Synthesis of N-alkyl-substituted 4-quinolones via tandem alkenyl and aryl C-N bond formation

Article abstract of DOI:10.1055/s-0031-1290775

N-Alkyl-substituted 4-quinolones are present as the key structural motif in many marketed drugs. An efficient one-step tandem amination approach was developed to afford N-alkyl-substituted 4-quinolones in high yields from easily accessible o-chloroaryl acetylenic ketones and functionalized alkyl amines. The approach complements and extends our previous work. Compared with other reported methods, the current method provides a very simple and convenient route. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290775

1798▌
SPECIAL TOPIC
special topic
Synthesis of N-Alkyl-Substituted 4-Quinolones via Tandem Alkenyl and Aryl
C–N Bond Formation
Synthesis of N-Alkyl-Substituted 4-Quinolones
Jun Shao,a Xiaomei Huang,a Xiaohu Hong,a Bingxin Liu,a Bin Xu*a,b,c
a
Department of Chemistry, Shanghai University, Shanghai 200444, P. R. of China
Fax +86(21)66132065; E-mail: xubin@shu.edu.cn
b
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai
200032, P. R. of China
c
Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai
200062, P. R. of China
Received: 04.01.2012; Accepted: 01.03.2012
ed 4-quinolones. Previously, we focused our study on the
Abstract: N-Alkyl-substituted 4-quinolones are present as the key
effective construction of nitrogen-containing molecules
structural motif in many marketed drugs. An efficient one-step tan-
via tandem C–N/C–N coupling reactions,11a C–N/Suzuki–
dem amination approach was developed to afford N-alkyl-substitut-
ed 4-quinolones in high yields from easily accessible o-chloroaryl
Miyaura coupling,11b C–N/Sonogashira coupling,11c and
acetylenic ketones and functionalized alkyl amines. The approach C–N/C–O coupling.11d Herein, we describe a successful
complements and extends our previous work. Compared with other
reported methods, the current method provides a very simple and
convenient route.
extension of this concept, whereby a sequential double C–
N bond was formed to give N-alkyl-substituted 4-quino-
lones in high yields from readily available substrates
(Scheme 1). To our knowledge, this tandem reaction rep-
Key words: alkynes, amination, cyclization, nitrogen heterocycles,
domino reactions
resents the first efficient example of a one-pot synthesis of
N-alkyl-substituted 4-quinolones from o-chloroaryl acet-
ylenic ketones and functionalized alkyl amines through a
double C–N bond-forming process.
The 4-quinolone structural motif appears as the core struc-
ture of several biologically active molecules and in vari-
ous natural products.1 Such compounds have a wide
variety of activities and have been developed as antibiot-
ics,2 anticancer agents,3 and various inhibitors.4 Typical
commercially available compounds with these character-
istics are drugs such as Ciprofloxacin, Norfloxacin, and
Moxifloxacin, which are used for the treatment of bacteri-
al infections with high efficiency (Figure 1). Such charac-
teristics have made the molecules significant synthetic
targets and the development of efficient synthetic meth-
ods for this structural moiety continues to be of tremen-
dous interest.5 In this context, some elegant one-pot
reactions for the construction of the 4-quinolone scaffold,
using 2′-aminoacetophenone derivatives,6 2′-bromoaceto-
phenones,7 o-halophenones,8 2-iodoanilines,9 as well as
the reactions of isatoic anhydrides with aryl ketones10a or
alkynes,10b have been intensely studied.
O
N
O
O
N
O
F
F
OH
OH
N
N
HN
HN
ciprofloxacin
norfloxacin
F
O
N
O
F
OH
N
MeO
moxifloxacin
Figure 1 Some bioactive compounds containing the 4-quinolone
Recently, we developed an efficient palladium-catalysed
tandem amination protocol for the direct synthesis of N-
aryl 4-quinolones (Scheme 1).11a However, when alkyl
amine was employed as the nitrogen unit, the yield was
significantly decreased (e.g., 42% yield for n-butyl-
amine),11a which was unfortunate because such N-alkyl-
substituted 4-quinolone moieties are privileged structures
in many clinically used drugs (Figure 1). To address this
problem, new synthetic strategies needed to be developed
that would enable the facile synthesis of N-alkyl-substitut-
moiety
We started our investigation by reacting 1a with n-butyl-
amine in the presence of Cs2CO3 in dimethyl sulfoxide
(DMSO) at 140 °C. To our delight, the reaction gave 1-
butyl-4-quinolone 3aa in 86% yield (Table 1, entry 1).
Amongst the other bases tested, K2CO3 (entry 2) and
K3PO4 (entry 6) proved to be the most efficient, whereas
Na2CO3, Li2CO3 and NaHCO3 gave diminished yields
(entries 3–5). The reaction using K3PO4 as base in DMSO
was slightly faster than with K2CO3. Screening a range of
solvents revealed that DMSO was the best solvent for this
reaction (entry 6). Using N-methyl-2-pyrrolidinone
(NMP), toluene, dioxane, or 2-methyl-2-butanol (t-AmOH)
SYNTHESIS 2012, 44, 1798–1808
Advanced online publication: 03.04.2012
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DOI: 10.1055/s-0031-1290775; Art ID: SS-2012-C0011-ST
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of N-Alkyl-Substituted 4-Quinolones
1799
O
Pd2(dba)3, PPh3
R1
previous
work
K2CO3, dioxane
reflux
N
R2
O
X
R3 = aryl
Ar
R1
R3NH2
+
R2
O
X = Br, Cl
K3PO4⋅3H2O
R1
this work
DMSO, 140 °C
N
R2
R
3 = alkyl
Alkyl
Scheme 1 A tandem amination strategy for the synthesis of N-functionalized 4-quinolones from alkynones and alkyl amines
as solvent gave much lower yields (entries 7–10), whereas To further explore the generality and scope of this ap-
MeNO2 failed to give any product (entry 11). In the pres- proach, a variety of ynones 1b–k11a were investigated. As
ence of a twofold excess of n-butylamine, the amount of shown in Table 3, this method was compatible with differ-
K3PO4 could be reduced to 1.5 equivalents and the reac- ent types of ynones substituted with aryl, alkyl, and TMS
tion afforded 3aa in 95% yield (entry 12). Lower temper- groups (Table 3, entries 1–11). Substrates containing ei-
atures retarded the reaction and gave 3aa in 80% yield ther electron-donating (entries 1 and 2) or electron-
(entry 13). The presence of tetrabutylammonium bromide
Table 1 Optimization of the Synthesis of 3aaa
(TBAB) as a phase-transfer catalyst allowed a reduction
in the reaction temperature, but afforded 3aa in 85% yield
O
O
with longer reaction time (entry 14).
n-BuNH2 (2.0 equiv)
The optimised reaction conditions, using K3PO4 in DMSO
(Table 1, entry 12), were very broadly applicable and tol-
erated a wide variety of substitution patterns and function-
alities, as shown in Table 2. Alkyl amines with a range of
aliphatic chain lengths reacted with 1a smoothly to afford
the corresponding quinolones 3aa–ac in excellent yields
(Table 2, entries 1–3). Isopropylamine also performed
well and gave 3ad in 70% yield (entry 4), perhaps due to
its low nucleophilicity.12 Cyclic amines with various ring
sizes reacted with comparable efficiency (entries 5 and 6),
although the steric hindrance associated with the cyclo-
hexyl group resulted in a lower reactivity in this reaction
(entry 6). Substrate 2g with an active hydroxy functional-
ity could be readily incorporated and produced 3ag selec-
tively in 94% yield (entry 7), without the formation of any
by-products through intermolecular nucleophilic attack of
the oxygen. Benzylamine and allylamine performed better
in this reaction, and generated 3ah and 3ai in 96 and 72%
yield, respectively (entries 8 and 9). The latter product
was characterised as the more thermodynamically stable
product in which the carbon–carbon double bond of the
allyl group had migrated (entry 9). However, the less ba-
sic aniline gave only a trace amount of product under the
optimised conditions, and 3aj could be afforded in only
8% yield using more reactive bromo-substituted substrate
1k; no major intermediate formed during the reactions
(entry 10). In the latter case, we found that improved
base (2.0 equiv)
solvent, temp
Ph
N
Ph
Cl
Bu
1a
3aa
Entry Solvent
Base
Temp
(°C)
Time
(h)
Yield
(%)b
1
2
Cs2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
140
4.5
4.5
2
86
93
35
<5
34
93
22
<5
<5
<5
0
140
3
Na2CO3
Li2CO3
NaHCO3
140
4
140
2
5
140
2
6
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
K3PO4·3H2O
140
2
7
140
2
8
toluene
dioxane
t-AmOH
MeNO2
DMSO
DMSO
DMSO
reflux
reflux
120
2
9
2
10
11
12
13
2
reflux
140
2
95c
80c
85c,d
2
120
11
6
yields could be achieved by using a modified stepwise 14
one-pot procedure for aniline (Scheme 2); the reason may
be due to the easy formation of the Michael addition prod-
uct in the absence of base. Extension of the primary amine
series to include benzamide or tosylamide, failed to give
the corresponding quinolone derivatives, and the reaction
generated a complex mixture.
120
a Reaction conditions: 1a (0.2 mmol), n-butylamine (2a; 0.4 mmol),
base (0.4 mmol), solvent (1.5 mL), reaction performed in a capped
tube.
b Isolated yield.
c Conditions A: 1a (0.2 mmol), n-butylamine (2a; 0.6 mmol),
K3PO4·3H2O (0.3 mmol), DMSO (1.5 mL), 140 °C.
d TBAB (1.0 equiv) was used.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1798–1808

1800
J. Shao et al.
SPECIAL TOPIC
Table 2 Reaction of 1a with Primary Aminesa
afforded a similar result to that obtained with 1a (cf. Table
3, entry 12 vs. Table 2, entry 1).
O
O
The produced quinolones 3 were also very useful synthet-
ic precursors, for example, the corresponding 3-function-
alized quinolones could be easily generated using well-
documented amination,15 cyanation,16 Heck,17 Sonogashira,18
and Suzuki–Miyaura reactions11a,19 from 3-halogenated
quinolones, which could be prepared by direct halogena-
tion of our products 3.11a,19a
K3PO4⋅3H2O
RNH2
+
Ph
DMSO, 140 °C
Cl
1a
N
R
Ph
2
3
Entry Amine
(R)
Product
(R)
Time Yield
(%)b
(h)
To investigate the mechanism, the reaction intermediate
420,21 was isolated in 81% yield after running the reaction
for three minutes from 1a and n-butylamine (2a) under
conditions A (Table 1, note c), together with 16% yield of
quinolone product 3aa (Scheme 3).22 Furthermore, the
isolated intermediate 4 could further transform into 3aa in
94% yield under conditions A (Scheme 3). The two-step
reaction could yield 3aa in approximately 92% overall
yield from 1a and 2a; a result that is comparable with the
one-step yield (95%; Table 2, entry 1). Based on these re-
sults, we envisioned that this tandem reaction may pre-
dominantly proceed through intermediate 4 to afford the
target quinolone 3aa.
1
2
2a
2b
2c
2d
2d
2f
n-Bu
3aa
3ab
3ac
3ad
3ae
3af
n-Bu
2
4
4
95
94
89
Me(CH2)7
Me(CH2)11
i-Pr
Me(CH2)7
Me(CH2)11
i-Pr
3
4
10.5 70
5
c-Pr
c-Pr
2
10
2
88
53
94
96
72c
6
c-Hex
c-Hex
7
2g
2h
2i
HOCH2CH2
Bn
3ag
3ah
HOCH2CH2
Bn
8
2
9
H2C=CHCH2 3ai
Ph 3aj
MeCH=CH
Ph
4.5
11
10
2j
trace
(8d)
conditions A
2 h, 94%
a Reaction conditions (0.5 mmol scale): amine (1.5–3.0 equiv),
K3PO4·3H2O (1.5 equiv), DMSO (3 mL), 140 °C.
b Isolated yield.
O
O
NHBu
Ph
1a
+
n-BuNH2
conditions A
3 min
+
c Double-bond migration product 3ai was obtained.
d 1-(2-Bromophenyl)-3-phenylpropynone (1k) was used.
Cl
N
Ph
Bu
16%
4
81%
3aa
conditions A
2 h, 95%
O
O
X
1) PhNH2, DMSO, 140 °C
2) K3PO4⋅3H2O, 140 °C
Scheme 3 Plausible mechanism for the synthesis of 3aa from 1a
N
Ph
Ph
3aj
In summary, we have developed an efficient method for
the straightforward synthesis of N-functionalized 4-qui-
nolones from easily accessible o-chloroaryl acetylenic
ketones and alkyl amines that provides a successful exten-
sion and complement to our previous work.11a A wide
range of electronically and structurally varied nitrogen
fragments could be introduced through this tandem C–N
bond-forming process. Compared with other reported
methods, the current approach provides a very simple and
convenient route. The produced N-alkyl-substituted 4-
quinolones are present as the key structural motif in many
marketed drugs, and the approach should find applications
in medicinal chemistry. Further studies on the application
of this method for the construction of bioactive com-
pounds are under investigation in our laboratory and will
be reported in due course.
X = Cl, 41%
X = Br, 78%
1a X = Cl
1k X = Br
Scheme 2 Stepwise one-pot synthesis of N-phenyl-4-quinolone
withdrawing groups (entries 3–7), or bearing para- (en-
tries 1–4), meta- (entries 5 and 7), or ortho- (entry 6) sub-
stituents on the aryl ring generally gave the products in
excellent yields. Heptyl-substituted ynone 1h afforded
3ha in 88% yield, albeit after longer reaction time (entry
8). Dichloro-substituted ynone 1i afforded the corre-
sponding quinolones 3ia and 3ie in excellent yields with-
out competitive reactions occurring on the second
chlorine atom (entries 9–10). A tandem double C–N bond
formation and desilylation process was observed with tri-
methylsilyl-substituted substrate 1j that gave the synthet-
ically useful product 3je in good yield (entry 11), which
proved to be a key intermediate for the direct synthesis of
Ciprofloxacin through sequential carboxylation with car-
bon dioxide13 and amination reaction with piperazine.14 It
should be noted that the bromo-substituted substrate 1k
All reagents and solvents were obtained from commercial sources
and were purified before use. Melting points were measured with a
WRS-1A or a WRS-1B digital melting point apparatus without cor-
rection. Infrared spectra were obtained with an AVATAR 370 FTIR
1
spectrometer. H, 13C, and 19F NMR spectra were recorded with a
Synthesis 2012, 44, 1798–1808
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of N-Alkyl-Substituted 4-Quinolones
1801
Table 3 Reaction of Alkynones with Alkylaminesa
O
O
K3PO4⋅3H2O
R1
R1
R2
Alkyl-NH2
+
DMSO, 140 °C
X
N
R2
Alkyl
1b–k
3
R1
R2
Yield (%)b
Entry
1
X
2
Product
Time (h)
1
2
1b
1c
1d
1e
1f
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
H
4-MeOC6H4
4-EtC6H4
4-FC6H4
4-ClC6H4
3-ClC6H4
2-ClC6H4
3-ClC6H4
n-C5H11
Ph
2a
2a
2a
2a
2a
2a
2e
2a
2a
2e
2e
2a
3ba
3ca
3da
3ea
3fa
3ga
3fe
3.5
6
99
98
98
80
96
90
91
88
94
94
61c
95
H
3
H
4
4
H
4
5
H
2
6
1g
1f
H
3
7
H
2
8
1h
1i
H
3ha
3ia
20
4.5
2
9
H
10
11
12
1i
4-Cl
Ph
3ie
3jec
3aa
1j
4-Cl-5-F
H
TMS
1
1k
Ph
2
a Reaction conditions (0.5 mmol scale): amine (1.5–3.0 equiv), K3PO4·3H2O (1.5 equiv), DMSO (3 mL), 140 °C.
b Isolated yield.
c Desilylation product 3je (R2 = H) was obtained.
Bruker AV-500 spectrometer operating at 500, 125 and 470 MHz,
respectively, with chemical shift values being reported in ppm
relative to the solvent CDCl3 (δH = 7.26 ppm; δC = 77.16 ppm) or
DMSO-d6 (δH = 2.50 ppm; δC = 39.52 ppm). Mass spectra were re-
corded with an Agilent 5975N fitted with an ES ion source unless
stated otherwise. Elemental analyses were carried out with an
Elementar Vario EL elemental analyzer. Silica gel plates (GF254)
were used for thin layer chromatography (TLC) and silica gel H or
300–400 mesh were used for flash column chromatography. Petro-
leum ether (PE), where used, had a boiling range of 60–90 °C.
1H NMR (500 MHz, CDCl3): δ = 8.10–8.08 (m, 1 H), 7.65–7.64 (m,
2 H), 7.50–7.46 (m, 3 H), 7.43–7.39 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 176.9, 135.9, 133.6, 133.5, 133.2,
132.7, 131.7, 131.1, 128.8, 126.9, 120.1, 94.1, 88.4.
MS (EI): m/z (%) = 242 (16) [M+ (37Cl)], 240 (47) [M+ (35Cl)], 212
(83), 129 (100).
1-(2-Chlorophenyl)-3-(4-methoxyphenyl)propynone (1b)
Following the same procedure used for 1a with 1-ethynyl-4-meth-
oxybenzene (571.0 mg, 4.32 mmol), n-BuLi (1.6 M in hexane, 3.24
mL), 2-chlorobenzaldehyde (668.0 mg, 4.75 mmol) and activated
manganese dioxide (4.79 g, commercial sample) gave 1b.
1-(2-Chlorophenyl)-3-phenylpropynone (1a)11a
To a solution of phenylacetylene (400.0 mg, 3.92 mmol) in freshly
dried THF (5 mL) was added slowly n-BuLi (2.5 M in hexane, 1.72
mL) at –78 °C under a nitrogen atmosphere and the solution was
stirred for 3 min. A solution of 2-chlorobenzaldehyde (460.0 mg,
3.27 mmol) in anhydrous THF (2 mL) was then added slowly while
maintaining the temperature at –78 °C, and the reaction was al-
lowed to proceed for 2 h and then warmed to r.t. The reaction mix-
ture was washed with sat. aq NH4Cl (5 mL) and extracted with
EtOAc (2 × 20 mL). The organic layer was dried over Na2SO4, and
the solvent was evaporated under vacuum to give a crude oil that
was used for next step without further purification. To a stirred so-
lution of the crude oil in CH2Cl2 (30 mL) was added activated man-
ganese dioxide (2.84 g, commercial sample), and the resulting
suspension was stirred at r.t. for 10 h and then filtered through a thin
pad of Celite. The residue was purified by column chromatography
on silica gel (EtOAc–PE, 1:15) to give 1a.
Yield: 893.0 mg (76%); yellow solid; mp 56–58 °C.
IR (KBr): 2190, 1644, 1601, 1567, 1510, 1172 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 7.5 Hz, 1 H), 7.59 (d,
J = 8.5 Hz, 2 H), 7.47–7.44 (m, 2 H), 7.40–7.38 (m, 1 H), 6.91 (d,
J = 9.0 Hz, 2 H), 3.84 (s, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.0, 162.0, 136.3, 135.4, 133.5,
133.3, 132.5, 131.6, 126.9, 114.6, 111.9, 95.5, 88.6, 55.6.
MS (EI): m/z (%) = 272 (26) [M+ (37Cl)], 270 (69) [M+ (35Cl)], 242
(42), 159 (100).
Anal. Calcd for C16H11ClO2: C, 70.99; H, 4.10. Found: C, 70.84; H,
3.89.
1-(2-Chlorophenyl)-3-(4-ethylphenyl)propynone (1c)
Following the same procedure used for 1a with 1-ethynyl-4-ethyl-
benzene (450.0 mg, 3.45 mmol), n-BuLi (1.6 M in hexane, 2.58
Yield: 512.6 mg (65%); yellow oil.
IR (KBr): 2196, 1649, 1587, 1303, 1009, 758, 741 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1798–1808

1802
J. Shao et al.
SPECIAL TOPIC
mL), 2-chlorobenzaldehyde (533.0 mg, 3.79 mmol) and activated
manganese dioxide (4.00 g, commercial sample) gave 1c.
in anhydrous THF (2 mL) was then added slowly while maintaining
the temperature at –78 °C, and the reaction was allowed to proceed
for 2 h and warmed to r.t. The reaction mixture was washed with sat.
aq NH4Cl (10 mL) and extracted with EtOAc (3 × 20 mL). The or-
ganic layer was dried over Na2SO4 and the solvent was evaporated
under vacuum to give a crude oil that was used for next step without
further purification. To a stirred solution of the crude product in
CH2Cl2 (30 mL), was added activated manganese dioxide (6.60 g,
commercial sample), and the resulting suspension was stirred at r.t.
for 3.5 h and then filtered through a thin pad of Celite. The residue
was purified by column chromatography on silica gel (EtOAc–PE,
1:15) to give 1e.
Yield: 600.0 mg (65%); yellow oil.
IR (film): 2968, 2932, 2873, 2194, 1648, 1604, 1587, 1506, 1465,
1303, 834 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.08–8.06 (m, 1 H), 7.57 (d,
J = 6.5 Hz, 2 H), 7.48–7.46 (m, 2 H), 7.41–7.25 (m, 1 H), 7.24 (d,
J = 8.5 Hz, 2 H), 2.69 (q, J = 7.5 Hz, 2 H), 1.25 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.0, 148.1, 136.1, 133.6,
133.41, 133.38, 132.6, 131.6, 128.4, 126.9, 117.2, 94.9, 88.4, 29.2,
15.3.
Yield: 251.3 mg (28%); yellow solid; mp 83–84 °C.
IR (KBr): 2202, 1635, 1588, 1306, 1012 cm–1.
MS (EI): m/z (%) = 270 (20) [M+ (37Cl)], 268 (57) [M+ (35Cl)], 225
(65), 157 (100).
1H NMR (500 MHz, CDCl3): δ = 8.06 (d, J = 7.5 Hz, 1 H), 7.57 (d,
J = 8.5 Hz, 2 H), 7.49–7.46 (m, 2 H), 7.43–7.38 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 176.7, 137.5, 135.8, 134.4, 133.8,
HRMS: m/z calcd for C17H13ClO: 268.0655; found: 268.0652.
1-(2-Chlorophenyl)-3-(4-fluorophenyl)propynone (1d)
To a solution of 1-(2,2-dibromovinyl)-4-fluorobenzene (2.0 g, 7.14
mmol) and benzyltriethylammonium chloride (1.79 g, 7.86 mmol)
in CH2Cl2 (15 mL), KOH (12.0 g, 0.21 mol) in H2O (8 mL) was
added at 0 °C. The solution was stirred for 1 h at 0 °C, and then ex-
tracted with CH2Cl2 (2 × 20 mL). The organic layer was dried over
Na2SO4, filtered through a thin pad of Celite, and concentrated un-
der vacuum to give the crude product. The crude alkynyl bromide
was dissolved in THF (5 mL) and n-BuLi (1.6 M in hexane, 5.28
mL) was added slowly at –78 °C under a nitrogen atmosphere and
the mixture was stirred for 3 min. A solution of the 2-bromobenzal-
dehyde (1.09 g, 7.73 mmol) in anhydrous THF (2 mL) was then
added slowly while maintaining the temperature at –78 °C, and the
reaction was allowed to proceed for 2 h and warmed to r.t. The re-
action mixture was washed with sat. aq NH4Cl (5 mL) and extracted
with EtOAc (2 × 20 mL). The organic layer was dried over Na2SO4
and the solvent was evaporated under vacuum to give a crude oil
that was used for the next step without further purification. To a
stirred solution of the crude product in CH2Cl2 (30 mL), was added
activated manganese dioxide (9.46 g, commercial sample) and the
resulting suspension was stirred at r.t. for 1.5 h and then filtered
through a thin pad of Celite. The residue was purified by column
chromatography on silica gel (EtOAc–PE, 1:15) to give 1d.
133.7, 132.6, 131.7, 129.3, 127.0, 118.6, 92.6, 89.1.
MS (EI): m/z (%) = 278 (5) [M+ (2 × 37Cl)], 276 (31) [M+ (37Cl,
35Cl)], 274 (51) [M+ (2 × 35Cl)], 246 (91), 163 (100).
3-(3-Chlorophenyl)-1-(2-chlorophenyl)propynone (1f)23
To a solution of 1-(2,2-dibromovinyl)-3-chlorobenzene (3.0 g,
10.12 mmol) and benzyltriethylammonium chloride (2.54 g, 11.13
mmol) in CH2Cl2 (20 mL), KOH (12.0 g, 0.21 mol) in H2O (8 mL)
was added at 0 °C. The solution was stirred for 2 h at 0 °C and then
extracted with CH2Cl2 (2 × 20 mL). The organic layer were dried
over Na2SO4, filtered through a thin pad of Celite, and concentrated
under vacuum to give the crude product. The crude alkynyl bromide
was dissolved in THF (5 mL) and n-BuLi (2.2 M in hexane, 5.1 mL)
was added slowly at –78 °C under a nitrogen atmosphere and stirred
for 3 min. A solution of 2-chlorobenzaldehyde (1.57 g, 11.13 mmol)
in anhydrous THF (2 mL) was then added slowly while maintaining
the temperature at –78 °C, and the reaction was allowed to proceed
for 2 h and warmed to r.t. The reaction mixture was washed with sat.
aq NH4Cl (10 mL) and extracted with EtOAc (3 × 20 mL). The or-
ganic layer was dried over Na2SO4 and the solvent was evaporated
under vacuum to give a crude oil that was used for the next step
without further purification. To a stirred solution of the crude prod-
uct in CH2Cl2 (30 mL) was added activated manganese dioxide
(13.20 g, commercial sample), and the resulting suspension was
stirred at r.t. for 13 h and then filtered through a thin pad of Celite.
The residue was purified by column chromatography on silica gel
(EtOAc–PE, 1:15) to give 1f.
Yield: 1.04 g (57%); yellow solid; mp 78–80 °C.
IR (KBr): 2202, 1637, 1596, 1526, 1503, 1309, 1228, 833,
737 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.06–8.05 (m, 1 H), 7.67–7.63 (m,
2 H), 7.49–7.47 (m, 2 H), 7.42–7.38 (m, 1 H), 7.13–7.08 (m, 2 H).
Yield: 1.93 g (69%); yellow solid; mp 77–79 °C.
IR (KBr): 2207, 1639, 1587, 1307, 1016 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.05 (d, J = 7.5 Hz, 1 H), 7.60 (s,
1 H), 7.52–7.47 (m, 3 H), 7.44–7.39 (m, 2 H), 7.34 (t, J = 7.5 Hz,
1 H).
1
13C NMR (125 MHz, CDCl3): δ = 176.8, 164.3 (d, JC–F
=
3
252.5 Hz), 135.9, 135.6 (d, JC–F = 8.75 Hz), 133.7, 133.6, 132.6,
131.7, 127.1 (d, 2JC–F = 27.5 Hz), 116.5, 116.3 (d, 4JC–F = 3.75 Hz),
93.0, 88.4.
19F NMR (470 MHz, CDCl3): δ = –105.7 (m, Ar-F).
MS (EI): m/z (%) = 260 (18) [M+ (37Cl)], 258 (59) [M+ (35Cl)], 232
13C NMR (125 MHz, CDCl3): δ = 176.5, 135.6, 134.7, 133.7, 132.7,
132.6, 131.7, 131.3, 131.2, 130.6, 127.0, 121.8, 91.8, 88.8.
(30), 230 (96), 147 (100).
MS (EI): m/z (%) = 278 (8) [M+ (2 × 37Cl)], 276 (33) [M+ (37Cl,
35Cl)], 274 (50) [M+ (2 × 35Cl)], 250 (11), 248 (65), 246 (100), 176
(32), 163 (82).
Anal. Calcd for C15H8ClFO: C, 69.65; H, 3.12. Found: C, 69.78; H,
3.18.
3-(4-Chlorophenyl)-1-(2-chlorophenyl)propynone (1e)23
1,3-Bis(2-chlorophenyl)propynone (1g)23
To a solution of 1-(2,2-dibromovinyl)-4-chlorobenzene (1.5 g, 5.06
mmol) and benzyltriethylammonium chloride (1.27 g, 5.06 mmol)
in CH2Cl2 (15 mL), KOH (12.0 g, 0.21 mol) in H2O (8 mL) was
added at 0 °C. The solution was stirred for 1 h at 0 °C and then ex-
tracted with CH2Cl2 (2 × 20 mL). The organic layer was dried over
Na2SO4, filtered through a thin pad of Celite, and concentrated un-
der vacuum to give the crude product. The crude alkynyl bromide
was dissolved in THF (5 mL) and n-BuLi (1.6 M in hexane, 3.8 mL)
was added slowly at –78 °C under a nitrogen atmosphere and stirred
for 3 min. A solution of 2-chlorobenzaldehyde (0.782 g, 5.57 mmol)
To a solution of 1-chloro-2-(2,2-dibromovinyl)benzene (3.0 g,
10.12 mmol) and benzyltriethylammonium chloride (2.54 g, 11.13
mmol) in CH2Cl2 (20 mL), KOH (12.0 g, 0.21 mol) in H2O (8 mL)
was added at 0 °C. The solution was stirred for 2 h at 0 °C and then
extracted with CH2Cl2 (2 × 20 mL). The organic layer was dried
over Na2SO4, filtered through a thin pad of Celite, and concentrated
under vacuum to give the crude product. The crude alkynyl bromide
was dissolved in THF (5 mL) and n-BuLi (2.2 M in hexane, 5.1 mL)
was added slowly at –78 °C under a nitrogen atmosphere and stirred
for 3 min. A solution of 2-bromobenzaldehyde (1.57 g, 11.13
Synthesis 2012, 44, 1798–1808
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of N-Alkyl-Substituted 4-Quinolones
1803
mmol) in anhydrous THF (2 mL) was then added slowly while
maintaining the temperature at –78 °C, and the reaction was al-
lowed to proceed for 2 h and warmed to r.t. The reaction mixture
was washed with sat. aq NH4Cl (10 mL) and extracted with EtOAc
(3 × 20 mL). The organic layer was dried over Na2SO4 and the sol-
vent was evaporated under vacuum to give a crude oil that was used
for next step without further purification. To a stirred solution of the
crude product in CH2Cl2 (30 mL) was added activated manganese
dioxide (13.20 g, commercial sample), and the resulting suspension
was stirred at r.t. for 11.5 h and then filtered through a thin pad of
Celite. The residue was purified by column chromatography on sil-
ica gel (EtOAc–PE, 1:15) to give 1g.
residue was purified by chromatography on silica gel (PE) to give
1j.
Yield: 748.3 mg (55%); yellow solid; mp 38.0–39.5 °C.
IR (KBr): 2155, 1665, 1596, 1568, 1468, 1376, 1255, 1185, 1054,
849 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.83 (d, J = 9.0 Hz, 1 H), 7.53 (d,
J = 6.5 Hz, 1 H), 0.30 (s, 9 H).
1
13C NMR (125 MHz, CDCl3): δ = 173.8, 156.4 (d, JC–F
=
=
3
4
250.0 Hz), 134.6 (d, JC–F = 6.0 Hz), 133.2, 129.2 (d, JC–F
2
2
3.75 Hz), 126.7 (d, JC–F = 18.75 Hz), 120.2 (d, JC–F = 23.75 Hz),
103.1, 101.3, –0.92.
19F NMR (470 MHz, CDCl3): δ = –115.8 (m, Ar-F).
Yield: 1.48 g (53%); yellow solid; mp 78–80 °C.
IR (KBr): 2200, 1650, 1586, 1205, 1002, 761, 735 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.25 (d, J = 8.0 Hz, 1 H), 7.67 (d,
J = 7.5 Hz, 1 H), 7.49–7.39 (m, 5 H), 7.30 (t, J = 7.5 Hz, 1 H).
13C NMR (125 MHz, CDCl3): δ = 176.5, 137.7, 135.3, 135.1, 133.9,
MS (EI): m/z (%) = 292 (4) [M+ (2 × 37Cl)], 290 (21) [M+ (37Cl,
35Cl)], 288 (32) [M+ (2 × 35Cl)], 273 (100).
HRMS: m/z calcd for C12H11Cl2FOSi: 287.9940; found: 287.9944.
133.7, 133.5, 132.0, 131.9, 129.8, 127.0, 126.9, 120.4, 92.1, 89.9.
1-(2-Bromophenyl)-3-phenylpropynone (1k)11a
To a solution of phenylacetylene (500.0 mg, 4.90 mmol) in freshly
dried THF (5 mL) was added slowly n-BuLi (2.5 M in hexane, 2.15
mL) at –78 °C under a nitrogen atmosphere and the mixture was
stirred for 3 min. A solution of 2-bromobenzaldehyde (824 mg, 4.45
mmol) in anhydrous THF (2 mL) was then added slowly while
maintaining the temperature at –78 °C, and the reaction was al-
lowed to proceed for 2 h and warmed to r.t. The reaction mixture
was washed with sat. aq NH4Cl (5 mL) and extracted with EtOAc
(3 × 20 mL). The organic layer was dried over Na2SO4, and the sol-
vent was evaporated under vacuum to give a crude oil that was used
for the next step without further purification. To a stirred solution of
the crude oil in CH2Cl2 (30 mL) was added activated manganese di-
oxide (3.87 g, commercial sample). The resulting suspension was
stirred at r.t. for 7 h and then filtered through a thin pad of Celite.
The residue was purified by column chromatography on silica gel
(EtOAc–PE, 1:15) to give 1k.
MS (EI): m/z (%) = 278 (5) [M+ (2 × 37Cl)], 276 (40) [M+ (37Cl,
35Cl)], 274 (58) [M+ (2 × 35Cl)], 250 (14), 248 (70), 246 (100), 163
(80), 111 (46), 83 (41), 71 (42), 57 (65).
1-(2-Chlorophenyl)oct-2-yn-1-one (1h)
Following the same procedure used for 1a with hept-1-yne (600.0
mg, 6.24 mmol), n-BuLi (2.2 M in hexane, 4.67 mL), 2-chlorobenz-
aldehyde (1.05 g, 7.49 mmol) and activated manganese dioxide
(8.15 g, commercial sample) gave 1h.
Yield: 1.15 g (78%); light-yellow oil.
IR (film): 2957, 2931, 2861, 2209, 1655, 1588, 1566, 1466, 1434,
1284, 1242, 743 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.0–7.99 (m, 1 H), 7.44–7.40 (m,
2 H), 7.38–7.32 (m, 1 H), 2.45 (t, J = 7.5 Hz, 2 H), 1.66 (quint,
J = 7.0 Hz, 2 H), 1.45–1.39 (m, 2 H), 1.37–1.30 (m, 2 H), 0.90 (t,
J = 7.5 Hz, 3 H).
Yield: 781.0 mg (62%); yellow oil.
13C NMR (125 MHz, CDCl3): δ = 177.1, 136.0, 133.4, 133.2, 132.8,
131.6, 126.8, 98.1, 81.2, 31.2, 27.4, 22.2, 19.4, 14.0.
MS (EI): m/z (%) = 236 (1) [M+ (37Cl)], 234 (2) [M+ (35Cl)], 139
(100).
1H NMR (500 MHz, CDCl3): δ = 8.07 (dd, J = 7.5, 1.5 Hz, 1 H),
7.68 (dd, J = 8.0, 1.0 Hz, 1 H), 7.63 (dd, J = 8.5, 1.5 Hz, 2 H), 7.49–
7.35 (m, 5 H).
13C NMR (125 MHz, CDCl3): δ = 177.6, 137.5, 135.0, 133.5, 133.2,
132.8, 131.1, 128.8, 127.5, 121.3, 120.0, 94.3, 88.0.
MS (ESI): m/z (%) = 286 (100) [M+ (81Br)], 284 (93) [M+ (79Br)].
HRMS: m/z calcd for C14H15ClO: 234.0811; found: 234.0810.
1-(2,4-Dichlorophenyl)-3-phenylpropynone (1i)24
1-Butyl-2-phenyl-1H-quinolin-4-one (3aa)11a
Following the same procedure used for 1a with phenylacetylene
(1.6 g, 15.71 mmol), n-BuLi (2.2 M in hexane, 7.2 mL), 2,4-dichlo-
robenzaldehyde (2.5 g, 14.28 mmol) and activated manganese diox-
ide (18.6 g, commercial sample) gave 1i.
To an oven-dried, capped tube containing 1a (120.4 mg, 0.5 mmol)
and K3PO4·3H2O (199.7 mg, 0.75 mmol) in DMSO (3.0 mL), bu-
tan-1-amine (109.5 mg, 1.5 mmol) was added. The reaction mixture
was stirred at 140 °C for 2 h and monitored by TLC. Upon comple-
tion, the reaction mixture was washed with H2O (5 mL) and extract-
ed with EtOAc (3 × 10 mL). The combined organic phase was
washed with brine and dried over Na2SO4. The solid was filtered off
through a thin pad of Celite, and the filtrate was evaporated under
vacuum to give the crude product that was purified by column chro-
matography on silica gel (EtOAc–PE, 1:1) to give 3aa.
Yield: 2.60 g (66%); light-yellow solid; mp 88–89 °C.
IR (KBr): 2196, 1639, 1582, 1302, 1203, 1066, 1014 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.04 (d, J = 8.5 Hz, 1 H), 7.64 (d,
J = 7.0 Hz, 2 H), 7.50–7.47 (m, 2 H), 7.43–7.37 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 175.6, 139.4, 134.7, 134.3, 133.6,
133.2, 131.5, 131.2, 128.9, 127.4, 120.0, 94.6, 88.2.
Yield: 131.8 mg (95%); yellow solid; mp 74–76 °C.
IR (KBr): 1629, 1594, 1482, 1414, 1174, 762 cm–1.
MS (EI): m/z (%) = 276 (29) [M+ (37Cl)], 274 (37) [M+ (35Cl)], 246
(90), 129 (100).
1H NMR (500 MHz, CDCl3): δ = 8.51 (dd, J = 8.0, 1.5 Hz, 1 H),
7.70–7.66 (m, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.50–7.48 (m, 3 H),
7.41–7.37 (m, 3 H), 6.23 (s, 1 H), 4.0 (t, J = 7.5 Hz, 2 H), 1.64
(quint, J = 7.5 Hz, 2 H), 1.18–1.10 (m, 2 H), 0.74 (t, J = 7.5 Hz,
3 H).
13C NMR (125 MHz, CDCl3): δ = 177.5, 154.7, 140.7, 136.1, 132.3,
129.5, 128.8, 128.4, 127.4, 127.1, 123.6, 116.4, 112.9, 48.0, 30.8,
19.8, 13.5.
1-(2,4-Dichloro-5-fluorophenyl)-3-trimethylsilanylpropynone
(1j)25
A stirred mixture of [Pd(PPh3)2Cl2] (65.6 mg, 0.0934 mmol) and
CuI (35.6 mg, 0.1868 mmol) in THF (20 mL) was degassed. Et3N
(516.1 mg, 5.1 mmol), 2,4-dichloro-5-fluorobenzoyl chloride
(1061.4 mg, 4.67 mmol), and trimethylsilyl acetylene (500.9 mg,
5.1 mmol) were added and the reaction mixture was stirred for 1 h
at r.t. The solvents were evaporated under reduced pressure and the
MS (EI): m/z (%) = 277 (14) [M+], 149 (100).
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1798–1808

1804
J. Shao et al.
SPECIAL TOPIC
MS (EI): m/z (%) = 261 (63) [M+], 260 (100), 232 (32).
Octyl-2-phenyl-1H-quinolin-4-one (3ab)
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), octyl-1-amine (96.9 mg, 0.75 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 4 h gave 3ab.
Anal. Calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C,
82.62; H, 5.84; N, 5.29.
Cyclohexyl-2-phenyl-1H-quinolin-4-one (3af)20
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), cyclohexanamine (148.8 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 10 h gave 3af.
Yield: 156.7 mg (94%); white solid; mp 73–75 °C.
IR (KBr): 2954, 2930, 2850, 1620, 1595, 761 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.53 (dd, J = 8.0, 1.5 Hz, 1 H),
7.72–7.68 (m, 1 H), 7.56–7.50 (m, 4 H), 7.42–7.39 (m, 3 H), 6.25
(s, 1 H), 4.01 (t, J = 7.5 Hz, 2 H), 1.67 (quint, J = 7.0 Hz, 2 H),
1.26–1.12 (m, 10 H), 0.86 (t, J = 7.0 Hz, 3 H).
Yield: 80.1 mg (53%); white solid; mp 200–202 °C.
IR (KBr): 3443, 2936, 2849, 1627, 1592, 764 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.50 (dd, J = 8.0, 1.5 Hz, 1 H),
7.95 (d, J = 9.0 Hz, 1 H), 7.63–7.60 (m, 1 H), 7.49–7.47 (m, 3 H),
7.39–7.35 (m, 3 H), 6.21 (s, 1 H), 4.14 (tt, J = 7.5, 3.5 Hz, 1 H),
2.44–2.37 (m, 2 H), 1.86–1.79 (m, 4 H), 1.61–1.59 (m, 1 H), 1.24–
1.13 (m, 1 H), 1.03–0.94 (m, 2 H).
13C NMR (125 MHz, CDCl3): δ = 177.4, 155.8, 141.1, 137.4, 131.0,
129.5, 128.9, 128.2, 127.7, 127.2, 123.4, 119.0, 113.4, 63.6, 31.2,
26.6, 25.2.
13C NMR (125 MHz, CDCl3): δ = 177.4, 154.6, 140.7, 136.2, 132.2,
129.5, 128.8, 128.4, 127.5, 127.1, 123.6, 116.3, 112.9, 48.2, 31.7,
29.0, 28.8, 28.7, 26.5, 22.6, 14.2.
MS (EI): m/z (%) = 333 (34) [M+], 234 (100).
Anal. Calcd for C23H27NO: C, 82.84; H, 8.16; N, 4.20. Found: C,
82.68; H, 7.94; N, 4.14.
Dodecyl-2-phenyl-1H-quinolin-4-one (3ac)
MS (EI): m/z (%) = 303 (39) [M+], 221 (100).
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), dodecyl-1-amine (139.0 mg, 0.75 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 4 h gave 3ac.
1-(2-Hydroxyethyl)-2-phenyl-1H-quinolin-4-one (3ag)
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), 2-aminoethanol (36.7 mg, 0.75 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 2 h gave 3ag.
Yield: 156.7 mg (89%); white solid; mp 83–84 °C.
IR (KBr): 2952, 2917, 2850, 1620, 1595, 761 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.51 (dd, J = 8.0, 1.5 Hz, 1 H),
7.70–7.66 (m, 1 H), 7.53–7.46 (m, 4 H), 7.40–7.37 (m, 3 H), 6.22
(s, 1 H), 3.98 (t, J = 7.5 Hz, 2 H), 1.66–1.64 (m, 2 H), 1.29–1.09 (m,
18 H), 0.86 (t, J = 7.0 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.4, 154.6, 140.7, 136.2, 132.3,
129.5, 128.8, 128.4, 127.5, 127.1, 123.6, 116.3, 113.0, 48.2, 32.0,
29.7, 29.6, 29.5, 29.4, 29.3, 28.9, 28.7, 26.5, 22.8, 14.2.
Yield: 125.0 mg (94%); white solid; mp 218–220 °C.
IR (KBr): 3204, 2920, 2868, 1618, 1596, 1563, 1054 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 8.25 (dd, J = 8.0, 1.5 Hz, 1 H),
7.87 (d, J = 8.5 Hz, 1 H), 7.78–7.75 (m, 1 H), 7.55–7.50 (m, 5 H),
7.43 (t, J = 7.5 Hz, 1 H), 5.91 (s, 1 H), 4.88 (t, J = 5.5 Hz, 1 H), 4.17
(t, J = 6.5 Hz, 2 H), 3.54 (q, J = 6.5 Hz, 2 H).
13C NMR (125 MHz, DMSO-d6): δ = 175.5, 155.1, 140.7, 136.1,
132.2, 129.2, 128.63, 128.57, 126.8, 125.6, 123.4, 117.7, 111.7,
58.3, 49.4.
MS (EI): m/z (%) = 388 (78) [M+ – Me], 234 (100).
Anal. Calcd for C27H35NO: C, 83.24; H, 9.06; N, 3.60. Found: C,
83.22; H, 8.87; N, 3.49.
MS (EI): m/z (%) = 265 (48) [M+], 234 (100).
Isopropyl-2-phenyl-1H-quinolin-4-one (3ad)26
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), propan-2-amine (88.7 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 10.5 h gave 3ad.
Anal. Calcd for C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C,
76.70; H, 5.80; N, 5.38.
Benzyl-2-phenyl-1H-quinolin-4-one (3ah)20
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), benzylamine (80.4 mg, 0.75 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 2 h gave 3ah.
Yield: 91.9 mg (70%); white solid; mp 217–218 °C.
IR (KBr): 2975, 2936, 2878, 1628, 1596 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.52 (dd, J = 8.0, 1.5 Hz, 1 H),
7.82 (d, J = 8.5 Hz, 1 H), 7.64–7.61 (m, 1 H), 7.48–7.47 (m, 3 H),
7.39–7.35 (m, 3 H), 6.18 (s, 1 H), 4.71–4.62 (m, 1 H), 1.59 (d,
J = 7.5 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 177.3, 155.5, 140.2, 137.2, 131.1,
129.4, 129.0, 128.3, 127.8, 127.3, 123.4, 118.6, 113.2, 53.7, 21.5.
Yield: 149.3 mg (96%); white solid; mp 159–161 °C.
IR (KBr): 1629, 1600, 1546, 1484, 1467, 1418 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.51 (d, J = 8.0 Hz, 1 H), 7.52–
7.49 (m, 1 H), 7.44–7.41 (m, 1 H), 7.37–7.32 (m, 6 H), 7.30–7.23
(m, 3 H), 6.98 (d, J = 7.5 Hz, 2 H), 6.34 (s, 1 H), 5.27 (s, 2 H).
13C NMR (125 MHz, CDCl3): δ = 177.7, 155.1, 141.1, 136.4, 135.6,
132.4, 129.7, 129.0, 128.7, 128.1, 127.6, 127.2, 126.8, 125.5, 123.8,
117.3, 113.1, 52.2.
MS (EI): m/z (%) = 263 (90) [M+], 221 (100), 193 (60).
Cyclopropyl-2-phenyl-1H-quinolin-4-one (3ae)
MS (EI): m/z (%) = 311 (50) [M+], 91 (100).
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), cyclopropanamine (85.7 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 2 h gave 3ae.
2-Phenyl-1-propenyl-1H-quinolin-4-one (3ai)
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), allylamine (85.7 mg, 1.5 mmol) and K3PO4·3H2O (199.7
mg, 0.75 mmol) in DMSO for 4.5 h gave 3ai.
Yield: 115.1 mg (88%); white solid; mp 173–175 °C.
IR (KBr): 3485, 3384, 3313, 2925, 2854, 1613, 1594, 1554 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.40 (d, J = 8.0 Hz, 1 H), 7.95 (d,
J = 8.5 Hz, 1 H), 7.68 (t, J = 8.0 Hz, 1 H), 7.50–7.45 (m, 5 H), 7.37
(t, J = 7.0 Hz, 1 H), 6.30 (s, 1 H), 3.33 (t, J = 3.5 Hz, 1 H), 0.92 (d,
J = 6.0 Hz, 2 H), 0.54 (d, J = 3.5 Hz, 2 H).
13C NMR (125 MHz, CDCl3): δ = 178.3, 155.7, 143.2, 136.9, 131.8,
129.3, 128.6, 128.4, 126.7, 126.4, 123.7, 118.0, 113.3, 32.5, 13.0.
Yield: 95.3 mg (72%); yellow solid; mp 159–161 °C.
IR (KBr): 1629, 1600, 1546, 1484, 1467, 1418 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.47 (dd, J = 8.0, 1.0 Hz, 1 H),
7.63–7.60 (m, 1 H), 7.52–7.50 (m, 1 H), 7.44–7.35 (m, 6 H), 6.38
(dd, J = 7.0, 1.5 Hz, 1 H), 6.35 (s, 1 H), 5.76 (dq, J = 7.0, 1.5 Hz,
1 H), 1.28 (dd, J = 7.0, 1.5 Hz, 3 H).
Synthesis 2012, 44, 1798–1808
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of N-Alkyl-Substituted 4-Quinolones
Butyl-2-(4-fluorophenyl)-1H-quinolin-4-one (3da)
Following the same procedure used for 3aa with 1d (129.4 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 4 h gave 3da.
1805
13C NMR (125 MHz, CDCl3): δ = 178.1, 154.0, 141.1, 136.0, 132.3,
130.6, 129.4, 128.7, 128.1, 127.3, 126.6, 126.2, 123.9, 117.3, 112.4,
12.6.
MS (EI): m/z (%) = 261 (100) [M+].
Yield: 146.1 mg (98%); yellow solid; mp 99–101 °C.
Anal. Calcd for C18H15NO: C, 82.73; H, 5.79; N, 5.36. Found: C,
82.38; H, 5.79; N, 5.45.
IR (KBr): 2960, 2932, 2872, 1626, 1598, 1507, 1485, 1467, 1421,
844, 761 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.48 (dd, J = 8.0, 1.0 Hz, 1 H),
7.70–7.66 (m, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.40–7.36 (m, 3 H),
7.20–7.16 (m, 2 H), 6.20 (s, 1 H), 3.99 (t, J = 7.5 Hz, 2 H), 1.63
1,2-Diphenyl-1H-quinolin-4-one (3aj)11a
Following the same procedure used for 3aa with 1k (120.4 mg, 0.5
mmol), aniline (140.0 mg, 1.5 mmol) and K3PO4·3H2O (199.7 mg,
0.75 mmol) in DMSO for 11 h gave 3aj.
(quint, J = 7.5 Hz, 2 H), 1.19–1.12 (m, 2 H), 0.76 (t, J = 7.5 Hz,
3 H).
Yield: 11.5 mg (8%); yellow solid; mp 270–272 °C.
IR (KBr): 1628, 1594, 1403, 1310, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.52 (dd, J = 8.0, 1.5 Hz, 1 H),
7.49–7.46 (m, 1 H), 7.40–7.31 (m, 4 H), 7.21–7.14 (m, 7 H), 6.91
(d, J = 8.5 Hz, 1 H), 6.44 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 178.1, 154.1, 142.7, 139.2, 135.8,
132.0, 130.1, 129.7, 129.3, 129.0, 128.7, 128.0, 126.3, 126.2, 123.9,
118.2, 112.6.
13C NMR (125 MHz, CDCl3): δ = 177.3, 163.1 (d, JC–F
=
1
248.8 Hz), 153.5, 140.6, 132.3, 132.1 (d, 4JC–F = 3.75 Hz), 130.4 (d,
3JC–F = 8.75 Hz), 127.3, 127.1, 123.7, 116.3, 115.9 (d, JC–F
=
2
21.25 Hz), 113.1, 47.9, 30.8, 19.7, 13.4.
19F NMR (470 MHz, CDCl3): δ = –110.9 (s, Ar-F).
MS (EI): m/z (%) = 295 (50) [M+], 252 (100), 57 (100), 55 (80).
Anal. Calcd for C19H18FNO: C, 77.27; H, 6.14; N, 4.74. Found: C,
77.22; H, 6.11; N, 4.69.
MS (EI): m/z (%) = 297 (44) [M+], 149 (30), 105 (78), 55 (100).
Butyl-2-(4-methoxy-phenyl)-1H-quinolin-4-one (3ba)
Following the same procedure used for 3aa with 1b (135.0 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 3.5 h gave 3ba.
1-Butyl-2-(4-chlorophenyl)-1H-quinolin-4-one (3ea)
Following the same procedure used for 3aa with 1e (137.6 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 4 h gave 3ea.
Yield: 153.0 mg (99%); yellow solid; mp 129–131 °C.
Yield: 125.3 mg (80%); yellow solid; mp 112–113 °C.
IR (KBr): 2958, 2932, 2872, 2838, 1624, 1600, 1509, 1485, 1421,
1380, 840 cm–1.
IR (KBr): 2958, 2930, 2871, 1624, 1601, 1483, 1420, 1090, 840,
760 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.50 (dd, J = 8.0, 1.5 Hz, 1 H),
7.69–7.65 (m, 1 H), 7.53 (d, J = 8.5 Hz, 1 H), 7.39 (d, J = 8.0 Hz,
1 H), 7.36 (d, J = 0.5 Hz, 2 H), 7.32–7.29 (m, 2 H), 6.22 (s, 1 H),
4.04 (t, J = 7.5 Hz, 2 H), 3.87 (s, 3 H), 1.63 (quint, J = 7.5 Hz, 2 H),
1.19–1.11 (m, 2 H), 0.76 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.5, 160.4, 154.7, 140.8, 132.2,
129.8, 128.5, 127.4, 127.1, 123.6, 116.4, 114.2, 113.2, 55.5, 48.0,
30.9, 19.8, 13.6.
1H NMR (500 MHz, CDCl3): δ = 8.51 (dd, J = 8.0, 1.0 Hz, 1 H),
7.71–7.68 (m, 1 H), 7.54–7.52 (m, 1 H), 7.49–7.47 (m, 2 H), 7.42–
7.33 (m, 3 H), 6.19 (s, 1 H), 3.99 (t, J = 7.5 Hz, 2 H), 1.63 (quint,
J = 7.5 Hz, 2 H), 1.20–1.13 (m, 2 H), 0.78 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.4, 153.4, 140.7, 136.0, 134.6,
132.5, 129.9, 129.2, 127.5, 127.2, 123.8, 116.4, 113.1, 48.1, 30.9,
19.82, 13.6.
MS (EI): m/z (%) = 313 (21) [M+ (37Cl)], 311 (64) [M+ (35Cl)], 233
(100).
MS (EI): m/z (%) = 307 (87) [M+], 264 (100).
Anal. Calcd for C20H21NO2: C, 78.15; H, 6.89; N, 4.56. Found: C,
78.22; H, 6.82; N, 4.51.
Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.20; H, 5.81; N, 4.40.
Butyl-2-(4-ethylphenyl)-1H-quinolin-4-one (3ca)
1-Butyl-2-(3-chlorophenyl)-1H-quinolin-4-one (3fa)
Following the same procedure used for 3aa with 1f (137.6 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 2 h gave 3fa.
Following the same procedure used for 3aa with 1c (138.0 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 6 h gave 3ca.
Yield: 153.6 mg (98%); yellow solid; mp 90–91 °C.
Yield: 149.8 mg (96%); light-yellow solid; mp 124–126 °C.
IR (KBr): 2962, 2931, 2872, 1626, 1599, 1509, 1484, 1466, 1420,
1378, 840 cm–1.
IR (KBr): 3051, 2960, 2932, 2869, 1624, 1593, 1570, 1492, 1475,
1427, 779, 762, 742 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.49 (dd, J = 8.0, 1.0 Hz, 1 H),
7.68–7.64 (m, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.37 (t, J = 7.5 Hz,
1 H), 7.29 (AA′ of AA′BB′, J = 8.5 Hz, 2 H), 7.27 (BB′ of AA′BB′,
J = 9.0 Hz, 2 H), 6.22 (s, 1 H), 4.02 (t, J = 8.0 Hz, 2 H), 2.71 (q,
J = 8.0 Hz, 2 H), 1.62 (quint, J = 7.5 Hz, 2 H), 1.28 (t, J = 7.5 Hz,
3 H), 1.17–1.10 (m, 2 H), 0.735 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.5, 155.0, 145.8, 140.7, 133.4,
132.2, 128.4, 128.2, 127.4, 127.1, 123.5, 116.4, 112.9, 48.0, 30.8,
28.8, 19.7, 15.4, 13.5.
1H NMR (500 MHz, CDCl3): δ = 8.48 (d, J = 8.0 Hz, 1 H), 7.70–
7.66 (m, 1 H), 7.52 (d, J = 8.5 Hz, 1 H), 7.48–7.37 (m, 4 H), 7.28 (d,
J = 7.0 Hz, 1 H), 6.18 (s, 1 H), 3.98 (t, J = 7.8 Hz, 2 H), 1.65 (quint,
J = 7.5 Hz, 2 H), 1.21–1.13 (m, 2 H), 0.76 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.3, 152.9, 140.7, 137.8, 134.9,
132.4, 130.2, 129.8, 128.6, 127.5, 127.2, 126.7, 123.8, 116.3, 113.0,
48.1, 30.9, 19.8, 13.5.
MS (EI): m/z (%) = 313 (20) [M+ (37Cl)], 311 (54) [M+ (35Cl)], 233
(100).
MS (EI): m/z (%) = 305 (74) [M+], 234 (62), 149 (71), 133 (77), 57
(100).
Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.25; H, 5.85; N, 4.50.
Anal. Calcd for C21H23NO: C, 82.58; H, 7.59; N, 4.59. Found: C,
82.44; H, 7.53; N, 4.53.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1798–1808

1806
J. Shao et al.
SPECIAL TOPIC
2-(3-Chlorophenyl)-1-cyclopropyl-1H-quinolin-4-one (3fe)
Following the same procedure used for 3aa with 1f (137.6 mg, 0.5
mmol), cyclopropylamine (85.6 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 4 h gave 3fe.
IR (KBr): 2967, 2935, 2874, 2858, 1627, 1593, 1502, 1482, 1453,
1436, 770 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.43–8.40 (m, 1 H), 7.49–7.50 (m,
4 H), 7.38–7.32 (m, 3 H), 6.20 (q, J = 2.0 Hz, 1 H), 3.95 (t,
J = 8.0 Hz, 2 H), 1.66–1.62 (m, 2 H), 1.16–1.12 (m, 2 H), 0.77–
0.73 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 176.8, 155.0, 141.5, 138.7, 135.8,
129.7, 128.90, 128.88, 128.4, 125.9, 124.3, 116.2, 113.5, 48.1, 30.7,
19.7, 13.5.
Yield: 133.7 mg (91%); light-yellow solid; mp 173–175 °C.
IR (KBr): 3041, 1627, 1595, 1572, 1475, 753 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.39 (d, J = 8.0 Hz, 1 H), 7.94 (d,
J = 8.5 Hz, 1 H), 7.71–7.68 (m, 1 H), 7.52 (s, 1 H), 7.45–7.37 (m,
4 H), 6.26 (s, 1 H), 3.34 (tt, J = 7.0, 3.5 Hz, 1 H), 0.98 (d,
J = 6.5 Hz, 2 H), 0.57 (d, J = 3.5 Hz, 2 H).
MS (EI): m/z (%) = 313 (1) [M+ (37Cl)], 311 (2) [M+ (35Cl)], 230
13C NMR (125 MHz, CDCl3): δ = 178.2, 153.9, 143.1, 138.7, 134.6,
132.0, 130.0, 129.5, 128.5, 126.8, 126.6, 126.5, 123.8, 117.9, 113.5,
32.4, 13.1.
(93), 147 (100).
Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.49; H, 5.93; N, 4.67.
MS (EI): m/z (%) = 297 (18) [M+ (37Cl)], 295 (65) [M+ (35Cl)], 294
(100).
7-Chloro-1-cyclopropyl-2-phenyl-1H-quinolin-4-one (3ie)
Following the same procedure used for 3aa with 1i (137.6 mg, 0.5
mmol), cyclopropylamine (85.6 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 2 h gave 3ie.
Anal. Calcd for C18H14ClNO: C, 73.10; H, 4.77; N, 4.74. Found: C,
73.02; H, 4.88; N, 4.59.
Yield: 138.5 mg (94%); light-yellow solid; mp 212–214 °C.
IR (KBr): 3077, 3052, 3013, 1626, 1593, 1453, 1436 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.32 (d, J = 8.5 Hz, 1 H), 7.92 (d,
J = 1.5 Hz, 1 H), 7.51–7.46 (m, 5 H), 7.32 (dd, J = 8.5, 1.5 Hz,
1 H), 6.27 (s, 1 H), 3.29 (tt, J = 7.0, 3.5 Hz, 1 H), 0.95 (d,
J = 7.0 Hz, 2 H), 0.56 (d, J = 3.5 Hz, 2 H).
1-Butyl-2-(2-chlorophenyl)-1H-quinolin-4-one (3ga)
Following the same procedure used for 3aa with 1g (137.6 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 4 h gave 3ga.
Yield: 140.6 mg (90%); light-yellow solid; mp 140–143 °C.
IR (KBr): 2960, 2931, 2861, 1623, 1603, 1590, 1490, 1473, 1417,
1183, 754 cm–1.
13C NMR (125 MHz, CDCl3): δ = 177.5, 155.8, 143.9, 138.1, 136.6,
1H NMR (500 MHz, CDCl3): δ = 8.52–8.48 (m, 1 H), 7.69–7.65 (m,
1 H), 7.53–7.48 (m, 2 H), 7.45–7.36 (m, 4 H), 6.17 (s, 1 H), 4.10–
4.04 (m, 1 H), 3.74–3.70 (m, 1 H), 1.74–1.71 (m, 1 H), 1.52–1.48
(m, 1 H), 1.18–1.10 (m, 2 H), 0.76–0.70 (m, 3 H).
13C NMR (125 MHz, CDCl3): δ = 177.6, 151.3, 140.5, 134.9, 133.0,
132.4, 131.1, 130.7, 130.0, 127.5, 127.3, 127.1, 123.7, 116.3, 112.8,
47.8, 30.5, 19.8, 13.4.
129.4, 128.7, 128.3, 128.1, 125.2, 124.2, 117.7, 113.8, 32.5, 13.0.
MS (EI): m/z (%) = 297 (34) [M+ (37Cl)], 295 (99) [M+ (35Cl)], 294
(100).
Anal. Calcd for C18H14ClNO: C, 73.10; H, 4.77; N, 4.74. Found: C,
73.02; H, 4.77; N, 4.62.
7-Chloro-1-cyclopropyl-6-fluoro-1H-quinolin-4-one (3je)
Following the same procedure used for 3aa with 1j (144.7 mg, 0.5
mmol), cyclopropylamine (85.6 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 1 h gave 3je.
MS (EI): m/z (%) = 313 (35) [M+ (37Cl)], 311 (90) [M+ (35Cl)], 233
(100).
Anal. Calcd for C19H18ClNO: C, 73.19; H, 5.82; N, 4.49. Found: C,
73.54; H, 5.86; N, 4.63.
Yield: 72.2 mg (61%); yellow solid; mp 192–193 °C.
IR (KBr): 1633, 1611, 1589, 1541, 1479, 1289, 1260, 825 cm–1.
1-Butyl-2-pentyl-1H-quinolin-4-one (3ha)
1H NMR (500 MHz, CDCl3): δ = 8.03 (d, J = 6.0 Hz, 1 H), 7.94 (d,
J = 6.0 Hz, 1 H), 7.64 (d, J = 7.5 Hz, 1 H), 6.13 (d, J = 9.5 Hz, 1 H),
3.36 (tt, J = 7.0, 3.5 Hz, 1 H), 1.31–1.27 (m, 2 H), 1.06–1.03 (m,
2 H).
Following the same procedure used for 3aa with 1h (117.4 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 20 h gave 3ha.
Yield: 135.7 mg (88%); light-yellow solid; mp 52–54 °C.
1
13C NMR (125 MHz, CDCl3): δ = 176.6, 154.7 (d, JC–F
=
3
IR (KBr): 2957, 2930, 2870, 1628, 1599, 1487, 1467, 1427,
760 cm–1.
247.5 Hz), 142.9, 138.2, 126.6, 126.5 (d, JC–F = 5.0 Hz), 118.6,
112.6 (d, 2JC–F = 22.5 Hz), 109.6, 33.9, 8.3.
1H NMR (500 MHz, CDCl3): δ = 8.42 (dd, J = 8.0, 1.5 Hz, 1 H),
7.63–7.59 (m, 1 H), 7.45 (d, J = 8.5 Hz, 1 H), 7.31 (t, J = 7.5 Hz,
1 H), 6.23 (s, 1 H), 4.10 (t, J = 8.0 Hz, 2 H), 2.65 (t, J = 8.0 Hz,
2 H), 1.75–1.65 (m, 4 H), 1.51–1.32 (m, 6 H), 1.00 (t, J = 7.5 Hz,
3 H), 0.90 (t, J = 7.0 Hz, 3 H).
19F NMR (470 MHz, CDCl3): δ = –120.2 (m, Ar-F).
MS (EI): m/z (%) = 239 (31) [M+ (37Cl)], 237 (100) [M+ (35Cl)].
Anal. Calcd for C12H9ClFNO: C, 60.65; H, 3.82; N, 5.89. Found: C,
60.70; H, 3.90; N, 5.80.
13C NMR (125 MHz, CDCl3): δ = 177.7, 154.6, 141.0, 132.0, 127.0,
126.9, 123.2, 115.6, 111.1, 46.1, 34.0, 31.6, 31.0, 28.7, 22.4, 20.1,
14.0, 13.8.
One-Pot Stepwise Synthesis of 1,2-Diphenylquinolin-4(1H)-one
(3aj)11a
From 1-(2-Chlorophenyl)-3-phenylpropynone (1a): To an oven-
dried, capped tube, 1a (60.2 mg, 0.25 mmol), aniline (27.9 mg, 0.3
mmol) and DMSO (2.0 mL) were added and the reaction mixture
was stirred at 140 °C for 10 h and monitored by TLC. K3PO4·3H2O
(99.9 mg, 0.38 mmol) was added and the mixture was stirred for
10.5 h. Upon completion, the reaction mixture was washed with
H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic phase was washed with brine (2 × 10 mL) and dried over
Na2SO4. The solid was filtered off through a thin pad of Celite and
the filtrate was evaporated under vacuum to give the crude product
that was purified by column chromatography on silica gel (EtOAc–
PE, 1:1) to give 3aj.
MS (EI): m/z (%) = 271 (14) [M+], 200 (42), 79 (100), 57 (42).
Anal. Calcd for C18H25NO: C, 79.66; H, 9.28; N, 5.16. Found: C,
79.33; H, 9.16; N, 5.04.
1-Butyl-7-chloro-2-phenyl-1H-quinolin-4-one (3ia)
Following the same procedure used for 3aa with 1i (137.6 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 4.5 h gave 3ia.
Yield: 145.4 mg (94%); light-yellow solid; mp 63–65 °C.
Synthesis 2012, 44, 1798–1808
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Synthesis of N-Alkyl-Substituted 4-Quinolones
1807
Yield: 29.6 mg (41%); yellow solid; mp 270–272 °C.
IR (KBr): 1628, 1594, 1403, 1310, 701 cm–1.
1H NMR (500 MHz, CDCl3): δ = 8.52 (dd, J = 8.0, 1.5 Hz, 1 H),
7.49–7.46 (m, 1 H), 7.40–7.31 (m, 4 H), 7.21–7.14 (m, 7 H), 6.91
(d, J = 8.5 Hz, 1 H), 6.44 (s, 1 H).
13C NMR (125 MHz, CDCl3): δ = 178.1, 154.1, 142.7, 139.2, 135.8,
132.0, 130.1, 129.7, 129.3, 129.0, 128.7, 128.0, 126.3, 126.2, 123.9,
118.2, 112.6.
(2) For selected examples, see: (a) Li, L.; Wang, H.-K.; Kuo, S.-
C.; Wu, T.-S.; Lednicer, D.; Lin, C. M.; Hamel, E.; Lee, K.-
H. J. Med. Chem. 1994, 37, 1126. (b) Xia, Y.; Yang, Z.-Y.;
Xia, P.; Hackl, T.; Hamel, E.; Mauger, A.; Wu, J.-H.; Lee,
K.-H. J. Med. Chem. 2001, 44, 3932. (c) Hadjeri, M.; Peiller,
E.-L.; Beney, C.; Deka, N.; Lawson, M. A.; Dumontet, C.;
Boumendjel, A. J. Med. Chem. 2004, 47, 4964.
(3) For selected examples, see: (a) Llinàs-Brunet, M.; Bailey,
M. D.; Ghiro, E.; Gorys, V.; Halmos, T.; Poirier, M.;
Rancourt, J.; Goudreau, N. J. Med. Chem. 2004, 47, 6584.
(b) Lucero, B. d. A.; Gomes, C. R. B.; Frugulhetti, I. C. d. P.
P.; Faro, L. V.; Alvarenga, L.; de Souza, M. C. B. V.; de
Souza, T. M. L.; Ferreira, V. F. Bioorg. Med. Chem. Lett.
2006, 16, 1010. (c) Frutos, R. P.; Haddad, N.; Houpis, I. N.;
Johnson, M.; Smith-Keenan, L. L.; Fuchs, V.; Yee, N. K.;
Farina, V.; Faucher, A.-M.; Brochu, C.; Haché, B.; Duceppe,
J.-S.; Beaulieu, P. Synthesis 2006, 2563.
(4) For selected examples, see: (a) Nakamura, S.; Kozuka, M.;
Bastow, K. F.; Tokuda, H.; Nishino, H.; Suzuki, M.;
Tatsuzaki, J.; Morris, Natschke. S. L.; Kuo, S.-C.; Lee, K.-
H. Bioorg. Med. Chem. Lett. 2005, 13, 4396. (b) Dubar, F.;
Anquetin, G.; Pradines, B.; Dive, D.; Khalife, J.; Biot, C. J.
Med. Chem. 2009, 52, 7954. (c) Dubar, F.; Wintjens, R.;
Martins-Duarte, E. S.; Vommaro, R. C.; de Souza, W.; Dive,
D.; Pierrot, C.; Pradines, B.; Wohlkonig, A.; Khalife, J.;
Biot, C. Med. Chem. Commun. 2011, 2, 430.
(5) (a) Fouda, A. Synthesis of New 4-Quinolones of Expected
Anticancer Activity: Synthesis, Drug Design and Biological
Assay; Lap Lambert Academic Publishing: Germany, 2010.
For selected reviews, see: (b) Boteva, A.; Krasnykh, O.
Chem. Heterocycl. Compd. (Engl. Transl.) 2009, 45, 757.
(c) Mphahlele, M. J. J. Heterocycl. Chem. 2010, 47, 1.
(6) Ding, D.; Li, X.; Wang, X.; Du, Y.; Shen, J. Tetrahedron
Lett. 2006, 47, 6997.
MS (EI): m/z (%) = 297 (44) [M+], 149 (30), 105 (78), 55 (100).
From 1-(2-Bromophenyl)-3-phenylpropynone (1k): To an oven-
dried, capped tube, 1k (142.0 mg, 0.5 mmol), aniline (140.0 mg, 1.5
mmol) and DMSO (3.0 mL) were added and the reaction mixture
was stirred at 140 °C for 12 h and monitored by TLC. K3PO4·3H2O
(99.9 mg, 0.38 mmol) was added and the mixture was stirred for
13.5 h. Upon completion, the reaction mixture was washed with
H2O (5 mL) and extracted with EtOAc (3 × 10 mL). The combined
organic phase was washed with brine (2 × 10 mL) and dried over
Na2SO4. The solid was filtered off through a thin pad of Celite and
the filtrate was evaporated under vacuum to give the crude product
that was purified by column chromatography on silica gel (EtOAc–
PE, 1:1) to give 3aj; yield: 115.7 mg (78%).
3-Butylamino-1-(2-chlorophenyl)-3-phenylpropenone (4)20
Following the same procedure used for 3aa with 1a (120.4 mg, 0.5
mmol), butan-1-amine (109.5 mg, 1.5 mmol) and K3PO4·3H2O
(199.7 mg, 0.75 mmol) in DMSO for 3 min gave a mixture of 3aa
(21.2 mg, 16%) and 4 (126.9 mg, 81%) as a light-yellow oil.
IR (film): 3062, 2959, 2931, 2872, 1594, 1569, 1484, 1330, 1258,
1090, 755 cm–1.
1H NMR (500 MHz, CDCl3): δ = 11.23 (s, 1 H), 7.53–7.50 (m, 1 H),
7.44–7.38 (m, 5 H), 7.37–7.34 (m, 1 H), 7.28–7.23 (m, 2 H), 5.41
(s, 1 H), 3.26–3.24 (m, 2 H), 1.61–1.55 (m, 2 H), 1.41–1.33 (m,
2 H), 0.88 (t, J = 7.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 189.1, 166.9, 141.4, 135.3, 130.9,
130.2, 130.0, 129.6, 129.4, 128.6, 127.8, 126.6, 97.3, 44.7, 32.8,
20.0, 13.8.
(7) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani, M.; Larsen,
R. D.; Faul, M. M. Org. Lett. 2008, 10, 2609.
(8) Jones, C. P.; Anderson, K. W.; Buchwald, S. L. J. Org.
Chem. 2007, 72, 7968.
(9) For selected examples, see: (a) Haddad, N.; Tan, J.; Farina,
V. J. Org. Chem. 2006, 71, 5031. (b) Genelot, M.; Dufaud,
V.; Djakovitch, L. Tetrahedron 2011, 67, 976.
MS (EI): m/z (%) = 315 (2) [M+ (37Cl)], 313 (6) [M+ (35Cl)], 101
(100).
(10) (a) Coppola, G. M. J. Heterocycl. Chem. 1982, 19, 727.
(b) Yoshino, Y.; Kurahashi, T.; Matsubara, S. J. Am. Chem.
Soc. 2009, 131, 7494.
(11) (a) Zhao, T.; Xu, B. Org. Lett. 2010, 12, 212. (b) Sun, C.;
Xu, B. J. Org. Chem. 2008, 73, 7361. (c) Wang, C.; Sun, C.;
Weng, F.; Gao, M.; Liu, B.; Xu, B. Tetrahedron Lett. 2011,
52, 2984. (d) Ye, W.; Mo, J.; Zhao, T.; Xu, B. Chem.
Commun. 2009, 3246.
(12) Kanzian, T.; Nigst, T. A.; Maier, A.; Pichl, S.; Mayr, H. Eur.
J. Org. Chem. 2009, 6379.
(13) Hu, A.; You, T.; Tan, Y.; Wang, Y. Chin. J. Synth. Chem.
2006, 14, 640.
3aa from Intermediate 4
Following the same procedure used for 3aa with 4 (156.6 mg, 0.5
mmol) and K3PO4·3H2O (199.7 mg, 0.75 mmol) in DMSO for 2 h,
the reaction gave 3aa as a light-yellow solid (131.8 mg, 94%).
Acknowledgment
We thank the National Natural Science Foundation of China (No.
20972093), the Shanghai Municipal Education Commission (No.
10YZ06 and J50102) and the Science and Technology Commission
of Shanghai Municipality (No. 09ZR1412700) for financial sup-
port. We also thank Prof. Hongmei Deng (Laboratory for Mi-
crostructures, SHU) for NMR support and Prof. Qin Zhang
(Department of Chemistry, SHU) for spectra support.
(14) Reddy, P. G.; Baskaran, S. Tetrahedron Lett. 2001, 42, 6775.
(15) Audisio, D.; Messaoudi, S.; Peyrat, J.-F. O.; Brion, J.-D.;
Alami, M. J. Org. Chem. 2011, 76, 4995.
(16) Carr, R. M.; Sutherland, D. R. J. Labelled Compd.
Radiopharm. 1994, 34, 961.
(17) For selected examples, see: (a) Almeida, A. I. S.; Silva, A.
M. S.; Cavaleiro, J. A. S. Synlett 2010, 462. (b) Cross, R. M.;
Monastyrskyi, A.; Mutka, T. S.; Burrows, J. N.; Kyle, D. E.;
Manetsch, R. J. Med. Chem. 2010, 53, 7076.
(18) Venkataraman, S.; Barange, D. K.; Pal, M. Tetrahedron Lett.
2006, 47, 7317.
(19) (a) Hessian, K. O.; Flynn, B. L. Org. Lett. 2005, 8, 243.
(b) Cross, R. M.; Manetsch, R. J. Org. Chem. 2010, 75,
8654.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.onmorinfaItngonmSronfiuIttapo
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© Georg Thieme Verlag Stuttgart · New York
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