4(1H)-quinolinones by a tandem reduction-addition-elimination reaction

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4(1H)-Quinolinones by a Tandem
Reduction-Addition-Elimination Reaction
a
a
Richard A. Bunce & Baskar Nammalwar
a
Department of Chemistry, Oklahoma State University, Stillwater,
Oklahoma, USA
Version of record first published: 15 Nov 2010.
To cite this article: Richard A. Bunce & Baskar Nammalwar (2010): 4(1H)-Quinolinones by a Tandem
Reduction-Addition-Elimination Reaction, Organic Preparations and Procedures International: The New
Journal for Organic Synthesis, 42:6, 557-563
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Organic Preparations and Procedures International, 42:557–563, 2010
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print
DOI: 10.1080/00304948.2010.526512
4
(1H)-Quinolinones by a Tandem
Reduction-Addition-Elimination Reaction
Richard A. Bunce and Baskar Nammalwar
Department of Chemistry, Oklahoma State University, Stillwater,
Oklahoma, USA
Compounds incorporating the 4(1H)-quinolinone ring system are commonly found in
1
–13
drug chemistry and express a broad spectrum of biological activities.
Thus, they have
become attractive targets for synthesis. In this paper, we report simple and efficient syn-
theses of 4(1H)-quinolinone (3), 2,4(1H,3H)-quinolinedione (8) and ethyl 1,4-dihydro-
4
-oxo-3-quinolinecarboxylate (10) using an adaptation of the Leimgruber-Batcho indole
14–17
synthesis.
Numerous methods have been described for the synthesis of 3. In the most practical
1
8,19
20
routes, aniline was reacted with Meldrum’s acid
or methyl propiolate to form an
adduct that underwent thermal cyclization to give the target heterocycle. Another useful
ꢀ
approach involved the condensation of 2 -nitroacetophenone with N,N-dimethylformamide
dimethyl acetal to give an enaminone followed by reduction and cyclization in refluxing
21
ethanol containing cyclohexene and 10% Pd/C. Though this reaction is similar to our
procedure, we were not able to achieve the yield reported for the preparation of 3. Fi-
ꢀ
nally, palladium-catalyzed coupling of 2 -bromoacetophenone with formamide followed
by intramolecular cyclization using sodium tert-butoxide also provided access to this ring
22
system. A disadvantage of this procedure was the expensive catalyst required for the
initial coupling reaction.
There are also many reported preparations for 2,4(1H,3H)-quinolinedione (8). In
the classical synthesis, 2-aminobenzoic acid was condensed with urea in a high-boiling
2
3–27
solvent.
This method appears to be the most viable approach since it is simple, inex-
28
pensive and scalable. Other preparations have been reported from 2-aminobenzamide,
-aminobenzonitrile,2 methyl 2-bromobenzoate and 1H-indole-2,3-dione. While el-
9,30
31
32
2
egant, most of these approaches used expensive or hazardous reagents that would not be
practical on a large scale.
Approaches to the synthesis of ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylate (10)
are more limited. All of the methods involved the addition of aniline to diethyl 2-
ethoxymethylene)propanedioate7
,9,33–35
followed by thermally induced ring closure. The
(
◦
drawbacks of this process were the high temperature conditions (>200 C) for the final
Received May 29, 2010; accepted August 20, 2010.
Address correspondence to Richard A. Bunce, Department of Chemistry, Oklahoma State Uni-
versity, Stillwater, Oklahoma 74078-3071, USA. E-mail: rab@okstate.edu
557

558
Bunce and Nammalwar
cyclization and the requirement of removing a high-boiling solvent (usually diphenyl ether)
from the product.
Our syntheses of 4(1H)-quinolinone (3), 2,4(1H,3H)-quinolinedione (8) and ethyl 1,4-
dihydroquinoline-4-oxo-3-carboxylate (10) are outlined in Schemes 1 and 2. The strategy
is an adaptation of the Leimgruber-Batcho reaction, which is normally used to prepare
1
4–17
indoles.
The synthesis of 3 was achieved via a two-step sequence in 71% overall yield.
ꢀ
The first step involved heating 2 -nitroacetophenone (1) with N,N-dimethylformamide
dimethyl acetal in DMF at 100 C for 45 min to give (E)-3-(dimethylamino)-1-(2-
◦
nitrophenyl)-2-propen-1-one (2) in 95% yield. Treatment of enaminone 2 with hydrazine
◦
hydrate and 10% Pd/C in ethanol at 23 C for 60 min then initiated a tandem sequence
involving reduction of the nitro function, addition of the resulting amino group to the
enaminone double bond, and elimination of dimethylamine to give 4(1H)-quinolinone (3)
in 75% yield.
Scheme 1
Synthesis of 4(1H)-quinolinone (3).
Scheme 2
Synthesis of 2,4(1H,3H)-quinolinedione (8) and ethyl 1,4-dihydro-4-oxo-3-quinolinecarboxylate (10).
The preparation of 8 and 10 was readily achieved from 3-(2-nitrophenyl)-3-
36
oxopropanoate (7). To prepare 7, ethyl hydrogen malonate (6) was converted to its dianion,
using n-butyllithium in THF, and reacted with 0.5 equivalents of 2-nitrobenzoyl chloride
(
5), prepared from 2-nitrobenzoic acid using oxalyl chloride in the presence of catalytic

4(1H)-Quinolinones by a Tandem Reduction-Addition-Elimination
559
DMF. This gave ketoester 7 in 87% yield. Treatment of 7 with 85% hydrazine hydrate and
◦
1
0% Pd/C in ethanol at 23 C for 20 min then gave dione 8 in 86% yield. The conversion
of 7 to 10 was analogous to the procedure used to prepare 3. Ketoester 7 was converted
to enaminone 9 in 89% yield by reaction with N,N-dimethylformamide dimethyl acetal in
◦
DMF at 100 C for 30 minutes. Though the double bond geometry of 9 was unclear, the
compound was used as isolated. Treatment of 9 with hydrazine hydrate and 10% Pd/C in
◦
ethanol at 23 C for 30 min then effected the reduction-cyclization sequence to give 10 in
37
7
8% yield. Both 8 and 10 were easily purified by recrystallization.
We have developed a simple and efficient method for the syntheses of quinolinones 3
and 10 and quinolinedione 8 using inexpensive starting materials. The yields are compar-
atively higher than previous methods. These ring systems can serve as building blocks for
the synthesis of a number of pharmaceutically active drug compounds.
Experimental Section
All reactions were run under dry N2 in oven-dried glassware. Commercial anhydrous N,N-
dimethylformamide (DMF) was stored under N2 and transferred by syringe into reactions
where it was used. Tetrahydrofuran (THF) was dried over KOH pellets and distilled from
lithium aluminum hydride under N2. Other reagents and solvents were used as received. Re-
actions were monitored by thin layer chromatography (TLC) on silica gel GF plates (Anal-
38
tech 21521). Preparative separations were performed using flash column chromatography
FC) on silica gel (Grade 62, 60–200 mesh) mixed with UV-active phosphor (Sorbent Tech-
nologies, UV-5); band elution was monitored using a hand-held UV lamp. Melting points
(
1
13
were uncorrected. IR spectra were run as thin films on NaCl disks. H and C NMR spec-
tra were measured at 300 MHz and 75 MHz, respectively, and were referenced to internal
tetramethylsilane; coupling constants (J) are reported in Hz. Low-resolution mass spectra
(EI/DP) were run at 30 eV.
(
E)-3-(Dimethylamino)-1-(2-nitrophenyl)-2-propen-1-one (2)
The procedure of Koskinen and coworkers21 was modified. In a one-necked round-
bottomed flask, equipped with a magnetic stirrer and a N2 inlet, 5.00 g (30.2 mmol) of
ꢀ
2
-nitroacetophenone (1) was dissolved in 25 mL of dry DMF. The solution was heated
◦
to 100 C (oil bath), 3.60 g (30.2 mmol) of N,N-dimethylformamide dimethyl acetal was
added and heating was continued at 100 C for 45 min. The crude reaction mixture was
◦
quenched with ice water, stirred for 5 min, and then extracted with ether (2 × 150 mL).
The aqueous layer was saturated with NaCl and extracted one final time with ether (1 ×
75 mL). The combined ether layers were washed with saturated NaCl, dried (MgSO4) and
concentrated under vacuum. Further drying under high vacuum for 30 min gave 6.30 g
◦
(
95%) of 2 as a yellow solid, mp 119–121 C, which was used directly in the next step.
−1 1
IR: 1645, 1556, 1527, 1355 cm ; H NMR (CDCl3): δ 7.96 (d, J = 7.0 Hz, 1 H), 7.62
(
(
1
apparent t, J ≈ 7.5 Hz, 2 H), 7.49 (m, 2 H), 5.27 (d, J = 12.6 Hz, 1 H), 3.10 (s, 3 H), 2.87
13
s, 3 H); C NMR (CDCl3): δ 188.5 (br), 154.8 (br), 147.2, 138.5 (br), 133.0, 129.3, 128.8,
+
24.0, 95.0 (br), 45.1, 37.1; MS: m/z 220 (M ).

560
Bunce and Nammalwar
Anal. Calcd for C11H12N2O3: C, 60.00; H, 5.45; N, 12.72. Found: C, 59.93; H, 5.40;
N, 12.81.
4(1H)-Quinolinone (3)
A 100 mL two-necked round-bottomed flask, equipped with a reflux condenser, a magnetic
stirrer and a N2 inlet, was charged with a solution of 2.00 g (9.10 mmol) of 2 in 15 mL
of ethanol and 0.27 g (0.26 mL, 5.44 mmol, 0.6 eq) of 85% hydrazine monohydrate. To
this solution, stirred under N2, was cautiously added 15 mg of 10% Pd/C and the reaction
◦
mixture was stirred at 23 C until TLC indicated the reaction was complete (ca 60 min).
During the reaction, much of the product precipitated from the solution. To remove the Pd/C,
the solution was heated to dissolve the precipitate, the hot solution was filtered through
ꢁR
Celite and the solvent was removed under vacuum. The crude product was purified by
FC on a 20 cm × 2 cm silica gel column eluted with 50–80% ether in hexanes to give 0.99
◦
20
◦
g (75%) of 3 as a white solid, mp 208–210 C [lit. mp 209–211 C]. IR: 3600–2410, 1613,
1
−1 1
587, 1507 cm ; H NMR (DMSO-d6): δ 11.81 (br s, 1 H), 8.12 (d, J = 8.2 Hz, 1 H), 7.93
(
6
t, J = 6.3 Hz, 1 H), 7.65 (td, J = 8.2, 1.3 Hz, 1 H), 7.57 (d, J = 8.4 Hz, 1 H), 7.33 (td, J =
13
.8, 1.3 Hz, 1 H), 6.07 (d, J = 7.4 Hz, 1 H); C NMR (DMSO-d6): δ 176.9, 140.0, 139.4,
131.6, 125.8, 124.9, 123.1, 118.3, 108.7.
Ethyl 3-(2-Nitrophenyl)-3-oxopropanoate (7)
The procedure of Domagala and coworkers was modified.36 A 250 mL one-necked round-
bottomed flask, equipped with a magnetic stirrer, a condenser and a N2 inlet, was charged
with 3.01 g (18.0 mmol) of 2-nitrobenzoic acid (4) and 100 mL of dichloromethane. The
resulting suspension was stirred and 2.76 g (1.84 mL, 21.7 mmol) of oxalyl chloride was
added dropwise over a period of 20 min followed by 5 drops of dry DMF. The reaction was
◦
stirred at 23 C for 12 h during which time gas evolution subsided and the acid completely
dissolved into the dichloromethane. The crude mixture was then concentrated under vacuum
to give 2-nitrobenzoyl chloride (5), which was used without further purification.
In a three-necked round-bottomed flask, equipped with a strong magnetic stirrer, 4.17 g
(
31.6 mmol) of ethyl hydrogen malonate (6) was dissolved in 125 mL of THF and 10 mg
◦
of bipyridyl was added as an internal indicator. The mixture was cooled to −30 C and
1
6.0 mL of 2.0 M n-butyllithium in hexanes (32.0 mmol) was added dropwise over 20
◦
min. The reaction mixture was then warmed to −5 C and a second 16.0 mL portion of
2
.0 M n-butyllithium (32.0 mmol) was added until a red color persisted for 5 min. The
◦
mixture was cooled to −78 C, and a solution of 5 (from above) in 15 mL of THF was
added dropwise over 25 min. [Note: The reaction became a thick yellow suspension and
◦
stirring was a problem with a weak magnetic stirrer]. The solution was kept at −78 C for
◦
3
0 min and then slowly warmed to −30 C and stirred for another 30 min. The reaction
mixture was poured into ice water containing 20 mL of concentrated HCl and extracted
with dichloromethane (3 × 100 mL). The combined organic extracts were washed with
water, 5% NaHCO3 and 1 N HCl. The dichloromethane layer was finally washed with
saturated NaCl, dried (MgSO4) and concentrated under vacuum to give 3.70 g (87%) of 3
as a thick yellow oil. The ketoester was used directly in the next reaction. An analytical
sample (0.25 g) was obtained as a ca 90:10 keto-enol mixture by FC of on a 20 cm × 2 cm

4(1H)-Quinolinones by a Tandem Reduction-Addition-Elimination
561
−1
silica gel column eluted with 5–10% ether in hexanes. IR: 1740, 1708, 1531, 1348 cm ;
1
H NMR (keto form, CDCl3): δ 8.16 (d, J = 8.4 Hz, 1 H), 7.77 (t, J = 7.6 Hz, 1 H), 7.65
(
(
1
td, J = 7.6, 1.2 Hz, 1 H), 7.53 (dd, J = 7.6, 1.3 Hz, 1 H), 4.16 (q, J = 7.1 Hz, 2 H), 3.83
13
s, 2 H), 1.23 (t, J = 7.1 Hz, 3 H); C NMR (keto form, CDCl3): δ 194.6, 166.5, 144.5,
+
34.5, 132.6, 130.9, 128.1, 124.2, 61.6, 49.0, 13.9; MS: m/z 237 (M ).
Anal. Calcd for C11H11NO5: C, 55.70; H, 4.64; N, 5.91. Found: C, 55.96; H, 4.66; N,
.83 for the keto-enol mixture.
5
2,4(1H,3H)-Quinolinedione (8)
The procedure used to prepare 3 was followed to convert 1.00 g (4.22 mmol) of 7 to 8. The
reaction was complete in 20 min, but no precipitate was observed in this case. Filtration
through Celite R and concentration under vacuum gave a viscous oil to which 10 mL of
ether was added to give a solid precipitate. The product was collected and washed with
ether and chloroform to give 0.59 g (86%) of 10 as a white solid. An analytical sample
ꢁ
◦
29
◦
was obtained by recrystallization from dioxane, mp 315–317 C (dec) [lit. mp 320 C
dec) (dioxane)]. IR: 3620–2360, 1657, 1630, 1508 cm . The H and 13C NMR data (in
−
1
1
(
29
DMSO-d6) matched those reported previously.
Ethyl 3-(Dimethylamino)-2-(2-nitrobenzoyl)acrylate (9)
A 100 mL single-necked round-bottomed flask, equipped with a reflux condenser, a mag-
netic stirrer and a N2 inlet, was charged with 1.00 g (4.22 mmol) of 7 and 5 mL of DMF.
◦
The resulting solution was heated to 100 C (oil bath), 0.51 g (0.57 mL, 4.22 mmol) of
◦
N,N-dimethylformamide dimethyl acetal was added and heating was continued at 100 C
for 30 min. The crude reaction mixture was quenched with ice water, stirred for 5 min
and extracted with ether (2 × 50 mL). The aqueous solution was saturated with NaCl and
extracted one final time with ether (1 × 50 mL). The combined ether layers were washed
with saturated NaCl, dried (MgSO4) and concentrated under vacuum. The resulting oil
◦
solidified to give 1.10 g (89%) of 8 as a yellow solid, mp 122–124 C. IR: 1682, 1633,
−
1 1
1
570, 1526, 1377, 1349 cm ; H NMR (CDCl3): δ 8.05 (d, J = 8.2 Hz, 1 H), 8.00 (s, 1
H), 7.62 (t, J = 7.6 Hz, 1 H), 7.48 (td, J = 7.4, 0.8 Hz, 1 H), 7.36 (d, J = 7.6 Hz, 1 H),
13
3
(
4
.83 (q, J = 7.1 Hz, 2 H), 3.38 (s, 3 H), 3.09 (s, 3 H), 0.82 (t, J = 7.1 Hz, 3 H); C NMR
CDCl3): δ 188.6, 166.7, 159.9, 146.3, 140.1, 133.3, 128.6, 127.7, 123.6, 100.2, 59.7, 48.2,
+
2.7, 13.6; MS: m/z 292 (M ).
Anal. Calcd for C14H16N2O5: C, 57.53; H, 5.48; N, 9.59. Found: C, 57.71; H, 5.57; N,
9.46.
The double bond geometry of this product was unclear, but the compound was used
directly in the next step.
Ethyl 1,4-Dihydro-4-oxo-3-quinolinecarboxylate (10)
The procedure used to prepare 3 was followed to convert 1.00 g (3.42 mmol) of 9 to
1
0. The reaction was complete in 30 min and much of the product precipitated from the
ꢁR
solution. After heating to dissolve the product, filtration through Celite and concentration
gave a tan solid. Recrystallization using chloroform-ether yielded 0.58 g (78%) of 10 as
◦
1
◦
−1
1
an off-white solid, mp 268–269 C [lit. mp 270–272 C]. IR: 3424, 1642 cm ; H NMR

562
Bunce and Nammalwar
(
DMSO-d6): δ 12.33 (br s, 1 H), 8.56 (s, 1 H), 8.16 (dd, J = 8.2, 1.0 Hz, 1 H), 7.71 (td,
J = 7.5, 1.4 Hz, 2 H), 7.63 (d, J = 8.2 Hz, 1 H), 7.42 (td, J = 7.5, 1.0 Hz, 1 H), 4.22 (q,
13
J = 7.1 Hz, 2 H), 1.29 (t, J = 7.1 Hz, 3 H); C NMR (DMSO-d6): δ 173.4, 164.8, 144.9,
+
1
38.9, 132.4, 127.2, 125.6, 124.7, 118.8, 109.7, 59.5, 14.3; MS: m/z 217 (M ).
Anal. Calcd for C12H11NO3: C, 66.36; H, 5.07; N, 6.45. Found: C, 66.34; H, 5.08; N,
6.40.
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.
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