Ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylates by a tandem addition-elimination-SNAr reaction

Article abstract of DOI:10.1002/jhet.626

The ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylate ring structure, important in several drug compounds, has been prepared in two steps from ethyl 2-(2-fluorobenzoyl)acetate. Treatment of this β-ketoester with N,N-dimethylformamide dimethyl acetal gives a

Full text of DOI:10.1002/jhet.626

620
Ethyl 1,4-Dihydro-4-oxo-3-quinolinecarboxylates by a Tandem
Addition-Elimination-SNAr Reaction
Vol 48
Richard A. Bunce,* Eric J. Lee, and Matthew T. Grant
Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071
*E-mail: rab@okstate.edu
Received June 9, 2010
DOI 10.1002/jhet.626
Published online 15 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
The ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylate ring structure, important in several drug com-
pounds, has been prepared in two steps from ethyl 2-(2-fluorobenzoyl)acetate. Treatment of this
b-ketoester with N,N-dimethylformamide dimethyl acetal gives a 97% yield of the 2-dimethylamino-
methylene derivative. Reaction of this b-enaminone with primary amines in N,N-dimethylformamide at
140ꢀC for 48 h then affords the 1,4-dihydro-4-oxo-3-quinolinecarboxylate esters in 60–74% yields by a
tandem addition-elimination-SNAr reaction. The synthesis of the starting material as well as procedural
details and a mechanistic scenario are presented.
J. Heterocyclic Chem., 48, 620 (2011).
INTRODUCTION
propiolate to give an b-enamino monoester, acylation
with a 2-fluorobenzoyl chloride derivative and ring clo-
sure by an SNAr reaction using potassium carbonate in
N,N-dimethylformamide (DMF) [2]. The combined yield
for this sequence was generally lower than that for the
two-step procedure described in this article.
Compounds based on the 1,4-dihydro-4-oxo-3-quinoli-
necarboxylate scaffold are known to have significant bio-
logical activity. In particular, these compounds have pro-
ven valuable as antibiotics [1] and, more recently, as
anti-ischemic agents for the treatment of heart attack and
stroke victims [2]. Recently, we reported an approach to
the syntheses of this ring system that involved a tandem
reduction-addition-elimination reaction from an enami-
none substrate, but this route proved to be quite limited
in scope [3]. The current project sought to develop an
alternative synthesis of these heterocycles involving a
tandem addition-elimination-SNAr reaction using a similar
enaminone substrate.
RESULTS AND DISCUSSION
The synthesis of our cyclization substrates is summar-
ized in Scheme 1. The fluoro-substituted compound was
targeted because fluorine is the most reactive halogen in
nucleophilic aromatic substitutions, especially for com-
pounds bearing only modest electron-withdrawing groups
[7,8]. Ethyl hydrogen malonate (1) [9] was converted to
Earlier syntheses [4] of N-substituted 1,4-dihydro-4-
oxo-3-quinolinecarboxylate esters have generally fol-
lowed two strategies. In the first, conjugate addition of
aniline to diethyl (ethoxymethylene)malonate to give a
b-enamino diester was followed by thermal ring closure
at 250ꢀC and N-alkylation (overall yield ca. 50%). The
disadvantage of this method is the high temperature
used for the cyclization reaction, and the highly variable
yields in the final alkylation [4,5]. For N-aryl cases,
where alkylation by an SN2 reaction is not possible,
diphenylamine (the only case reported) was used to pre-
pare the initial b-enamino diester [6]. The yield for this
reaction was not given, but this procedure would require
the use of symmetrical diarylamines to avoid mixtures in
the cyclization step. A second approach to these com-
pounds involved addition of a primary amine to ethyl
Scheme 1. Synthesis of cyclization substrates.
C
V
2011 HeteroCorporation

May 2011
Ethyl 1,4-Dihydro-4-oxo-3-quinolinecarboxylates by a Tandem
Addition-Elimination-SNAr Reaction
621
Scheme 2. Proposed mechanism for the cyclization.
zylic (entries i–l), and aromatic (entries m–p) R groups. In
fact, the target heterocycles were produced in similar yields
from all amines used, except when R was a tertiary alkyl
group. tert-Butylamine (entry h) reacted poorly to give
<5% of 6h under our standard conditions (140ꢀC, 48 h) and
only 13% under more forcing conditions (180ꢀC, 96 h); a
longer reaction time did not significantly improve this yield.
Surprisingly, hindered aromatic amines, such as ortho-tolui-
dine (entry p), afforded the corresponding 1,4-dihydro-4-
oxo-3-quinolinecarboxylate 6p in a respectable 68% 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.
Figure 1. Cyclization of ethyl 1,4-dihydro-4-oxo-3-quinoline-
carboxylates.
its dianion 3 by reaction with two equivalents of n-butyl-
lithium in tetrahydrofuran (THF). Subsequent treatment
of 3 with 0.5 equivalents of 2-fluorobenzoyl chloride (2)
furnished ethyl 2-(2-fluorobenzoyl)acetate (4) in 85%
yield [10]. Condensation of this b-ketoester with N,N-
dimethylformamide dimethyl acetal in DMF at 100ꢀC for
30 min then afforded b-enaminone substrate 5 in 97%
The proposed mechanism of the process is summar-
ized in Scheme 2. The sequence involves an initial con-
jugate addition of the amine to enaminone 5 followed
by elimination of the dimethylamino group to give
adduct 7. If the reaction is performed at 80ꢀC, a signifi-
cant quantity of this addition-elimination product is iso-
lated from the reaction. At 140ꢀC, however, adduct 7
continues on to give 6 by an SNAr ring closure reaction.
Because the addition process is reversible, E- and Z-7
can equilibrate to the E adduct required for cyclization.
1
yield [11]. Many of the H- and 13C-NMR signals for this
compound were very broad, making it difficult to assign E
and Z double bond isomers and determine their ratio.
However, because both isomers react to give the target
heterocycles, the E/Z mixture was used as isolated.
The results of our cyclization study are given in Figure 1.
Treatment of enaminone 5 with an equimolar quantity of a
primary amine (RNH2) in DMF under argon at 140ꢀC for
48 h afforded the target ethyl 1,4-dihydro-4-oxo-3-quinoli-
necarboxylates 6 in 60–70% yields [12]. 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, f, and h). The dihydroqui-
nolines derived from most of the amines studied were
crystalline and, thus, easily purified by trituration in ether.
Products that were not solid were readily purified by prep-
arative thin layer chromatography eluted with ethyl acetate
followed by trituration in ether–petroleum ether mixtures.
The reaction was successful for primary amines incorpo-
rating cyclic (entries a–b), straight-chain (entries c–g), ben-
CONCLUSION
We have developed an alternative synthesis of N-sub-
stituted ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylates,
which could potentially provide access to new derivatives
of these valuable pharmaceutical building blocks. The
synthesis is simple and gives the target heterocycles in
60–74% yields, which represents a slight improvement
over previous methods. The synthesis appears to be gen-
eral for all primary amines except those where the R of
the primary amine is a tertiary alkyl group.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

622
R. A. Bunce, E. J. Lee, and M. T. Grant
Vol 48
EXPERIMENTAL
Ethyl 3-(dimethylamino)-2-(2-fluorobenzoyl)acrylate (5). The
procedure of Koskinen and coworkers [11] was modified. A
50-mL single-necked round-bottomed flask, equipped with a
reflux condenser and a magnetic stirrer, was charged with 1.05
g (5.00 mmol) of 4 and 5 mL of DMF. The resulting solution
was heated to 100ꢀC (oil bath), 0.60 g (0.66 mL, 5.00 mmol)
of dimethylformamide dimethyl acetal was added, and heating
was continued at 100ꢀC for 30 min. The crude reaction mix-
ture was quenched with ice water, stirred for 5 min and
extracted with 50 mL of ether. The aqueous solution was satu-
rated with sodium chloride and extracted with additional ether
(2 ꢁ 50 mL). The combined ether layers were washed with
saturated aqueous sodium chloride, dried (magnesium sulfate),
and concentrated under vacuum. Further concentration under
high vacuum removed traces of DMF to give 1.28 g (97%) of
5 as a mixture of double bond isomers. This oil was used with-
out further purification. IR: 1688, 1629, 1619, 1587, 1281
All reactions were run under dry nitrogen or argon in oven-
dried glassware. Commercial anhydrous N,N-dimethylforma-
mide (DMF) was stored under nitrogen and transferred by sy-
ringe into reactions where it was used. Tetrahydrofuran (THF)
was dried over potassium hydroxide pellets and distilled from
lithium aluminum hydride under nitrogen. Other reagents and
solvents were used as received. Reactions were monitored by
thin layer chromatography on silica gel GF plates (Analtech
No. 21521). Preparative separations were performed using
flash column chromatography [13] on silica gel (Grade 62, 60–
200 mesh) mixed with ultraviolet-active phosphor (Sorbent
Technologies No. UV-5) or preparative thin layer chromatog-
raphy on 20-cm ꢁ 20-cm silica gel GF plates (Analtech No.
02015); band elution for both methods was monitored using a
hand-held ultraviolet lamp. Melting points were uncorrected.
IR spectra were run as thin films on sodium chloride disks.
1H- and 13C-NMR spectra were measured in deuteriochloro-
form at 300 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.
1
cmꢂ1; H-NMR: d 7.76 (s, 1H), 7.60 (br s, 1H), 7.37 (m, 1H),
7.17 (td, 1H, J ¼ 7.7, 1.1), 7.02 (t, 1H, J ¼ 8.2), 3.96 (q, 2H,
J ¼ 7.1), 3.27 (br s, 3H), 2.95 (br s, 3H), 0.89 (t, 3H, J ¼
7.1); 13C-NMR: d 188.0 (br), 167.8 (br), 160.0 (br d, J ¼
255.1), 157.5, 131.7 (br), 130.5 (d, J ¼ 12.8), 129.8, 123.7 (d,
J ¼ 3.4), 115.3 (d, J ¼ 22.6), 103.1 (br), 59.7, 47.9 (br), 42.8
(br), 13.6.
Ethyl 2-(2-fluorobenzoyl)acetate (4). The procedure of
Domagala et al. [10] was modified. In a three-necked round-
bottomed flask equipped with an efficient magnetic stirrer
(2.5 cm or larger stir bar), 4.17 g (31.6 mmol) of ethyl hydro-
gen malonate (1) was dissolved in 200 mL of THF and 10 mg
of bipyridyl was added as an internal indicator. The mixture
was cooled to ꢂ30ꢀC and 16.0 mL of 2.0 M n-butyllithium
(32.0 mmol) was added dropwise over 20 min. The reaction
mixture was then warmed to ꢂ5ꢀC and another portion of
16.0 mL of 2.0 M n-butyllithium (32.0 mmol) was added until
a red color persisted for 5 min. The mixture was cooled to
ꢂ78ꢀC, and a solution of 2.85 g (18.0 mmol) of 2-fluoroben-
zoyl chloride (2) in 15 mL of THF was added dropwise over
25 min. [Note: The solution became a thick yellow liquid, and
stirring was a problem without an efficient magnetic stirrer].
The solution was kept at ꢂ78ꢀC for 30 min and then slowly
warmed to ꢂ30ꢀC and stirred for 30 min. The reaction mixture
was poured into 200 mL of ice cold 1 M hydrochloric acid
and extracted with dichloromethane (3 ꢁ 200 mL). The com-
bined organic extracts were washed with water (1 ꢁ 200 mL),
5% aqueous sodium bicarbonate (1 ꢁ 150 mL) and 1 N aque-
ous hydrochloric acid (1 ꢁ 150 mL). The dichloromethane
layer was finally washed with saturated aqueous sodium chlo-
ride (1 ꢁ 150 mL), dried (magnesium sulfate), and then con-
centrated under vacuum to give a thick yellow oil. The product
was purified by flash chromatography on a 40 ꢁ 2.5-cm2 silica
gel column eluted with increasing concentrations of ether in
hexane to give 3.21 g (85%) of 4 as colorless oil consisting of
a 3:1 mixture of the keto and enol. IR: 1743, 1690, 1629,
General procedure for the tandem addition-elimination-
SNAr reaction: ethyl 1-cyclopropyl-1,4-dihydro-4-oxo-3-quin-
olinecarboxylate (6a). A 15-mL, Pyrex pressure vessel (Chem-
glass CG-1880-01), equipped with a magnetic stirrer, was
charged with 132 mg (0.50 mmol) of 5, 2.0 mL of anhydrous
DMF and 28.5 mg (0.035 mL, 0.50 mmol) of cyclopropyl-
amine. The vessel was purged with argon, the cap was tight-
ened, and the reaction was heated at 140ꢀC for 48 h. After
cooling, the crude reaction mixture was poured over 20 g of
ice and extracted with 15 mL of ethyl acetate. The aqueous
layer was saturated with sodium chloride and extracted with
additional ethyl acetate (2 ꢁ15 mL). The combined organic
layers were washed with saturated aqueous sodium chloride,
dried (magnesium sulfate), and concentrated under vacuum to
give a light brown solid. Trituration with ether and vacuum
filtration then gave 88 mg (68%) of 6a as a tan solid, mp 164–
166ꢀC (lit [14] mp 167–168ꢀC). IR: 1721, 1621, 1611 cmꢂ1
;
1H-NMR: d 8.61 (s, 1H), 8.51 (dd, 1H, J ¼ 8.2, 1.6), 7.93 (d,
1H, J ¼ 8.2), 7.71 (ddd, 1H, J ¼ 8.8, 8.0, 1.6), 7.45 (t, 1H,
J ¼ 7.7), 4.40 (q, 2H, J ¼ 7.1), 3.48 (m, 1H), 1.42 (t, 3H, J ¼
7.1), 1.34 (m, 2H), 1.15 (m, 2H); 13C-NMR: d 174.6, 166.0,
148.6, 140.5, 132.4, 128.6, 127.6, 125.2, 116.3, 111.0, 60.9,
34.4, 14.4, 8.2; ms: m/z 257 (Mþ). Anal. Calcd. for
C15H15NO3: C, 70.04; H, 5.84; N, 5.45. Found: C, 69.99; H,
5.81; N, 5.49.
Ethyl 1-cyclohexyl-1,4-dihydro-4-oxo-3-quinolinecarboxyl-
ate (6b). This compound (90 mg, 60%) was prepared from
132 mg (0.50 mmol) of 5 and 49.5 mg (0.057 mL, 0.50 mmol)
of cyclohexylamine. The product was isolated as a light yellow
oil following preparative thin layer chromatography eluted
1614, 1256 cmꢂ1
;
1H-NMR (keto): d 7.94 (td, 1H, J ¼ 7.9,
2.0), 7.57 (m, 1H), 7.25 (m, 1H), 7.15 (m, 1H), 4.21 (q, 2H, J
¼ 7.1), 3.99 (d, 2H, J ¼ 3.6), 1.26 (t, 3H, J ¼ 7.1); 13C-NMR
(keto and enol): d 190.3, 173.3, 167.3 (d, J ¼ 1.5), 166.3 (d, J ¼
1.5), 162.1 (d, J ¼ 254.5), 160.7 (d, J ¼ 254.6), 135.4 (d, J ¼
9.4), 132.3 (d, J ¼ 9.2), 130.9 (d, J ¼ 1.5), 129.1 (d, J ¼ 1.5),
124.6 (d, J ¼ 3.1), 124.2 (d, J ¼ 3.4), 116.6 (d, J ¼ 19.2), 116
(d, J ¼ 18.3), 92.6, 92.4, 61.2, 60.4, 49.9, 49.8, 14.2, 14.0; ms:
210 (Mþ). Anal. Calcd. for C11H11FO3: C, 62.86; H, 5.24.
Found: C, 62.96; H, 5.26.
with ethyl acetate. IR: 1725, 1686, 1630, 1608 cmꢂ1
;
1H-NMR: d 8.70 (s, 1H), 8.58 (dd, 1H, J ¼ 7.7, 1.1), 7.70
(ddd, 1H, J ¼ 8.8, 7.7, 1.6), 7.57 (d, 1H, J ¼ 8.8), 7.44 (td,
1H, J ¼ 7.7, 1.1), 4.45 (obscured m, 1H), 4.41 (q, 2H, J ¼
7.1), 2.19 (apparent d, 2H, J ¼ 11.0), 2.06 (apparent d, 2H,
J ¼ 13.1), 2.00–1.70 (complex, 3H), 1.55 (m, 2H), 1.43
(t, 3H, J ¼ 7.1), 1.36 (obscured m, 1H); 13C-NMR: d 173.9,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
Ethyl 1,4-Dihydro-4-oxo-3-quinolinecarboxylates by a Tandem
Addition-Elimination-SNAr Reaction
623
166.3, 144.5, 139.2, 132.4, 129.4, 128.2, 124.8, 114.8, 110.7,
60.8, 59.3, 32.7, 25.8, 25.2, 14.4; ms: m/z 299 (Mþ). Anal.
Calcd. for C18H21NO3: C, 72.24; H, 7.02; N, 4.68. Found: C,
72.27; H, 7.06; N, 4.61.
ms: m/z 230 (Mþ-C3H7). Anal. Calcd. for C16H19NO3: C,
70.33; H, 6.96; N, 5.13. Found: C, 70.41; H, 7.01; N, 5.05.
Ethyl 1,4-dihydro-4-oxo-1-(2-phenylethyl)-3-quinolinecar-
boxylate (6g). This compound (112 mg, 70%) was prepared
from 132 mg (0.50 mmol) of 5 and 60.5 mg (0.063 mL,
0.50 mmol) of 2-phenylethylamine. The product was isolated
as a light yellow oil following preparative thin layer chroma-
tography eluted with ethyl acetate. IR: 1723, 1690, 1628, 1611
Ethyl
1,4-dihydro-4-oxo-1-(2-propenyl)-3-quinolinecar-
boxylate (6c). This compound (80 mg, 62%) was prepared
from 132 mg (0.50 mmol) of 5 and 28.5 mg (0.038 mL, 0.50
mmol) of allylamine. The product was isolated as a light yel-
low solid following preparative thin layer chromatography
eluted with ethyl acetate, mp 101–103ꢂꢀC1 (lit [5] mp 98–
cmꢂ1
;
1H-NMR: d 8.55 (dd, 1H, J ¼ 8.2, 1.6), 8.13 (s, 1H),
7.71 (ddd, 1H, J ¼ 8.2, 7.4, 1.6), 7.51 (d, 1H, J ¼ 8.8), 7.44
(t, 1H), J ¼ 7.4), 7.28 (m, 4H), 7.08 (dd, 1H, J ¼ 7.7, 1.6),
4.40 (t, 2H, J ¼ 7.1), 4.32 (q, 2H, J ¼ 7.1), 3.16 (t, 2H, J ¼
7.1), 1.35 (t, 3H, J ¼ 7.1); 13C-NMR: d 174.2, 165.4, 149.0,
138.5, 136.3, 132.6, 129.1, 129.0, 128.6, 128.1, 127.4, 125.0,
115.4, 110.5, 60.6, 55.1, 35.0, 14.3; ms: m/z 230 (Mþ-C7H7).
Anal. Calcd. for C20H19NO3: C, 74.77; H, 5.92; N, 4.36.
Found: C, 74.81; H, 5.90; N, 4.31.
100ꢀC). IR: 1722, 1690, 1619, 1610 cm
;
1H-NMR: d 8.53
(dd, 1H, J ¼ 8.2, 1.6), 8.47 (s, 1H), 7.63 (ddd, 1H, J ¼ 8.8,
8.0, 1.6), 7.42 (t, 1H, J ¼ 7.1), 7.40 (d, 1H, J ¼ 7.7), 6.02
(ddt, 1H, J ¼ 17.0, 10.4, 4.9), 5.36 (d, 1H, J ¼ 10.4), 5.20 (d,
1H, J ¼ 17.0), 4.81 (d, 2H, J ¼ 4.9), 4.40 (q, 2H, J ¼ 7.1),
1.42 (t, 3H, J ¼ 7.1); 13C-NMR: d 174.3, 165.7, 149.1, 139.0,
132.4, 130.5, 129.0, 127.8, 125.0, 119.3, 116.1, 111.1, 60.8,
55.6, 14.4; ms: m/z 257 (Mþ). Anal. Calcd. for C15H15NO3: C,
70.04; H, 5.84; N, 5.45. Found: C, 70.06; H, 5.85; N, 5.42.
Ethyl 1-tert-butyl-1,4-dihydro-4-oxo-3-quinolinecarboxyl-
ate (6h). This compound (18 mg, 13%) was prepared from
132 mg (0.5 mmol) of 5 and 36.5 mg (0.054 mL, 0.50 mmol)
of tert-butylamine. This reaction was unique in requiring a
higher temperature and a longer reaction time (180ꢀC, 96 h).
The product was isolated as a light yellow solid following
preparative thin layer chromatography eluted with ethyl aꢂce1-
Ethyl 1-hexyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate
(6d). This compound (104 mg, 69%) was prepared from 132 mg
(0.50 mmol) of 5 and 50.5 mg (0.066 mL, 0.50 mmol) of hexyl-
amine. The product was isolated as a white solid following workup
and trituration with 1:2 ether:petroleum ether, mp 79–80ꢀC. IR:
1727, 1691, 1632, 1609 cmꢂ1; 1H-NMR: d 8.54 (dd, 1H, J ¼ 8.2,
1.1), 8.47 (s, 1H), 7.68 (ddd, 1H, J ¼ 8.2, 7.4, 1.6), 7.44 (d, 1H, J
¼ 7.7), 7.43 (obscured t, 1H, J ¼ 7.1), 4.41 (q, 2H, J ¼ 7.1), 4.18
(t, 2H, J ¼ 7.1), 1.89 (quintet, 2H, J ¼ 7.1), 1.42 (t, 3H, J ¼ 7.1),
1.34 (m, 6H), 0.89 (distorted t, 3H, J ¼ 7.1); 13C-NMR: d 174.2,
165.9, 149.0, 138.7, 132.4, 129.3, 128.0, 124.9, 115.6, 110.7, 60.8,
54.0, 31.2, 28.8, 26.2, 22.4, 14.4, 13.8; ms: m/z 230 (Mþ-C5H11).
Anal. Calcd. for C18H23NO3: C, 71.76; H, 7.64; N, 4.65. Found: C,
71.79; H, 7.67; N, 4.59.
tate, mp 172–174ꢀC. IR: 1728, 1687, 1638, 1602 cm
;
1H-NMR: d 8.93 (s, 1H), 8.64 (dd, 1H, J ¼ 8.2, 1.6), 7.93
(d, 1H, J ¼ 8.8), 7.65 (ddd, 1H, J ¼ 8.8, 7.1, 1.6), 7.43 (t, 1H,
J ¼ 7.1), 4.41 (q, 2H, J ¼ 7.1), 1.89 (s, 9H), 1.43 (t, 3H, J ¼
7.1); 13C-NMR: d 173.9, 166.7, 146.1, 138.9, 130.9, 130.7,
128.5, 124.6, 119.7, 109.8, 63.0, 60.9, 30.7 (3C), 14.4; ms: m/z
258 (Mþ-CH3). Anal. Calcd. for C16H19NO3: C, 70.33; H,
6.96; N, 5.13. Found: C, 70.36; H, 6.97; N, 5.10.
Ethyl 1-benzyl-1,4-dihydro-4-oxo-3-quinolinecarboxylate
(6i). This compound (100 mg, 65%) was prepared from 132
mg (0.50 mmol) of 5 and 53.5 mg (0.055 mL, 0.50 mmol) of
benzylamine. The product was isolated as a tan solid following
workup and trituration with ether, mp 168–17ꢂ01ꢀC (lit [4] mp
Ethyl 1,4-dihydro-1-(3-isopropoxypropyl)-4-oxo-3-quino-
linecarboxylate (6e). This compound (110 mg, 69%) was pre-
pared from 132 mg (0.50 mmol) of 5 and 58.5 mg (0.069 mL,
0.50 mmol) of 3-isopropoxypropylamine. The product was iso-
lated as a light yellow solid following preparative thin layer
chromatography eluted with ethyl acetate, mp 64–66ꢀC. IR:
120–121ꢀC). IR: 1724, 1690, 1629, 1614 cm
;
1H-NMR: d
8.60 (s, 1H), 8.53 (dd, 1H, J ¼ 8.2, 1.6), 7.54 (ddd, 1H, J ¼
8.8, 7.1, 1.6), 7.42–7.28 (complex, 6H), 7.17 (dd, 1H, J ¼ 7.7,
1.6), 5.41 (s, 2H), 4.40 (q, 2H, J ¼ 7.1), 1.41 (t, 3H, J ¼ 7.1);
13C-NMR: d 174.3, 165.7, 149.7, 139.1, 134.2, 132.5, 129.3,
129.2, 128.5, 127.8, 126.0, 125.1, 116.5, 111.1, 60.9, 57.3,
14.4; ms: m/z 307 (Mþ). Anal. Calcd. for C19H17NO3: C,
74.27; H, 5.54; N, 4.56. Found: C, 74.31; H, 5.55; N, 4.52.
1
1726, 1692, 1631, 1613 cmꢂ1; H-NMR: d 8.54 (obscured dd,
1H, J ¼ 7.7, 1.6), 8.53 (s, 1H), 7.68 (ddd, 1H, J ¼ 8.2, 7.7,
1.6), 7.53 (d, 1H, J ¼ 8.2), 7.42 (td, 1H, J ¼ 7.7, 1.1), 4.41
(t, 2H, J ¼ 7.1, 4.37 (q, 2H, J ¼ 7.1), 3.55 (septet, 1H, J ¼
6.0), 3.38 (t, 2H, J ¼ 5.5), 2.12 (quintet, 2H, J ¼ 5.5), 1.41 (t,
3H, J ¼ 7.1), 1.19 (d, 6H, J ¼ 6.0); 13C-NMR: d 174.4, 165.6,
149.7, 138.7, 132.4, 129.2, 128.0, 124.9, 115.7, 110.5, 71.9,
63.1, 60.7, 50.5, 28.7, 21.9, 14.4; ms: m/z 230 (Mþ-C5H11O).
Anal. Calcd. for C18H23NO4: C, 68.14; H, 7.26; N, 4.42.
Found: C, 68.18; H, 7.29; N, 4.36.
Ethyl 1,4-dihydro-1-(4-methoxybenzyl)-4-oxo-3-quinoline-
carboxylate (6j). This compound (111 mg, 66%) was prepared
from 132 mg (0.50 mmol) of 5 and 68.5 mg (0.065 mL, 0.50
mmol) of 4-methoxybenzylamine. The product was isolated as a
tan solid following workup and trituration with ether, mp 124–
125ꢀC. IR: 2838, 1723, 1689, 1621, 1611 cmꢂ1; 1H-NMR d 8.60
(s, 1H), 8.53 (dd, 1H, J ¼ 7.7, 1.1), 7.56 (ddd, 1H, J ¼ 8.2, 7.7,
1.1), 7.38 (m, 2H), 7.12 (d, 2H, J ¼ 8.8), 6.88 (d, 2H, J ¼ 8.8),
5.34 (s, 2H), 4.41 (q, 2H, J ¼ 7.1), 3.78 (s, 3H), 1.42 (t, 3H, J ¼
7.1); 13C-NMR: d 174.4, 165.9, 159.7, 149.5, 139.1, 132.5, 129.3,
127.9, 127.6, 126.0, 125.1, 116.5, 114.7, 111.1, 60.9, 56.9, 55.3,
14.4; ms: m/z 337 (Mþ). Anal. Calcd. for C20H19NO4: C, 71.22;
H, 5.64; N, 4.15. Found: C, 71.17; H, 5.65; N, 4.09.
Ethyl 1,4-dihydro-1-isobutyl-4-oxo-3-quinolinecarboxylate
(6f). This compound (95 mg, 70%) was prepared from 132 mg
(0.50 mmol) of 5 and 36.5 mg (0.050 mL, 0.50 mmol) of iso-
butylamine. The product was isolated as a light yellow solid
following preparative thin layer chromatography eluted wꢂit1h
ethyl acetate, mp 90–91ꢀC. IR: 1724, 1689, 1626, 1610 cm
;
1H-NMR: d 8.54 (dd, 1H, J ¼ 8.2, 1.6), 8.43 (s, 1H), 7.68
(ddd, 1H, J ¼ 8.8, 7.9, 1.6), 7.43 (d, 1H, J ¼ 8.8), 7.43 (t, 1H,
J ¼ 7.1), 4.40 (q, 2H, J ¼ 7.1), 3.99 (d, 2H, J ¼ 7.7), 2.29
(nonet, 1H, J ¼ 7.1), 1.42 (t, 3H, J ¼ 7.1), 1.01 (d, 6H, J ¼
6.8); 13C-NMR: d 174.2, 165.9, 149.4, 138.8, 132.3, 129.1,
127.9, 124.9, 115.8, 110.3, 61.2, 60.7, 27.5, 20.0 (2C), 14.3;
Ethyl 1-(4-chlorobenzyl)-1,4-dihydro-4-oxo-3-quinoline-
carboxylate (6k). This compound (109 mg, 64%) was pre-
pared from 132 mg (0.50 mmol) of 5 and 70.8 mg (0.061 mL,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

624
R. A. Bunce, E. J. Lee, and M. T. Grant
Vol 48
0.50 mmol) of 4-chlorobenzylamine. The product was isolated
as a tan solid following workup and trituration with ether, mp
208–210ꢀC (lit [15] mp 145–146ꢀC). IR: 1722, 1688, 1621,
8.54 (dd, 1H, J ¼ 7.7, 1.6), 8.47 (s, 1H), 7.62 (d, 2H, J ¼
8.8), 7.54 (ddd, 1H, J ¼ 8.8, 7.1, 1.6), 7.43 (td, 1H, J ¼ 7.7,
1.1), 7.41 (d, 2H, J ¼ 8.8), 6.97 (d, 1H, J ¼ 8.8), 4.39 (q, 2H,
J ¼ 7.1), 1.40 (t, 3H, J ¼ 7.1); 13C-NMR: d 174.3, 165.4,
148.4, 140.4, 139.1, 136.2, 132.4, 130.7, 128.8, 128.3, 127.6,
125.4, 117.3, 111.6, 61.0, 14.4; ms: m/z 327, 329 (ca 3:1,
Mþ). Anal. Calcd. for C18H14ClNO3: C, 65.95; H, 4.27; N,
4.27. Found: C, 66.01; H, 4.30; N, 4.19.
1611 cmꢂ1
;
1H-NMR: d 8.60 (s, 1H), 8.54 (dd, 1H, J ¼ 7.7,
1.1), 7.56 (ddd, 1H, J ¼ 8.2, 7.7, 1.1), 7.41 (t, 1H, J ¼ 7.1),
7.34 (d, 2H, J ¼ 8.2), 7.26 (d, 1H, J ¼ 8.2), 7.11 (d, 2H, J ¼
8.2), 5.38 (s, 2H), 4.42 (q, 2H, J ¼ 7.1), 1.42 (t, 3H, J ¼ 7.1);
13C-NMR: d 174.8, 165.8, 149.6, 138.9, 134.6, 132.8, 132.7,
129.6, 129.3, 128.1, 127.4, 125.3, 116.3, 111.5, 61.0, 56.7,
14.4; ms: m/z 341, 343 (ca 3:1, Mþ). Anal. Calcd. for
C19H16ClNO3: C, 66.76; H, 4.69; N, 4.10. Found: C, 66.81; H,
4.72; N, 4.03.
Ethyl 1,4-dihydro-1-(2-methylphenyl)-4-oxo-3-quinoline-
carboxylate (6p). This compound (104 mg, 68%) was pre-
pared from 132 mg (0.50 mmol) of 5 and 53.5 mg (0.054 mL,
0.50 mmol) of 2-methylaniline. The product was isolated as a
light yellow solid following workup and trituration with ether,
Ethyl
1,4-dihydro-4-oxo-1-(4-trifluoromethylbenzyl)-3-
mp 182–184ꢀC. IR: 1729, 1691, 1634, 1610 cmꢂ1 1H-NMR:
;
quinolinecarboxylate (6l). This compound (122 mg, 65%)
was prepared from 132 mg (0.50 mmol) of 5 and 87.5 mg
(0.071 mL, 0.50 mmol) of 4-(trifluoromethyl)benzylamine. The
product was isolated as a tan solid following workup and tritu-
ration with ether, mp 246–248ꢀC. IR: 1722, 1678, 1642, 1611
d 8.57 (dd, 1H, J ¼ 7.7, 1.6), 8.44 (s, 1H), 7.55–7.40 (com-
plex, 5H), 7.33 (d, 1H, J ¼ 7.7), 6.78 (d, 1H, J ¼ 7.7), 4.40
(q, 2H, J ¼ 7.1), 2.07 (s, 3H), 1.41 (t, 3H, J ¼ 7.1);
13C-NMR: d 174.4, 165.6, 148.4, 140.2, 139.3, 135.7, 132.5,
131.9, 130.3, 128.4, 128.0, 127.9, 127.5, 125.2, 117.1, 111.5,
60.9, 17.1, 14.4; ms: m/z 307 (Mþ). Anal. Calcd. for
C19H17NO3: C, 74.27; H, 5.54; N, 4.56. Found: C, 74.31; H,
5.55; N, 4.52.
cmꢂ1
;
1H-NMR: d 8.61 (s, 1H), 8.56 (d, 1H, J ¼ 7.7), 7.64
(d, 2H, J ¼ 7.7), 7.56 (t, 1H, J ¼ 7.4), 7.42 (t, 1H, J ¼ 7.4),
7.29 (d, 2H, J ¼ 7.7), 7.22 (d, 1H, J ¼ 7.7), 5.47 (s, 2H), 4.42
(q, 2H, J ¼ 7.1), 1.43 (t, 3H, J ¼ 7.1); 13C-NMR [16]: d
174.3, 165.7, 149.6, 138.9, 138.4, 132.8, 131.0 (q, J ¼ 33.2),
129.3, 128.2, 126.4 (q, J ¼ 3.7), 126.3, 125.4, 123.6 (q, J ¼
271.6), 116.1, 111.7, 61.1, 56.8, 14.4; ms: m/z 375 (Mþ).
Anal. Calcd. for C20H16F3NO3: C, 64.00; H, 4.27; N, 3.73.
Found: C, 64.11; H, 4.29; N, 3.68. On storage, this compound
converts to a highly insoluble unidentified material.
Acknowledgments. E. J. L. and M. T. G. are both undergraduate
research participants. E. J. L. thanks Oklahoma State University
for a Wentz Project Scholarship. Funding for the 300 MHz NMR
spectrometer of the Oklahoma Statewide Shared NMR Facility
was provided by the NSF (BIR-9512269), the Oklahoma State
Regents for Higher Education, the W. M. Keck Foundation and
Conoco, Inc. Finally, the authors thank the OSU College of Arts
and Sciences for funds to upgrade the FT-IR and GC-MS
instruments.
Ethyl 1,4-dihydro-4-oxo-1-phenyl-3-quinolinecarboxylate
(6m). This compound (95 mg, 65%) was prepared from 132
mg (0.50 mmol) of 5 and 46.5 mg (0.045 mL, 0.50 mmol) of
aniline. The product was isolated as a tan solid following
workup and trituration with ether, mp 208–209ꢀC. IR: 1726,
1690, 1623, 1608 cmꢂ1
;
1H-NMR: d 8.56 (dd, 1H, J ¼ 7.7,
REFERENCES AND NOTES
1.6), 8.53 (s, 1H), 7.67–7.60 (complex, 3H), 7.52 (ddd, 1H,
J ¼ 8.8, 7.1, 1.6), 7.43 (complex, 3H), 6.99 (d, 1H, J ¼ 8.2),
4.40 (q, 2H, J ¼ 7.1), 1.41 (t, 3H, J ¼ 7.1); 13C-NMR: d
174.4, 165.7, 148.7, 140.7, 135.7, 132.3, 130.4, 130.0, 128.4,
127.5, 127.4, 125.2, 117.6, 111.4, 60.9, 14.4; ms: m/z 293
(Mþ). Anal. Calcd. for C18H15NO3: C, 73.72; H, 5.12; N, 4.78.
Found: C, 73.68; H, 5.13; N, 4.74.
[1] Lednicer, D. Strategies for Organic Drug Synthesis and
Design; Wiley-Interscience: New York, 1998; p 330.
[2] Park, C.-H.; Lee, J.; Jung, H. Y.; Kim, M. J.; Lim, S. H.;
Yeo, H. T.; Choi, E. C.; Yoon, E. J.; Kim, K. W.; Cha, J. H.; Kim, S.-
H.; Chang, D.-J.; Kwon, D.-Y.; Li, F.; Suh, Y.-G. Bioorg Med Chem
2007, 15, 6517.
Ethyl 1,4-dihydro-1-(4-methoxyphenyl)-4-oxo-3-quinoline-
carboxylate (6n). This compound (119 mg, 74%) was pre-
pared from 132 mg (0.50 mmol) of 5 and 61.5 mg (0.50
mmol) of 4-methoxyaniline. The product was isolated as a
light yellow solid following workup and trituration with ether,
[3] Bunce, R. A.; Nammalwar, B. Org Prep Proced Int 2010,
42, 557. Additional biological studies of these target molecules are
summarized in this article.
[4] Stern, E.; Muccioli, G. G.; Millet, R.; Goossens, J.-F.;
Farce, A.; Chavatte, P.; Poupaert, J. H.; Lambert, D. M.; Depreux, P.;
´
Henichart, J.-P. J Med Chem 2006, 49, 70.
mp 202–204ꢀC. IR: 2840, 1728, 1690, 1633, 1611 cmꢂ1 1H-
;
[5] Alkylation with thallium(I)ethoxide in ethanol: Tamura, Y.;
Fujita, M.; Chen, L. C.; Ueno, K.; Kita, Y. Chem Pharm Bull 1981,
29, 739.
NMR: d 8.55 (dd, 1H, J ¼ 7.7, 1.6), 8.51 (s, 1H), 7.52 (ddd,
1H, J ¼ 8.8, 7.1, 1.6), 7.42 (td, 1H, J ¼ 7.7, 1.1), 7.34 (d, 2H,
J ¼ 8.8), 7.10 (d, 2H, J ¼ 8.8), 6.99 (d, 1H, J ¼ 8.8), 4.39 (q,
2H, J ¼ 7.1), 3.92 (s, 3H), 1.40 (t, 3H, J ¼ 7.1); 13C-NMR: d
174.4, 165.7, 160.4, 149.0, 141.0, 133.3, 132.2, 128.5, 128.4,
127.4, 125.1, 117.7, 115.4, 111.2, 60.9, 55.7, 14.4; ms: m/z
323 (Mþ). Anal. Calcd. for C19H17NO4: C, 70.59; H, 5.26; N,
4.33. Found: 70.66; H, 5.29; N, 4.28.
`
[6] Crespo, M. I.; Gracia, J.; Puig, C.; Vega, A.; Bou, J.;
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Ethyl 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-3-quinoline-
carboxylate (6o). This compound (108 mg, 66%) was pre-
pared from 132 mg (0.50 mmol) of 5 and 64.0 mg (0.50
mmol) of 4-chloroaniline. The product was isolated as a light
yellow solid following workup and triturationꢂw1 ith ether, mp
[8] Bunce, R. A.; Easton, K. M. Org Prep Proced Int 2004, 36, 76.
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Spense, F. G.; Szotek, D.; Wemple, J. J Med Chem 1991, 34, 1142.
186–188ꢀC. IR: 1728, 1693, 1633, 1610 cm
;
1H-NMR: d
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

May 2011
Ethyl 1,4-Dihydro-4-oxo-3-quinolinecarboxylates by a Tandem
Addition-Elimination-SNAr Reaction
625
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´
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Structure Determination of Organic Compounds: Tables of Spectral
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´
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet