Ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylates by a tandem S NAr-addition-elimination reaction

Article abstract of DOI:10.1002/jhet.917

A series of N-substituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate esters has been prepared in two steps from ethyl 2-(2-chloronicotinoyl)acetate. Treatment of the β-ketoester with N,N-dimethylformamide dimethyl acetal in N,N-dimethylformamide (DMF) gave a 95% yield of the 2-dimethylaminomethylene derivative. Subsequent reaction of this β-enaminone with primary amines in DMF at 120^oC for 24 h then afforded the target compounds in 47-82% yields by a tandem S_NAr-addition-elimination reaction. Synthetic and procedural details as well as a mechanistic rationale are presented.

Full text of DOI:10.1002/jhet.917

658
Ethyl 1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylates by a
Tandem SNAr-Addition-Elimination Reaction
Vol 49
*
Richard A. Bunce and Baskar Nammalwar
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma, 74078-3071
*
E-mail: rab@okstate.edu
Received December 31, 2010
DOI 10.1002/jhet
View this article online at wileyonlinelibrary.com.
A series of N-substituted 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate esters has been prepared in
two steps from ethyl 2-(2-chloronicotinoyl)acetate. Treatment of the b-ketoester with N,N-dimethylforma-
mide dimethyl acetal in N,N-dimethylformamide (DMF) gave a 95% yield of the 2-dimethylaminomethylene
derivative. Subsequent reaction of this b-enaminone with primary amines in DMF at 120oC for 24 h then
afforded the target compounds in 47–82% yields by a tandem SNAr-addition-elimination reaction. Synthetic
and procedural details as well as a mechanistic rationale are presented.
J. Heterocyclic Chem., 49, 658 (2012)
INTRODUCTION
the desired heterocycles in moderate yields of 60–65%
[2b]. Finally, acylation a to the ester group of ethyl 3-
(dimethylamino)acrylate with 2-chloronicotinoyl chloride
and subsequent reaction with a functionalized aniline also
afforded the target ring system [5b], but the overall yields
were variable and generally modest (45–78%).
We recently reported a two-step synthesis of 1-alkyl-
and 1-aryl-1,4-dihydro-4-oxo-3-quinolinecarboxylate esters
from ethyl 2-(2-fluorobenzoyl)acetate involving conversion
to a b-enaminone followed by reaction with a primary amine
(e.g., RNH2) [1]. This strategy avoided the intermediacy of an
alkoxymethylene derivative and afforded the final products in
higher yields (by 5–15%) over previous preparations. The
current project sought to extend this method to the synthesis
of 1-alkyl- and 1-aryl-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylates, which would feature a tandem SNAr-
addition-elimination reaction with a 2-chloropyridine moiety
as the acceptor in the SNAr step. Like the dihydroquinolines
described previously [1], the target dihydronaphthyridines
have high potential as antibiotics [2] as well as anti-HIV [3]
and anti-inflammatory drugs [4,5]. Thus, improved access to
these structures is highly desirable.
Earlier syntheses of these ring systems followed three
basic strategies and focused on the preparation of 1-aryl-
1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylates. The
first method began with a substituted 2-(2-chloronicoti-
noyl)acetate substrate and involved generation of the
alkoxymethylene derivative, conversion to an intermediate
alkylaminomethylene congener and finally ring closure.
Although similar to our procedure, this protocol incorpo-
rated an extra step, and gave the dihydronaphthyridines
in only 45–60% yields [2a,2f,3]. The second preparation
entailed addition of a 2-aminopyridine to diethyl ethoxy-
methylenemalonate, followed by thermal ring closure.
While requiring only two steps, this approach furnished
RESULTS AND DISCUSSION
The synthesis of the required cyclization substrate is out-
lined in Scheme 1. Conversion of ethyl hydrogen malonate
(1) [6] to its dianion 2 with excess n-butyllithium and reac-
tion with 2-chloronicotinoyl chloride (4) derived from acid
3 afforded ethyl 2-(2-chloronicotinoyl)acetate (5) in 83%
yield [7]. Condensation of 5 with N,N-dimethylformamide
dimethyl acetal in DMF at 100ꢀC for 30 min then afforded
b-enaminone 6 in 95% yield [8]. Although enaminone 6 (a
vinylogous amide) appeared to be a single isomer, the E-Z
stereochemistry was unknown.
The results of our cyclization study are summarized in
Figure 1. Since two bonds must be formed to close the
ring, primary amines were required for the cyclizations.
Treatment of enaminone 6 with an equimolar quantity of
each amine in DMF under argon at 120oC generally
afforded the target ethyl 1,4-dihydro-4-oxo-1,8-naphthyri-
dine-3-carboxylates 7 in 70–82% yields. One notable ex-
ception was the cyclization using tert-butylamine (Fig. 1,
entry g), which gave the heterocycle in only 47% yield,
presumably due to steric hindrance around the nucleophilic
© 2012 HeteroCorporation

May 2012
Ethyl 1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylates by a
Tandem SNAr-Addition-Elimination Reaction
659
Scheme 1. Synthesis of the cyclization substrates.
reactions under more dilute ([substrate]/2) conditions
where the chloride concentration remained low, though
12–24% of residual ester cleavage was still observed. More
importantly, however, experiments designed to favor acid
formation using excess chloride (up to five equivalents)
in several of the other reactions proceeded normally to give
esters under our standard conditions. This last result led us
to rule out the SN2 dealkylation process as the source of the
acid products.
A second plausible explanation relates to the source of
the amines. While most of our amines were from freshly
opened bottles, the hexylamine and 2-phenylethylamine
came from previously opened containers. Thus, it was pos-
sible that water absorbed by these older reagents was pro-
moting hydrolysis of the ester products [10]. This
rationale would be consistent with the results of our dilu-
tion experiments, since additional dry solvent in the reac-
tion would lower the water concentration and decrease,
but not completely suppress, ester cleavage. Validation of
this proposal came when repetition of these two runs using
anhydrous amines gave the ester products without signifi-
cant acid formation.
amine nitrogen. Reactions were conveniently run in a
Pyrex pressure vessel, though this was only necessary for
amines with boiling points less than 100ꢀC (Fig. 1, entries
a, c, e, and g). The dihydronaphthyridine products were all
solids and, thus, easily purified by trituration in ether or by
preparative thin layer chromatography followed by tritura-
tion in ether.
The proposed mechanism for the process is summarized
in Scheme 2. Though the reaction chronology is somewhat
speculative, the sequence likely involves an initial SNAr
The reaction was successful for primary amines incorpo-
rating cyclic (Fig. 1, entries a-b), minimally branched
straight chain (entries c-f), benzylic (entries h-k), and aro-
matic (entries l-o) R groups. In fact, the target heterocycles
were produced in similar yields from all amines when the
R group was primary, secondary or aromatic. Our previous
work [1] indicated that primary amines incorporating a ter-
tiary R group reacted poorly, and this was borne out in this
study where tert-butylamine (entry g) gave the lowest
yield. Nevertheless, hindered aromatic amines, such as 2-
methylaniline (o-toluidine, entry o), afforded dihydro-
naphthyridine 7o in a respectable 78% yield, despite the
steric congestion created by the ortho methyl group. Thus,
the current method appears to be a general route to these
compounds except when R is tertiary.
Although most of our reactions proceeded cleanly, early
reactions using hexylamine and 2-phenylethylamine (Fig.
1, entries d and f) gave the carboxylic acids rather than
the ester products. This anomaly was not encountered in
our previous work to prepare 1,4-dihydro-4-oxo-3-quinoli-
necarboxylate esters [1], or from any other amine in this
study. Attempts to suppress this process by running the re-
action at lower temperature (90–100ꢀC) were unsuccessful
and gave ester-acid mixtures. Initially, we believed that
these acids resulted from SN2 dealkylation of the esters
[9] by chloride ion produced in the reaction. Chloride is a
potent nucleophile in polar aprotic solvents and could eas-
ily displace the carboxylate anion from an unhindered
primary carbon [10]. In support of this hypothesis, the
esters were isolated in 50–60% yields from these same
Figure 1. Cyclization of ethyl 1,4-dihydro-4-oxo-1,8-naphthyridne-3-
carboxylates.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

660
R. A. Bunce and B. Nammalwar
Vol 49
Scheme 2. Proposed mechanism of the cyclization.
hydride prior to use. Other commercial reagents and solvents
were used as received. Note: Unless the amines are used from
freshly opened bottles, they should be dried over calcium hydride
(12 h, 60ꢀC) and distilled prior to use. Reactions were monitored
by thin layer chromatography on silica gel GF plates (Analtech
No. 21521). Preparative separations were performed using flash
chromatography [14] on silica gel (Grade 62, 60–200 mesh)
mixed with UV-active phosphor (Sorbent Technologies No. UV-5)
or preparative thin layer chromatography on 20-cm ꢂ 20-cm
silica gel GF plates (Analtech No. 02015); band elution for both
methods was monitored using a hand-held UV lamp. Melting
points were uncorrected. IR spectra were run as thin films on
sodium chloride disks. Unless otherwise indicated, 1H- and
13CNMR spectra were measured in deuteriochloroform at 300
MHz and 75 MHz, respectively, and were referenced to internal
tetramethylsilane; coupling constants (J) are reported in Hz.
Low resolution mass spectra (electron impact/direct probe) were
run at 30 eV.
Ethyl 2-(2-chloronicotinoyl)acetate (5). The procedure of
Domagala and coworkers was modified [7]. A 100-mL, single-
necked, round-bottomed flask, equipped with a reflux condenser
and a magnetic stirrer, was charged with 5.00 g (31.7 mmoles)
of 2-chloronicotinic acid (2) and 25 mL of thionyl chloride. A
drop of DMF was added and the reaction was heated at reflux
(oil bath) for 3 h. At the end of this period, 25 mL of benzene
was added and the excess thionyl chloride was removed by
distillation. This process was repeated three times before final
concentration under vacuum gave 2-chloronicotinoyl chloride
(3) as a tan solid. The isolated material was used without further
purification.
reaction with the activated aromatic ring to give 8 [11]. At
120oC, intermediate 8 would then rapidly undergo ring clo-
sure by an addition-elimination reaction with the side chain
enaminone to give 7. Since resonance reduces the double
bond character of the a,b bond in 8, the E and Z forms of
this intermediate should readily equilibrate to allow for cy-
clization, presumably via the Z isomer (NMe2 trans to the
ketone). The observation that the current reaction occurs at
lower temperature and in shorter reaction time than for
mononitroarene substrates [1] suggests that 2-chloropyri-
dines are significantly more reactive in SNAr reactions
[12]. This would be expected based on the greater electron
deficiency of the pyridine ring and the more polarized na-
ture of the aromatic C¼N bond [13].
In a 500-mL, three-necked, round-bottomed flask, equipped
with an efficient magnetic stirrer, 6.70 g (50.7 mmoles) of ethyl
hydrogen malonate (1) [6] was dissolved in 200 mL of THF
and 10 mg of bipyridyl was added as an internal indicator. The
mixture was cooled to ꢃ30ꢀC and 22.5 mL of 2.27M n-butyl-
lithium (51.0 mmoles) was added dropwise over 20 min. The re-
action mixture was warmed to ꢃ5ꢀC and another portion of 22.5
mL of 2.27M n-butyllithium (51.0 mmoles) was added until a red
color persisted for 5–10 min. The resulting solution of 2 was
cooled to ꢃ78ꢀC and a solution of 5.58 g (31.7 mmoles) of 2-
chloronicotinoyl chloride (4) in 25 mL of THF was added drop-
wise over 25 min. The reaction was kept at ꢃ78ꢀC for 30 min
and then slowly warmed to ꢃ30ꢀC and stirred for 30 min. The
crude mixture was poured into ice containing 250 mL of 1M
hydrochloric acid and extracted with dichloromethane (3 ꢂ 200
mL). The combined organic extracts were washed with water
(1 ꢂ 200 mL), 5% aqueous sodium bicarbonate (1 ꢂ 200 mL)
and 1M hydrochloric acid (1 ꢂ 200 mL). The dichloromethane
layer was finally washed with saturated aqueous sodium chloride
(1 ꢂ 200 mL), dried (magnesium sulfate) and concentrated under
vacuum to give a dark yellow oil. The product was purified by
flash chromatography on a 50 cm ꢂ 2.5 cm silica gel column
eluted with increasing concentrations of ether in hexanes to give
5.98 g (83%) of 5 as a colorless oil consisting of a 1:1 keto:enol
CONCLUSION
We have developed an alternative synthesis of N-substi-
tuted ethyl 1,4-dihydro-4-oxo-1,8-naphthyridine-3-carbox-
ylates, thus providing access to new derivatives of these
valuable pharmaceutical building blocks. The synthesis is
operationally simple and gives the target heterocycles in
ꢁ70% overall yields, which represents a 5–15% improve-
ment over previous methods. The synthesis appears to be
general for all primary amines (e.g., RNH2), though yields
are reduced when the R of the primary amine is a tertiary
alkyl group.
1
mixture. IR: 1743, 1707, 1633 cmꢃ1; HNMR (keto-enol mix-
ture): d 12.5 (s, 0.5H), 8.53 (dd, 0.5H, J = 4.8, 2.0), 8.45 (dd,
0.5H, J = 4.8, 2.0), 7.99 (dd, 0.5H, J = 7.5, 2.0), 7.95 (dd, 0.5H,
J = 7.5, 2.0), 7.39 (dd, 0.5H, J = 7.5, 4.8), 5.70 (s, 0.5H), 4.29
(q, 1H, J = 7.1), 4.19 (q, 1H, J = 7.1), 4.10 (s, 1.5H), 1.35
(t, 1.5H, J = 7.1), 1.25 (t, 1.5H, J = 7.1); 13CNMR (keto-enol mix-
ture): d 193.5, 172.3, 168.0, 166.5, 151.8, 150.4, 148.5, 147.5,
139.1, 138.7, 134.0, 130.1, 122.6, 122.2, 94.0, 61.5, 60.7, 48.6,
EXPERIMENTAL
All reactions were run under dry nitrogen in oven-dried glass-
ware. Commercial anhydrous N,N-dimethylformamide (DMF)
was stored under nitrogen and transferred by syringe into reac-
tions where it was used. Tetrahydrofuran (THF) was dried over
potassium hydroxide pellets and distilled from lithium aluminium
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Ethyl 1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylates by a
Tandem SNAr-Addition-Elimination Reaction
661
14.1, 13.9; ms: m/z 227, 229 (ca 3:1, M+). Anal. Calcd. for
C10H10ClNO3: C, 52.75; H, 4.40; N, 6.15. Found: C, 52.83; H,
4.47; N, 6.02.
Ethyl 1-allyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylate
(7c). This compound (101 mg, 78%) was prepared from 142 mg
(0.50 mmoles) of 6 and 29 mg (0.038 mL, 0.50 mmoles) of
allylamine. The product was isolated as a white solid following
preparative thin layer chromatography eluted with ethyl acetate and
Ethyl 2-(2-chloronicotinoyl)-3-(dimethylamino)acrylate (6).
A 100-mL, single-necked, round-bottomed flask, equipped with a
reflux condenser and a magnetic stirrer, was charged with 3.00 g
(13.2 mmoles) of 5 dissolved in 10 mL of DMF and the solution
was heated to 100ꢀC (oil bath). To this was added 1.57 g (1.75 mL,
13.2 mmoles) of N,N-dimethylformamide dimethyl acetal and the
reaction mixture was stirred with continued heating for 30 min. The
crude reaction mixture was quenched with ice water, stirred for 5
min and extracted with ether (2 ꢂ 100 mL). The aqueous solution
was saturated with sodium chloride and extracted one final time with
100 mL of 1:1 ether:ethyl acetate. The combined organic layers were
washed with saturated sodium chloride (1 ꢂ 100 mL), dried
(magnesium sulfate) and concentrated under vacuum. Further
concentration under high vacuum removed traces of DMF to give
3.53 g (95%) of 6 as an orange oil. This material appeared to be a
single isomer of the enaminone, but the E-Z stereochemistry was not
determined and the oil was used without further purification. IR:
trituration with ether, mp 86–87ꢀC. IR: 1725, 1694, 1623, 1607 cmꢃ1
;
1HNMR: d 8.78 (dd, 1H, J= 7.7, 1.1), 8.74 (dd, 1H, J= 4.4, 1.1), 8.64
(s, 1H), 7.42 (dd, 1H, J= 7.7, 4.4), 6.07 (ddt, 1H, J= 16.5, 10.4, 5.5),
5.32 (d, 1H, J= 10.4), 5.25 (d, 1H, J= 16.5), 5.07 (d, 2H, J=5.5),
4.41 (q, 2H, J= 7.1), 1.41 (t, 3H, J=7.1); 13CNMR: d 174.7, 165.3,
152.3, 149.1 (2C), 136.9, 131.7, 123.6, 121.0, 119.3, 112.3, 61.0,
52.5, 14.3; ms: m/z 258 (M+). Anal. Calcd. for C14H14N2O3: C, 65.12;
H, 5.43; N, 10.85. Found: C, 65.16; H, 5.42; N, 10.81.
Ethyl 1,4-dihydro-1-hexyl-4-oxo-1,8-naphthyridine-3-carboxylate
(7d) and the corresponding acid. This compound (106 mg, 70%)
was prepared from 142 mg (0.50 mmoles) of 6 and 51 mg (0.066 mL,
0.50 mmoles) of dried n-hexylamine. The product was isolated as a
white solid following preparative thin layer chromatography eluted with
ethyl acetate and trituration with ether, mp 68–69oC. IR: 1728, 1694,
1
1634, 1612 cmꢃ1; HNMR: d 8.78 (dd, 1H, J= 7.7, 1.6), 8.74 (dd,
1
1673, 1628, 1577 cm-1; HNMR: d 8.38 (dd, 1H, J= 4.9, 1.6), 8.01
1H, J=4.4, 1.6), 8.65 (s, 1H), 7.41 (dd, 1H, J= 7.7, 4.4), 4.43 (t, 2H,
J= 7.1), 4.41 (q, 2H, J= 7.1), 1.88 (quintet, 2H, J= 6.6), 1.42 (t, 3H,
J= 7.1), 1.42-1.22 (complex, 6H), 0.89 (distorted t, 3H, J=6.6);
13CNMR: d 174.6, 165.3, 152.2, 149.4, 149.2, 136.7, 120.8, 120.7,
111.8, 60.9, 51.6, 31.2, 29.5, 26.1, 22.4, 14.3, 13.8; ms: m/z 302 (M+).
Anal. Calcd. for C17H22N2O3: C, 67.55; H, 7.28; N, 9.27. Found: C,
67.51; H, 7.25; N, 9.18.
and 7.92 (2 s, 1H), 7.72 (dd, 1H, J= 7.7, 1.6), 7.28 (dd, 1H, J=7.7,
4.9), 3.93 (q, 2H, J= 7.1), 3.39 (br s, 3H), 3.01 (br s, 3H), 0.86
(t, 3H, J=7.1); 13CNMR: d 188.1, 166.7, 159.5, 148.9, 146.9, 138.8,
137.1, 122.1, 101.7, 59.7, 48.0, 42.7, 13.5; ms: m/z 283, 285 (ca 3:1, M+).
Anal. Calcd. for C13H16ClN2O3: C, 55.03; H, 5.64; N, 9.88. Found: C,
55.24; H, 5.72; N, 9.64.
General procedure for the tandem SNAr-addition-elimination
reaction: Ethyl 1-cyclopropyl-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylate (7a). A 15-mL Pyrex pressure vessel (Chemglass
CG-1880-01), equipped with a magnetic stirrer, was charged with
142 mg (0.50 mmoles) of 6, 2.5 mL of anhydrous DMF and 29 mg
(0.035 mL, 0.50 mmoles) of cyclopropylamine. The vessel was
purged with nitrogen, the cap was tightened and the reaction was
heated at 120ꢀC for 14 h. After cooling, the crude reaction mixture
was poured over 25 g of ice and extracted with 30 mL of ethyl
acetate. The aqueous layer was saturated with sodium chloride and
extracted with additional ethyl acetate (2 ꢂ 25 mL). The combined
organic layers were washed with saturated sodium chloride, dried
(magnesium sulfate) and concentrated under vacuum. The resulting
solid was triturated in ether to give 97 ꢃm1g (75%) of 7a as a tan solid,
The corresponding acid was produced when an older, undried
sample of the amine was used. The acid was isolated as a white
solid following preparative thin layer chromatography eluted with
ethyl acetate and trituration with ether, mp 124–125ꢀC. IR:
3490-2405, 1720, 1630 cm–1 1HNMR: d 14.5 (s, 1H), 8.93
;
(s, 1H), 8.91 (dd, 1H, J= 4.4, 2.0), 8.83 (dd, 1H, J= 7.8, 2.0), 7.57
(dd, 1H, J= 7.8, 4.4), 4.56 (t, 2H, J= 7.3), 1.92 (m, 2H), 1.38
(m, 6H), 0.89 (distorted t, 3H, J=6.4); 13CNMR: d 178.8, 166.3,
153.9, 149.07, 149.05, 136.3, 121.9, 121.5, 109.6, 52.6, 31.2, 29.8,
26.2, 22.4, 13.9; ms: m/z 274 (M+). Anal. Calcd. for C15H18N2O3:
C, 65.69; H, 6.57; N, 10.22. Found: C, 65.73; H, 6.55; N, 10.13.
Ethyl 1,4-dihydro-1-isobutyl-4-oxo-1,8-naphthyridine-
3-carboxylate (7e). This compound (105 mg, 76%) was
prepared from 142 mg (0.50 mmoles) of 6 and 37 mg (0.051
mL, 0.50 mmoles) of isobutylamine. The product was
isolated as a white solid following workup and trituration
mp 135–136ꢀC. IR: 1724, 1627 cm
;
1HNMR: d 8.80 (d, 1H,
J= 4.4), 8.76 (d, 1H, J= 7.7), 8.72 (s, 1H), 7.44 (dd, 1H, J= 7.7, 4.4),
4.41 (q, 2H, J= 7.1), 3.71 (m, 1H), 1.41 (t, 3H, J= 7.1), 1.36
(m, 2H), 1.06 (m, 2H); 13CNMR: d 174.6, 165.3, 152.4, 150.8,
149.0, 136.7, 123.5, 121.1, 111.9, 61.0, 34.1, 14.4, 7.6; ms: m/z 258
(M+). Anal. Calcd. for C14H14N2O3: C, 65.12; H, 5.43; N, 10.85.
Found: C, 65.14; H, 5.44; N, 10.82.
with ether, mp 73–75ꢀC. IR: 1727, 1694, 1628, 1611 cmꢃ1
;
1HNMR: d 8.75 (dd, 1H, J = 7.7, 1.6), 8.73 (dd, 1H, J = 4.4,
1.6), 8.60 (s, 1H), 7.40 (dd, 1H, J = 7.7, 4.4), 4.42 (q, 2H,
J = 7.1), 4.24 (d, 2H, J = 7.1), 2.32 (nonet, 1H, J = 7.1), 1.43
(t, 3H, J = 7.1), 0.98 (d, 6H, J = 7.1); 13CNMR: d 174.6,
165.4, 152.2, 149.8, 149.4, 136.8, 123.7, 120.9, 111.5, 60.9,
58.5, 28.3, 19.8, 14.3; ms: m/z 274 (M+). Anal. Calcd. for
C15H18N2O3: C, 65.69; H, 6.57; N, 10.22. Found: C, 65.66;
H, 6.55; N, 10.19.
Ethyl 1-cyclohexyl-1,4-dihydro-4-oxo-1,8-naphthyridine-
3-carboxylate (7b). This compound (112 mg, 75%) was prepared
from 142 mg (0.50 mmoles) of 6 and 50 mg (0.057 mL, 0.50
mmoles) of cyclohexylamine. The product was isolated as a white
solid following preparative thin layer chromatography eluted with
ethyl acetate and trituration with ether, mp 60–61ꢀC. IR: 1730,
Ethyl 1,4-dihydro-4-oxo-1-(2-phenylethyl)-1,8-naphthyridine-
3-carboxylate (7f) and the corresponding acid. This compound
(116 mg, 72%) was prepared from 142 mg (0.50 mmoles) of 6 and
61 mg (0.063 mL, 0.50 mmoles) of dried 2-phenylethylamine. The
product was isolated as a white solid following preparative thin
layer chromatography eluted with ethyl acetate and trituration with
ether, mp 97–98oC. IR: 1725, 1692, 1631, 1601 cmꢃ1; 1HNMR: d
8.78 (m, 2H), 8.30 (s, 1H), 7.43 (dd, 1H, J = 8.2, 4.9), 7.27 (m,
3H), 7.12 (d, 2H, J = 6.6), 4.64 (t, 2 H, J = 7.1), 4.31 (q, 2H,
J = 7.1), 3.17 (t, 2H, J = 7.1), 1.37 (t, 3H, J = 7.1); 13CNMR: d
1
1692, 1640, 1607 cmꢃ1; HNMR: d 8.79 (dd, 1H, J=7.7, 1.1),
8.75 (s, 1H), 8.74 (obscured dd, 1H, J= 1.1), 7.41 (dd, 1H, J=7.7,
4.4), 5.52 (tt, 1H, J= 11.5, 3.5), 4.42 (q, 2H, J= 7.1), 2.07 (d, 2H,
J= 11.5), 1.99 (d, 2H, J= 13.2), 1.84-1.50 (complex, 5H), 1.43
(t, 3H, J= 7.1), 1.33 (tt, 1H, J= 13.2, 3.5); 13CNMR: d 174.1, 165.7,
151.9, 149.1, 145.8, 137.0, 123.7, 120.8, 111.9, 60.9, 56.0, 32.6,
25.8, 25.2, 14.4; ms: m/z 300 (M+). Anal. Calcd. for C17H20N2O3: C,
68.00; H, 6.67; N, 9.33. Found: C, 68.11; H, 6.69; N, 9.28.
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R. A. Bunce and B. Nammalwar
Vol 49
174.6, 164.9, 152.3, 149.5, 149.0, 137.1, 136.9, 128.8 (2C), 127.0,
123.6, 120.9, 111.5, 60.8, 53.1, 35.6, 14.3; ms: m/z 231 (M+-C7H7).
Anal. Calcd. for C19H18N2O3: C, 70.81; H, 5.59; N, 8.70. Found: C,
70.86; H, 5.62; N, 8.61.
m/z 342, 344 (ca. 3:1, M+). Anal. Calcd. for C18H15ClN2O3: C, 63.07;
H, 4.38; N, 8.18. Found: C, 63.10; H, 4.41; N, 8.12.
Ethyl 1,4-dihydro-4-oxo-1-(4-trifluoromethylbenzyl)-1,8-
naphthyridine-3-carboxylate (7k). This compound (151 mg, 80%)
was prepared from 142 mg (0.50 mmoles) of 6 and 88 mg
(0.071 mL, 0.50 mmoles) of 4-(trifluoromethyl)benzylamine.
The product was isolated as a white solid following workup
and trituration with ether, mp 202–204ꢀC. IR: 1678, 1651,
The corresponding acid was produced when an older, undried
sample of the amine was used. The acid was isolated as a white
solid following preparative thin layer chromatography eluted with
ethyl acetate and trituration with ether, mp 180–182ꢀC. IR: 2924
1
1610, 1334 cmꢃ1; HNMR: d 8.80 (dd, 1H, J = 7.7, 1.6), 8.72
1
1717, 1625, 1600 cmꢃ1; HNMR: d 14.3 (s, 1H), 8.93 (dd, 1H,
(s, 1H), 8.71 (obscured dd, 1H, J = 4.9, 1.6), 7.61 (d, 1H,
J = 8.2), 7.42 (dd, 1H, J = 7.7, 4.9), 7.41 (d, 2H, J = 8.2), 5.69
(s, 2H), 4.40 (q, 2H, J= 7.1), 1.41 (t, 3H, J=7.1); 13CNMR:
J = 4.1, 1.8), 8.83 (dd, 1H, J = 8.2, 1.8), 8.66 (s, 1H), 7.58 (dd,
1H, J=7.7, 4.1), 7.28 (m, 3H), 7.11 (d, 2H, J= 7.7), 4.77 (t, 2H,
J= 7.3), 3.20 (t, 2H, J=7.3); 13CNMR: d 178.8, 166.6, 153.9,
149.2, 136.4 (2C), 129.0 (2C), 128.7, 127.4, 121.9, 121.5, 109.5,
53.9, 35.8; ms: m/z 203 (M+-C7H7). Anal. Calcd. for C17H14N2O3:
C, 69.39; H, 4.76; N, 9.52. Found: C, 69.41; H, 4.75; N, 9.47.
Ethyl 1-tert-butyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate (7g). This compound (64 mg, 47%) was prepared
from 142 mg (0.50 mmoles) of 6 and 37 mg (0.053 mL,
0.50 mmoles) of tert-butylamine. The product was isolated
as a white solid following workup and trituration with
d
174.5, 165.0, 152.4, 149.2, 149.1, 139.6, 137.0, 130.5
(q, J= 32.4), 127.7, 125.9 (q, J= 3.7), 123.8 (q, J= 271.6), 123.7,
121.3, 112.8, 61.1, 53.3, 14.3; ms: m/z 376 (M+). Anal. Calcd. for
C19H15F3N2O3: C, 60.64; H, 3.99; N, 7.45. Found: C, 60.71; H,
4.04; N, 7.39.
Ethyl 1,4-dihydro-4-oxo-1-phenyl-1,8-naphthyridine-3-
carboxylate (7l). This compound (118 mg, 80%) was prepared
from 142 mg (0.50 mmoles) of 6 and 47 mg (0.046 mL,
0.50 mmoles) of aniline. The product was isolated as a white solid
following workup and trituration with ether, mp 216–217ꢀC. IR:
ether, mp 154–155oC. IR 1733, 1687, 1630, 1595 cmꢃ1
;
1HNMR d 9.01 (s 1H), 8.83 (dd, 1H, J= 7.7, 1.6), 8.75 (dd, 1H,
J= 4.4, 1.6), 7.40 (dd, 1H, J = 7.7, 4.4), 4.42 (q, 2H, J= 7.1), 1.92
(s, 9H), 1.43 (t, 3H, J=7.1); 13CNMR: d 174.4, 166.2, 150.5,
150.3, 147.1, 136.8, 124.9, 120.6, 110.8, 64.6, 61.0, 29.9, 14.4; ms:
m/z 259 (M+-CH3). Anal. Calcd. for C15H18N2O3: C, 65.69; H,
6.57; N, 10.22. Found: C, 65.68; H, 6.57; N, 10.20.
1
1731, 1694, 1642, 1608 cmꢃ1; HNMR: d 8.83 (dd, 1H, J=7.7,
1.1), 8.71 (s, 1H), 8.64 (dd, 1H, J=4.4, 1.1), 7.59 (m, 2H), 7.45 (m,
3H), 7.42 (dd, 1H, J= 7.7, 4.4), 4.41 (q, 2H, J= 7.1), 1.41 (t, 3H,
J=7.1); 13CNMR: d 174.8, 165.0, 152.6, 150.2, 149.6, 140.3, 136.9,
129.7, 129.4, 127.4, 123.2, 121.3, 112.6, 61.1, 14.4; ms: m/z 294
(M+). Anal. Calcd. for C17H14N2O3: C, 69.39; H, 4.76; N, 9.52.
Ethyl 1-benzyl-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate (7h). This compound (113 mg, 73%) was prepared
from 142 mg (0.50 mmoles) of 6 and 54 mg (0.054 mL,
0.50 mmoles) of benzylamine. The product was isolated as
a white solid following preparative thin layer chromatography eluted
with ethyl acetate and trituration with ether, mp 154–155ꢀC. IR:
Found: C, 69.35; H, 4.71; N, 9.51.
Ethyl 1,4-dihydro-1-(4-methoxyphenyl)-4-oxo-1,8-naphthyridine-3-
carboxylate (7m). This compound (133 mg, 82%) was prepared from
142 mg (0.50 mmoles) of 6 and 62 mg (0.057 mL, 0.50 mmoles) of
4-methoxyaniline. The product was isolated as a pale yellow solid
following workup and trituration with ether, mp 203–205ꢀC. IR: 2837,
1
1725, 1691, 1628, 1611 cmꢃ1; HNMR: d 8.79 (dd, 1H, J=7.7,
1
1730, 1693, 1640, 1606 cmꢃ1; HNMR: d 8.82 (d, 1H, J= 7.7), 8.69
1.6), 8.73 (dd, 1H, J= 4.4, 1.6), 8.72 (s, 1H), 7.41 (dd, 1H, J=7.7,
4.4), 7.32 (m, 5H), 5.65 (s, 2H), 4.39 (q, 2H, J= 7.1), 1.40 (t, 3H,
J=7.1); 13CNMR: d 174.7, 165.2, 152.4, 149.3 (2C), 136.9, 135.5,
129.0, 128.4, 127.6, 123.7, 121.1, 112.5, 61.0, 53.6, 14.4; ms: m/z
308 (M+). Anal. Calcd. for C18H16N2O3: C, 70.13; H, 5.19; N, 9.09.
Found: C, 70.14; N, 5.21; N, 9.04.
(s, 1H), 8.65 (d, 1H, J= 4.4), 7.41 (dd, 1H, J= 7.7, 4.4), 7.36 (d, 2H,
J=8.2), 7.08 (d, 2H, J= 8.2), 4.40 (q, 2H, J= 7.1), 3.90 (s, 3H), 1.40
(t, 3H, J=7.1); 13CNMR: d 174.8, 165.0, 160.0, 152.6, 150.5, 150.0,
136.9, 133.0, 128.5, 123.3, 121.2, 114.8, 112.4, 61.1, 55.6, 14.4; ms: m/z
324 (M+). Anal. Calcd. for C18H16N2O4: C, 66.67; H, 4.94; N, 8.64.
Found: C, 66.73; H, 4.98; N, 8.55.
Ethyl 1,4-dihydro-1-(4-methoxybenzyl)-4-oxo-1,8-naphthyridine-3-
carboxylate (7i). This compound (132 mg, 78%) was prepared from
142 mg (0.50 mmoles) of 6 and 69 mg (0.065 mL, 0.50 mmoles) of
4-methoxybenzylamine. The product was isolated as a tan solid
following workup and trituration with ether, mp 155–156ꢀC. IR: 2837,
Ethyl 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate (7n). This compound (123 mg, 75%) was prepared
from 142 mg (0.50 mmoles) of 6 and 64 mg (0.045 mL, 0.50
mmoles) of 4-chloroaniline. The product was isolated as a tan solid
following workup and trituration with ether, mp 193-194ꢀC. IR: 1731,
1692, 1638, 1597 cmꢃ1; 1HNMR: d 8.81 (dd, 1H, J= 7.7, 1.6), 8.67
(s, 1H), 8.64 (dd, 1H, J= 4.4, 1.6), 7.57 (dd, 2H, J= 8.8), 7.42
(obscured dd, 1H, J= 7.7, 4.4), 7.41 (d, 2H, J= 8.8), 4.40 (q, 2H,
J= 7.1), 1.40 (t, 3H, J=7.1); 13CNMR: d 174.6, 164.8, 152.5, 150.0,
149.2, 138.7, 137.0, 135.4, 129.9, 128.8, 123.2, 121.4, 112.9, 61.2,
14.3; ms: m/z 328, 330 (ca 3:1, M+). Anal. Calcd. for C17H13ClN2O3:
1
1727, 1693, 1629, 1611 cmꢃ1; HNMR: d 8.78 (dd, 1H, J=7.7, 1.6),
8.75 (dd, 1H, J= 4.4, 1.6), 8.71 (s, 1H), 7.41 (dd, 1H, J= 7.7, 4.4), 7.29
(d, 2H, J= 8.4), 6.87 (d, 2H, J= 8.4), 5.51 (s, 2H), 4.39 (q, 2H, J=7.1),
3.78 (s, 3H), 1.40 (t, 3H, J=7.1); 13CNMR: d 174.6, 165.3, 159.6,
152.3, 149.3, 149.1, 136.9, 129.4, 127.4, 123.7, 121.0, 114.3, 112.4,
61.0, 55.3, 53.1, 14.6; ms: m/z 338 (M+). Anal. Calcd. for C19H18N2O4:
C, 67.46; H, 5.33; N, 8.28. Found: C, 67.49; H, 5.35; N, 8.21.
C, 62.10; H, 3.96; N, 8.52. Found: C, 62.16; H, 4.03; N, 8.40.
Ethyl 1-(4-chlorobenzyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-
carboxylate (7j). This compound (130 mg, 75%) was prepared from
142 mg (0.50 mmoles) of 6 and 71 mg (0.061 mL, 0.50 mmoles) of
4-chlorobenzylamine. The product was isolated as a tan solid following
workup and trituration with ether, mp 182–184ꢀC. IR: 1726, 1693,
Ethyl 1,4-dihydro-1-(2-methylphenyl)-4-oxo-1,8-naphthyridine-
3-carboxylate (7o). This compound (122 mg, 79%) was prepared
from 142 mg (0.50 mmoles) of 6 and 54 mg (0.053 mL, 0.50
mmoles) of 2-methylaniline (o-toluidine). The product was isolated as
a tan solid following workup and trituration with ether, mp
1
1
1632, 1614 cmꢃ1; HNMR: d 8.77 (dd, 1H, J= 7.7, 1.6), 8.71 (dd,
210–212ꢀC. IR: 1732, 1694, 1643, 1604 cmꢃ1; HNMR: d 8.81
1H, J=4.4, 1.6), 8.71 (s, 1H), 7.41 (dd, 1H, J= 7.7, 4.4), 7.31 (d, 1H,
J=8.4), 7.26 (d, 1H, J= 8.4), 5.60 (s, 2H), 4.38 (q, 2H, J=7.1), 1.40
(t, 3H, J=7.1); 13CNMR: d 174.5, 165.1, 152.4, 149.1 (2C), 137.0,
134.3, 134.0, 129.1, 129.0, 123.7, 121.2, 112.6, 61.0, 53.1, 14.3; ms:
(dd, 1H, J= 7.7, 1.6), 8.70 (s, 1H), 8.64 (dd, 1H, J= 4.4, 1.6), 7.38
(m, 5H), 4.39 (q, 2H, J= 7.1), 2.48 (s, 3H), 1.40 (t, 3H, J=7.1);
13CNMR: d 174.6, 164.8, 152.5, 150.2, 149.7, 139.5, 137.7, 136.7,
130.2, 127.0, 123.2, 121.1, 112.3, 60.9, 21.1, 14.2; ms: m/z 308
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2012
Ethyl 1,4-Dihydro-4-oxo-1,8-naphthyridine-3-carboxylates by a
Tandem SNAr-Addition-Elimination Reaction
663
(M+). Anal. Calcd. for C18H16NO3: C, 70.13; H, 5.19; N, 9.09.
Found: C, 70.22; H, 5.21; N, 9.06.
129983; (b) Albaneze-Walker, J.; Murry, J. A.; Soheili, A.; Ceglia, S.;
Springfield, S. A.; Bazaral, C.; Dormer, P. G.; Hughes, D. L. Tetrahedron
2005, 61, 6330.
Acknowledgments. B.N. thanks Oklahoma State University for a
research assistantship and the Department of Chemistry for an O. C.
Dermer Scholarship. Funding for the 300 MHz NMR spectrometer
of the Oklahoma Statewide Shared NMR Facility was provided by
NSF (BIR-9512269), the Oklahoma State Regents for Higher
Education, the W. M. Keck Foundation, and Conoco, Inc. Finally,
the authors wish to thank the OSU College of Arts and Sciences for
funds to upgrade our departmental FT-IR and GC-MS instruments.
[6] Strube, R. E. Organic Syntheses; Wiley: New York, 1973, Coll
Vol IV, p 417.
[7] Domagala, J. M.; Bridges, A. J.; Culbertson, T. P.; Gambino,
L.; Hagen, S. E.; Karrick, G.; Porter, K.; Sanchez, J. P.; Sesnie, J. A.;
Spense, F. G.; Szotek, D.; Wemple, J. J Med Chem 1991, 34, 1142.
[8] Tois, J.; Vahermo, M.; Koskinen, A. Tetrahedron Lett 2005,
46, 735.
[9] (a) McMurry, J. Organic Reactions 1976, 24, 187; (b) Bunce,
R. A.; Dowdy, E. D.; Jones, P. B.; Holt, E. M. J Org Chem 1993, 58,
7143; (c) Bunce, R. A.; Schilling, C. L., III. J Org Chem 1995, 60,
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(e) Bunce, R. A.; Schilling, C. L., III. Tetrahedron 1997, 53, 9477;
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1998, 63, 144.
[10] We wish to thank one of the referees for suggesting the pres-
ence of water in these amines as a possible cause for the observed ester
hydrolysis. We did not initially suspect this problem, since acids were
not produced in earlier work with related materials.
[11] Although reaction at the side chain could also occur as the first
step, the fact that no dimethylamine addition was observed suggests that
the sequence is initiated by addition to the aromatic ring. On the other
hand, dimethylamine is highly volatile (bp 7ꢀC) and would not be
expected to build up significant concentrations in the reaction at 120ꢀC.
Additionally, intramolecular ring closure is most likely faster than inter-
molecular addition of dimethylamine to the activated aromatic ring. Thus,
initial attack at the side chain is also possible.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet