar H), 7.96 (1H, d, J = 9.8, Ar H), 7.31 (1H, d, J = 8.2, Ar H), 6.95
(1H, d, J = 9.6, Ar H), 4.56 (2H, q, J = 7.1, OCH2), 2.58 (3H, s, CH3),
1.52 (3H, t, J = 7.1, CH3); δC (125 MHz; CD2Cl2) 165.8 (s), 159.7 (s),
148.1 (d), 143.7 (s), 141.0 (s), 139.6 (d), 138.8 (s), 132.8 (s), 130.7 (d),
130.6 (s), 128.1 (d), 127.4 (d), 121.6 (s), 121.1 (s), 117.2 (d), 62.4
(OCH2), 22.5 (CH3), 14.6 (CH3); m/z (EI) 307 (MHþ, 62%), 297 (5),
279 (100), 261 (6), 233 (9), 205 (13), 192 (4), 179 (4), 152 (6), 127
(9), 77 (6), 57 (6).
4.5.3. Ethyl 9-Methoxy-6-oxo-6H-indolo[3,2,1-de][1,5]naphthy-
ridine-1-carboxylate (1f). (30.5 mg, 73%) as bright colored yellow
needles, mp 187ꢀ188 °C (EtOH), Rf 0.45 (t-BuOMe); (found: C,
67.2; H, 4.5; N, 8.6. C18H14N2O4 requires C, 67.1; H, 4.4; N, 8.7);
λmax (DCM)/nm 231 (log ε 3.36), 261 inf (3.34), 268 (3.43), 278
(3.50), 308 (3.10), 318 (3.12), 376 (3.29); νmax/cmꢀ1 2976w, 2945w,
1721s (CdO), 1694 m (NCdO), 1624 m, 1608 m, 1557w, 1495 m,
1470w, 1439 m, 1418 m, 1393 m, 1369w, 1335w, 1292s, 1243s,
1186w, 1167w, 1150s, 1115 m, 1099 m, 1057 m, 1032 m, 1015w, 930w,
875w, 854w, 837s, 800w; δH (300 MHz; CD2Cl2) 9.27 (1H, s, Ar H),
8.82 (1H, d, J = 8.7, Ar H), 8.18 (1H, d, J = 2.4, Ar H), 7.96 (1H, d, J = 9.9,
Ar H), 7.04 (1H, dd, J = 9.0, 2.4, Ar H), 6.95 (1H, d, J = 9.9, Ar H), 4.56
(2H, q, J = 7.1, OCH2), 3.99 (3H, s, OCH3), 1.52 (3H, t,
J = 7.1, CH3); δC (125 MHz; CD2Cl2) 165.9 (s), 163.6 (s), 159.7 (s),
148.2 (d), 142.6 (s), 139.9 (d), 138.2 (s), 133.0 (s), 130.6 (s), 130.3 (d),
129.5 (d), 120.4 (s), 116.9 (s), 114.1 (d), 101.0 (d), 62.3 (OCH2), 56.4
(OCH3), 14.6 (CH3); m/z (EI) 323 (MHþ, 80%), 295 (100), 277 (5),
263 (2), 252 (8), 249 (6), 207 (7), 179 (10), 125 (5), 99 (5), 75 (5),
57 (4).
4.5. Ethyl 9-Chloro-6-oxo-6H-indolo[3,2,1-de][1,5]naph-
thyridine-1-carboxylate (1c) (Typical Procedure for Entries
4ꢀ20; See Table 3). To a stirred solution of ethyl 4-(2-chlorophenyl)-6-
oxo-5,6-dihydro-1,5-naphthyridine-3-carboxylate (5b) (43 mg, 0.13 mmol)
and Cs2CO3 (85 mg, 0.26 mmol) in dioxane (1 mL)/ H2O (2.4 μL,
0.13 mmol) was added a deep blue solution of CuI (2.5 mg, 0.013 mmol)
and DMCDA (4 μL, 0.026 mmol) in dioxane (1 mL)/ H2O (2.4 μL,
0.13 mmol). The stirred reaction mixture was refluxed (preheated oil
bath) until the reaction was complete (TLC, 1 h) and then allowed to
cool to ca. 20 °C. The mixture was diluted (DCM), dried (Na2SO4),
filtered, and adsorbed onto silica gel. Dry flash chromatography
(t-BuOMe) gave the title compound 1c (28 mg, 74%) as bright yellow
needles, mp 217.5ꢀ218.5 °C (EtOH), Rf 0.70 (t-BuOMe); (found: C,
62.5; H, 3.5; N, 8.5. C17H11ClN2O3 requires C, 62.5; H, 3.4; N, 8.6);
λmax (DCM)/nm 231 (log ε 2.30), 243 inf (3.28), 252 inf (3.30), 256
(3.32), 266 (3.27), 274 (3.18), 307 inf (3.14), 315 (3.16), 348 inf (2.96),
361 (3.09), 378 (3.26), 398 (3.21); νmax/cmꢀ1 3117w, 3069w, 3042w,
2992w, 1722 m (CdO), 1692s (NCdO), 1624w, 1599w, 1555w,
1474w, 1429 m, 1414 m, 1395 m, 1366w, 1323w, 1308 m, 1288s,
1271 m, 1250w, 1217w, 1196w, 1159 m, 1105 m, 1069w, 1053 m,
1016w, 937w, 910w, 868 m, 853 m, 837s, 797 m, 766 m; δH (300 MHz;
CD2Cl2) 9.39 (1H, s, Ar H), 8.98 (1H, d, J = 8.4, Ar H), 8.73 (1H, d, J =
1.8, Ar H), 8.05 (1H, d, J = 9.9, Ar H), 7.55 (1H, dd, J = 8.7, 2.1, Ar H),
7.04 (1H, d, J = 9.9, Ar H), 4.61 (2H, q, J = 7.1, OCH2), 1.56 (3H, t, J =
7.2, CH3); δC (125 MHz; CD2Cl2) 165.5 (s), 159.4 (s), 148.2 (d), 140.9
(s), 139.9 (d), 139.1 (s), 137.9 (s), 132.9 (s), 130.6 (d), 129.5 (s), 129.4
(d), 126.5 (d), 122.6 (s), 121.4 (s), 117.0 (d), 62.5 (OCH2), 14.5
(CH3); m/z (EI) 328 (Mþ þ 2, 33%), 326 (Mþ, 100), 313 (3), 311 (8),
300 (11), 298 (32), 283 (20), 281 (55), 272 (5), 270 (14), 253 (32), 247
(4), 225 (24), 198 (13), 189 (10), 174 (5), 163 (9), 138 (10), 112 (6),
99 (7), 86 (5), 63 (5).
4.5.4. Ethyl 9-Fluoro-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-
1-carboxylate (1g). (28 mg, 70%) as colorless needles, mp203ꢀ204.5 °C
(EtOH), Rf 0.75 (t-BuOMe); (found: C, 65.9; H, 3.5; N, 8.9. C17H11F-
N2O3 requires C, 65.8; H, 3.6; N, 9.0); λmax (DCM)/nm 254 (log ε
3.60), 263 (3.58), 271 (3.52), 292 inf (3.37), 299 (3.40), 307 inf (3.34),
345 inf (306), 356 (3.22); νmax/cmꢀ1 3042w, 2988w, 2918w, 1724 m
(CdO), 1694s, 1628w, 1607w, 1557w, 1541w, 1522w, 1472w, 1456w,
1435w, 1422 m, 1396 m, 1331w, 1314w, 1267w, 1233 m, 1161w, 1150
m, 1117w, 1105w, 1059w, 1015w, 934w, 878w, 856 m, 843s, 831 m,
802w, 768 m; δH (300 MHz; CD2Cl2) 9.34 (1H, s, Ar H), 9.00 (1H, dd,
3JHH 8.9, 4JHF 5.6, Ar H), 8.38 (1H, dd, 3JHF 9.1, 4JHH 2.5, Ar H), 8.01
(1H, d, J = 10.0, Ar H), 7.26 (1H, ddd, 3JHF 9.0, 3JHH 9.0, 4JHH 2.5, Ar H),
6.99 (1H, d, J = 9.8, Ar H), 4.57 (2H, q, J = 7.1, OCH2), 1.52 (3H, t, J =
7.2, CH3); δC (75 MHz; CD2Cl2) 165.6 (s), 165.2 (d, 1JCF 250.9, FC),
4.5.1. Ethyl 6-Oxo-9-(trifluoromethyl)-6H-indolo[3,2,1-de][1,5]naph-
thyridine-1-carboxylate (1d). (42 mg, 90%) as colorless needles, mp
187.5ꢀ189 °C (EtOH), Rf 0.68 (t-BuOMe); (found: C, 59.9; H, 3.0; N,
7.6. C18H11F3N2O3 requires C, 60.0; H, 3.1; N, 7.8); λmax (DCM)/nm
230 (log ε 3.43), 243 (3.41), 251 (3.39), 265 (3.13), 274 (3.03), 298
(3.22), 307 (3.21), 365 inf (3.07), 378 (3.33), 398 (3.33); νmax/cmꢀ1
2988w, 2924w, 2860w, 1717 m (CdO), 1686 m (CdO), 1608w,
1587w, 1558w, 1472w, 1420 m, 1393w, 1368w, 1337s, 1290s, 1269s,
5120
dx.doi.org/10.1021/jo200824b |J. Org. Chem. 2011, 76, 5113–5122

The Journal of Organic Chemistry
ARTICLE
3
159.5 (s), 148.3 (d), 141.5 (d, JCF 13.7, FCCHCq, C-7a), 140.0 (d),
(EI) 294 (Mþ þ 1, 21%), 293 (Mþ, 100), 265 (40), 248 (76), 237 (20),
220 (37), 192 (22), 165 (17), 138 (7), 114 (6), 96 (6), 87 (7), 63 (5).
4.5.8. Ethyl 6-Oxo-6H-pyrido[40,30:4,5]pyrrolo[3,2,1-de][1,5]naph-
thyridine-1-carboxylate (1k). (21 mg, 56%) as a fine bright yellow
powder, mp (DSC) 206.5 °C (onset), peak 213.6 °C (EtOH), Rf 0.34
(MeOH/t-BuOMe, 1:9); (found: C, 65.7; H, 3.7; N, 14.2. C16H11N3O3
requires C, 65.5; H, 3.8; N, 14.3); λmax (DCM)/nm 245 (log ε 2.98),
272 inf (2.98), 276 (2.99), 284 inf (2.97), 296 inf (2.88), 369 inf (2.52),
382 (2.76), 402 (2.77); νmax/cmꢀ1 3034w, 2976w, 2918w, 1718s (CdO),
1688s (NCdO), 1624w, 1589w, 1553w, 1466w, 1427s, 1398w, 1368w,
1325 m, 1308s, 1292 m, 1265 m, 1233w, 1204w, 1179w, 1134 m, 1109w,
1059 m, 1013w, 989 m, 934w, 922w, 864 m, 851s, 806w; δH (500 MHz;
CD2Cl2) 9.94 (1H, br s, Ar H), 9.41 (1H, s, Ar H), 8.82 (2H, br s, Ar H),
8.05 (1H, d, J = 10.0, Ar H), 7.11 (1H, d, J = 9.8, Ar H), 4.60 (2H, q, J =
7.2, OCH2), 1.54 (3H, t, J = 7.2, CH3); δC (75 MHz; CD2Cl2) 165.3 (s),
159.0 (s), 148.3 (d), 146.8 (d), 140.5 (s), 139.9 (d), 139.4 (d), 136.0 (s),
132.7 (s), 131.2 (d), 130.4 (s), 128.7 (s), 122.8 (s), 121.7 (d), 62.8
(OCH2), 14.6 (CH3); m/z (EI) 294 (Mþ þ 1, 20%), 293 (Mþ, 100),
265 (45), 248 (50), 237 (23), 220 (29), 192 (15), 165 (21), 138 (10),
110 (5), 87 (8), 63 (4).
4.6. 6-Oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-1-car-
boxylic Acid (6). To a stirred suspension of ethyl canthin-6-one-1-
carboxylate 1b (50 mg, 0.17 mmol) in DCM/methanol (9:1, 2 mL) at ca.
20 °C was added NaOH (27.2 mg, 0.68 mmol). After 24 h a yellow
precipitate was formed. The solvent was then removed in vacuo to leave
a residue, which was dissolved in H2O (5 mL), acidified using 10%
HCl and extracted with EtOAc (2 ꢁ 15 mL). The combined organic
phases were dried (Na2SO4), filtered and evaporated in vacuo to give the
title compound 6 as yellow plates (44 mg, 99%), mp >300 °C (EtOH),
Rf 0.20 (MeOH/t-BuOMe, 1:9); (found: C, 68.1; H, 3.0; N, 10.5.
C15H8N2O3 requires C, 68.2; H, 3.1; N, 10.6); λmax (DCM)/nm 231 inf
(log ε 3.60), 247 inf (3.70), 250 (3.70), 263 (3.65), 270 (3.60), 300
(3.47), 310 inf (3.43), 361 inf (3.29), 376 (3.44), 394 (3.37); νmax/cmꢀ1
3042w, 2907w, 2776w, 1730 m (CdO), 1713 m, 1688s (NCdO), 1643
m, 1632 m, 1620 m, 1591 m, 1557 m, 1470w, 1445w, 1418s, 1344w,
1329 m, 1304s, 1250s, 1217s, 1143s, 1111w, 1101w, 1047w, 1022w,
989w, 937w, 895w, 835s, 808w, 770s; δH (500 MHz; DMSO-d6) OH
missing 9.08 (1H, s, Ar H), 8.60 (1H, d, J = 8.1, Ar H), 8.36 (1H, d,
J = 8.1, Ar H), 8.00 (1H, d, J = 9.8, Ar H), 7.65 (1H, t, J = 7.9, Ar H), 7.45
(1H, t, J = 7.6, Ar H), 6.95 (1H, d, J = 9.8, Ar H); δC (125 MHz; DMSO-
d6) 166.3 (CO2H), 158.6 (s), 147.2 (d), 139.2 (s), 139.1 (d), 138.0 (s),
131.7 (s), 131.5 (d), 130.1 (d), 128.7 (d), 127.7 (d), 125.5 (s), 122.9 (s),
121.3 (s), 115.7 (d); m/z (EI) 264 (Mþ, 100%), 247 (7), 236 (38), 219
(12), 191 (14), 164 (15), 139 (5), 132 (6), 113 (5), 104 (5), 95 (4), 88
(4), 63 (7).
138.8 (s), 132.7 (s), 130.5 (d), 130.2 (d, 3JCF 10.4, FCCHCH, C-11),
129.8 (s), 121.3 (s), 120.4 (s), 113.9 (d, 2JCF 23.6, FCCH, C-8 or 10),
104.5 (d, 2JCF 28.6, FCCH, C-8 or 10), 62.5 (OCH2), 14.6 (CH3); m/z
(EI) 311 (Mþ þ 1, 20%) 310 (Mþ, 75), 295 (9), 282 (42), 265 (73), 254
(18), 237 (42), 209 (37), 182 (36), 158 (10), 156 (13), 131 (11), 119
(9), 106 (8), 81 (7), 57 (9).
4.5.5. Ethyl 10-Chloro-6-oxo-6H-indolo[3,2,1-de][1,5]naphthyridine-
1-carboxylate (1h). (38 mg, 89%) as light yellow needles, mp
191ꢀ193 °C (EtOH), Rf 0.70 (t-BuOMe); (found: C, 62.4; H, 3.3;
N, 8.5. C17H11ClN2O3 requires C, 62.5; H, 3.4; N, 8.6); λmax (DCM)/
nm 399 (log ε 2.35), 381 (3.40), 306 (2.18), 228 (3.16); νmax/cmꢀ1
3115w, 3051w (Ar CH), 2983w, 2947w, 2859w, 1719 m (CdO), 1679s
(NCdO), 1624w, 1587w, 1557w, 1458w, 1439 m, 1402 m, 1387 m,
1366w, 1329s, 1296s, 1254s, 1225w, 1198w, 1150s, 1121 m, 1105w,
1074 m, 1049w, 1016w, 991w, 941w, 897w, 856 m, 847 m, 829 m, 806w,
766 m; δH (300 MHz; CD2Cl2) 9.33 (1H, s, Ar H), 8.95 (1H, d, J = 2.1,
Ar H), 8.55 (1H, d, J = 8.7, Ar H), 7.99 (1H, d, J = 9.9, Ar H), 7.66 (1H,
dd, J = 8.7, 2.1, Ar H), 6.98 (1H, d, J = 9.9, Ar H), 4.58 (2H, q, J = 7.1,
OCH2), 1.54 (3H, t, J = 7.2, CH3); δC (75 MHz; CD2Cl2) 165.4 (s),
159.2 (s), 148.2 (d), 139.7 (d), 139.2 (s), 138.6 (s), 132.6 (s), 131.9 (d),
131.6 (s), 130.8 (d), 129.0 (s), 128.2 (d), 125.2 (s), 121.5 (s), 117.6 (d),
62.7 (OCH2), 14.5 (CH3); m/z (EI) 328 (Mþ þ 2, 42%), 326 (Mþ,
100), 300 (15), 298 (41), 283 (16), 281 (46), 272 (8), 270 (26), 253
(31), 247 (10), 225 (22), 198 (15), 190 (12), 163 (10), 149 (10), 138
(11), 126 (7), 112 (8), 99 (7), 88 (6), 63 (5).
4.5.6. Ethyl 6-Oxo-10-(trifluoromethyl)-6H-indolo[3,2,1-de][1,5]naph-
thyridine-1-carboxylate (1i). (44.5 mg, 95%) as beige needles, mp
188.5ꢀ190 °C (EtOH), Rf 0.70 (t-BuOMe); (found: C, 60.0; H, 3.0; N,
7.8. C18H11F3N2O3 requires C, 60.0; H, 3.1; N, 7.8); λmax (DCM)/nm
231 (log ε 3.26), 234 inf (3.24), 241 inf (3.19), 250 inf (3.14), 260 inf
(3.00), 270 inf (2.86), 299 (3.03), 307 (3.03), 344 inf (2.61), 359 (2.88),
376 (3.14), 394 (3.13); νmax/cmꢀ1 3119w, 3057w, 2999w, 1713 m
(CdO), 1682 m (NCdO), 1628w, 1612w, 1589w, 1560w, 1474w,
1449w, 1406 m, 1393 m, 1342 m, 1323s, 1298s, 1260 m, 1219w, 1200w,
1163s, 1144s, 1123s, 1101 m, 1063 m, 1049w, 1013w, 995w, 922w,
897w, 880w, 845s, 837 m, 806w, 768 m; δH (500 MHz; CD2Cl2) 9.38
(1H, s, Ar H), 9.32 (1H, s, Ar H), 8.77 (1H, d, J = 8.6, Ar H), 8.03 (1H, d,
J = 9.8, Ar H), 7.98 (1H, d, J = 8.5, Ar H), 7.01 (1H, d, J = 9.8, Ar H), 4.61
(2H, q, J = 7.1, OCH2), 1.55 (3H, t, J = 7.1, CH3); δC (125 MHz;
CD2Cl2) 165.5 (s), 159.5 (s), 148.6 (d), 142.1 (s), 140.1 (d), 139.6 (s),
133.1 (s), 130.9 (d), 129.3 (s), 128.9 (q, 3JCF 3.3, F3CCCH, C-9 or 11),
128.1 (q, 2JCF 32.5, F3CC, C-10), 126.0 (q, 3JCF 4.2, F3CCCH, C-9 or
1
11), 124.8 (q, JCF 272.6, F3C), 124.3 (s), 121.8 (s), 117.3 (d), 62.9
(OCH2), 14.5 (CH3); m/z (EI) 361 (Mþ þ 1, 21%), 360 (Mþ, 100),
345 (11), 332 (54), 315 (70), 304 (13), 287 (34), 259 (32), 239 (4), 232
(17), 209 (7), 180 (4), 157 (5), 143 (8), 130 (5), 111 (3).
’ ASSOCIATED CONTENT
4.5.7. Ethyl 6-Oxo-6H-pyrido[30,20:4,5]pyrrolo[3,2,1-de][1,5]naph-
thyridine-1-carboxylate (1j). (26 mg, 69%) as a fine brown powder,
mp (DSC) 263.6 °C (onset), peak 268.7 °C (EtOH), Rf 0.38 (MeOH/
t-BuOMe, 1:9); (found: C, 65.6; H, 3.7; N, 14.2. C16H11N3O3 requires
C, 65.5; H, 3.8; N, 14.3); λmax (DCM)/nm 238 (log ε 4.02), 254 inf
(3.95), 257 (3.98), 284 (3.79), 294 (3.82), 328 inf (3.54), 340 (3.76),
354 (3.94), 365 (3.73), 372 (3.92); νmax/cmꢀ1 3078w, 2924w, 2853w,
1690s (CdO), 1672s (CdO), 1632s, 1587w, 1483w, 1462w, 1435 m,
1400 m, 1337 m, 1321w, 1298 m, 1231 m, 1190 m, 1152w, 1115 m, 1057
m, 970w, 893w, 862 m, 847 m, 824 m, 804 m; δH (500 MHz; CD2Cl2)
9.40 (1H, s, Ar H), 9.37 (1H, dd, J = 8.1, 1.8, Ar H), 8.82 (1H, dd, J = 4.8,
1.7, Ar H), 8.02 (1H, d, J = 9.8, Ar H), 7.54 (1H, dd, J = 8.1, 4.8, Ar H),
7.03 (1H, d, J = 10.0, Ar H), 4.58 (2H, q, J = 7.2, OCH2), 1.52 (3H, t, J =
7.2, CH3); δC (125 MHz; CD2Cl2) 165.6 (s), 158.2 (s), 153.3 (s), 151.7
(d), 148.2 (d), 139.8 (d), 139.6 (Cq), 137.5 (d), 131.9 (Cq), 131.8 (CH),
127.5(Cq), 121.5 (d), 121.6 (s), 117.8 (s), 62.6 (OCH2), 14.6 (CH3);m/z
Supporting Information. 1H and 13C NMR spectra of all
S
b
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: koutenti@ucy.ac.cy.
’ ACKNOWLEDGMENT
The authors wish to thank the Cyprus Research Promotion
Foundation (Grant No. EΠIXEIPHΣEIΣ/EΦAPM/0308/19)
and the following organizations in Cyprus for generous dona-
tions of chemicals and glassware: The State General Laboratory,
the Agricultural Research Institute, the Ministry of Agriculture,
5121
dx.doi.org/10.1021/jo200824b |J. Org. Chem. 2011, 76, 5113–5122

The Journal of Organic Chemistry
ARTICLE
and Biotronics Ltd. Furthermore, we thank the A. G. Leventis
Foundation for helping to establish the NMR facility at the
University of Cyprus.
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