One-pot synthesis of 3-hydroxyquinolin-2(1 H)-ones from N-phenylacetoacetamide via PhI(OCOCF3)2-mediated α-hydroxylation and H2SO4-promoted intramolecular cyclization

Article abstract of DOI:10.1021/jo400541s

A clean, one-pot synthesis of the biologically important 3-hydroxyquinolin-2(1H)-one compounds has been realized from the readily available N-phenylacetoacetamide derivatives through a PhI(OCOCF ₃)₂-mediated α-hydroxylation and a H ₂SO₄-promoted intramolecular condensation. The hydroxyl group in the generated α-hydroxylated intermediate can be well tolerated in the second H₂SO₄-promoted cyclization step.

Full text of DOI:10.1021/jo400541s

Article
pubs.acs.org/joc
One-Pot Synthesis of 3‑Hydroxyquinolin-2(1H)‑ones from N-
Phenylacetoacetamide via PhI(OCOCF3)2‑Mediated α‑Hydroxylation
and H2SO4‑Promoted Intramolecular Cyclization
Yucheng Yuan, Rui Yang, Daisy Zhang-Negrerie, Junwei Wang, Yunfei Du,* and Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin
University, Tianjin 300072, China
S
* Supporting Information
ABSTRACT: A clean, one-pot synthesis of the biologically
important 3-hydroxyquinolin-2(1H)-one compounds has been
realized from the readily available N-phenylacetoacetamide
derivatives through a PhI(OCOCF3)2-mediated α-hydroxylation
and a H2SO4-promoted intramolecular condensation. The hydroxyl
group in the generated α-hydroxylated intermediate can be well
tolerated in the second H2SO4-promoted cyclization step.
3-Hydroxyquinolin-2(1H)-ones are a biologically important
class of compounds that have attracted much attention in
recent years.1 For examples, naturally occurring viridicatin (1),
viridicatol (2), and 3-O-methylviridicatin (3) (Figure 1), fungal
Figure 1. Representative 3-hydroxyquinolin-2(1H)-one compounds
Figure 2. General strategies for the synthesis of the 3-hydroxyquinolin-
found in natural product and pharmaceutical agents.
2(1H)-one skeleton.
metabolites isolated from penicillium species, have been
presence of a base and by heating under reflux (Figure 2, path
reported to inhibit the replication of human immunodeficiency
virus (HIV).2 Furthermore, compounds containing the 3-
hydroxyquinolin-2(1H)-one skeleton have also been intensively
b). Recently, an efficient synthesis of 3-hydroxy-4-arylquinolin-
2(1H)-ones through a one-pot Knoevenagel condensation/
epoxidation of cyanoacetanilides followed by decyanative
studied as pharmaceutical agents such as the antiallergenic
agent, TA-270 (4) (Figure 1),3 selective inhibitors of HIV-1
epoxide-arene cyclization was reported by Kobayashi and
Harayama (Figure 2, path c).9 Another method utilized a
Pd2(dba)3-catalyzed coupling reaction mediated by tert-butyl X-
Phos; 3-hydroxyquinolin-2(1H)-one could be prepared from its
bromo precursor in good yield (Figure 2, path d).10 Finally,
viridicatin and viridicatol could be transformed from cyclopenin
and cyclopenol respectively through a decarboxylation/
rearrangement process (Figure 2, path e).11 Although the
existing methods have their own merits in the preparation of
certain 3-hydroxyquinolin-2(1H)-one derivative(s), the search
for a general method that is applicable to the construction of
reverse transcriptase,4 potent D-amino acid oxidase (DAAO)
inhibitors,5 and maxi-K channel openers with antibacterial
activities.6
Although the significance of this class of compounds is
obvious, only a few synthetic strategies have been developed for
the construction of the skeleton. Among them, one of the
methods was through ring expansion of isatin with aryldiazo-
methanes, but unfortunately the 3-hydroxyquinolin-2(1H)-one
derivatives as products were formed in unsatisfactory yields
(Figure 2, path a).7 Huntress and co-workers8 reported that 2-
(N-chloroacetamino)-benzaldehyde, an intermediate from the
reaction of 2-aminobenzaldehyde with chloroacetic anhydride,
could be converted to 3-hydroxyquinolin-2(1H)-one in the
Received: March 15, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
the 3-hydroxyquinolin-2(1H)-one ring bearing a variety of R2
and R3 substituents remains highly desirable. Herein, we report
a new strategy developed for the convenient synthesis of
variously functionalized 3-hydroxyquinolin-2(1H)-ones starting
from the readily available N-phenylacetoacetamide substrates
(Figure 2, path f). In a one-pot manner, the reactions proceed
through a hypervalent iodine reagent-mediated α-hydroxylation
and followed by a H2SO4-promoted intramolecular annulation
step.
mediated α-hydroxylation step, it was not efficient for the
second step since only a trace amount of the desired product 9a
was obtained after conc. H2SO4 was added to the reaction
mixture (Table 1, entry 1).
a
Table 1. Optimization of Reaction Conditions
In our previous work, the reaction of phenyliodine
bis(trifluoroacetate) (PIFA) with anilide 5 in CF3CH2OH
was found to give 3-hydroxy-2-oxindole derivative 6 through an
oxidative C−C bond formation and the subsequent oxidative
hydroxylation (Scheme 1a).12 However, when the terminal
b
entry oxidant
solvent
time 1
acid
time 2
yield (%)
1
2
3
4
5
6
7
8
9
PIFA
PIFA
PIFA
PIFA
PIFA
PIDA
PIFA
PIFA
PIFA
TFE
2 h
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
H2SO4
PPA
1 h
trace
88
c
DCM
toluene
MeCN
EtOAc
DCM
DCM
DCM
DCM
10 min
10 min
1 h
15 min
15 min
2 h
Scheme 1. Different Reaction Pathways of PIFA with
Anilides Bearing Ethoxycarbonyl versus Acetyl Group
72
<10
d
10 min
2 h
2 h
ND
−
3 h
ND
52
e
f
10 min
10 min
10 min
AlCl3
2 h
ND
ND
f
FeCl3
2 h
a
Reaction conditions: all reactions were carried out with the
termination of the first step, by mixing 7a (0.5 mmol) and oxidant
(0.55 mmol) in solvent (2.5 mL) and then adding conc. H2SO4 (10
b
equiv) at rt unless otherwise stated. Isolated overall yields over two
c
steps. 8a could be obtained in 94% yield if isolated after the first step.
d
e
No desired product. Reaction was performed at 100 °C after the
f
evaporation of DCM and introduction of PPA (10 equiv). 3 equiv of
Lewis acid was used.
ethoxycarbonyl group in anilide 5 was changed to an acetyl
group, the corresponding N-methyl-3-oxo-N-phenylbutanamide
7a was, unexpectedly, converted predominantly to the
uncyclized hydroxylated product 8a under the same conditions,
with no cyclized 3-hydroxy-2-oxindole product detected
(Scheme 1b).
Initially, we visualized the α-hydroxyl anilide 8a to undergo
cyclization under acidic dehydrative conditions to give the 2-
oxindole product 9a′.13 But to our surprise, upon treatment of
8a with concentrated H2SO4, an unexpected 3-hydroxyquino-
lin-2(1H)-one 9a was instead achieved in an excellent 93%
yield (Scheme 2).14 The finding that the hydroxyl functionality
Switching the solvent to the nonpolar DCM not only
furnished the α-hydroxylated intermediate 8a in a comparably
excellent yield (94%) within a short period of reaction time (10
min) but also smoothly converted the intermediate 8a to the
desired cyclized product 9a, separated in an overall 88% yield
after the introduction of 10 equiv15 of conc. H2SO4 to the
reaction mixture (Table 1, entry 2). Further solvent screening
showed that nonpolar toluene also worked well for this one-pot
protocol, while other polar solvents including MeCN and
EtOAc were not suitable, mainly because they were not
effective for the second H2SO4-promoted dehydration step
(Table 1, entries 4 and 5). The less potent PIDA, although
effective for the N-unsubstituted anologs of 7a to undergo α-
acetoxylation,16 was found to be ineffective for substrate 7a in
which the N-atom was substituted with a methyl group, to
undergo α-hydroxylation (Table 1, entry 6). Polyphosphoric
acid (PPA), which had been successively used for the
dehydrative cyclization of acetoacetamide,17 was also inves-
tigated in our reaction. However, the cyclization did not occur
at room temperature, and raising the reaction temperature to
100 °C only afforded an overall 52% yield of the desired
product (Table 1, entry 7). Lewis acids such as AlCl3 and FeCl3
(Table 1, entries 8 and 9) and other protonic acids including
TFA and AcOH were also studied, but no desired cyclized
product was observed in any of the cases (not shown).
Scheme 2. Formation of 3-Hydroxy-1,4-dimethylquinolin-
2(1H)-one
in α-hydroxyl anilide 8a can be well tolerated in the acidic
environment during the cyclization step opens the door to a
new approach for the convenient construction of the
biologically active 3-hydroxyquinolin-2(1H)-one compounds,
that is, from the readily available N-phenylacetoacetamides
through α-hydroxylation and the subsequent dehydrative
cyclization.
In an effort to develop a one-pot protocol for the two-step
reaction mentioned above, we used substrate 7a to further
screen for the optimal reaction conditions. Although
CF3CH2OH (TFE) was a desirable solvent for the PIFA-
With the optimized conditions established (Table 1, entry 2),
the substrate scope of the reaction with regard to the
substituents on the aromatic ring (R1), on the nitrogen atom
(R2), and on the carbonyl moiety (R3) of anilides 7 was
investigated (Table 2). It seems that both the electron-donating
and -withdrawing groups were tolerated in the process, as the
desired products were obtained in good to excellent yields
B
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Table 2. Synthesis of 3-Hydroxyquinolin-2-(1H)-ones via α-Hydroxylation and Intramolecular Cyclization of N-
a
Phenylacetoacetamide
a
b
General conditions: (1) Substrate 1 (0.5 mmol), PIFA (0.55 mmol) in DCM (2.5 mL) at rt for 12 min; (2) Conc. H2SO4 (266 μL), rt. Time for
c
the second step. (1) Purified via silica gel column chromatography; (2) Isolated yields over two steps.
(Table 2, entries 2 and 3). When the R3 group in 7a was
replaced with a phenyl group, the corresponding 7d also
underwent cyclization to give product 9d, but in a much lower
yield (Table 2, entry 4). On the other hand, when the methyl
C
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
group on the N-atom in 7a was changed to the bulkier phenyl
or benzyl group, the reaction was not affected and the cyclized
product could be obtained in good yields (Table 2, entries 5−
7).
7a, as opposed to 5, we postulated that the relatively more
potent electron-withdrawing carbonyl group of the acetyl
moiety in B probably facilitates the conversion of B into its
ylide salt C. With the nucleophilic attack by the enolate on the
iodine(III) center, intermediate C was concerted into the
highly electrophilic enolate D.19 Further nucleophilic attack of
the trifluoroacetic acid on the sp2 carbon center of D realizes
the trifluoroacetoxylation of intermediate E, along with the
generation of phenyl iodide and the trifluoroacetate anion.
Since water was found to be unnecessary for the α-
hydroxylation step, we propose here that the trifluoroacetate
anion acts as a nucleophile to attack the electron-deficient
carbonyl center of the trifluoroacetate moiety in E, which then
undergoes the elimination of one molecule of trifluoroacetic
anhydride to give α-hydroxyl N-phenylacetoacetamide inter-
mediate 8a.
In summary, we have demonstrated a new strategy for the
construction of the 3-hydroxyquinolin-2(1H)-ones skeleton
through the PhI(OCOCF3)2-mediated α-hydroxylation of N-
phenylacetoacetamides, followed by H2SO4-promoted dehy-
drative cyclization reactions. The main advantages of this
strategy are the ready availability of the substrates, a convenient
one-pot protocol, the diversity of substitutions, and simple
workup, and the most significant feature of this method is that
it allows for a convenient access to the naturally occurring
viridicatin and its derivatives. In view of the versatile biological
activities associated with 3-hydroxyquinolin-2(1H)-one com-
pounds, our method may find its application in exploring the
synthesis of many other biologically potent compounds bearing
various substituents on the benzene rings.
Our next step was to examine the reactions with a series of
N-unsubstituted 3-hydroxyquinolin-2-(1H)-ones, as the prod-
uct structure resembles that of viridicatin. As summarized in
Table 2, the method was also applicable to the synthesis of a
variety of 3-hydroxyquinolin-2-(1H)-ones with a free NH
moiety (entries 8−20). Specifically, for the substrates bearing
no substitution or electron-withdrawing group on the aromatic
ring, the reaction afforded the cyclized products in satisfactory
yields (Table 2, entries 8 and 9). However, when the sterically
hindered ortho-substituted substrates were applied, the yields
obtained were relatively lower (Table 2, entries 10 and 11).
Especially, when the substrates bearing a methoxy group on the
aromatic ring, the reaction afforded the desired product in
much lower yields (Table 2, entries 12 and 13), which is
probably due to the formation of an array of unidentified
byproducts as a result of overoxidations of the electron-rich
aromatic ring. When the R3 group in 7h was replaced with a
isobutyl group, the reaction gave the desired product 9n in a
satisfactory yield (Table 2, entry 14). Subjecting substrate 7o to
the reaction conditions smoothly afforded the biologically
active Viridicatin (1) in 60% yield (Table 2, entry 15), which is
quite different from the case in regard to the reaction of 7d in
terms of the effect of the phenyl group on the reaction yield.
Using the same approach, other Viridicatin derivatives bearing
various substitutions were also conveniently synthesized in
satisfactory yields (Table 2, entries 16−19). Although in a
relatively lower yield, 3-hydroxyquinolin-2-(1H)-one 9t, the
precursor of viridicatol 2, was achieved from the readily
available substrate 7t using this method. It is worth noting that
the obtained compound 9t can readily undergo demethylation
in the presence of BBr3 to afford viridicatol 2 in a satisfactory
80% yield.18 Thus, both the naturally occurring viridicatin 1 and
viridicatol 2 can be efficiently and concisely obtained by this
one-pot approach.
EXPERIENMENTAL SECTION
■
General Information. All reactions were stirred magnetically
under an air atmosphere and performed in standard glassware heated
at 80 °C for 3 h before use. Different substituted N-methylaniline,20 N-
benzyl aniline,21 acetoacetic acid,22 and 3-oxo-3-arylpropanoic acid23
were synthesized according to the literature procedures. Other
reagents and solvents were purchased as reagent grade and were
used without further purification. Flash chromatography was
performed on silica gel 200−300 m, and the eluent was a mixture of
ethyl acetate (EA) and petroleum ether (PE). Thin layer
chromatography (TLC) was performed on glass backed plates
precoated with silica (GF254), which were developed using standard
visualizing agents. 1H and 13C NMR spectra were recorded on a 600 or
400 MHz spectrometer at 25 °C. Chemical shifts are reported in ppm
with the solvent resonance as the internal standard (CHCl3: δ = 7.26
ppm for 1H and CDCl3: δ = 77.0 ppm for 13C as well as DMSO-d6: δ =
2.50 ppm for 1H and DMSO-d6: δ = 39.5 ppm for 13C). High-
resolution mass spectra (HRMS) were performed on a Q-TOF
microspectrometer. Melting points were performed on recrystallized
solids and recorded on a national standard melting point apparatus
and are uncorrected.
Based on the mechanism12 described for the PIFA-mediated
synthesis of 3-hydroxy-2-oxindoles and spirooxindoles from
anilides, we propose a mechanistic sequence for the α-
hydroxylation step (Scheme 3). First, the reaction of 7a with
PIFA gives the iminium salt A, which turns into the enamine
intermediate B after losing a proton. Considering the fact that
no cyclized 3-hydroxy-2-oxindole product was produced from
Scheme 3. Proposed Mechanistic Pathway from 7a to 8a
General Procedures for the Preparation of Substrates.
Procedure A.12,24 Adapted from a previously reported procedure
with some modifications. To a solution of N-substituted aniline (10
mmol) in DCM (50 mL) was added successively acetoacetic acid (0.51
g, 10 mmol) and DCC (2.06 g, 10 mmol). The reaction mixture was
stirred at room temperature until TLC indicated the total
consumption of the substrate. The mixture was filtrated through a
short pad of silica gel, and the filtrate was evaporated to partially
remove the solvent. The residue was treated with saturated aq.
NaHCO3 (50 mL) and extracted with EtOAc (50 mL × 3). The
combined organic layer was dried with anhydrous Na2SO4. The
solvent was removed under vacuum, and the crude product was
purified by silica gel flash column chromatography.
D
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Procedure B:25 A mixture of ethylacetoacetate (1.30 g, 10 mmol)
and aniline (10 mmol) was taken into a round-bottom flask and
refluxed under stirring for 24 h. The mixture was concentrated under
vacuum, and then the crude product was purified by column
chromatography using EA/PE to give acetoacetanilide 7.
dure A, a mixture of 7e and 7e′ was purified by silica gel
chromatography (EA/PE = 10/90). Yield: 87%, 2.204 g, (ketone/
enol = 3:2), white solid, mp 83−84 °C; 1H NMR (400 MHz, CDCl3)
isomer (ketone) δ 7.39−7.20 (m, 10H), 3.48 (s, 2H), 2.14 (s, 3H);
isomer (enol) δ 14.11 (s, 1H), 7.39−7.20 (m, 10H), 4.86 (s, 1H), 1.87
(s, 3H).
Procedure C.26 Acetoacetanilide (10 mmol) was dissolved in
aqueous sodium hydroxide solution (20% W/W, 6 mL). The resulting
solution was externally cooled by an ice bath and stirred persistently.
When the temperature of the solution reached 2 °C, aroylchloride (10
mmol) was added gradually while the temperature of the reaction
mixture was kept below 5 °C. After all the acid chloride was added, the
mixture was stirred for 0.5 h at 5 °C and for an additional 30 min at
room temperature. The reaction mixture was then diluted with
aqueous ammonium hydroxide solution (25% W/W, 1.5 mL)
containing ammonium chloride (10 mmol) and stirred for 5 min.
The resulting mixture was heated to 40−50 °C, left to stand overnight
at room temperature, and filtered. The crude product was purified by
column chromatography using EA/PE to give aroylacetanilides.
N-Methyl-3-oxo-N-phenylbutanamide (7a).27 By following the
general procedure B, 7a was purified by silica gel chromatography
N-Benzyl-3-oxo-N-phenylbutanamide (7f) and (Z)-N-Benzyl-
3-hydroxy-N-phenylbut-2-enamide (7f′):12 By following general
procedure A, a mixture of 7f and 7f′ was purified by silica gel
chromatography (EA/PE = 10/90). Yield: 78%, 2.085 g, (ketone/enol
1
= 2.5:1), white solid, mp 56−58 °C; H NMR (400 MHz, CDCl3)
major isomer (ketone) δ 7.32−7.23 (m, 8H), 6.99−6.97 (m, 2H), 4.91
(s, 2H), 3.31 (s, 2H), 2.09 (s, 3H); minor isomer (enol) δ 14.31 (s,
1H), 7.32−7.23 (m, 8H), 7.03−7.00 (m, 2H), 4.91 (s, 2H), 4.64 (s,
1H), 1.80 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 202.2, 174.4,
171.7, 166.7, 141.8, 137.5, 137.0, 129.7, 129.5, 128.8, 128.5, 128.4,
128.4, 127.9, 127.5, 127.4, 89.1, 53.0, 52.2, 50.1, 30.4, 21.7 (four
carbon peaks were missing due to overlapping); HRMS (ESI) m/z
+
calcd for C17H17NNaO2 [M + Na+] 290.1151, found 290.1156.
N-Benzyl-N-(3-fluorophenyl)-3-oxobutanamide (7g) and (Z)-
N-benzyl-N-(3-fluorophenyl)-3-hydroxybut-2-enamide (7g′).
By following general procedure A, a mixture of 7g and 7g′ was
purified by silica gel chromatography (EA/PE = 10/90). Yield: 80%,
1
(EA/PE = 10/90). Yield: 50%, 0.956 g, colorless oil; H NMR (600
MHz, CDCl3) δ 7.42 (t, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.20
(d, J = 7.2 Hz, 2H), 3.30 (s, 2H), 3.30 (s, 3H), 2.10 (s, 3H).
2-Hydroxy-N-methyl-3-oxo-N-phenylbutanamide (8a). By
following the literature procedure,12 8a was purified by silica gel
chromatography (EA/PE = 15/85). Yield: 92%, 190 mg, yellow oil; 1H
NMR (600 MHz, CDCl3) δ 7.45 (t, J = 7.2 Hz, 2H), 7.41 (t, J = 7.2
Hz, 1H), 7.26 (d, J = 7.2 Hz, 2H), 4.55 (s, 1H), 4.06 (br s, 1H), 3.36
(s, 3H), 2.09 (s, 3H); 13C NMR (150 MHz, CDCl3) δ 203.9, 168.7,
141.9, 130.0, 128.7, 127.6, 75.2, 38.1, 26.0; HRMS (ESI) m/z calcd for
C11H13NO3Na [M + Na+] 230.0788, found 230.0793.
1
2.283 g, (ketone/enol = 2: 1), colorless oil; H NMR (400 MHz,
CDCl3) major isomer (ketone) δ 7.29−7.21 (m, 6H), 7.03 (t, J = 8.0
Hz, 1H), 6.79 (d, J = 8.0 Hz, 1H), 6.73 (d, J = 9.2 Hz, 1H), 4.90 (s,
2H), 3.34 (s, 2H), 2.13 (s, 3H); minor isomer (enol) δ 14.20 (s, 1H),
7.29−7.21 (m, 6H), 7.03 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 1H),
6.79 (d, J = 9.2 Hz, 1H), 4.90 (s, 2H), 4.67 (s, 1H), 1.83 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 202.0, 175.0, 171.6, 166.4, 162.8 (d, JC−F
= 247.8 Hz), 143.2 (d, JC−F = 9.8 Hz), 137.1, 136.6, 130.8 (d, JC−F
8.9 Hz), 130.6 (d, JC−F = 10.0 Hz), 128.7, 128.5, 128.3, 127.7, 127.5,
124.3 (d, JC−F = 3.1 Hz), 115.8 (d, JC−F = 21.8 Hz), 115.7 (d, JC−F
=
N-Methyl-3-oxo-N-p-tolylbutanamide (7b) and (Z)-3-Hy-
droxy-N-methyl-N-p-tolylbut-2-enamide (7b′). By following
general procedure A, a mixture of 7b and 7b′ was purified by silica
gel chromatography (EA/PE = 10/90). Yield: 80%, 1.642 g, (ketone/
=
20.9 Hz), 114.9, 88.8, 53.0, 52.1, 50.0, 30.4, 21.8 (five carbon peaks
were missing due to overlapping); HRMS (ESI) m/z calcd for
C17H1619FNO2Na [M + Na+] 308.1057, found 308.1059.
1
enol = 3.75: 1), colorless oil; H NMR (400 MHz, CDCl3) major
3-Oxo-N-phenylbutanamide (7h).25 By following general
procedure B, 7h was purified by silica gel chromatography (EA/PE
isomer (ketone) δ 7.21 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H),
3.30 (s, 2H), 3.28 (s, 3H), 2.38 (s, 3H), 2.11 (s, 3H); minor isomer
(enol) δ 14.27 (s, 1H), 7.21 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz,
2H), 4.68 (s, 1H), 3.27 (s, 3H), 2.39 (s, 3H), 1.80 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 202.4, 173.5, 171.9, 166.8, 141.0, 140.8, 138.3,
137.5, 130.5, 130.2, 127.1, 126.9, 88.9, 49.8, 37.3, 36.3, 30.3, 21.6, 21.0
(two peaks overlapped); HRMS (ESI) m/z calcd for C12H15NO2Na
[M + Na+] 228.1000, found 228.1007.
1
= 20/80). Yield: 44%, 0.779 g, white solid, mp 85−86 °C; H NMR
(400 MHz, CDCl3) δ 9.10 (br s, 1H), 7.54 (d, J = 7.8 Hz, 2H), 7.33 (t,
J = 7.8 Hz, 2H), 7.12 (t, J = 7.8 Hz, 1H), 3.59 (s, 2H), 2.33 (s, 3H).
N-(3-Fluorophenyl)-3-oxobutanamide (7i).29 By following
general procedure A, 7i was purified by silica gel chromatography
(EA/PE = 20/80). Yield: 86%, 1.678 g, white solid, mp 65−67 °C; 1H
NMR (600 MHz, CDCl3) δ 9.27 (br s, 1H), 7.52 (m, 1H), 7.30−7.24
(m, 1H), 7.18 (d, J = 12 Hz, 1H), 6.82 (ddd, J = 12, 2.4 Hz, 1H), 3.60
(s, 2H), 2.34 (s, 3H).
N-(4-Bromophenyl)-N-methyl-3-oxobutanamide (7c) and
(Z)-N-(4-Bromophenyl)-3-hydroxyl -N-methylbut-2-enamide
(7c′). By following general procedure A, a mixture of 7c and 7c′
was purified by silica gel chromatography (EA/PE = 10/90). Yield:
3-Oxo-N-o-tolylbutanamide (7j).30 By following general proce-
dure A, 7j was purified by silica gel chromatography (EA/PE = 20/80).
1
82%, 2.215 g, (ketone/enol = 2.5: 1), colorless oil; H NMR (400
MHz, CDCl3) major isomer (ketone) δ 7.55 (d, J = 8.0 Hz, 2H), 7.10
(d, J = 8.0 Hz, 2H), 3.32 (s, 2H), 3.28 (s, 3H), 2.13 (s, 3H); minor
isomer (enol) δ 14.18 (s, 1H), 7.55 (d, J = 8.0 Hz, 2H), 7.10 (d, J =
8.0 Hz, 2H), 4.70 (s, 1H), 3.28 (s, 3H), 1.83 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 202.1, 171.7, 166.4, 142.6, 142.4, 137.4, 133.1, 132.8,
130.2, 129.1, 129.0, 122.1, 88.6, 49.8, 37.3, 36.3, 30.4, 21.7; HRMS
(ESI) m/z calcd for C11H1279BrNO2Na [M + Na+] 291.9944, found
291.9947.
N-Methyl-3-oxo-N,3-diphenylpropanamide (7d) and (Z)-3-
Hydroxy-N-methyl-N,3-diphenylacrylamide (7d′). By following
general procedure A, a mixture of 7d and 7d′ was purified by silica gel
chromatography (EA/PE = 10/90). Yield: 82%, 2.077 g, (ketone/enol
= 1: 1), colorless oil; 1H NMR (400 MHz, CDCl3) isomer (ketone) δ
7.76−7.26 (m, 10H), 3.86 (s, 2H), 3.36 (s, 3H); isomer (enol) δ 14.69
(s, 1H), 7.76−7.26 (m, 10H), 5.39 (s, 1H), 3.36 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 194.2, 172.1, 170.2, 167.1, 143.7, 143.4, 136.4,
134.6, 133.3, 130.6, 129.9, 129.8, 128.6 (two peaks overlapped), 128.3,
128.3, 127.8, 127.3, 127.3, 125.9, 86.9, 45.5, 37.4, 36.6; HRMS (ESI)
m/z calcd for C16H15NO2Na [M + Na+] 276.1000, found 276.1007.
3-Oxo-N,N-diphenylbutanamide (7e) and (Z)-3-Hydroxy-
N,N-diphenylbut-2-enamide (7e′).28 By following general proce-
1
Yield: 82%, 1.566 g, white solid, mp 105−106 °C; H NMR (600
MHz, CDCl3) δ 9.16 (br s, 1H), 7.91 (d, J = 7.2 Hz, 1H), 7.21−7.18
(m, 2H), 7.06 (t, J = 7.2 Hz, 1H), 3.62 (s, 2H), 2.33 (s, 6H).
N-(2-Chlorophenyl)-3-oxobutanamide (7k).25 By following
general procedure A, 7k was purified by silica gel chromatography
(EA/PE = 20/80). Yield: 80%, 1.693 g, white solid, mp 105−107 °C;
1H NMR (600 MHz, CDCl3) δ 9.60 (br s, 1H), 8.33 (d, J = 7.8 Hz,
1H), 7.38 (dd, J = 7.8, 1.2 Hz, 1H), 7.26 (td, J = 7.8, 1.2 Hz, 1H), 7.05
(td, J = 7.8, 1.2 Hz, 1H), 3.65 (s, 2H), 2.34 (s, 3H).
N-(4-Methoxyphenyl)-3-oxobutanamide (7l).25 By following
the general procedure B, 7l was purified by silica gel chromatography
(EA/PE = 20/80). Yield: 45%, 0.932 g, white solid, mp 116−117 °C;
1H NMR (400 MHz, CDCl3) δ 8.97 (br s, 1H), 7.44 (d, J = 8.8 Hz,
2H), 7.85 (d, J = 8.8 Hz, 2H), 3.79 (s, 3H), 3.57 (s, 2H), 2.32 (s, 3H).
N-(3-Methoxyphenyl)-3-oxobutanamide (7m).29 By following
the general procedure B, 7m was purified by silica gel chromatography
(EA/PE = 20/80). Yield: 47%, 0.974 g, white solid, mp 76−77 °C; 1H
NMR (600 MHz, CDCl3) δ 9.07 (br s, 1H), 7.28 (s, 1H), 7.22 (t, J =
7.8 Hz, 1H), 7.04 (d, J = 7.8 Hz, 1H), 6.68 (d, J = 7.8 Hz, 1H), 3.81 (s,
3H), 3.59 (s, 2H), 2.33 (s, 3H).
E
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
5-Methyl-3-oxo-N-phenylhexanamide (7n).31 By following
general procedure A, 7n was purified by silica gel chromatography
(EA/PE = 20/80). Yield: 85%, 1.863 g, white solid, mp 90−92 °C; 1H
NMR (600 MHz, CDCl3) δ 9.18 (br s, 1H), 7.55 (d, J = 7.8 Hz, 2H),
7.32 (t, J = 7.8 Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 3.53 (s, 2H), 2.45 (d,
J = 6.6 Hz, 2H), 2.18 (m, 1H), 0.96 (s, 3H), 0.95 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 207.5, 163.5, 137.6, 129.0, 124.5, 120.1, 53.0,
49.4, 24.4, 22.4.
10.5; HRMS (ESI) m/z calcd for C11H11NO2Na [M + Na+] 212.0682,
found 212.0687.
3-Hydroxy-1,4,6-trimethylquinolin-2(1H)-one (9b). By follow-
ing the general procedure, 9b was purified by silica gel chromatog-
raphy (EA/PE = 20/80). Yield: 90%, 92 mg, white solid, mp 198−200
°C; 1H NMR (400 MHz, DMSO-d6) δ 9.01 (s, 1H), 7.46 (s, 1H), 7.37
(d, J = 6.8 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 3.67 (s, 3H), 2.39 (s,
3H), 2.28 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 157.8, 142.5,
132.7, 131.9, 128.3, 124.0, 122.1, 118.4, 114.9, 30.1, 21.0, 11.0; HRMS
(ESI) m/z calcd for C12H13NO2Na [M + Na+] 226.0838, found
226.0843.
3-Oxo-N,3-diphenylpropanamide (7o).31 By following general
procedure A, 7o was purified by silica gel chromatography (EA/PE =
1
20/80). Yield: 89%, 2.219 g, white solid, mp 106−107 °C; H NMR
(400 MHz, CDCl3) δ 9.28 (br s, 1H), 8.05 (d, J = 7.8 Hz, 2H), 7.65 (t,
J = 7.8 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.53 (t, J = 7.8 Hz, 2H), 7.34
(t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 4.13 (s, 2H).
6-Bromo-3-hydroxy-1,4-dimethylquinolin-2(1H)-one (9c). By
following the general procedure, 9c was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 72%, 97 mg, white solid,
N-(4-Iodophenyl)-3-oxo-3-phenylpropanamide (7p).32 By
following general procedure A, 7p was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 89%, 3.2499 g, white
1
mp 212−214 °C; H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.55
(d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 7.17 (br s, 1H), 3.81 (s,
3H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.4, 142.3,
133.2, 129.8, 126.5, 124.4, 117.5, 116.3, 115.8, 30.3, 10.8; HRMS
(ESI) m/z calcd for C11H1079BrNO2Na [M + Na+] 289.9787, found
289.9791.
1
solid, mp 174−176 °C; H NMR (600 MHz, CDCl3) δ 9.42 (br s,
1H), 8.02 (d, J = 7.8 Hz, 2H), 7.66−7.62 (m, 3H), 7.52 (t, J = 7.8 Hz,
2H), 7.38 (d, J = 7.8 Hz, 2H), 4.09 (s, 2H); 13C NMR (150 MHz,
CDCl3) δ 196.5, 163.7, 137.9, 137.4, 136.0, 134.5, 129.0, 128.6, 122.0,
87.8, 45.2.
3-Hydroxy-1-methyl-4-phenylquinolin-2(1H)-one (9d):9 By
following the general procedure, 9d was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 25%, 32 mg, white solid,
mp 200−202 °C; 1H NMR (400 MHz, CDCl3) δ 7.56 (t, J = 7.2 Hz,
2H), 7.52−7.39 (m, 6H), 7.26−7.19 (m, 1H), 7.18 (br s, 1H), 3.92 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.1, 140.9, 134.5, 133.0,
130.0, 128.6, 128.3, 127.3, 126.2, 123.3, 123.1, 122.1, 114.2, 30.5.
3-Hydroxy-4-methyl-1-phenylquinolin-2(1H)-one (9e). By
following the general procedure, 9e was purified by silica gel
chromatography (EA/PE = 25/75). Yield: 82%, 103 mg, white solid,
3-Oxo-N-phenyl-3-p-tolylpropanamide (7q).33 By following
the general procedure A, 7q was purified by silica gel chromatography
(EA/PE = 20/80). Yield: 90%, 2.279 g, white solid, mp 114−115 °C;
1H NMR (600 MHz, CDCl3) δ 9.35 (br s, 1H), 7.92 (d, J = 7.8 Hz,
2H), 7.58 (d, J = 7.8 Hz, 2H), 7.32 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 8.4
Hz, 2H), 7.11 (t, J = 7.8 Hz, 1H), 4.07 (s, 2H), 2.43 (s, 3H).
3-(4-Fluorophenyl)-3-oxo-N-phenylpropanamide (7r).34 By
following general procedure C, 7r was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 49%, 1.260 g, white solid,
mp 132−134 °C; 1H NMR (600 MHz, CDCl3) δ 9.15 (br s, 1H), 8.07
(t, J = 7.8 Hz, 2H), 7.57 (d, J = 7.8 Hz, 2H), 7.33 (t, J = 7.8 Hz, 2H),
7.19 (t, J = 7.8 Hz, 2H), 7.13 (t, J = 7.8 Hz, 1H), 4.08 (s, 2H).
3-(3-Bromophenyl)-3-oxo-N-phenylpropanamide (7s).26 By
following general procedure A, 7s was purified by silica gel
chromatography (EA/PE = 20/80). Yield: 88%, 2.799 g, white solid,
mp 123−124 °C; 1H NMR (600 MHz, CDCl3) δ 9.06 (br s, 1H), 8.17
(s, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.57 (d, J =
7.8 Hz, 2H), 7.41 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.13 (t,
J = 7.8 Hz, 1H), 4.09 (s, 2H).
1
mp 184−185 °C; H NMR (600 MHz, DMSO-d6) δ 9.20 (br s, 1H),
7.74−7.72 (m, 1H), 7.64 (t, J = 7.8 Hz, 2H), 7.57 (t, J = 7.8 Hz, 1H),
7.34 (d, J = 7.8 Hz, 2H), 7.27−7.23 (m, 2H), 6.49 (d, J = 7.8 Hz, 1H),
2.28 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 157.5, 142.3, 137.5,
135.4, 130.3, 128.9, 128.8, 126.4, 123.7, 122.6, 121.7, 119.2, 115.2,
10.7; HRMS (ESI) m/z calcd for C16H13NO2Na [M + Na+] 274.0838,
found 274.0839.
1-Benzyl-3-hydroxy-4-methylquinolin-2(1H)-one (9f). By fol-
lowing the general procedure, 9f was purified by silica gel
chromatography (EA/PE = 20/80). Yield: 79%, 105 mg, white solid,
mp 177−179 °C; 1H NMR (400 MHz, CDCl3) δ 7.71 (d, J = 8.0 Hz,
1H), 7.39−7.21 (m, 8H), 7.16 (br s, 1H), 5.66 (s, 2H), 2.49 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 158.9, 141.5, 136.0, 133.6, 128.9,
127.4, 127.2, 126.6, 124.1, 123.1, 122.8, 119.3, 115.5, 46.7, 10.9;
HRMS (ESI) m/z calcd for C17H15NO2Na [M + Na+] 288.0995,
found 288.0998.
1-Benzyl-7-fluoro-3-hydroxy-4-methylquinolin-2(1H)-one
(9g). By following the general procedure, 9g was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 67%, 95 mg, white solid,
mp 202−204 °C; 1H NMR (400 MHz, CDCl3) δ 7.65 (dd, J = 9.2, 6.0
Hz, 1H), 7.34 (t, J = 7.2 Hz, 2H), 7.28 (t, J = 7.2 Hz, 1H) 7.22 (d, J =
7.2 Hz, 2H), 7.07 (br s, 1H), 7.04−7.00 (m, 2H), 5.59 (s, 2H), 2.46 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 161.8 (d, JC−F = 244.0 Hz),
159.2, 140.8, 135.3, 134.8 (d, JC−F = 10.0 Hz), 129.0, 127.7, 126.5 (two
peaks overlapped), 125.7 (d, JC−F = 10.0 Hz), 119.2 (d, JC−F = 8.5 Hz),
111.1 (d, JC−F = 22.4 Hz), 102.2 (d, JC−F = 26.8 Hz), 47.0, 11.1; HRMS
(ESI) m/z calcd for C17H1419FNO2Na [M + Na+] 306.0901, found
306.0903.
3-(3-Methoxyphenyl)-3-oxo-N-phenylpropanamide (7t).35
By following the general procedure C, 7t was purified by silica gel
chromatography (EA/PE = 20/80). Yield: 45%, 1.211 g, white solid,
1
mp 97−99 °C; H NMR (600 MHz, CDCl3) δ 9.28 (br s, 1H), 7.61
(d, J = 7.8 Hz, 1H), 7.58 (d, J = 7.8 Hz, 2H), 7.54 (d, J = 2.4 Hz, 1H),
7.42 (t, J = 7.8 Hz, 1H), 7.34 (t, J = 7.8 Hz, 2H), 7.18 (dd, J = 7.8, 2.4
Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 4.11 (s, 2H), 3.87 (s, 3H); 13C
NMR (150 MHz, CDCl3) δ 196.4, 163.7, 160.1, 137.6, 137.4, 130.0,
129.0, 124.6, 121.3, 121.0, 120.2, 112.6, 55.5, 45.7; HRMS (ESI) m/z
calcd for C16H15NO3Na [M + Na+] 292.0944, found 292.0947.
General Procedure for the Preparation of the Products. To a
solution of N-phenylacetoacetamide 7 (0.5 mmol) in DCM (2.5 mL)
was added PIFA (237 mg, 0.55 mmol), and the reaction mixture was
stirred at room temperature. Then conc. H2SO4 (266 μL) was added
to the reaction mixture when TLC indicated the total consumption of
the N-phenylacetoacetamide 7. The reaction was monitored by TLC.
The solution was diluted with cooled water (50 mL) until the
complete consumption of 8 and extracted with EtOAc (50 mL × 3).
The combined organic layer was dried with anhydrous Na2SO4. The
solvent was removed under vacuum, and the crude product was
purified by flash column chromatography on silica gel using a mixture
of PE and EA as eluent to give the desired product.
3-Hydroxy-4-methylquinolin-2(1H)-one (9h). By following the
general procedure, 9h was purified by silica gel chromatography (EA/
1
PE = 30/70). Yield: 70%, 62 mg, white solid, mp 249−250 °C; H
NMR (400 MHz, DMSO-d6) δ 11.97 (br s, 1H), 9.08 (br s, 1H), 7.59
(d, J = 7.8 Hz, 1H), 7.33 (t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H),
7.19 (t, J = 7.8 Hz, 1H), 2.28 (s, 3H); 13C NMR (100 MHz, DMSO-
d6) δ 157.8, 142.2, 132.7, 126.5, 123.2, 122.4, 121.2, 120.0, 115.1, 10.4;
HRMS (ESI) m/z calcd for C10H9NO2Na [M + Na+] 198.0531, found
198.0540.
3-Hydroxy-1,4-dimethylquinolin-2(1H)-one (9a). By following
the general procedure, 9a was purified by silica gel chromatography
(EA/PE = 5/95). Yield: 88%, 83 mg, white solid, mp 209−210 °C; 1H
NMR (600 MHz, DMSO-d6) δ 9.09 (br s, 1H), 7.67 (d, J = 7.2 Hz,
1H), 7.49 (d, J = 7.2 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.29 (d, J = 7.2
Hz, 1H), 3.71 (s, 3H), 2.30 (s, 3H); 13C NMR (150 MHz, DMSO-d6)
δ 157.5, 142.0, 134.1, 126.7, 123.6, 122.4, 121.7, 118.1, 114.4, 29.6,
7-Fluoro-3-hydroxy-4-methylquinolin-2(1H)-one (9i). By fol-
lowing the general procedure, 9i was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 74%, 72 mg, white solid,
F
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
mp 249−252 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.05 (br s, 1H),
9.14 (br s, 1H), 7.62 (s, 1H), 7.05−7.04 (m, 2H), 2.27 (s, 3H); 13C
NMR (150 MHz, DMSO-d6) δ 160.5 (d, JC−F = 240.9 Hz), 158.0,
7.11−7.06 (m, 2H), 2.39 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ
158.2, 142.4, 136.9, 133.2, 130.7, 129.7, 128.9, 126.3, 124.4, 123.9,
+
122.1, 121.0, 115.2, 20.9; HRMS (ESI) m/z calcd for C16H13NNaO2
142.1, 134.0 (d, JC−F = 10.8 Hz), 125.2, 119.3, 118.1, 109.8 (d, JC−F
=
[M + Na+] 274.0838, found 274.0841.
21.2 Hz), 101.0 (d, JC−F = 25.7 Hz), 10.6; HRMS (ESI) m/z calcd for
4-(4-Fluorophenyl)-3-hydroxyquinolin-2(1H)-one (9r). By
following the general procedure, 9r was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 78%, 100 mg, white solid,
mp 242−245 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.24 (br s, 1H),
9.29 (br s, 1H), 7.40−7.32 (m, 6H), 7.10−7.05 (m, 2H); 13C NMR
(150 MHz, DMSO-d6) δ 161.58 (d, JC−F = 91.2 Hz), 159.17, 142.66,
133.13, 131.44 (d, JC−F = 31.8 Hz), 129.92 (d, JC−F = 12 Hz), 126.47,
124.14, 122.91, 122.18, 120.82, 115.35, 115.24 (d, JC−F = 35.8 Hz);
C10H819FNO2Na [M + Na+] 216.0431, found 216.0436.
3-Hydroxy-4,8-dimethylquinolin-2(1H)-one (9j). By following
the general procedure, 9j was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 50%, 47 mg, white solid, mp 230−232 °C;
1H NMR (600 MHz, DMSO-d6) δ 11.12 (br s, 1H), 9.11 (br s, 1H),
7.46 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 7.8 Hz, 1H), 7.11 (t, J = 7.8 Hz,
1H), 2.44 (s, 3H), 2.29 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ
158.2, 142.5, 131.3, 127.9, 123.2, 121.8, 121.3, 121.2, 119.7, 17.5, 10.7;
HRMS (ESI) m/z calcd for C11H11NO2Na [M + Na+] 212.0682,
found 212.0682.
8-Chloro-3-hydroxy-4-methylquinolin-2(1H)-one (9k). By
following the general procedure, 9k was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 40%, 42 mg, white solid,
mp 224−226 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.26 (br s, 1H),
9.48 (br s, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.21
(t, J = 7.8 Hz, 1H), 2.30 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ
157.9, 143.5, 129.3, 126.6, 123.1, 122.7, 122.5, 119.4, 118.4, 10.8;
HRMS (ESI) m/z calcd for C10H835ClNO2Na [M + Na+] 232.0136,
found 232.0137.
3-Hydroxy-6-methoxy-4-methylquinolin-2(1H)-one (9l). By
following the general procedure, 9l was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 35%, 36 mg, white solid,
mp 225−227 °C; 1H NMR (400 MHz, DMSO-d6) δ 11.87 (br s, 1H),
9.06 (br s, 1H), 7.21 (d, J = 8.8 Hz, 1H), 7.03 (d, J = 2.4 Hz, 1H), 6.98
(dd, J = 8.8, 2.4 Hz, 1H), 3.81 (s, 3H), 2.27 (s, 3H); 13C NMR (100
MHz, DMSO-d6) δ 157.8, 155.1, 143.7, 127.7, 122.7, 119.5, 116.8,
115.2, 106.3, 55.9, 11.1; HRMS (ESI) m/z calcd for C11H11NO3Na
[M + Na+] 228.0631, found 228.0634.
3-Hydroxy-7-methoxy-4-methylquinolin-2(1H)-one (9m). By
following the general procedure, 9m was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 30%, 31 mg, white solid,
mp 221−223 °C; 1H NMR (600 MHz, DMSO-d6) δ 11.82 (br s, 1H),
8.75 (br s, 1H), 7.51−7.45 (m, 1H), 6.83−6.80 (m, 2H), 3.77 (s, 3H),
2.24 (s, 3H); 13C NMR (150 MHz, DMSO-d6) δ 158.1, 140.8, 134.3,
124.4, 119.8, 115.1, 110.4, 98.5, 55.1, 10.5 (one carbon peaks was
missing due to overlapping); HRMS (ESI) m/z calcd for
C11H11NO3Na [M + Na+] 228.0631, found 228.0634.
+
HRMS (ESI) m/z calcd for C15H1019FNNaO2 [M + Na+] 278.0588,
found 278.0592.
4-(3-Bromophenyl)-3-hydroxyquinolin-2(1H)-one (9s). By
following the general procedure, 9s was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 60%, 95 mg, white solid,
mp 220−222 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.27 (br s, 1H),
9.43 (br s, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.55 (s, 1H), 7.49 (t, J = 7.8
Hz, 1H), 7.36−7.33 (m, 3H), 7.10 (t, J = 7.8 Hz, 1H), 7.04 (d, J = 7.8
Hz, 1H); 13C NMR (150 MHz, DMSO-d6) δ 158.1, 142.7, 136.2,
133.1, 132.4, 130.6, 130.5, 129.0, 126.5, 124.0, 122.4, 122.3, 121.6,
+
120.5, 115.3; HRMS (ESI) m/z calcd for C15H1079BrNNaO2 [M +
Na+] 337.9787, found 337.9789.
3-Hydroxy-4-(3-methoxyphenyl)quinolin-2(1H)-one (9t):36
By following the general procedure, 9t was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 40%, 54 mg, white solid,
mp 239−240 °C; 1H NMR (600 MHz, DMSO-d6) δ 12.21 (br s, 1H),
9.18 (br s, 1H), 7.43 (t, J = 7.8 Hz, 1H), 7.36−7.31 (m, 2H), 7.08 (d, J
= 3.6 Hz, 2H), 7.02 (d, J = 7.8 Hz, 1H), 6.90−6.88 (m, 2H), 3.79 (s,
3H); 13C NMR (150 MHz, DMSO-d6) δ 159.7, 158.7, 142.8, 135.6,
133.6, 129.9, 126.9, 124.9, 124.3, 122.6, 122.5, 121.3, 115.9, 115.7,
+
113.6, 55.6; HRMS (ESI) m/z calcd for C16H13NNaO3 [M + Na+]
290.0788, found 290.0791.
2 (Viridicatol):9 Yield: 80%, 41 mg, white solid, mp 268−271 °C;
1H NMR (600 MHz, DMSO-d6) δ 12.19 (br s, 1H), 9.50 (br s, 1H),
9.12 (br s, 1H), 7.34−7.28 (m, 3H), 7.11−7.07 (m, 2H), 6.82 (d, J =
7.8 Hz, 1H), 6.72 (d, J = 7.8 Hz, 2H).
ASSOCIATED CONTENT
* Supporting Information
Spectral data for all synthesized compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
3-Hydroxy-4-isobutylquinolin-2(1H)-one (9n). By following
the general procedure, 9n was purified by silica gel chromatography
(EA/PE = 30/70). Yield: 64%, 70 mg, white solid, mp 192−193 °C;
1H NMR (600 MHz, DMSO-d6) δ 12.03 (br s, 1H), 9.01 (br s, 1H),
7.62 (d, J = 7.8 Hz, 1H), 7.32 (t, J = 7.8 Hz, 2H), 7.19 (t, J = 7.8 Hz,
1H), 2.72 (d, J = 7.2 Hz, 2H), 1.97 (m, 1H), 0.93 (s, 6H); 13C NMR
(150 MHz, DMSO-d6) δ 157.8, 143.2, 133.1, 126.1, 123.3, 122.8,
122.0, 120.8, 115.3, 33.1, 27.8, 22.5; HRMS (ESI) m/z calcd for
C13H15NO2Na [M + Na+] 240.0995, found 240.0998.
AUTHOR INFORMATION
Corresponding Author
*E-mail: duyunfeier@tju.edu.cn; kangzhao@tju.edu.cn.
■
Notes
The authors declare no competing financial interest.
Viridicatin (9o).9 By following the general procedure, 9o was
purified by silica gel chromatography (EA/PE = 30/70). Yield: 60%,
72 mg, white solid, mp 268−269 °C; 1H NMR (400 MHz, DMSO-d6)
δ 12.23 (br s, 1H), 9.20 (br s, 1H), 7.53−7.42 (m, 7H), 7.10−7.04 (m,
2H).
ACKNOWLEDGMENTS
■
Y.D. acknowledges the National Natural Science Foundation of
China (#21072148) and Cultivation Foundation (B) for Young
Faculty of Tianjin University (TJU-YFF-08B68) for financial
support.
3-Hydroxy-6-iodo-4-phenylquinolin-2(1H)-one (9p). By fol-
lowing the general procedure, 9p was purified by silica gel
chromatography (EA/PE = 30/70). Yield: 65%, 118 mg, white solid,
REFERENCES
1
mp >300 °C; H NMR (600 MHz, DMSO-d6) δ 12.34 (br s, 1H),
■
(1) For selected examples, see: (a) Sit, S. Y.; Ehrgott, F. J.; Gao, J.;
Meanwell, N. A. Bioorg. Med. Chem. Lett. 1996, 6, 499. (b) Ribeiro, N.;
Tabaka, H.; Peluso, J.; Fetzer, L.; Nebigil, C.; Dumont, S.; Muller, C.
D.; Desaubry, L. Bioorg. Med. Chem. Lett. 2007, 17, 5523. (c) Chen, M.
H.; Fitzgerald, P.; Singh, S. B.; O’Neill, E. A.; Schwartz, C. D.;
Thompson, C. M.; O’Keefe, S. J.; Zaller, D. M.; Doherty, J. B. Bioorg.
Med. Chem. Lett. 2008, 18, 2222. (d) Anzini, M.; Cappelli, A.; Vomero,
S.; Giorgi, G.; Langer, T.; Hamon, M.; Merahi, N.; Emerit, B. M.;
Cagnotto, A.; Skorupska, M.; Mennini, T.; Pinto, J. C. J. Med. Chem.
1995, 38, 2692. (e) He, J.; Lion, U.; Sattler, I.; Gollmick, F. A.;
9.48 (br s, 1H), 7.63−7.47 (m, 4H), 7.34 (d, 2H), 7.29 (s, 1H), 7.18
(d, 1H); 13C NMR (150 MHz, DMSO-d6) δ 158.1, 143.2, 134.5,
133.2, 132.6, 132.1, 129.8, 128.5, 127.9, 123.4, 122.7, 117.5, 85.7;
+
HRMS (ESI) m/z calcd for C15H10127INNaO2 [M + Na+] 385.9648,
found 385.9655.
3-Hydroxy-4-p-tolylquinolin-2(1H)-one (9q). By following the
general procedure, 9q was purified by silica gel chromatography (EA/
1
PE = 30/70). Yield: 75%, 95 mg, white solid, mp 240−242 °C; H
NMR (600 MHz, DMSO-d6) δ 12.22 (br s, 1H), 9.13 (br s, 1H), 7.36
(d, J = 7.8 Hz, 1H), 7.34−7.32 (m, 3H), 7.23 (d, J = 7.8 Hz, 2H),
G
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Grabley, S.; Cai, J.; Meiners, M.; Schunke, H.; Schaumann, K.;
Dechert, U.; Krohn, M. J. Nat. Prod. 2005, 68, 1397. (f) Toum, J.;
Moquette, A.; Lamotte, Y.; Mirguet, O. Tetrahedron Lett. 2012, 53,
1920. (g) Gioiello, A.; Venturoni, F.; Marinozzi, M.; Natalini, B.;
Pellicciari, R. J. Org. Chem. 2011, 76, 7431.
(2) Heguy, A.; Cai, P.; Meyn, P.; Houck, D.; Russo, S.; Michitsch, R.;
Pearce, C.; Katz, B.; Bringmann, G.; Feineis, D.; Taylor, D. L.; Tyms,
A. S. Antiviral Chem. Chemother. 1998, 9, 149.
(3) (a) Aoki, Y.; Ishiwara, M.; Koda, A.; Takagaki, H. Eur. J.
Pharmacol. 2000, 409, 325. (b) Ishiwara, M.; Aoki, Y.; Takagaki, H.;
Ui, M.; Okajima, F. J. Pharmacol. Exp. Ther. 2003, 307, 583.
(c) Kimura, N.; Fukui, H.; Takagaki, H.; Yonemochi, E.; Terada, K.
Chem. Pharm. Bull. 2001, 49, 1321. (d) Mizutani, N.; Aoki, Y.; Nabe,
T.; Ishiwara, M.; Yoshino, S.; Takagaki, H.; Kohno, S. Eur. J.
Pharmacol. 2009, 602, 138.
(4) Suchaud, V.; Bailly, F.; Lion, C.; Tramontano, E.; Esposito, F.;
Corona, A.; Christ, F.; Debyser, Z.; Cotelle, P. Bioorg. Med. Chem. Lett.
2008, 22, 3988.
(26) Shawali, A. S. A. S.; Naoum, M. M.; Ibrahim, S. A. Bull. Chem.
Soc. Jpn. 1972, 45, 2504.
(27) Maiti, A.; Reddy, P. V. N.; Cushman, M.; Sturdy, M.; Pegan, S.
D.; Mesecar, A. D.; Marler, L.; Pezzuto, J. M. J. Med. Chem. 2009, 52,
1873.
(28) Etkin, N.; Badu, S. D.; Fooks, C. J.; Durst, T. J. Org. Chem. 1990,
55, 1093.
(29) Evertsson, E.; Ingharnd, T.; Lindberg, J.; Linusson, A.;
Giordanetto, F. E.P. Patent 704,678, 2005.
(30) Heitbaum, M.; Froehlich, R.; Glorius, F. Adv. Synth. Catal. 2010,
352, 357.
(31) Angelov, P. Synlett 2010, 8, 1273.
(32) Staskun, B.; Meltzer, P. C. Tetrahedron 1977, 33, 2429.
(33) Andreichikov, Yu. S. Zh. Org. Khim. 1988, 24, 210.
(34) Steinhuebel, D.; Sun, Y.; Matsumura, K.; Sayo, N.; Saito, T. J.
Am. Chem. Soc. 2009, 131, 11316.
(35) Abou-Elenien, G. M.; El-Anadouli, B. E.; Bahgat, E.; Baraka, R.
M. J. Chem. Soc., Perkin Trans. 2 1957, 79, 2919.
(36) Luchner, M.; Mohammed, Y. S. Tetrahedron Lett. 1964, 29,
1987.
(5) Duplantier, A. J.; Becker, S. L.; Bohanon, M. J.; Borzilleri, K. A.;
Chrunyk, B. A.; Downs, J. T.; Hu, L. Y.; El-Kattan, A.; James, L. C.;
Liu, S.; Maklad, N.; Mansour, M. N.; Mente, S.; Piotrowski, M. A.;
Sakya, S. M.; Sheehan, S.; Steyn, S. J.; Strick, C. A.; Williams, V. A.;
Zhang, L. J. Med. Chem. 2009, 52, 3576.
(6) Sit, S. Y.; Meanwell, N. A. U.S. Patent 5,892,045, 1999.
(7) (a) Greibrokk, T.; Undheim, K. Acta Chem. Scand. 1971, 25,
2935. (b) Johnsen, B. A.; Undheim, K. Acta Chem. Scand. 1984, 38,
109.
(8) Huntress, E. H.; Bornstein, J.; Hearon, W. M. J. Am. Chem. Soc.
1956, 78, 2225.
(9) Kobayashi, Y.; Harayama, T. Org. Lett. 2009, 11, 1603.
(10) Arshad, N.; Hashim, J.; Kappe, C. O. J. Org. Chem. 2008, 73,
4755.
(11) (a) White, J. D.; Dimsdale, M. J. Chem. Commun. 1969, 1285.
(b) Martin, P. K.; Rapoport, H.; Smith, H. W.; Wong, J. L. J. Org.
Chem. 1969, 34, 1359. (c) Smith, H. W.; Rapoport, H. J. Am. Chem.
Soc. 1969, 81, 6083. (d) Terada, A.; Yabe, Y.; Miyadera, T.; Tachikawa,
R. Chem. Pharm. Bull. 1973, 21, 807.
(12) Wang, J.; Yuan, Y.; Xiong, R.; Zhang-Neigrerie, D.; Du, Y.;
Zhao, K. Org. Lett. 2012, 14, 2210.
(13) Sai, K. K. S.; Esteves, P. M.; Penha, E. T.; Klumpp, D. A. J. Org.
Chem. 2008, 73, 6506.
(14) For selected examples of Knorr cyclization leading to quinolin-
2(1H)-ones, see: (a) Knorr, L. Ann. Chem. 1886, 236, 69. (b) Kaslow,
C. E.; Cook, D. J. J. Am. Chem. Soc. 1945, 67, 1969. (c) Hauser, C. R.;
Reynolds, G. A. J. Am. Chem. Soc. 1948, 70, 2402.
(15) The dosage of H2SO4 was also examined, and it was found that
the reaction with the use of 8 equiv of H2SO4 required 0.7 h for
completion and furnished 9a in 85% yield while the use of 12 equiv
afforded 9a in 75% yield.
(16) Liu, W. B.; Chen, C.; Zhang, Q.; Zhu, Z. B. Beilstein J. Org.
Chem. 2011, 7, 1436.
(17) (a) Forbis, R. M.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1973, 95,
5003. (b) Nadzan, A. M.; Rinehart, K. L., Jr. J. Am. Chem. Soc. 1977,
99, 4647. (c) Maiti, A.; Reddy, P. V. N.; Sturdy, M.; Marler, L.; Pegan,
S. D.; Pezzuto, J. M.; Cushman, M. J. Med. Chem. 2009, 52, 31873.
(18) Kurouchi, H.; Kawamoto, K.; Sugimoto, H.; Nakamura, S.;
Otani, Y.; Ohwada, T. J. Org. Chem. 2012, 77, 9313.
(19) It may also be possible that the intermediate D was formed via
the direct reaction of the enol form of N-phenylacetoacetamide with
PIFA.
(20) Barluenga, J.; Bayon, A. M.; Asensio, G. Chem. Commun. 1984,
1334.
(21) Panfilov, A. V.; Markovich, Yu. D.; Zhirov, A. A.; Ivashev, I. P.;
Kirsanov, A. T.; Kondrat’ev, V. B. Pharm. Chem. J. 2000, 34, 371.
(22) Robert, C. K. J. Am. Chem. Soc. 1952, 74, 5536.
(23) Yu, W.; Du, Y.; Zhao, K. Org. Lett. 2009, 11, 2417.
(24) Anwar, M.; Moloney, M. G. Tetrahedron Lett. 2007, 48, 7259.
(25) Yadlapalli, R. K.; Chourasia, O. P.; Vemuri, K.; Sritharan, M.;
Perali, R. S. Bioorg. Med. Chem. Lett. 2012, 22, 2708.
H
dx.doi.org/10.1021/jo400541s | J. Org. Chem. XXXX, XXX, XXX−XXX