(±)-2-Aryl-2,3-dihydro-4(1H)-quinolinones by a tandem reduction-Michael addition reaction

Article abstract of DOI:10.1002/jhet.624

An efficient synthesis of (±)-2-aryl-2,3-dihydro-4(1H)-quinolinones has been developed from chalcones prepared from 2′-nitroacetophenone and a series of substituted benzaldehydes. The cyclization sequence is initiated by reduction of the nitro group under dissolving metal conditions using iron powder in concentrated hydrochloric acid. Milder conditions, using acetic acid or acetic acid-phosphoric acid as the reaction medium, were less satisfactory. Procedural details as well as a mechanistic discussion and reaction optimization studies are presented.

Full text of DOI:10.1002/jhet.624

May 2011
(6)-2-Aryl-2,3-dihydro-4(1H)-quinolinones by a Tandem
Reduction–Michael Addition Reaction
613
Richard A. Bunce* and Baskar Nammalwar
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071
*E-mail: rab@okstate.edu
Received June 10, 2010
DOI 10.1002/jhet.624
Published online 15 March 2011 in Wiley Online Library (wileyonlinelibrary.com).
An efficient synthesis of (6)-2-aryl-2,3-dihydro-4(1H)-quinolinones has been developed from chal-
cones prepared from 20-nitroacetophenone and a series of substituted benzaldehydes. The cyclization
sequence is initiated by reduction of the nitro group under dissolving metal conditions using iron pow-
der in concentrated hydrochloric acid. Milder conditions, using acetic acid or acetic acid–phosphoric
acid as the reaction medium, were less satisfactory. Procedural details as well as a mechanistic discus-
sion and reaction optimization studies are presented.
J. Heterocyclic Chem., 48, 613 (2011).
INTRODUCTION
2,3-dihydro-4(1H)-quinolinones [10] as cis–trans mixtures
in 25–95% yields. Finally, condensation of 20-aminoaceto-
phenone with various benzaldehydes in the presence of L-
proline was reported as a potential route to chiral 2-aryldi-
hydroquinolinones [11], and although yields were in the
79–93% range, the asymmetric induction was poor (less
than 10% enantiomeric excess). To date, there have been
few reports detailing the synthesis of 2-aryldihydroquinoli-
nones from 20-nitrochalcones [12], and this is the route we
sought to exploit.
Over the past several years, we have described a num-
ber of tandem reaction approaches to nitrogen hetero-
cycles initiated by dissolving metal reduction of nitroar-
enes [1]. In this project, we sought to extend this strategy
to the synthesis of 2,3-dihydro-4(1H)-quinolinone as well
as several (6)-2-aryl-2,3-dihydro-4(1H)-quinolinones by
reductive cyclization of 1-(2-nitrophenyl)-2-propen-1-one
derivatives. Dihydroquinolinones, similar to those pre-
pared in this study, have attracted considerable interest as
potential antimalarial [2] and anticancer drugs [3].
The title compounds have been common targets for
synthesis, and numerous approaches have been reported,
primarily from 20-aminochalcone derivatives. In the origi-
nal synthesis [4], 20-aminochalcone was treated with so-
dium ethoxide to give (6)-2,3-dihydro-2-phenyl-4(1H)-
quinolinone in a modest 45% yield. Work by others
[5a,6] described the cyclization of anions derived by
treatment of N-acylated 20-aminochalcones with base, and
the yields improved to 50–60%. Further studies [5b,6]
revealed that similar yields could be achieved by cycliz-
ing 20-aminochalcones with 1:1 acetic acid–phosphoric
acid. More recently, montmorillonite K-10 under micro-
wave irradiation [7] and Lewis acids on silica or alumina
[8] have been used to promote this cyclization in 60–
90% yields. Additionally, the ring closure of 20-amino-
chalcones has also been performed in 80–90% yields by
heating in PEG-400 solvent at 130ꢀC with no additives
[9]. Using an alternative strategy, metathesis of 2-alkynyl-
anilines with aldehydes in the presence of an antimony
pentafluoride-methanol catalyst gave (6)-2,3-disubstituted-
RESULTS AND DISCUSSION
The synthesis of the cyclization substrates is shown in
Figure 1. To prepare the precursor to 2,3-dihydro-4(1H)-
quinolinone, vinylmagnesium bromide was added to 2-
nitrobenzaldehyde (1) in tetrahydrofuran (THF) to give
alcohol 2, which was further oxidized to 1-(2-nitro-
phenyl)-2-propen-1-one (3) in 71% overall yield [13].
The 20-nitrochalcones 6a–f for the preparation of the
(6)-2-aryl-2,3-dihydro-4(1H)-quinolinones were pre-
pared in 92–97% yields from 20-nitroacetophenone (4)
and a series of benzaldehyde derivatives (5a–f) using
standard conditions with sodium hydroxide in ethanol. It
should be noted that only substrates derived from ben-
zaldehydes bearing resonance electron-donating substitu-
ents were examined. This was due to the fact that many
electron-withdrawing groups, such as ester and cyano,
would degrade under the basic conditions used to pre-
pare the chalcones and others, such as nitro, would be
reduced in the cyclization reaction.
C
V
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614
R. A. Bunce and B. Nammalwar
Vol 48
Scheme 2. Reduction of 6a with iron in acetic acid.
We began our study on the conversion of 20-nitrochal-
cone 6a to (6)-2,3-dihydro-2-phenyl-4(1H)-quinolinone
by attempting to effect the cyclization using iron powder
in acetic acid as above [1]. These conditions, however,
yielded only mixtures of 20-aminochalcone (8a) and its
double-bond reduction product 9a (see Scheme 2). None
of the desired 2,3-dihydro-2-phenyl-4(1H)-quinolinone
was observed. Similar results were obtained with sub-
strates 6e and 6f.
We also explored the use of iron powder in various
mixtures of acetic acid and phosphoric acid, because
this had been successful for the ring closure of 3. Under
these conditions, the reaction proceeded to give the
reductive cyclization product in 24–78% yield. The best
result was achieved using a 70:30 ratio of acetic acid–
phosphoric acid. Higher proportions of phosphoric acid
led to the formation of an intractable precipitate that
decreased product recovery (see Fig. 2).
Figure 1. Synthesis of cyclization substrates.
The cyclization of 3 to the parent 2,3-dihydro-4(1H)-
quinolinone (7) was initially attempted using iron pow-
der in acetic acid, because these conditions had been
successful in our earlier work [1]. Unfortunately, this
protocol gave a complex mixture of products containing
a significant amount of polymeric material. Literature
reports by others [5b,6] suggested that stronger acid
conditions might facilitate the final cyclization. Thus,
the reaction was repeated in 1:1 v/v acetic acid–phos-
phoric acid, and the desired product was isolated in
72% yield after chromatography. During the course of
this conversion, however, a heavy insoluble precipitate
was formed that disrupted stirring and hampered isola-
tion of the product. To circumvent this problem, we
decided to rerun the reaction in concentrated hydrochlo-
ric acid, because this had proven effective in one of our
earlier reductive cyclizations [1c]. When the reaction
was performed using iron powder in concentrated hydro-
chloric acid at 100ꢀC, the reaction was complete in 30
min, and the target heterocycle was produced in 83%
yield after chromatography. Critical to the success of
the reaction was the addition of the iron to the hot solu-
tion, which minimized the formation of side products
(see Scheme 1).
On the basis of the enhanced conversion of 3 to 7 in
stronger acid, we decided to explore the use of iron
powder in concentrated hydrochloric acid for the cycli-
zation of 20-nitrochalcones 6 and found that the yields
improved to 72–88%. The optimized conditions
involved treating 1 equiv of 6 with 4 equiv of iron pow-
der in concentrated hydrochloric acid at 100ꢀC for 30
min. Again, it was important to add the iron to the hot
mixture to achieve optimum results. Surprisingly, no
cleavage of any of the ether groups was observed. After
quenching with ice water, extractive workup, and recrys-
tallization, the 2-aryldihydroquinolinones 10 were
Scheme 1. Reductive cyclization of 3 with iron in concentrated hydro-
chloric acid.
Figure 2. Reductive cyclization of 6a with various v/v mixtures of
acetic acid and phosphoric acid.
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DOI 10.1002/jhet

May 2011
(6)-2-Aryl-2,3-dihydro-4(1H)-quinolinones by a Tandem Reduction–Michael
Addition Reaction
615
CONCLUSION
We have successfully developed a synthesis of 2,3-
dihydro-4(1H)-quinolinone from 1-(2-nitrophenyl)-2-
propen-1-one and a series of (6)-2-aryl-2,3-dihydro-
4(1H)-quinolinones from 20-nitrochalcones. Reductive
cyclization of these derivatives using iron powder in
concentrated hydrochloric acid gave the best results,
affording the target heterocycles in 72–88% yields. The
products were obtained in good yields without the need
for extensive purification. This synthetic approach is
limited to chalcone substrates bearing electron-donating
groups on the C3 aromatic ring, as these are most stable
to the base used in their preparation and the reductive
conditions used for the final cyclization.
Figure 3. Reductive cyclization of 6 with iron in concentrated hydro-
chloric acid.
EXPERIMENTAL
isolated in nearly pure form. Chromatography was
generally not necessary because all reactions went to
completion and gave highly crystalline products. Our
results are summarized in Figure 3.
All reactions were run under dry nitrogen or air in oven-
dried glassware. THF was dried over potassium hydroxide
pellets and distilled from lithium aluminum hydride under
nitrogen. All other commercial reagents and solvents were
used as received. Reactions were monitored by thin layer chro-
matography on silica gel GF plates (Analtech No 21521) using
UV detection. Preparative separations were performed using
flash chromatography [14] on silica gel (Grade 62, 60–200
mesh) mixed with ultraviolet-active phosphor (Sorbent Tech-
nologies No UV-05) or preparative thin layer chromatography
on 20-cm ꢁ 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 other-
wise specified, 1H- and 13C-NMR spectra were measured in
deuteriochloroform at 300 and 75 MHz, respectively; coupling
constants (J) are reported in Hertz. Low-resolution mass spec-
tra (direct probe/electron impact) were obtained at 30 or 70 eV
as indicated.
Following reduction of the nitro group in 6a, two
mechanistic pathways can be envisoned for the ring clo-
sure of aminochalcone 8a. Iron does not appear to play
a significant role in the cyclization because 8a has been
successfully cyclized to 10a using 1:1 v/v acetic acid–
phosphoric acid [6] and concentrated hydrochloric acid
(this study) without iron. In the first mechanistic sce-
nario, strong acid would protonate the enone carbonyl in
8a to give 11, which would be activated toward conju-
gate addition by the amino group. Because the amine
function in 8a is part of a vinylogous amide, it is not as
basic as a typical aniline nitrogen, and thus, some of the
unprotonated form should be present to add to the acti-
vated enone system. Alternatively, strong acid condi-
tions could also protonate the enone double bond to
give the benzylic carbocation 12, which would then be
attacked by the nucleophilic aniline nitrogen. These
mechanistic possibilities for the cyclization of 8a to 10a
are outlined in Scheme 3.
1-(2-Nitrophenyl)-2-propen-1-ol (2). The general procedure
of Danishefsky and coworkers [13] was used. A 250-mL three-
necked round-bottomed flask, equipped with a rubber septum,
a reflux condenser, a nitrogen inlet, and a magnetic stirrer, was
charged with 50 mL of dry THF and 3.00 g (19.9 mmol) of 2-
nitrobenzaldehyde (1). The resulting solution was cooled to
ꢂ78ꢀC, and 29.5 mL of 1.0 M vinylmagnesium bromide (29.5
mmol) was added dropwise via syringe over a period of 20
min. The reaction was stirred for 2 h at ꢂ78ꢀC at which time
thin layer chromatography indicated the reaction was com-
plete. The reaction mixture was poured into 75 mL of 1 M
hydrochloric acid, stirred for 10 min, and extracted with
50 mL of ether. The aqueous layer was then saturated with
sodium chloride and extracted with additional ether (2 ꢁ
50 mL). The combined ether layers were washed with satu-
rated sodium chloride solution, dried (magnesium sulfate), and
concentrated under vacuum to yield 3.32 g (93%) of 2 as a
viscous yellow oil. This product was spectroscopically pure
and was used in the next step without further purification. IR:
Scheme 3. Mechanistic possibilities for ring closure of 20-aminochal-
cone in concentrated hydrochloric acid.
3415, 1639, 1609, 1524, 1349 cmꢂ1 1H-NMR (400 MHz): d
;
7.90 (d, 1H, J ¼ 7.7), 7.76 (d, 1H, J ¼ 7.7), 7.64 (t, 1H, J ¼
7.9), 7.44 (t, 1H, J ¼ 7.9), 6.07 (ddd, 1H, J ¼ 17.2, 10.4, 5.3),
Journal of Heterocyclic Chemistry
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R. A. Bunce and B. Nammalwar
Vol 48
5.79 (d, 1H, J ¼ 5.3), 5.41 (d, 1H, J ¼ 17.2), 5.25 (d, 1H, J ¼
10.4), 2.82 (br s, 1H); 13C-NMR (100 MHz): d 148.2, 138.0,
137.6, 133.5, 128.8, 128.4, 124.5, 116.1, 69.9; ms (30 eV): m/z
179 (Mþ). Anal. Calcd. for C9H9NO3: C, 60.34; H, 5.03; N,
7.82. Found: C, 60.51; H, 5.07; N, 7.69.
(d, 2H, J ¼ 8.2), 6.97 (d, 1H, J ¼ 15.9), 2.37 (s, 3H); 13C-
NMR: d 193.0, 146.52, 146.49, 141.7, 136.4, 133.9, 131.2,
130.4, 129.7, 128.8, 128.6, 125.3, 124.5, 21.5; ms: m/z 267
(Mþ).
(2E)-3-(4-Methoxyphenyl)-1-(2-nitrophenyl)-2-propen-1-
one (6c). This compound (1.27 g, 93%) was prepared from
800 mg (4.85 mmol) of 4 and 692 mg (5.09 mmol) of 4-
methoxybenzaldehyde (5c) and isolated as an off-white solid,
mp 101–103ꢀC (lit. [16] mp 105ꢀC). IR: 2840, 1645, 1600,
1-(2-Nitrophenyl)-2-propen-1-one (3). A 100-mL two-
necked round-bottomed flask, fitted with an addition funnel, a
reflux condenser, a nitrogen inlet, and a magnetic stirrer, was
charged with 3.00 g (16.8 mmol) of 2 and 20 mL of acetone.
To the resulting solution was slowly added 8.5 mL of 2.97 M
Jones reagent (25.2 mmol) over a period of 25 min at 23ꢀC.
[Note: The addition was done very slowly. Faster addition
led to significant heating, loss of solvent, and a reduced
yield.] After 1 h at 23ꢀC, thin layer chromatography indicated
that the reaction was complete. Excess Jones reagent was
quenched with saturated sodium bisulfite solution (ca. 3 mL),
and the crude reaction mixture was extracted with 50 mL of
ether. The aqueous layer was then saturated with sodium
chloride and extracted with additional ether (2 ꢁ 50 mL).
The combined ether layers were washed with saturated so-
dium chloride, then dried (magnesium sulfate), and concen-
trated under vacuum. The crude product was purified by flash
chromatography on a 20-cm ꢁ 2-cm silica gel column using
increasing concentrations of ether in hexanes to give 2.26 g
(76%) of 3 as a yellow oil. IR: 1672, 1613, 1527, 1347
1528, 1348 cmꢂ1
;
1H-NMR (400 MHz): d 8.16 (dd, 1H, J ¼
8.2, 1.2), 7.75 (dt, 1H, J ¼ 7.5, 1.2), 7.64 (ddd, 1H, J ¼ 8.2,
7.5, 1.4), 7.50 (dd, 1H, J ¼ 7.5, 1.4), 7.45 (d, 2H, J ¼ 8.8),
7.24 (d, 1H, J ¼ 16.2), 6.90 (d, 1H, J ¼ 16.2), 6.87 (d, 2H, J
¼ 8.8), 3.83 (s, 3H); 13C-NMR (100 MHz): d 192.9, 162.0,
146.6, 146.3, 136.5, 133.9, 130.40, 130.38, 128.8, 126.6,
124.5, 123.9, 114.4, 55.4; ms: m/z 283 (Mþ). Anal. Calcd. for
C16H13NO4: C, 67.84; H, 4.59; N, 4.95. Found: C, 67.88; H,
4.62; N, 4.87.
(2E)-3-(3,4-Dimethoxyphenyl)-1-(2-nitrophenyl)-2-propen-
1-one (6d). This compound (1.44 g, 95%) was prepared from
800 mg (4.85 mmol) of 4 and 845 mg (5.09 mmol) of 3,4-
dimethoxybenzaldehyde (5d) and isolated as a yellow solid,
mp 120–122ꢀC (lit. [16] mp 124ꢀC]. IR: 2839, 1645, 1594,
1
1512, 1347 cmꢂ1; H-NMR: d 8.18 (d, 1H, J ¼ 7.7), 7.76 (td,
1H, J ¼ 7.7, 1.1), 7.65 (td, 1H, J ¼ 7.7, 1.6), 7.51 (dd, 1H, J
¼ 7.7, 1.1), 7.19 (d, 1H, J ¼ 15.9), 7.10–7.01 (complex, 2H),
6.89 (d, 1H, J ¼ 15.9), 6.85 (d, 1H, J ¼ 7.7), 3.91 (s, 3H),
3.90 (s, 3H); 13C-NMR: d 192.8, 151.8, 149.3, 146.6, 146.5,
136.5, 133.9, 130.4, 128.8, 126.7, 124.5, 124.2, 123.6, 111.0,
109.8, 56.0, 55.9; ms: m/z 313 (Mþ). Anal. Calcd. for
C17H15NO5: 65.18; H, 4.79; N, 4.47. Found: C, 65.23; H,
4.78; N, 4.44.
1
cmꢂ1; H-NMR: d 8.16 (dd, 1H, J ¼ 8.2, 1.3), 7.75 (td, 1H,
J ¼ 7.5, 1.3), 7.65 (ddd, 1H, J ¼ 8.2, 7.5, 1.5), 7.45 (dd, 1H,
J ¼ 7.5, 1.5), 6.65 (dd, 1H, J ¼ 17.6, 10.6), 6.05 (d, 1H, J ¼
10.6), 5.85 (d, 1H, J ¼ 17.6); 13C-NMR: d 193.4, 146.8,
136.5, 135.4, 134.1, 131.2, 130.7, 128.8, 124.4; ms: m/z 177
(Mþ). Anal. Calcd. for C9H7NO3: C, 61.01; H, 3.95; N, 7.91.
Found: C, 61.12; H, 3.98; N, 7.83.
Representative aldol condensation: (2E)-1-(2-Nitrophenyl)-
3-phenyl-2-propen-1-one (6a). A 100-mL two-necked round-
bottomed flask, equipped with an addition funnel, a nitrogen
inlet, and a magnetic stirrer, was charged with 800 mg (4.85
mmol) of 20-nitroacetophenone (4) and 15 mL of ethanol, and
the resulting solution was cooled to 0ꢀC. Stirring was begun
and 232 mg (5.80 mmol, 1.2 equiv) of sodium hydroxide pow-
der was added and allowed to dissolve. To this mixture was
slowly added a solution of 540 mg (5.09 mmol, 1.05 equiv) of
benzaldehyde (5a) in 5 mL of ethanol. The reaction was
stirred for 3 h at 0ꢀC during which time the product crystal-
lized from the mixture. The product was filtered, and the crys-
tals were washed thoroughly with ice-cold ethanol to give 1.16
g (95%) of 6a as a white solid, mp 125–127ꢀC (lit. [15] mp
(2E)-3-(1,3-Benzodioxol-5-yl)-1-(2-nitrophenyl)-2-propen-1-
one (6e). This compound (1.36 g, 94%) was prepared from
800 mg (4.85 mmol) of 4 and 764 mg (5.09 mmol) of pipero-
nal (5e) and isolated as a pale yellow solid, mp 128–130ꢂꢀC1
(lit. [12b] mp 128–130ꢀC). IR: 1650, 1599, 1528, 1384 cm
;
1H-NMR: d 8.17 (d, 1H, J ¼ 8.2), 7.76 (td, 1H, J ¼ 7.7, 1.1),
7.64 (td, 1H, J ¼ 8.2, 1.1), 7.51 (dd, 1H, J ¼ 7.7, 1.6), 7.17
(d, 1H, J ¼ 15.9), 7.03 (d, 1H, J ¼ 1.6), 6.96 (dd, 1H, J ¼
7.7, 1.1), 6.84 (d, 1H, J ¼ 15.9), 6.79 (d, 1H, J ¼ 8.2), 6.02
(s, 2H); 13C-NMR: d 192.7, 150.3, 148.5, 146.7, 146.1, 136.5,
133.9, 130.4, 128.8, 128.4, 125.5, 124.5, 124.2, 108.6, 106.7,
101.7; ms: m/z 297 (Mþ). Anal. Calcd. for C16H11NO5: C,
64.65; H, 3.70; N, 4.71. Found: C, 64.71; H, 3.73; N, 4.66.
(2E)-3-(2-Chlorophenyl)-1-(2-nitrophenyl)-2-propen-1-one
(6f). This compound (1.28 g, 92%) was prepared from 800 mg
(4.85 mmol) of 4 and 715 mg (5.09 mmol) of 2-chlorobenzal-
dehyde (5f) and isolated as a pale yellow solid, mp 87–88ꢀC
128ꢀC). IR: 1652, 1608, 1527, 1347 cmꢂ1 1H-NMR (400
;
MHz): d 8.18 (dd, 1H, J ¼ 8.2, 1.1), 7.77 (td, 1H, J ¼ 7.6,
1.1), 7.66 (td, 1H, J ¼ 7.6, 1.1), 7.53–7.46 (complex, 3H),
7.42–7.34 (complex, 3H), 7.24 (d, 1H, J ¼ 16.2), 7.01 (d, 1H,
J ¼ 16.2); 13C-NMR (100 MHz): d 192.9, 146.7, 146.3, 136.3,
134.0, 133.9, 131.0, 130.5, 129.0, 128.8, 128.5, 126.2, 124.5;
ms: m/z 253 (Mþ).
1
(lit. [15] mp 88–89ꢀC). IR: 1657, 1605, 1527, 1347 cmꢂ1; H-
NMR: d 8.20 (d, 1H, J ¼ 7.7), 7.79 (t, 1H, J ¼ 7.1), 7.75–
7.60 (complex, 3H), 7.53 (d, 1H, J ¼ 7.1), 7.42–7.23 (com-
plex, 3H), 6.97 (d, 1H, J ¼ 16.5); 13C-NMR: d 192.8, 146.7,
141.8, 136.0, 135.2, 134.1, 132.2, 131.7, 130.7, 130.2, 128.9,
128.6, 127.8, 127.2, 124.5; ms: m/z 287, 289 (ca. 3:1, Mþ).
2,3-Dihydro-4(1H)-quinolinone (7). A 100-mL two-necked
round-bottomed flask, equipped with a reflux condenser, a dry-
ing tube, and a magnetic stirrer, was charged with 400 mg
(2.26 mmol) of 3 and 10 mL of concentrated hydrochloric
acid, and the mixture was heated to 80–85ꢀC (oil bath). The
heat was briefly removed and 630 mg (1.13 mmol, 5 equiv) of
(2E)-3-(4-Methylphenyl)-1-(2-nitrophenyl)-2-propen-1-one
(6b). This compound (1.25 g, 97%) was prepared from 800
mg (4.85 mmol) of 4 and 611 mg (5.09 mmol) of 4-methyl-
benzaldeꢀhyde (5b) and isolated as a pale yellow solid, mp
133–135 C (lit. [15] mp 134–135ꢀC). IR: 1652, 1599, 1528,
1
1348 cmꢂ1; H-NMR: d 8.16 (dd, 1H, J ¼ 7.7, 1.1), 7.76 (td,
1H, J ¼ 7.7, 1.1), 7.65 (td, 1H, J ¼ 7.7, 1.1), 7.50 (dd, 1H, J
¼ 7.7, 1.1), 7.39 (d, 2H, J ¼ 8.2), 7.21 (d, 1H, J ¼ 15.9), 7.18
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(6)-2-Aryl-2,3-dihydro-4(1H)-quinolinones by a Tandem Reduction–Michael
Addition Reaction
617
iron powder (>100 mesh) was added. [Caution! The addition
was sufficiently exothermic to boil the mixture and some froth-
ing occurred as the iron was added. The reaction flask should
be at least 10 times the volume of the reactants at this scale.]
Heating was resumed at 100ꢀC until thin layer chromatography
indicated the reaction was complete (ca. 1 h). The reaction
mixture was cooled, poured into ice water, and extracted with
50 mL of ether. The aqueous layer was then saturated with so-
dium chloride and extracted again with ether (1 ꢁ 50 mL) and
ethyl acetate (1 ꢁ 50 mL). The combined organic layers were
washed with saturated sodium chloride solution, dried (magne-
sium sulfate), and concentrated under vacuum. The resulting
oil was flash chromatographed on a 20-cm ꢁ 2-cm silica gel
column eluted with increasing concentrations of ether in hex-
anes to give 276 mg (83%) of 7 as a yellow solid, mp 42–
The spectral data for 9a were as follows: IR: 3475, 3346,
1647, 1614 cmꢂ1
;
1H-NMR (400 MHz): d 7.73 (dd, 1H, J ¼
6.6, 8.2), 7.33–7.16 (complex, 6H), 6.65 (d, 1H, J ¼ 7.2), 6.63
(td, 1H, J ¼ 7.7, 1.0), 6.26 (br s, 2H), 3.28 (t, 2H, J ¼ 7.4),
3.04 (t, 2H, J ¼ 7.4); 13C-NMR (100 MHz): d 201.5, 150.3,
141.5, 134.3, 131.0, 128.5, 128.4, 126.0, 117.8, 117.3,
115.8, 41.0, 30.6; ms: m/z 225 (Mþ). Anal. Calcd. for
C15H15NO: C, 80.00; H, 6.67; N, 6.22. Found: C, 79.93; H,
6.69; N, 6.17.
(2E)-1-(2-Aminophenyl)-3-(1,3-benzodioxol-5-yl)-2-propen-
1-one (8e) and 1-(2-aminophenyl)-3-(1,3-benzodioxol-5-yl)-1-
propanone (9e). Reduction of 500 mg (1.68 mmol) of 6e
using 375 mg (6.72 mmol) of iron powder gave 207 mg (46%)
of 8e as a yellow solid, mp 110–112ꢀC, and 171 mg (40%) of
9e as a yellow solid, mp 85–87ꢀC. The spectral data for 8e
1
44ꢀC (lit. [17] mp 43–44.5ꢀC). IR: 3347, 1659, 1611 cmꢂ1
;
were as follows: IR: 3468, 3339, 1643, 1614 cmꢂ1; H-NMR:
1H-NMR: d 7.84 (dd, 1H, J ¼ 8.2, 1.1), 7.29 (td, 1H, J ¼ 7.7,
1.1), 6.74 (t, 1H, J ¼ 7.7), 6.67 (d, 1H, J ¼ 8.2), 4.43 (br s,
1H), 3.58 (t, 2H, J ¼ 6.6), 2.70 (t, 2H, J ¼ 6.6); 13C-NMR: d
193.7, 152.0, 135.1, 127.6, 119.4, 117.9, 115.8, 42.3, 38.1; ms:
m/z 147 (Mþ). Anal. Calcd. for C9H9NO: C, 73.47; H, 6.12;
N, 9.52. Found: C, 73.51; H, 6.11; N, 9.47.
This same reductive cyclization was carried out using 5
equiv of iron powder in 1:1 v/v acetic acid–phosphoric acid,
but the product yield was only 72% because of the formation
of a heavy insoluble precipitate during the heating period.
When the reaction was carried out using iron in acetic acid
without a stronger acid, a complex mixture of products con-
d 7.85 (dd, 1H, J ¼ 8.2, 1.1), 7.67 (d, 1H, J ¼ 15.4), 7.45 (d,
1H, J ¼ 15.4), 7.29 (dt, 1H, J ¼ 8.2, 1.6), 7.16 (d, 1H, J ¼
1.6), 7.11 (dd, 1H, J ¼ 8.2, 1.6), 6.84 (d, 1H, J ¼ 8.2), 6.70
(m, 2H), 6.31 (br s, 2H), 6.02 (s, 2H); 13C-NMR: d 191.6,
150.9, 149.5, 148.3, 142.8, 134.1, 130.9, 129.7, 124.7, 121.1,
119.2, 117.3, 115.8, 108.6, 106.6, 101.5; ms: m/z 267 (Mþ).
Anal. Calcd. for C16H13NO3: C, 71.91; H, 4.87; N, 5.24.
Found: C, 71.98; H, 4.89; N, 5.15.
The spectral data for 9e were as follows: IR: 3468, 3352,
1
1645, 1614 cmꢂ1; H-NMR: d 7.72 (d, 1H, J ¼ 7.7), 7.26 (t,
1H, J ¼ 7.7), 6.78–6.59 (complex, 5H), 6.27 (br s, 2H), 5.92
(s, 2H), 3.23 (t, 2H, J ¼ 7.6), 2.96 (t, 2H, J ¼ 7.6); 13C-NMR:
d 201.4, 150.3, 147.6, 146.3 135.3, 134.2, 131.0, 121.1, 117.8,
117.3, 115.8, 108.9, 108.2, 100.8, 41.2, 30.3; ms: m/z 269
(Mþ). Anal. Calcd. for C16H15NO3: C, 71.38; H, 5.58; N,
5.20. Found: C, 71.44; H, 5.61; N, 5.14.
taining
isolated.
a significant amount of polymeric material was
Attempted reductive cyclization of 6a with iron powder
in acetic acid: (2E)-1-(2-Aminophenyl)-2-propen-1-one (8a)
and 1-(2-aminophenyl)-1-propanone (9a). A 100-mL two-
necked round-bottomed flask, equipped with a reflux con-
denser, a nitrogen inlet, and a magnetic stirrer, was charged
with 500 mg (1.98 mmol) of 6a and 10 mL of acetic acid, and
the solution was heated to 100ꢀC (oil bath). The heat was
briefly removed and 440 mg (7.88 mmol) of iron powder
(>100 mesh) was added. [Caution! The addition was suffi-
ciently exothermic to boil the mixture and some frothing
occurred as the iron was added. The reaction flask should be
at least 10 times the volume of the reactants at this scale.]
Heating was resumed at 115ꢀC until thin layer chromatography
indicated the reaction was complete (ca. 10 min). The reaction
mixture was cooled, poured into ice-cold water, and extracted
with ether (3 ꢁ 25 mL). The combined ether layers were
washed with saturated sodium bicarbonate (three times) and
saturated sodium chloride (one time), then dried (magnesium
sulfate), and concentrated under vacuum. The crude product
was purified by flash chromatography on a 40-cm ꢁ 2-cm
silica gel column eluted with increasing concentrations of ether
in hexanes to give 220 mg (50%) of 8a as a yellow solid, mp
70–71ꢀC (lit. [6] mp 71–72ꢀC), and 169 mg (38%) of 9a as a
yellow solid, mp 85–86ꢀC. The spectral data for 8a were as
(2E)-1-(2-Aminophenyl)-3-(2-chlorophenyl)-2-propen-1-one
(8f) and 1-(2-aminophenyl)-3-(2-chlorophenyl)-1-propanone
(9f). Reduction of 500 mg (1.74 mmol) of 6f using 389 mg
(6.96 mmol) of iron gave 235 mg (53%) of 8f as a yellow
solid, mp 87–89ꢀC, and 156 mg (34%) of 9f as a yellow solid,
mp 86–87ꢀC. The spectral data for 8f were as follows: IR:
3464, 3338, 1644, 1615 cmꢂ1
;
1H-NMR: d 8.11 (d, 1H, J ¼
15.4), 7.84 (d, 1H, J ¼ 8.2), 7.73 (m, 1H), 7.59 (d, 1H, J ¼
15.4), 7.43 (m, 1H), 7.36–7.25 (complex, 3H), 6.70 (d, 1H, J
¼ 7.7), 6.69 (t, 1H, J ¼ 7.7), 6.37 (br s, 2H); 13C-NMR: d
191.3, 151.1, 138.7, 135.2, 134.5, 133.6, 131.1, 130.7, 130.2,
127.7, 127.0, 125.8, 118.8, 117.3, 115.8; ms: m/z 257, 259 (ca.
3:1, Mþ). Anal. Calcd. for C15H12ClNO: C, 69.90; H, 4.66; N,
5.44. Found: C, 69.97; H, 4.67; N, 5.39.
The spectral data for 9f were as follows: IR: 3478, 3348,
1647, 1615 cmꢂ1
;
1H-NMR: d 7.73 (d, 1H, J ¼ 8.2), 7.38–
7.12 (complex, 5H), 6.64 (d, 1H, J ¼ 8.2), 6.62 (t, 1H, J ¼
7.7), 6.28 (br s, 2H), 3.27 (m, 2H), 3.14 (m, 2H); 13C-NMR: d
201.2, 150.3, 139.0, 134.3, 133.9, 131.0, 130.6, 129.5, 127.6,
126.9, 117.7, 117.3, 115.8, 39.0, 28.7; ms: m/z 259, 261 (ca.
3:1, Mþ). Anal. Calcd. for C15H14ClNO: C, 69.36; H, 5.39; N,
5.39. Found: C, 69.45; H, 5.44; N, 5.30.
follows: IR: 3471, 3334, 1645, 1614 cmꢂ1
;
1H-NMR (400
Attempted reductive ring closure with iron powder in
acetic acid–phosphoric acid mixtures: (6)-2,3-Dihydro-2-
phenyl-4(1H)-quinolinone (10a). Using the procedure given
for the reduction of 6a with iron and acetic acid above, 500
mg (1.97 mmol) of 6a and 440 mg (7.88 mmol) of iron pow-
der (>100 mesh), with 10 mL of each acetic acid–phosphoric
acid mixture given in Figure 2, were reacted for 30 min at
MHz): d 7.85 (dd, 1H, J ¼ 8.4, 1.4), 7.74 (d, 1H, J ¼ 15.6),
7.62 (d, 1H, J ¼ 15.6). 7.60 (obscured signal, 1H), 7.43–7.33
(complex, 4H), 7.28 (ddd, 1H, J ¼ 8.4, 7.2, 1.6), 6.69 (over-
lapping d and t, 2H, J ꢃ 8.0), 6.34 (br s, 2H); 13C-NMR (100
MHz): d 191.6, 150.9, 142.8, 135.2, 134.3, 130.9, 130.0,
128.8, 128.2, 123.0, 118.9, 117.2, 115.8; ms: m/z 223 (Mþ).
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

618
R. A. Bunce and B. Nammalwar
Vol 48
120ꢀC. Workup and purification afforded 10a. The yield for
each run is given in Figure 2.
119.0, 118.9, 118.4, 115.9, 111.2, 109.4, 58.3, 55.97, 55.94,
46.7; ms: m/z 283 (Mþ). Anal. Calcd. for C17H17NO3: C,
72.08; H, 6.01; N, 4.95. Found: C, 72.11; H, 6.02; N, 4.91.
(6)-2-(1,3-Benzodioxol-5-yl)-2,3,dihydro-4(1H)-quinolinone
(10e). Reductive cyclization of 423 mg (1.68 mmol) of 6e and
375 mg (6.72 mmol) of iron gave 374 mg (83%) of 10e as an
off-white solid, mp 128–130ꢀC (lit. [12b] mp 118–119ꢀC). IR:
Representative reductive ring closure using iron powder
in concentrated hydrochloric acid: (6)-2,3-Dihydro-2-phe-
nyl-4(1H)-quinolinone (10a). Using the procedure given for
the preparation of 7, a mixture of 500 mg (1.97 mmol) of 6a
and 10 mL of concentrated hydrochloric acid in a 100-mL two-
necked round-bottomed flask was heated to 80–85ꢀC. The heat
was briefly removed and 440 mg (7.88 mmol, 4 equiv) of iron
powder (>100 mesh) was added. [Caution! The addition was
sufficiently exothermic to boil the mixture and some frothing
occurred as the iron was added. The reaction flask should be at
least 10 times the volume of the reactants at this scale.] Heating
was resumed at 100ꢀC until thin layer chromatography indicated
the reaction was complete (ca. 30 min). Workup and purification
by flash chromatography on a 20-cm ꢁ 2-cm silica gel column
eluted with increasing concentrations of ether in hexanes gave
386 mg (88%) of 10a as a pale yellow solid, mp 149–151ꢀC (lit.
3328, 1663, 1610 cmꢂ1
;
1H-NMR: d 7.86 (d, 1H, J ¼ 7.7),
7.34 (td, 1H, J ¼ 7.7, 1.6), 6.97 (d, 1H, J ¼ 1.1), 6.89 (dd, 1H,
J ¼ 8.0, 1.6), 6.79 (overlapping d and t, 2H, J ꢃ 8.2), 6.71 (d,
1H, J ¼ 8.2), 5.98 (s, 2H), 4.65 (dd, 1H, J ¼ 13.4, 3.7), 4.49
(br s, 1H), 2.83 (dd, 1H, J ¼ 16.2, 13.4), 2.71 (dd, 1H, J ¼
16.2, 3.7); 13C-NMR: d 193.3, 151.5, 148.0, 147.6, 135.4,
134.9, 127.6, 120.1, 119.0, 118.4, 115.9, 108.5, 106.9, 101.2,
58.3, 46.6; ms: m/z 267 (Mþ). Anal. Calcd. for C16H13NO3: C,
71.91; H, 4.87; N, 5.24. Found: C, 71.92; H, 4.89; N, 5.22.
(6)-2-(2-Chlorophenyl)-2,3-dihydro-4(1H)-quinolinone
(10f). Reductive cyclization of 399 mg (1.73 mmol) of 6f and
386 mg (6.92 mmol) of iron gave 357 mg (80%) of 10f as a
[3a] mp 149–150ꢀC). IR: 3326, 1661, 1608, 1482 cmꢂ1 1H-
;
1
yellow solid, mp 126–128ꢀC. IR: 3429, 1659, 1609 cmꢂ1. H-
NMR (400 MHz): d 7.87 (dd, 1H, J ¼ 8.0, 1.5), 7.45 (dd, 2H, J
¼ 7.6, 1.5), 7.42–7.31 (complex, 4H), 6.78 (t, 1H, J ¼ 7.6), 6.71
(d, 1H, J ¼ 8.2), 4.74 (dd, 1H, J ¼ 13.8, 3.7), 4.55 (br s, 1H),
2.87 (dd, 1H, J ¼ 16.2, 13.8), 2.77 (dm, 1H, J ¼ 16.2); 13C-
NMR (100 MHz): d 193.3, 151.5, 141.0, 135.4, 128.9, 128.4,
127.6, 126.6, 119.0, 118.4, 115.9, 58.4, 46.4; ms: m/z 223 (Mþ).
(6)-2,3-Dihydro-2-(4-methylphenyl)-4(1H)-quinolinone
(10b). Reductive cyclization of 415 mg (1.87 mmol) of 6b
with 418 mg (7.48 mmol) of iron gave 378 mg (85%) of 10b
as an off-white solid, mp 147–149ꢀC (lit. [8c] mp 148–149ꢀC).
NMR: d 7.88 (d, 1H, J ¼ 7.7), 7.68 (dd, 1H, J ¼ 7.1, 1.6),
7.44–7.23 (complex, 4H), 6.81 (t, 1H, J ¼ 7.1), 6.74 (d, 1H, J
¼ 8.2), 5.27 (dd, 1H, J ¼ 12.1, 3.7), 4.52 (br s, 1H), 2.96
(ddd, 1H, J ¼ 16.2, 3.7, 1.5), 2.78 (dd, 1H, J ¼ 16.2, 12.1);
13C-NMR: d 192.7, 151.5, 138.3, 135.4, 132.8, 130.0, 129.3,
127.6, 127.5, 127.4, 119.1, 118.7, 116.0, 54.2, 44.0; ms: m/z
257, 259 (ca. 3:1, Mþ). Anal. Calcd. for C15H12ClNO: C,
69.90; H, 4.66; N, 5.44. Found: C, 69.97; H, 4.69; N, 5.39.
Cyclization of 8a using concentrated hydrochloric acid:
(6)-2,3-Dihydro-2-phenyl-4(1H)-quinolinone (10a). Using the
procedure for the conversion of 6a to 10a, a mixture of 150
mg (0.67 mmol) of 8a and 6 mL of concentrated hydrochloric
acid was treated at 85ꢀC with 150 mg (2.69 mmol, 4 equiv) of
iron powder and then heated at 100ꢀC for 30 min. Workup and
purification by preparative thin layer chromatography eluted
with 30% ether in hexanes yielded 128 mg (85%) of 10a as a
pale yellow solid. The physical properties and spectral data
matched those reported above. The cyclization of 8a to 10a
can also be carried out in the same fashion without iron.
IR: 3331, 1655, 1608 cmꢂ1
;
1H-NMR: d 7.87 (d, 1H, J ¼
7.7), 7.35 (d, 2H, J ¼ 7.7), 7.34 (obscured signal, 1H), 7.21
(d, 2H, J ¼ 7.7), 6.79 (t, 1H, J ¼ 7.7), 6.70 (d, 1H, J ¼ 8.2),
4.72 (dd, 1H, J ¼ 13.7, 3.7), 4.47 (br s, 1H), 2.88 (dd, 1H, J
¼ 16.2, 13.7), 2.75 (dd, 1H, J ¼ 16.2, 3.7), 2.37 (s, 3H); 13C-
NMR: d 193.4, 151.6, 138.3, 138.0, 135.3, 129.6, 127.6,
126.5, 119.0, 118.4, 115.9, 58.2, 46.5, 21.1; ms: m/z 237
(Mþ). Anal. Calcd. for C16H15NO: C, 81.01; H, 6.33; N, 5.91.
Found: 80.94; H, 6.32; N, 5.85.
(6)-2,3-Dihydro-2-(4-methoxyphenyl)-4(1H)-quinolinone
(10c). Reductive cyclization of 415 mg (1.76 mmol) of 6c
with 393 mg (7.04 mmol) of iron gave 365 mg (82%) of 10c
as a yellow solid, mp 147–148ꢀC (lit. [8c] mp 147ꢀC). IR:
Acknowledgment. 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 spec-
trometer 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 thank the OSU College of Arts and Sci-
ences for funds to upgrade their departmental FT-IR and GC-MS
instruments.
3329, 2836, 1660, 1608 cmꢂ1 1H-NMR (400 MHz): d 7.87
;
(dd, 1H, J ¼ 8.0, 1.6), 7.37 (d, 2H, J ¼ 8.6), 7.33 (td, 1H, J
¼ 7.7, 1.2), 6.92 (d, 2H, J ¼ 8.6), 6.78 (t, 1H, J ¼ 7.7), 6.70
(d, 1H, J ¼ 8.2), 4.69 (dd, 1H, J ¼ 13.8, 3.7), 4.48 (br s, 1H),
3.82 (s, 3H), 2.87 (dd, 1H, J ¼ 16.2, 13.8), 2.74 (dd, 1H, J ¼
16.2, 3.7); 13C-NMR (100 MHz): d 193.5, 159.6, 151.6, 135.3,
133.0, 127.8, 127.6, 119.0, 118.3, 115.9, 114.2, 57.9, 55.3,
46.5; ms: m/z 253 (Mþ). Anal. Calcd. for C16H15NO2: C,
75.89; H, 5.93; N, 5.53. Found: C, 75.83; H, 5.94; N, 5.49.
(6)-2,3-Dihydro-2-(3,4-dimethoxyphenyl)-4(1H)-quinoli-
none (10d). Reductive cyclization of 426 mg (1.59 mmol) of
6d and 355 mg (6.36 mmol) of iron gave 326 mg (72%) of
10d as a white solid, mp 145–147ꢀC. IR: 3348, 2836, 1660,
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet