1,2-Disubstituted 4-quinolones via copper-catalyzed cyclization of 1-(2-halophenyl)-2-en-3-amin-1-ones

Article abstract of DOI:10.1055/s-0028-1087990

1,2-Disubstituted 4-quinolones have been prepared via copper-catalyzed heterocyclization of 1-(2-bromophenyl)- and 1-(2-chlorophenyl)-2-en-3-amin-1- ones, readily obtained from α,β-ynones and primary amines. The reaction tolerates a variety of useful functionalities including ester, keto, cyano, and chloro substituents. Quinolone derivatives can also be prepared via a sequential process from α,β-ynones and primary amines, omitting the isolation of the 1-(2-halophenyl)-2-en-3-amin-1-one intermediates. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087990

PAPER
1209
1,2-Disubstituted 4-Quinolones via Copper-Catalyzed Cyclization of
1-(2-Halophenyl)-2-en-3-amin-1-ones
C
opper-Catalyze
ob
Synthesis erta Bernini,a Sandro Cacchi,*b Giancarlo Fabrizi,b Alessio Sferrazzaa
a
Dipartimento A.B.A.C., Università degli Studi della Tuscia e Consorzio Universitario ‘La Chimica per l’Ambiente’,
Via S. Camillo De Lellis, 01100 Viterbo, Italy
b
Dipartimento di Chimica e Tecnologie del Farmaco, Università degli Studi ‘La Sapienza’, P.le A. Moro 5, 00185 Rome, Italy
Fax +39(06)49912780; E-mail: sandro.cacchi@uniroma1.it
Received 28 November 2008
Abstract: 1,2-Disubstituted 4-quinolones have been prepared via
copper-catalyzed heterocyclization of 1-(2-bromophenyl)- and 1-
(2-chlorophenyl)-2-en-3-amin-1-ones, readily obtained from a,b-
ynones and primary amines. The reaction tolerates a variety of use-
ful functionalities including ester, keto, cyano, and chloro substitu-
ents. Quinolone derivatives can also be prepared via a sequential
process from a,b-ynones and primary amines, omitting the isolation
of the 1-(2-halophenyl)-2-en-3-amin-1-one intermediates.
X
O
O
R2
N
R1
R2
HN
R1
1 X = Br, Cl
2
Key words: copper, catalysis, enaminones, 4-quinolones, cycliza-
tions
Scheme 2
plexity) have been shown to have positive cardiac
Because of their multifunctional character, 2-en-3-amin- effects10 and exhibit antimitotic,11 antiplatelet,12 and
1-ones are useful synthetic intermediates.1 They have antiviral13 activity. Despite the existence of a variety of
been used in a variety of intra-2 and intermolecular3 synthetic routes for the synthesis of the quinolone scaf-
reactions. A number of transition-metal-promoted4 and fold,14 the utility of 4-quinolone derivatives justifies ef-
-catalyzed2g,5 processes have also been described. Recent- forts to develop new and more versatile methods. In this
ly, we reported on the use of N-propargylic 2-en-3-amin- context, the transition-metal-catalyzed cyclization of
1-ones as common intermediates for the synthesis of readily available multifunctional precursors is a promis-
polysubstituted pyrroles and pyridines (Scheme 1).6
ing synthetic strategy.
Herein we report a simple approach to the preparation of
1,2-disubstituted 4-quinolones that is based on the copper-
catalyzed cyclization of readily available 1-(2-halophe-
nyl)-2-en-3-amin-1-ones 1 (Scheme 2). 1-(2-Bromophe-
nyl)- and 1-(2-chlorophenyl)-2-en-3-amin-1-ones 1 were
prepared by conjugate addition of primary amines to a,b-
ynones 3,5c obtained by Sonogashira cross-coupling of
terminal alkynes with commercially available 2-bromo-
and 2-chlorobenzoyl chlorides15 (Scheme 3).
R3
N
R2
O
O
CuBr
DMSO
Cs2CO3
DMSO
r.t.
R2
R1
R3
R2
O
60–80 °C
R1
R1
NH
N
H
R3
Scheme 1
Compounds 1 were always isolated as single isomers. The
Z stereochemistry of 1a (R1 = R2 = Ph) has been assigned
by NOESY experiments, which also showed the presence
Following this study, we decided to investigate the poten-
tial of 1-(2-halophenyl)-2-en-3-amin-1-ones 1 as building
blocks for the construction of the 4-quinolone skeleton 2
according to the intramolecular C–N bond-forming reac-
tion shown in Scheme 2.
X
O
X
O
[PdCl2(PPh3)2]
CuI, Et3N
Cl
R2
R2
4-Quinolone derivatives are abundant in many biological-
ly active compounds.7 Some of them have been investi-
gated as antiviral8 and antidiabetic9 agents. Compounds
containing the 3-unsubstituted 2-aryl-4-quinolone motif
(structurally similar to flavones with, in addition, a nitro-
gen group that is available for increasing molecular com-
THF, r.t.
80–95%
3
X
O
R1NH2
R2
HN
R1
MeOH, 80 °C, 1–4 h
80–95%
SYNTHESIS 2009, No. 7, pp 1209–1219
Advanced online publication: 06.03.2009
x
x
.
x
x
.2
0
0
9
1
DOI: 10.1055/s-0028-1087990; Art ID: Z26108SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 3

1210
R. Bernini et al.
PAPER
of an intramolecular hydrogen bond (N–H···O). That of prepared. No examples of 3-unsubstituted 4-quinolones
the other 1-(2-halophenyl)-2-en-3-amin-1-ones has been have been described.
assigned on the basis of these data.
Using the optimized conditions, we next explored the
We started our study by examining the conversion of 1a scope and generality of the process. Our preparative re-
(1, R1 = R2 = Ph; X = Br) into the corresponding quinolo- sults are summarized in Table 2. A variety of quinolone
ne derivative 2a (2, R1 = R2 = Ph) (Scheme 2) in the pres- products 2 containing neutral, electron-rich, and electron-
ence of copper(I) iodide16 and potassium carbonate. The poor aryl substituents could be isolated in high to excel-
influence of ligands and solvents on the reaction outcome lent yields. Alkyl substituents are also tolerated, but our
was investigated. Representative optimization experi- method shows some limitations with them. Indeed, enam-
ments are summarized in Table 1. Best results were ob- inones derived from primary alkylamines require a stron-
tained when the cyclization was carried out in the
Table 2 Synthesis of 1,2-Disubstituted 4-Quinolones 2 from 1-(2-
presence of copper(I) iodide (0.05 equiv), N,N¢-dimethyl-
ethylenediamine (DMEDA; 0.05 equiv), and potassium
carbonate (2 equiv) in dimethyl sulfoxide at 80 °C
(Table 1, entry 8). Compound 2a was isolated in only 40%
yield when the reaction was carried out under the same
conditions, but in the absence of copper(I) iodide and
N,N¢-dimethylethylenediamine (Table 1, entry 9). There
are examples in the literature of cyclizations promoted by
the base of related enaminones. However, higher reaction
temperatures (110 °C)14e,h and/or stronger bases (NaO-
Et,14c t-BuOK,14d NaH14f) are usually required. In addi-
tion, fused 4-quinolones14c,f,h or quinolone derivatives
bearing ethoxycarbonyl or cyano groups at C-314e,f,h,i were
Bromophenyl)-2-en-3-amin-1-ones 1a
Entry R1
R2
1
Time 2 Yieldb
(X = Br) (h) (%)
1
2
Ph
Ph
Ph
Ph
Ph
1a
1b
1c
1d
1e
1f
2.5 2a 93
1.5 2b 92
2c 89
1.5 2d 87
3-F3CC6H4
4-MeOC6H4
4-AcC6H4
3
2
4
5
4-chloro-1-naphthyl Ph
2
2
2e 92
2f 82
6
4-NCC6H4
2,4-F2C6H3
Ph
Ph
7
1g
1h
1i
1.5 2g 72
Table 1 The Influence of Ligands and Solvents on the Copper-
Catalyzed Cyclization of 1a to Quinolone Derivative 2aa,b
8
3,4,5-(MeO)3C6H2 Ph
2
2
1
1
2
5
2h 81
2i 91
2j 86c
2k 53c
2l 36c
2m –c,d
9
4-ClC6H4
n-Bu
Ph
Entry Ligand
Solvent
Time
(h)
Yieldc
(%) of 2a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph
1j
1
2
1,10-phenanthroline DMF
8
60
Bn
Ph
1k
1l
Cy
Ph
DMF
DMF
48
72d
CO2H
NH2
N
t-Bu
Ph
1m
1n
1o
1p
H
3-MeOC6H4
4-Tol
4-ClC6H4
4-ClC6H4
4-ClC6H4
2.5 2n 87
1.5 2o 85
3
4
6
4
69
78
NH2
4-FC6H4
4-MeO2CC6H4
3-F3CC6H4
4-FC6H4
4-ClC6H4
4-MeOC6H4
Ph
2
2p 87
3-MeOC6H4 1q
3-MeOC6H4 1r
3-MeOC6H4 1s
2.5 2q 75
2.5 2r 72
DMF
NH2
NH2
4
2
2s 83
2t 81
5
6
7
8
9
TMEDA
DMEDA
DMEDA
DMEDA
–
DMF
4
6
79
82
4-AcC6H4
4-AcC6H4
(CH2)4Me
(CH2)4Me
1t
DMF
e
1u
1v
1w
2.5 2u 70
dioxane
DMSO
DMSO
12
2.5
2.5
–
c,e
–
–
2v
–
93
4-MeOC6H4
2w –c,f
40f
a See Scheme 2 for structures of 1 (X = Br) and 2. Reagents and con-
ditions: 1 (0.25 mmol), CuI (0.05 equiv), DMEDA (0.05 equiv),
K2CO3 (2 equiv), DMSO (2.5 mL), 80 °C.
a See Scheme 2; Starting material enaminone 1a (1, R1 = R2 = Ph;
X = Br); product quinolone 2a (2, R1 = R2 = Ph).
b Reagents and conditions: 1a (0.25 mmol), CuI (0.05 equiv), ligand
(0.05 equiv), K2CO3 (2 equiv), solvent (2.5 mL), 80 °C.
c Yields of isolated products.
b Yields of isolated products.
c t-BuONa (2 equiv) was used instead of K2CO3.
d Starting material 1m was recovered in 90% yield.
e Starting material 1v was recovered in 92% yield.
f Starting material 1w was recovered in 91% yield.
d Proline (0.1 equiv) was used.
e The starting material was recovered in 95% yield.
f In the absence of CuI and DMEDA.
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Quinolone Synthesis
1211
ger base (Table 2, entries 10–12). In addition, the
bulkiness of the alkyl substituent appears to have a detri-
mental effect on the cyclization process: with the N-cyclo-
hexyl derivative 1l, the desired quinolone was isolated in
low yield (Table 2, entry 12), while the starting enone
with the N-tert-butylamino group was recovered in almost
quantitative yield (Table 2, entry 13). No quinolone
formed from enaminones containing 3-alkyl substituents
(Table 2, entries 22 and 23).
1. PhNH2
O
Br
O
MeOH, 80 °C, 1 h
2. CuI, K2CO3, DMEDA
DMSO, 80 °C, 3 h
Ph
N
Ph
2a 88%
Ph
Scheme 4
observations on related copper-catalyzed heterocycliza-
tions involving Caromatic–X bonds,19 a plausible mecha-
nism for this quinolone ring formation begins with the
initial coordination of nitrogen to copper (Scheme 5). The
resulting complex A undergoes an oxidative addition of
the C–X bond to copper to afford the Cu(III) intermediate
B. Subsequent reductive elimination releases the product
with concomitant regeneration of the Cu(I) species.
1-(2-Chlorophenyl)-2-en-3-amin-1-ones can also be used
for this synthesis under the same conditions. Reaction
rates are lower, but yields are equally high to excellent, at
least with the examples that we tested (Table 3).
Table 3 Synthesis of 1,2-Disubstituted 4-Quinolones 2 from 1-(2-
Chlorophenyl)-2-en-3-amin-1-ones 1a
Entry R1
R2
1
Time
2
Yieldb
(%)
(X = Cl) (h)
O
1
2
3
4
5
Ph
Ph
Ph
Ph
Ph
Ph
1x
6
7
3
3
3
2a
2c
2d
2i
95
83
83
92
89c
X
4-MeOC6H4
4-AcC6H4
4-ClC6H4
n-Bu
1y
O
N
R
Ar
1z
2
HN
R
CuI
Ar
1za
1zb
B
O
1
2j
BH
a See Scheme 2 for structures of 1 (X = Cl) and 2. Reagents and con-
ditions: 1 (0.25 mmol), CuI (0.05 equiv), DMEDA (0.05 equiv),
K2CO3 (2 equiv), DMSO (2.5 mL), 80 °C.
CuIII
O
O
X
N
Ar
R
CuI
b Yields of isolated products.
B
X
CuI
X
c t-BuONa (2 equiv) was used instead of K2CO3.
Ar
Ar
N
N
R
R
A
To make this overall approach to 4-quinolones more at-
tractive from a synthetic point of view, we explored their
formation through a process that would omit the isolation
of the enaminone intermediates. Adding dimethyl sulfox-
ide and the reagents required for the cyclization step to the
crude methanolic mixture resulting from the reaction of
the primary amine and the a,b-ynone led to moderate
yields. For example, 2a was isolated in only 47% overall
yield when this protocol was used (in comparison with the
87% overall yield in the stepwise process). In addition, no
quinolone product was formed when the overall process
was carried out with methanol or dimethyl sulfoxide as
the sole solvent for the two steps. Control experiments
revealed that the cyclization does not proceed in methanol
and that the enaminone product is formed in low yields in
dimethyl sulfoxide. Finally, we found that excellent re-
sults could be obtained if dimethyl sulfoxide, copper(I)
iodide, N,N¢-dimethylethylenediamine, and potassium
carbonate are added to the crude mixture derived from the
reaction of primary amines with a,b-ynones after evapo-
ration of the volatile materials. Under these conditions, 2a
was isolated in 88% overall yield (Scheme 4).
Scheme 5
To sum up, an efficient approach to the construction of the
3-unsubstituted 1,2-disubstituted 4-quinolone skeleton
from readily available 1-(2-bromophenyl)- and 1-(2-chlo-
rophenyl)-2-en-3-amin-1-ones has been developed. The
new method tolerates a variety of useful functionalities in-
cluding ester, keto, cyano, and chloro substituents. In ad-
dition, quinolones can be prepared from a,b-ynones and
primary amines by a sequential process that omits the iso-
lation of the 1-(2-halophenyl)-2-en-3-amin-1-one inter-
mediates. Since 3-unsubstituted 1,2-disubstituted 4-
quinolones are essentially formed by assembling 2-ha-
loaroyl chlorides, terminal alkynes, and primary amines, a
wide variety of quinolone derivatives can be synthesized
by this protocol, which could be particularly useful for the
preparation of libraries.
Melting points were determined on a Büchi B-545 apparatus and are
uncorrected. All the reagents and solvents are commercially avail-
able and were used as purchased, without further purification. The
1-(2-halophenyl)-2-en-3-amin-1-ones and 1,2-disustituted 4-quino-
lones were purified on axially compressed columns, packed with
silica gel (25–40 mm, Macherey Nagel), connected to a Gilson sol-
vent delivery system and to a Gilson refractive index detector, and
were eluted with n-hexane–EtOAc mixtures. 1H NMR (400.13
On the basis of the recently reported tendency of N-aryl-
enaminones to coordinate to palladium(II) electrophiles,17
the lack of reactivity of the bromo substituent at the 4-po-
sition under copper-catalyzed conditions,18 and previous
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York

1212
R. Bernini et al.
PAPER
MHz), 13C NMR (100.6 MHz), and 19F NMR (376.5 MHz) spectra
were recorded on a Bruker Avance 400 spectrometer. IR spectra
were recorded on a JASCO FT/IR-430 spectrophotometer. Mass
spectra were determined on a QP2010 Gas Chromatograph Mass
spectrometer (EI) and a Thermo Finnigan LXQ spectrometer (ESI).
13C NMR (100 MHz, CDCl3): d = 192.4, 160.7, 142.7, 140.0, 134.7,
133.6, 131.3 (q, JCF = 32 Hz), 130.9, 130.3, 129.4, 129.3, 128.9,
128.4, 127.4, 126.1, 123.6 (q, JCF = 271 Hz), 120.7 (q, JCF = 4 Hz),
119.8 (q, JCF = 4 Hz), 119.5, 101.8.
Anal. Calcd for C22H15BrF3NO: C, 59.31; H, 3.39. Found: C, 59.21;
H, 3.21.
1-(2-Bromophenyl)-3-phenylprop-2-yn-1-one; Typical Proce-
dure for the Preparation of an a,b-Ynone 3
(Z)-1-(2-Bromophenyl)-3-(4-methoxyanilino)-3-phenylprop-2-
en-1-one (1c)
Yield: 94% (1 h); mp 150–151 °C; yellow-orange solid.
A mixture of 2-bromobenzoyl chloride (264 mg, 1.2 mmol),
[PdCl2(PPh3)2] (14 mg, 0.02 mmol), and Et3N (167 mL, 1.2 mmol)
in anhyd THF (4 mL) was stirred for 10 min under argon at r.t. CuI
(7.6 mg, 0.04 mmol) was added and the reaction mixture was stirred
for other 10 min before ethynylbenzene (102.2 mg, 1.0 mmol) was
added. After 2 h at r.t., the reaction mixture was diluted with EtOAc
(50 mL) and washed with 0.1 N HCl (2 × 10 mL) and a sat. NH4Cl
soln (10 mL). The organic phase was separated, dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue was
purified by chromatography (silica gel, n-hexane–EtOAc, 95:5);
this gave 1-(2-bromophenyl)-3-phenylprop-2-yn-1-one.
IR (KBr): 3433, 1589, 1566, 1512, 1479, 1458, 1321, 1246, 1033
cm–1.
1H NMR (400 MHz, CDCl3): d = 12.64 (s, 1 H), 7.62 (d, J = 8.0 Hz,
1 H), 7.55 (dd, J = 7.6, 1.2 Hz, 1 H), 7.39–7.24 (m, 7 H), 6.80 (d,
J = 8.9 Hz, 2 H), 6.70 (d, J = 8.9 Hz, 2 H), 5.72 (s, 1 H), 3.74 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 191.3, 162.1, 156.8, 143.1, 135.3,
133.5, 132.2, 130.5, 129.8, 129.4, 128.6, 128.5, 127.3, 125.2, 119.6,
114.1, 99.9, 55.4.
Yield: 231 mg (81%); orange oil.
IR (KBr): 2931, 2861, 1644 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.09 (dd, J = 7.7, 1.8 Hz, 1 H),
7.72 (dd, J = 7.8, 1.2 Hz, 1 H), 7.68–7.65 (m, 2 H), 7.52–7.39 (m, 5
Anal. Calcd for C22H18BrNO2: C, 64.72; H, 4.44. Found: C, 64.81;
H, 4.31.
(Z)-3-(4-Acetylanilino)-1-(2-bromophenyl)-3-phenylprop-2-en-
1-one (1d)
Yield: 91% (12 h); mp 154–155 °C; yellow solid.
H).
13C NMR (100 MHz, CDCl3): d = 177.6, 137.6, 135.0, 133.4, 133.2,
132.8, 131.1, 128.8, 127.5, 121.3, 120.0, 94.3, 88.0.
MS: m/z (%) = 285 [M+] (25), 199 (21), 157 (35), 115 (38), 105
(100).
IR (KBr): 3448, 1676, 1587, 1562, 1317, 1296, 1266, 758, 704
cm–1.
1H NMR (400 MHz, CDCl3): d = 12.58 (s, 1 H), 7.75 (d, J = 8.6 Hz,
2 H), 7.62 (d, J = 7.8 Hz, 1 H), 7.54 (dd, J = 7.6, 1.5 Hz, 1 H), 7.45–
7.34 (m, 6 H), 7.26 (m, 1 H), 6.82 (d, J = 8.6 Hz, 2 H), 5.86 (s, 1 H),
2.51 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 196.8, 192.5, 160.0, 143.8, 142.6,
135.0, 133.6, 132.6, 131.0, 130.4, 129.4, 128.9, 128.5, 128.3, 127.4,
122.1, 119.5, 102.7, 26.4.
Anal. Calcd for C15H9BrO: C, 63.18; H, 3.18. Found: C, 63.09; H,
3.01.
1-(2-Halophenyl)-2-en-3-amin-1-ones 1a–z,za,zb; General Pro-
cedure
An oven-dried Schlenk tube was charged with the appropriate 1-(2-
halophenyl)-a,b-ynone 3 (1 mmol), the substituted amine (1 mmol),
and anhyd MeOH (1 mL). The tube was sealed and stirred at 80 °C
for the period of time indicated below for each product 1. Then the
reaction mixture was cooled to r.t., the solvent was evaporated, and
the residue was purified by chromatography (silica gel, n-hexane–
EtOAc).
Anal. Calcd for C23H18BrNO2: C, 65.73; H, 4.32. Found: C, 65.65;
H, 4.41.
(Z)-1-(2-Bromophenyl)-3-[(4-chloro-1-naphthyl)amino]-3-phe-
nylprop-2-en-1-one (1e)
Yield: 95% (3 h); mp 140–141 °C; yellow solid.
IR (KBr): 3448, 1591, 1560, 1479, 1311, 1082, 766 cm–1.
3-Anilino-1-(2-bromophenyl)-3-phenylprop-2-en-1-one (1a)
Yield: 94% (4 h); mp 118–119 °C; pale yellow solid.
IR (KBr): 3448, 1608, 1587, 1569, 1479, 1325, 758, 698 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.66 (s, 1 H), 7.64 (d, J = 8.0 Hz,
1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.42–7.31 (m, 6 H), 7.26 (t, J = 7.7
Hz, 1 H), 7.17 (t, J = 7.6 Hz, 2 H), 7.04 (t, J = 7.4 Hz, 1 H), 6.85 (d,
J = 8.0 Hz, 2 H), 5.78 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 191.7, 161.5, 143.1, 139.3, 135.3,
133.6, 130.6, 129.9, 129.4, 128.8, 128.6, 128.5, 127.3, 124.5, 123.5,
119.6, 100.8.
1H NMR (400 MHz, CDCl3): d = 13.09 (s, 1 H), 8.47 (m, 1 H), 8.30
(d, J = 7.6 Hz, 1 H), 7.71–7.63 (m, 4 H), 7.41–7.22 (m, 8 H), 6.64
(d, J = 8.0 Hz, 1 H), 5.99 (s, 1H).
13C NMR (100 MHz, CDCl3): d = 192.1, 162.5, 142.7, 135.1, 134.6,
133.5, 131.1, 130.7, 129.9, 129.5, 129.4, 128.7, 128.6, 128.1, 127.6,
127.6, 127.3, 125.3, 125.0, 122.8, 122.4, 119.5, 101.6.
Anal. Calcd for C25H17BrClNO: C, 64.89; H, 3.70. Found: C, 64.75;
H, 3.51.
Anal. Calcd for C21H16BrNO: C, 66.68; H, 4.26. Found: C, 66.79;
H, 4.21.
(Z)-1-(2-Bromophenyl)-3-(4-cyanoanilino)-3-phenylprop-2-en-
1-one (1f)
Yield: 85% (9 h); mp 133–134 °C; yellow solid.
IR (KBr): 3433, 2220, 1593, 1516, 1024 cm–1.
(Z)-1-(2-Bromophenyl)-3-phenyl-3-[3-(trifluoromethyl)anili-
no]prop-2-en-1-one (1b)
Yield: 94% (4 h); mp 57–58 °C; pale yellow solid.
IR (KBr): 3435, 1585, 1315, 1271, 1167, 1113, 1068 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.65 (s, 1 H), 7.64 (dd, J = 8.0,
0.7 Hz, 1 H), 7.56 (dd, J = 7.6, 1.6 Hz, 1 H), 7.43–7.34 (m, 6 H),
7.29–7.26 (m, 3 H), 7.06 (s, 1 H), 6.99–6.96 (m, 1 H), 5.86 (s, 1 H).
1H NMR (400 MHz, CDCl3): d = 12.53 (s, 1 H), 7.63 (d, J = 7.5 Hz,
1 H), 7.54 (d, J = 7.2 Hz, 1 H), 7.45–7.40 (m, 8 H), 7.28 (m, 1 H),
6.82 (d, J = 7.9 Hz, 2 H), 5.90 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 192.8, 159.4, 143.7, 142.4, 134.6,
133.7, 132.9, 131.1, 130.6, 129.4, 129.1, 128.2, 127.5, 122.5, 119.5,
118.8, 106.7, 103.4.
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Quinolone Synthesis
1213
Anal. Calcd for C22H15BrN2O: C, 65.52; H, 3.75. Found: C, 65.61;
H, 3.81
(Z)-3-(Benzylamino)-1-(2-bromophenyl)-3-phenylprop-2-en-1-
one (1k)
Yield: 96% (1 h); pale yellow wax.
(Z)-1-(2-Bromophenyl)-3-(2,4-difluoroanilino)-3-phenylprop-
2-en-1-one (1g)
Yield: 100% (6 h); mp 146–147 °C; yellow solid.
IR (neat): 3423, 3027, 1589, 1560, 1483, 1334, 758, 696 cm–1.
1H NMR (400 MHz, CDCl3): d = 11.52 (s, 1 H), 7.60 (d, J = 8.0 Hz,
1 H), 7.52 (dd, J = 7.6, 1.4 Hz, 1 H), 7.46–7.43 (m, 5 H), 7.38–7.27
(m, 6 H), 7.21 (t, J = 8.3 Hz, 1 H), 5.51 (s, 1 H), 4.48 (d, J = 6.4 Hz,
2 H)
13C NMR (100 MHz, CDCl3): d = 190.6, 166.7, 143.2, 138.1, 134.9,
133.3, 130.1, 129.7, 129.2, 128.7, 128.5, 127.8, 127.5, 127.1, 126.9,
119.5, 97.8, 48.5
IR (KBr): 3448, 1608, 1593, 1568, 1520, 1475, 1315, 1259, 1194,
850, 744 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.33 (s, 1 H), 7.63 (d, J = 7.9 Hz,
1 H), 7.55 (dd, J = 7.6, 1.6 Hz, 1 H), 7.41–7.31 (m, 6 H), 7.26 (dt,
J = 7.7, 1.6 Hz, 1 H), 6.81 (m, 1 H), 6.72–6.60 (m, 2 H), 5.85 (s, 1
H).
13C NMR (100 MHz, CDCl3): d = 192.2, 161.7, 159.6 (dd,
JCF = 250, 11 Hz), 155.5 (dd, JCF = 240, 12 Hz), 142.8, 134.9,
133.6, 130.8, 130.1, 129.4, 128.6, 128.2, 127.4, 126.7 (dd, JCF = 10,
2 Hz), 124.1 (dd, JCF = 12, 4 Hz), 119.5, 111.0 (dd, JCF = 22, 4 Hz),
104.5 (d, JCF = 2.6 Hz), 104.5 (d, JCF = 50 Hz), 101.3.
Anal. Calcd for C22H18BrNO: C, 67.36; H, 4.62. Found: C, 67.29;
H, 4.51.
(Z)-1-(2-Bromophenyl)-3-(cyclohexylamino)-3-phenylprop-2-
en-1-one (1l)
Yield: 95% (5 h); pale yellow wax.
Anal. Calcd for C21H14BrF2NO: C, 60.89; H, 3.41. Found: C, 60.71;
H, 3.28.
IR (neat): 3448, 2927, 2852, 1568, 1485, 1333, 756 cm–1.
1H NMR (400 MHz, CDCl3): d = 11.21 (d, J = 8.6 Hz, 1 H), 7.57 (d,
J = 7.9 Hz, 1 H), 7.51–7.42 (m, 6 H), 7.29 (t, J = 7.6 Hz, 1 H), 7.18
(t, J = 7.6 Hz, 1 H), 5.34 (s, 1 H), 3.35 (m, 1 H), 1.86 (m, 2 H), 1.75
(m, 2 H), 1.47 (m, 2 H), 1.22 (m, 4 H).
(Z)-1-(2-Bromophenyl)-3-phenyl-3-(3,4,5-trimethoxyanili-
no)prop-2-en-1-one (1h)
Yield: 89% (1 h); mp 144–145 °C; yellow solid.
13C NMR (100 MHz, CDCl3): d = 189.8, 165.8, 143.5, 135.7, 133.3,
130.0, 129.5, 129.3, 128.5, 127.6, 127.1, 119.6, 97.3, 53.1, 34.3,
25.3, 24.5.
IR (KBr,): 3432, 1569, 1508, 1317, 1235, 1129 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.64 (s, 1 H), 7.62 (d, J = 7.8 Hz,
1 H), 7.54 (d, J = 7.1 Hz, 1 H), 7.45–7.40 (m, 6 H), 7.25 (t, J = 7.5
Hz, 1 H), 6.04 (s, 2 H), 5.74 (s, 1 H), 3.78 (s, 3 H), 3.58 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 191.5, 161.2, 153.0, 142.8, 135.5,
134.8, 134.8, 133.5, 130.5, 129.7, 129.2, 128.5, 128.3, 127.2, 119.4,
100.8, 100.4, 60.9, 55.8.
Anal. Calcd for C21H22BrNO: C, 65.63; H, 5.77. Found: C, 65.70;
H, 5.82.
(Z)-1-(2-Bromophenyl)-3-(tert-butylamino)-3-phenylprop-2-
en-1-one (1m)
Anal. Calcd for C24H22BrNO4: C, 61.55; H, 4.73. Found: C, 61.51;
H, 4.58.
Yield: 66% (5 h); pale yellow wax.
IR (neat): 3413, 2966, 1589, 1344, 754 cm–1.
1H NMR (400 MHz, CDCl3): d = 11.51 (s, 1 H), 7.56 (d, J = 7.9 Hz,
1 H), 7.48 (dd, J = 7.5, 1.6 Hz, 1 H), 7.41 (m, 5 H), 7.28 (m, 1 H),
7.17 (dt, J = 7.7, 1.5 Hz, 1 H), 5.22 (s, 1 H), 1.26 (s, 9 H).
13C NMR (100 MHz, CDCl3): d = 189.5, 166.9, 143.5, 137.2, 133.3,
130.0, 129.0, 128.2, 127.9, 127.1, 119.5, 99.1, 54.4, 31.8.
(Z)-1-(2-Bromophenyl)-3-(4-chloroanilino)-3-phenylprop-2-en-
1-one (1i)
Yield: 98% (3 h); mp 140–141 °C; yellow solid.
IR (KBr) 3435, 1604, 1587, 1558, 1502, 1475, 1309, 1292, 1211,
764, 754 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.58 (s, 1 H), 7.63 (d, J = 7.5 Hz,
1 H), 7.55 (d, J = 7.3 Hz, 1 H), 7.37–7.25 (m, 7 H), 7.11 (d, J = 7.2
Hz, 2 H), 6.76 (d, J = 7.2 Hz, 2 H), 5.80 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 192.0, 161.0, 142.8, 138.0, 134.9,
133.6, 130.8, 130.1, 129.8, 129.4, 128.9, 128.8, 128.5, 127.4, 124.6,
119.6, 101.3.
Anal. Calcd for C19H20BrNO: C, 63.70; H, 5.63. Found: C, 63.80;
H, 5.52.
(Z)-1-(2-Bromophenyl)-3-(4-chlorophenyl)-3-(3-methoxyanili-
no)prop-2-en-1-one (1n)
Yield: 92% (2 h); mp 84–85 °C; yellow solid.
IR (KBr): 3448, 1595, 1558, 1313, 746 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.51 (s, 1 H), 7.64 (d, J = 8.0 Hz,
1 H), 7.54 (dd, J = 7.6, 1.5 Hz, 1 H), 7.40–7.25 (m, 6 H), 7.08 (m, 1
H), 6.62 (dd, J = 15.0, 2.2 Hz, 1 H), 6.41 (m, 2 H), 5.74 (s, 1 H),
3.67 (m, 3 H).
Anal. Calcd for C21H15BrClNO: C, 61.11; H, 3.66. Found: C, 61.21;
H, 3.61.
(Z)-1-(2-Bromophenyl)-3-(butylamino)-3-phenylprop-2-en-1-
one (1j)
13C NMR (100 MHz, CDCl3): d = 191.9, 160.0, 159.9, 142.8, 140.2,
136.0, 133.9, 133.6, 130.7, 129.8, 129.6, 129.3, 128.9, 127.4, 119.5,
116.0, 110.8, 109.1, 101.0, 55.2.
Yield: 100% (1 h); pale yellow oil.
IR (neat): 3060, 2958, 2929, 2871, 1567, 1484, 1330, 754, 701 cm–1.
1H NMR (400 MHz, CDCl3): d = 11.21 (br s, 1 H), 7.57 (d, J = 7.9
Hz, 1 H), 7.50–7.41 (m, 6 H), 7.30 (t, J = 8.3 Hz, 1 H), 7.18 (dt,
J = 7.4, 1.3 Hz, 1 H), 5.37 (s, 1 H), 3.25 (q, J = 6.5 Hz, 2 H), 1.58
(m, 2 H), 1.38 (m, 2 H), 0.89 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.1, 166.9, 143.5, 135.3, 133.3,
130.0, 129.6, 129.3, 128.5, 127.8, 127.1, 119.6, 97.0, 44.7, 32.8,
19.9, 13.7.
Anal. Calcd for C22H17BrClNO2: C, 59.68; H, 3.87. Found: C,
59.79; H, 3.99.
(Z)-1-(2-Bromophenyl)-3-(4-chlorophenyl)-3-(4-toluidi-
no)prop-2-en-1-one (1o)
Yield: 99% (2 h); mp 148–149 °C; pale yellow solid.
IR (KBr): 3448, 1591, 1554, 1477, 1319, 1205, 756 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.54 (s, 1 H), 7.63 (dd, J = 8.5,
0.8 Hz, 1 H), 7.54 (dd, J = 8.4, 1.6 Hz, 1 H), 7.40–7.24 (m, 6 H),
Anal. Calcd for C19H20BrNO: C, 63.70; H, 5.63. Found: C, 63.51;
H, 5.51.
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York

1214
R. Bernini et al.
PAPER
6.99 (d, J = 8.1 Hz, 2 H), 6.74 (d, J = 8.2 Hz, 2 H), 5.71 (s, 1 H),
2.29 (s, 3 H).
Anal. Calcd for C22H17BrFNO2: C, 61.99; H, 4.02. Found: C, 62.11;
H, 3.81.
13C NMR (100 MHz, CDCl3): d = 191.6, 160.3, 143.0, 136.4, 135.9,
134.6, 133.9, 133.5, 130.6, 129.9, 129.6, 129.3, 128.9, 127.3, 123.7,
119.5, 110.4, 20.9.
(Z)-3-(3-Acetylphenyl)-1-(2-bromophenyl)-3-(4-chloroanili-
no)prop-2-en-1-one (1t)
Yield: 88% (2 h); mp 170–171 °C; yellow solid.
IR (KBr): 3435, 1591, 1554, 1327, 1261, 1217 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.48 (s, 1 H), 7.91 (d, J = 8.2 Hz,
2 H), 7.62 (d, J = 7.9 Hz, 1 H), 7.53 (dd, J = 7.6, 1.5 Hz, 1 H), 7.47
(d, J = 8.2 Hz, 2 H), 7.37 (t, J = 7.5 Hz, 2 H), 7.26 (dt, J = 7.9, 1.7
Hz, 1 H), 7.11 (d, J = 8.7 Hz, 2 H), 6.74 (d, J = 8.7 Hz, 2 H), 5.80
(s, 1 H), 2.60 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 197.2, 192.2, 159.5, 142.5, 139.5,
138.0, 137.6, 133.6, 131.0, 130.2, 129.4, 129.1, 128.8, 128.7, 127.4,
124.6, 119.5, 101.6, 26.7.
Anal. Calcd for C22H17BrClNO: C, 61.92; H, 4.02. Found: C, 61.79;
H, 3.92.
(Z)-1-(2-Bromophenyl)-3-(4-chlorophenyl)-3-(4-fluoroanili-
no)prop-2-en-1-one (1p)
Yield: 87% (3 h); mp 138–139 °C; pale yellow solid.
IR (KBr): 3448, 1579, 1558, 1512, 1477, 1321, 1203, 756 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.51 (s, 1 H), 7.63 (d, J = 7.9 Hz,
1 H), 7.54 (d, J = 7.5 Hz, 1 H), 7.38 (t, J = 7.4 Hz, 1 H), 7.31–7.25
(m, 5 H), 6.91–6.80 (m, 4 H), 5.75 (s, 1 H).
Anal. Calcd for C23H17BrClNO2: C, 60.75; H, 3.77. Found: C,
60.59; H, 3.52.
13C NMR (100 MHz, CDCl3): d = 191.9, 160.2, 159.9 (d, JCF = 244
Hz), 142.7, 136.1, 135.1, 133.6, 133.5, 130.8, 129.9, 129.3, 129.0,
127.4, 125.4 (d, JCF = 8 Hz), 119.5, 115.8 (d, JCF = 23 Hz), 100.7.
(Z)-3-(3-Acetylphenyl)-1-(2-bromophenyl)-3-(4-methoxyanili-
no)prop-2-en-1-one (1u)
Yield: 92% (1 h); mp 157–158 °C; yellow-orange solid.
Anal. Calcd for C21H14BrClFNO: C, 58.56; H, 3.28. Found: C,
58.39; H, 3.42.
IR (KBr): 3448, 1684, 1597, 1556, 1510, 1323, 1248 cm–1.
(Z)-1-(2-Bromophenyl)-3-[4-(methoxycarbonyl)anilino]-3-(3-
methoxyphenyl)prop-2-en-1-one (1q)
Yield: 82% (24 h); mp 132–133 °C; pale yellow solid.
IR (KBr): 3423, 1714, 1593, 1282, 1242, 1180, 767 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.56 (s, 1 H), 7.84 (d, J = 8.6 Hz,
2 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.54 (dd, J = 7.6, 1.5 Hz, 1 H), 7.38
(t, J = 6.8 Hz, 1 H), 7.29–7.25 (m, 2 H), 6.99–6.94 (m, 3 H), 6.85
(d, J = 8.6 Hz, 2 H), 5.87 (s, 1 H), 3.88 (s, 3 H), 3.74 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 192.4, 166.6, 160.0, 159.8, 143.7,
142.6, 136.3, 133.6, 130.9, 130.5, 130.0, 129.4, 127.4, 125.4, 122.0,
120.7, 119.5, 115.9, 113.7, 102.3, 55.4, 52.0.
1H NMR (400 MHz, CDCl3): d = 12.54 (s, 1 H), 7.87 (d, J = 7.9 Hz,
2 H), 7.60 (d, J = 7.7 Hz, 1 H), 7.53 (dd, J = 7.8, 1.3 Hz, 1 H), 7.45
(d, J = 8.0 Hz, 2 H), 7.35 (t, J = 7.2 Hz, 2 H), 7.24 (t, J = 7.3 Hz, 1
H), 6.77 (d, J = 8.2 Hz, 2 H), 6.68 (d, J = 8.1 Hz, 2 H), 5.71 (s, 1H),
3.71 (s, 3 H), 2.57 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 197.3, 191.6, 160.6, 157.1, 142.9,
140.0, 137.7, 133.6, 131.8, 130.7, 129.4, 128.9, 128.4, 127.4, 125.3,
119.5, 114.2, 100.1, 55.4, 26.7.
Anal. Calcd for C24H20BrNO3: C, 64.01; H, 4.48. Found: C, 63.89;
H, 4.52.
Anal. Calcd for C24H20BrNO4: C, 61.81; H, 4.32. Found: C, 61.89;
H, 4.22.
(Z)-3-Anilino-1-(2-bromophenyl)oct-2-en-1-one (1v)
Yield: 82% (2 h); yellow oil.
IR (neat): 2956, 2929, 1591, 1491, 1294, 1108, 1026, 750 cm–1.
(Z)-1-(2-Bromophenyl)-3-(3-methoxyphenyl)-3-[3-(trifluoro-
methyl)anilino]prop-2-en-1-one (1r)
Yield: 88% (2 h); pale yellow viscous oil.
IR (neat): 3443, 1574, 1454, 1313, 1238, 1124, 1070 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.62 (s, 1 H), 7.64 (d, J = 8.0 Hz,
1 H), 7.56 (d, J = 7.9 Hz, 1 H), 7.39 (t, J = 7.6 Hz, 1 H), 7.29–7.25
(m, 4 H), 7.10 (s, 1 H), 6.99–6.92 (m, 4 H), 5.87 (s, 1 H), 3.74 (s, 3
H).
1H NMR (400 MHz, CDCl3): d = 12.83 (br s, 1 H), 7.61 (d, J = 6.3
Hz, 1 H), 7.50 (dd, J = 7.6, 1.4 Hz, 1 H), 7.42–7.04 (m, 3 H), 7.29–
7.21 (m, 4 H), 5.55 (s, 1 H), 2.40 (t, J = 7.8 Hz, 2 H), 1.55 (m, 2 H),
1.25 (m, 4 H), 0.85 (t, J = 6.9 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.8, 167.3, 143.4, 138.3, 133.4,
130.2, 129.3, 129.2, 127.2, 126.4, 125.6, 119.5, 96.8, 32.1, 31.4,
27.8, 22.2, 13.9.
Anal. Calcd for C20H22BrNO: C, 64.52; H, 5.96. Found: C, 64.41;
H, 5.91.
13C NMR (100 MHz, CDCl3): d = 192.4, 160.5, 159.8, 142.6, 140.0,
136.0, 133.6, 131.3 (q, JCF = 32 Hz), 130.9, 130.0, 129.4, 129.3,
127.4, 126.0, 123.7 (q, JCF = 271 Hz), 120.7, 119.7, 119.7, 119.5,
116.0, 113.8, 101.7, 55.4.
(Z)-1-(2-Bromophenyl)-3-(4-methoxyanilino)oct-2-en-1-one
(1w)
Yield: 87% (1 h); yellow oil.
IR (neat): 2956, 2931, 1595, 1566, 1514, 1248, 1034, 754 cm–1.
Anal. Calcd for C23H17BrF3NO2: C, 58.00; H, 3.60. Found: C,
58.19; H, 3.42.
(Z)-1-(2-Bromophenyl)-3-(3-fluoroanilino)-3-(3-methoxyphe-
nyl)prop-2-en-1-one (1s)
Yield: 91% (2 h); mp 112–113 °C; pale yellow solid.
IR (KBr): 3434, 1569, 1512, 1333, 1246, 1205, 1022 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.57 (s, 1 H), 7.64 (d, J = 7.9 Hz,
1 H), 7.55 (d, J = 7.6 Hz, 1 H), 7.37 (t, J = 7.4 Hz, 1 H), 7.28–7.22
(m, 2 H), 6.95–6.82 (m, 7 H), 5.78 (s, 1 H), 3.73 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 191.8, 161.5, 159.8 (d, JCF = 244
Hz), 159.6, 142.9, 136.3, 135.4 (d, JCF = 3 Hz), 133.6, 130.7, 129.8,
129.4, 127.3, 125.2 (d, JCF = 8 Hz), 120.9, 119.6, 115.7 (d, JCF = 5
Hz), 115.6, 113.9, 100.5, 55.3.
1H NMR (400 MHz, CDCl3): d = 12.65 (br s, 1 H), 7.60 (d, J = 7.9
Hz, 1 H), 7.50 (dd, J = 7.8, 1.5 Hz, 1 H), 7.35 (t, J = 7.4 Hz, 1 H),
7.21 (dt, J = 7.7, 1.6 Hz, 1 H), 7.14 (d, J = 8.8 Hz, 2 H), 6.92 (d,
J = 8.8 Hz, 2 H), 5.50 (s, 1 H), 3.84 (s, 3 H), 2.32 (t, J = 7.7 Hz, 2
H), 1.51 (m, 2 H), 1.24 (m, 4 H), 0.84 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.5, 168.1, 158.2, 143.5, 133.4,
131.0, 130.1, 129.2, 127.3, 127.2, 119.5, 114.4, 96.2, 55.5, 32.0,
31.4, 27.7, 22.2, 13.9.
Anal. Calcd for C21H24BrNO2: C, 62.69; H, 6.01. Found: C, 62.61;
H, 5.91.
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York

PAPER
Copper-Catalyzed Quinolone Synthesis
1215
(Z)-3-Anilino-1-(2-chlorophenyl)-3-phenylprop-2-en-1-one (1x)
Yield: 93% (2 h); mp 124–125 °C; yellow solid.
IR (KBr): 3435, 1591, 1558, 1479, 1313, 1211, 1036, 746 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.72 (s, 1 H), 7.62 (m, 1 H),
7.46–7.21 (m, 8 H), 7.16 (t, J = 7.8 Hz, 2 H), 7.04 (t, J = 7.4 Hz, 1
H), 6.85 (d, J = 7.9 Hz, 2 H), 5.84 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 190.7, 161.4, 141.0, 139.3, 135.3,
131.1, 130.6, 129.9, 129.5, 128.9, 128.6, 128.5, 126.8, 124.5, 123.5,
101.1.
1H NMR (400 MHz, CDCl3): d = 11.26 (br s, 1 H), 7.53 (d, J = 7.7
Hz, 1 H), 7.45–7.37 (m, 6 H), 7.26 (dd, J = 7.7, 1.3 Hz, 1 H), 5.43
(s, 1 H), 3.25 (q, J = 6.5 Hz, 2 H), 1.58 (m, 2 H), 1.38 (m, 2 H), 0.89
(t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 189.1, 166.9, 141.4, 135.3, 130.9,
130.1, 129.9, 129.6, 129.4, 128.5, 127.7, 126.6, 97.3, 44.6, 32.8,
19.9, 13.7.
Anal. Calcd for C19H20ClNO: C, 72.72; H, 6.42. Found: C, 72.80;
H, 6.33.
Anal. Calcd for C21H16ClNO: C, 75.65; H, 4.83. Found: C, 75.59;
H, 4.61.
1,2-Disubstituted 4-Quinolones 2a–i,n–u; General Procedure
An oven-dried Schlenk tube was charged with the appropriate
1-(2-halophenyl)-2-en-3-amin-1-one 1 (1 equiv), CuI (5 mol%),
DMEDA (5 mol%), K2CO3 (2 equiv), and DMSO (0.1 M). The tube
was sealed and stirred at 80 °C for the period of time indicated be-
low (and in Tables 2 and 3) for each product 2. The reaction mixture
was cooled to r.t., diluted with Et2O (50 mL) and washed with 1 N
HCl (2 × 10 mL) (except for 2h) and a sat. NaCl soln (10 mL). The
organic phase was separated, dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by chroma-
tography (silica gel, n-hexane–EtOAc).
(Z)-1-(2-Chlorophenyl)-3-(4-methoxyanilino)-3-phenylprop-2-
en-1-one (1y)
Yield: 92% (1 h); mp 136–137 °C; yellow-orange solid.
IR (KBr): 3423, 1604, 1570, 1508, 1483, 1331, 1213, 1032, 762
cm–1.
1H NMR (400 MHz, CDCl3): d = 12.71 (s, 1 H), 7.60 (m, 1 H),
7.44–7.29 (m, 8 H), 6.80 (d, J = 8.9 Hz, 2 H), 6.70 (d, J = 8.8 Hz, 2
H), 5.77 (s, 1 H), 3.73 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 190.3, 162.0, 156.8, 141.1, 135.4,
132.2, 131.0, 130.4, 130.3, 129.8, 129.5, 129.5, 128.6, 128.5, 126.8,
125.1, 114.1, 100.1, 55.4.
1,2-Diphenyl-4-quinolone (2a)
Yield: 93% (2.5 h) from 1a; 95% (6 h) from 1x; mp 280–281 °C;
white-brownish solid.
Anal. Calcd for C22H18ClNO2: C, 76.62; H, 4.99. Found: C, 76.71;
H, 5.10.
IR (KBr): 1627, 1596, 1490, 1477, 1458, 1402, 1314, 1135, 705
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.50 (d, J = 7.4 Hz, 1 H), 7.48 (d,
J = 7.5 Hz, 1 H), 7.39–7.35 (m, 4 H), 7.20–7.16 (m, 7 H), 6.91 (d,
J = 8.6 Hz, 1 H), 6.45 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 154.0, 142.6, 139.2, 135.7,
131.9, 130.0, 129.6, 129.2, 129.0, 128.6, 127.9, 126.3, 126.1, 123.8,
118.1, 112.6.
(Z)-3-(4-Acetylanilino)-1-(2-chlorophenyl)-3-phenylprop-2-en-
1-one (1z)
Yield: 75% (12 h); mp 157–158 °C; yellow-brown solid.
IR (KBr): 3448, 1676, 1589, 1566, 1319, 1268 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.63 (s, 1 H), 7.75 (d, J = 8.5 Hz,
2 H), 7.59 (m, 1 H), 7.42–7.28 (m, 8 H), 6.82 (d, J = 8.5 Hz, 2 H),
5.91 (s, 1 H), 2.51 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 196.7, 191.5, 159.9, 143.9, 140.5,
135.0, 132.6, 131.1, 130.9, 130.5, 130.3, 129.5, 129.4, 128.9, 128.3,
126.9, 122.0, 102.9, 26.4.
MS (EI, 70 eV): m/z (%) = 297 (100), 269 (96), 51 (57), 102 (51),
77 (50).
Anal. Calcd for C21H15NO: C, 84.82; H, 5.08. Found: C, 84.69; H,
4.99.
Anal. Calcd for C23H18ClNO2: C, 73.50; H, 4.83. Found: C, 73.68;
H, 4.71.
2-Phenyl-1-[3-(trifluoromethyl)phenyl]-4-quinolone (2b)
Yield: 92% (1.5 h); mp 235–236 °C; white solid.
IR (KBr): 3042, 1629, 1329, 1116, 752, 706 cm–1.
(Z)-3-(4-Chloroanilino)-1-(2-chlorophenyl)-3-phenylprop-2-en-
1-one (1za)
Yield: 87% (4 h); mp 124–125 °C; yellow solid.
1H NMR (400 MHz, CDCl3): d = 8.49 (d, J = 7.9 Hz, 1 H), 7.59 (m,
1 H), 7.55–7.48 (m, 2 H), 7.45–7.36 (m, 3 H), 7.21–7.14 (m, 5 H),
6.84 (d, J = 8.6 Hz, 1 H), 6.44 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 177.9, 153.6, 142.3, 139.9, 135.2,
133.6, 132.3 (q, JCF = 33 Hz), 132.2, 130.4, 129.1, 128.9, 128.2,
127.3 (q, JCF = 4 Hz), 126.6, 126.1, 125.6 (q, JCF = 4 Hz), 124.1,
123.2 (q, JCF = 271 Hz), 117.5, 112.8.
IR (KBr): 3448, 1604, 1589, 1552, 1500, 1309, 1211, 1080, 1039,
758 cm–1.
1H NMR (400 MHz, CDCl3): d = 12.63 (s, 1 H), 7.60 (m, 1 H),
7.45–7.33 (m, 8 H), 7.11 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.6 Hz, 2
H), 5.85 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 191.1, 161.0, 140.8, 138.0, 135.0,
131.1, 130.7, 130.4, 130.1, 129.8, 129.5, 128.9, 128.8, 128.5, 126.8,
124.5, 101.5.
19F NMR (376 MHz, CDCl3): d = –62.92.
MS (EI, 70 eV): m/z (%) = 365 (100), 337 (94).
Anal. Calcd for C22H14F3NO: C, 72.32; H, 3.86. Found: C, 72.19; H,
3.95.
Anal. Calcd for C21H15Cl2NO: C, 68.49; H, 4.11. Found: C, 68.29;
H, 4.01.
1-(4-Methoxyphenyl)-2-phenyl-4-quinolone (2c)
Yield: 89% (2 h) from 1c; 83% (7 h) from 1y; mp 201–202 °C
(Lit.20 202–204 °C); white solid.
IR (KBr): 1625, 1507, 1458, 1405, 1251, 1027, 838, 758, 695 cm–1.
(Z)-3-(Butylamino)-1-(2-chlorophenyl)-3-phenylprop-2-en-1-
one (1zb)
Yield: 92% (2 h); pale yellow oil.
1H NMR (400 MHz, CDCl3): d = 8.49 (dd, J = 8.0, 1.2 Hz, 1 H),
7.44 (t, J = 7.1 Hz, 1 H), 7.35 (t, J = 7.8 Hz, 1 H), 7.21–7.16 (m, 5
H), 7.05 (d, J = 8.8 Hz, 2 H), 6.93 (d, J = 8.6 Hz, 1 H), 6.84 (d,
J = 8.8 Hz, 2 H), 6.42 (s, 1 H), 3.78 (s, 3 H).
IR (neat): 3060, 2958, 2931, 2871, 1567, 1484, 1331, 1089, 1035,
756, 702 cm–1.
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13C NMR (100 MHz, CDCl3): d = 178.0, 159.5, 154.4, 143.0, 135.9,
131.9, 131.8, 131.0, 129.2, 128.6, 128.0, 126.2, 123.7, 118.2, 114.7,
112.5, 55.5.
(dd, JCF = 13, 4 Hz), 116.8, 112.8, 112.3 (dd, JCF = 22, 4 Hz), 105.2
(dd, JCF = 26, 23 Hz).
19F NMR (376 MHz, CDCl3): d = –105.3, –113.4.
MS (EI, 70 eV): m/z (%) = 327 (89), 299 (49), 102 (100).
MS (EI, 70 eV): m/z (%) = 339 (100), 327 (88), 331 (56), 299 (32).
Anal. Calcd for C22H17NO2: C, 80.71; H, 5.23. Found: C, 80.80; H,
5.19.
Anal. Calcd for C21H13F2NO: C, 75.67; H, 3.93. Found: C, 75.75; H,
3.99.
1-(4-Acetylphenyl)-2-phenyl-4-quinolone (2d)
Yield: 87% (1.5 h) from 1d; 83% (3 h) from 1z; mp 221–222 °C;
white solid.
IR (KBr): 1683, 1628, 1597, 1462, 1400, 1262, 763, 707 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.48 (dd, J = 7.9, 1.3 Hz, 1 H),
7.95 (d, J = 8.4 Hz, 2 H), 7.44 (t, J = 7.7 Hz, 1 H), 7.36 (t, J = 7.3
Hz, 1 H), 7.29 (d, J = 8.5 Hz, 2 H), 7.20–7.15 (m, 5 H), 6.84 (d,
J = 8.5 Hz, 1 H), 6.41 (s, 1 H), 2.59 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 196.7, 177.8, 153.5, 143.3, 142.2,
137.1, 135.3, 132.1, 130.5, 129.6, 129.1, 129.0, 128.1, 126.4, 126.1,
124.0, 117.7, 112.8, 26.7.
2-Phenyl-1-(3,4,5-trimethoxyphenyl)-4-quinolone (2h)
Yield: 81% (2 h); mp 222–223 °C; white solid.
IR (KBr): 1626, 1598, 1503, 1464, 1421, 1265, 1239, 1125, 753,
704 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.45 (d, J = 7.6 Hz, 1 H), 7.49 (t,
J = 7.7 Hz, 2 H), 7.34 (t, J = 7.9 Hz, 1 H), 7.26–7.19 (m, 5 H), 7.05
(d, J = 8.6 Hz, 1 H), 6.38 (s, 3 H), 3.81 (s, 3 H), 3.69 (s, 6 H).
13C NMR (100 MHz, CDCl3): d = 177.9, 153.9, 153.7, 142.5, 138.5,
135.9, 134.4, 131.9, 128.9, 128.7, 127.9, 126.3, 126.1, 123.8, 118.1,
112.6, 107.8, 61.1, 56.5.
MS (EI, 70 eV): m/z (%) = 387 (100).
MS (EI, 70 eV): m/z (%) = 339 (100), 327 (73), 311 (59), 102 (79).
Anal. Calcd for C24H21NO4: C, 74.40; H, 5.46. Found: C, 74.21; H,
5.23.
Anal. Calcd for C23H17NO2: C, 81.40; H, 5.05. Found: C, 81.29; H,
4.99.
1-(4-Chlorophenyl)-2-phenyl-4-quinolone (2i)
Yield: 91% (2 h) from 1i; 92% (3 h) from 1za; mp 206–207 °C;
white solid.
1-(4-Chloro-1-naphthyl)-2-phenyl-4-quinolone (2e)
Yield: 92% (2 h); mp 239–240 °C; white solid.
IR (KBr): 1617, 1595, 1478, 1459, 1410, 1383, 1319, 1278, 1136,
762, 702 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.55 (m, 1 H), 8.27 (d, J = 8.5 Hz,
1 H), 7.62 (t, J = 7.4 Hz, 1 H), 7.52 (m, 2 H), 7.43 (m, 1 H), 7.36–
7.29 (m, 3 H), 7.10–6.99 (m, 5 H), 6.43 (m, 1 H), 6.51 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 178.1, 154.7, 142.6, 135.3, 134.7,
133.6, 132.3, 132.2, 131.4, 129.0, 128.8, 128.6, 128.4, 128.1, 127.8,
126.4, 126.1, 125.6, 125.4, 124.1, 123.2, 118.1, 113.0.
IR (KBr): 3044, 1267, 1599, 1487, 1466, 1413, 1318, 840, 748
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.47 (d, J = 7.4 Hz, 1 H), 7.47 (dt,
J = 7.1, 1.5 Hz, 1 H), 7.37–7.33 (m, 3 H), 7.23–7.11 (m, 7 H), 6.87
(d, J = 8.6 Hz, 1 H), 6.40 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 177.9, 153.8, 143.3, 142.5, 137.8,
135.4, 135.0, 132.1, 131.4, 129.9, 129.2, 128.9, 128.2, 126.4, 126.1,
124.0, 117.8, 112.8.
MS (EI, 70 eV): m/z (%) = 381 (100), 353 (49), 327 (20), 102 (59).
MS (EI, 70 eV): m/z (%) = 373 (100), 345 (67), 330 (41).
Anal. Calcd for C25H16ClNO: C, 78.63; H, 4.22. Found: C, 78.75;
H, 4.29.
Anal. Calcd for C21H14ClNO: C, 76.02; H, 4.25. Found: C, 76.09;
H, 4.32.
1-(4-Cyanophenyl)-2-phenyl-4-quinolone (2f)
Yield: 82% (2 h); mp 255–256 °C; white solid.
2-(4-Chlorophenyl)-1-(3-methoxyphenyl)-4-quinolone (2n)
Yield: 87% (2.5 h); mp 211–212 °C; white solid.
IR (KBr): 3038, 2234, 1628, 1600, 1508, 1481, 1466, 1413, 1318,
768, 748, 737, 707 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.45 (d, J = 7.9 Hz, 1 H), 7.67 (d,
J = 8.3 Hz, 2 H), 7.49 (t, J = 8.3 Hz, 1 H), 7.36 (m, 3 H), 7.28–7.21
(m, 3 H), 7.15 (m, 2 H), 6.80 (d, J = 8.5 Hz, 1 H), 6.40 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 177.8, 153.2, 143.3, 142.0, 135.0,
133.5, 132.3, 131.3, 129.2, 129.1, 128.4, 126.7, 126.1, 124.3, 117.5,
117.3, 113.2, 113.1.
IR (KBr): 1631, 1597, 1480, 1418, 1251, 852, 828, 747 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.47 (dd, J = 8.0, 1.3 Hz, 1 H),
7.48 (dt, J = 7.1, 1.4 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 1 H), 7.30 (t,
J = 8.1 Hz, 1 H), 7.21–7.14 (m, 4 H), 6.96 (d, J = 8.6 Hz, 1 H), 6.90
(dd, J = 8.3, 2.4 Hz, 1 H), 6.78 (dd, J = 8.3, 1.0 Hz, 1 H), 6.69 (m,
1 H), 6.37 (s, 1 H), 3.75 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.8, 160.6, 152.6, 142.5, 139.9,
134.9, 134.2, 132.1, 130.4, 128.3, 126.3, 126.1, 124.0, 122.2, 118.1,
115.8, 114.8, 112.7, 55.6.
MS (EI, 70 eV): m/z (%) = 322 (100), 294 (88).
Anal. Calcd for C22H14N2O: C, 81.97; H, 4.38. Found: C, 81.79; H,
4.22.
MS (EI, 70 eV): m/z (%) = 395 (100), 367 (63).
Anal. Calcd for C22H16ClNO2: C, 73.03; H, 4.46. Found: C, 74.88;
H, 4.32.
1-(2,4-Difluorophenyl)-2-phenyl-4-quinolone (2g)
Yield: 72% (1.5 h); mp 187–188 °C; white solid.
IR (KBr): 1683, 1628, 1597, 1462, 1400, 1262, 763, 707 cm–1.
2-(4-Chlorophenyl)-1-(4-tolyl)-4-quinolone (2o)
Yield: 85% (1.5 h); mp 211–212 °C; white solid.
1H NMR (400 MHz, CDCl3): d: 8.51 (d, J = 7.6 Hz, 1 H), 7.52 (t,
J = 7.7 Hz, 1 H), 7.40 (t, J = 7.8 Hz, 1 H), 7.29–7.17 (m, 6 H), 6.91–
6.83 (m, 3 H), 6.43 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 178.0, 163.3 (dd, JCF = 252, 11
Hz), 158.7 (dd, JCF = 251, 11 Hz), 154.0, 142.1, 135.0, 132.5 (d,
JCF = 10 Hz), 132.3, 129.1, 128.4, 128.1, 126.5, 126.0, 124.0, 123.4
IR (KBr): 3035, 1629, 1514, 1480, 1420, 1319, 1094, 828, 747
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.47 (dd, J = 8.0, 1.4 Hz, 1 H),
7.45 (dt, J = 7.8, 1.5 Hz, 1 H), 7.34 (t, J = 7.8 Hz, 1 H), 7.19–7.11
(m, 6 H), 7.02 (d, J = 8.2 Hz, 2 H), 6.90 (d, J = 8.6 Hz, 1 H), 6.37
(s, 1 H), 2.36 (s, 3 H).
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Copper-Catalyzed Quinolone Synthesis
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13C NMR (100 MHz, CDCl3): d = 177.8, 152.9, 142.8, 139.3, 136.3,
134.8, 134.3, 132.0, 130.6, 130.5, 129.6, 128.3, 126.2, 126.1, 123.9,
118.2, 112.6, 21.3.
IR (KBr): 3042, 1631, 1597, 1509, 1465, 1403, 1219, 1039, 849,
808, 748 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.46 (dd, J = 7.4, 1.2 Hz, 1 H),
7.48 (dt, J = 7.8, 1.4 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.20–7.05
(m, 5 H), 6.88 (d, J = 8.6 Hz, 1 H), 6.78–6.71 (m, 3 H), 6.41 (s, 1
H), 3.71 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.9, 162.2 (d, JCF = 249 Hz),
159.0, 153.8, 142.7, 136.7, 135.2 (d, JCF = 4 Hz), 132.0, 131.8 (d,
JCF = 9 Hz), 129.2, 126.4, 126.2, 123.9, 121.7, 117.8, 116.7 (d,
JCF = 23 Hz), 115.0, 114.4, 112.6, 55.3.
MS (EI, 70 eV): m/z (%) = 345 (100), 317 (79), 281 (13).
Anal. Calcd for C22H16ClNO: C, 76.41; H, 4.66. Found: C, 76.29;
H, 4.77.
2-(4-Chlorophenyl)-1-(4-fluorophenyl)-4-quinolone (2p)
Yield: 87% (2 h); mp 252–253 °C; white solid.
IR (KBr): 1630, 1510, 1480, 1419, 1230, 1159, 1092, 1021, 840,
819, 747 cm–1.
19F NMR (376 MHz, CDCl3): d = –110.9.
1H NMR (400 MHz, CDCl3): d = 8.44 (dd, J = 7.4, 1.2 Hz, 1 H),
7.48 (dt, J = 7.2, 1.4 Hz, 1 H), 7.34 (t, J = 7.7 Hz, 1 H), 7.21–7.07
(m, 8 H), 6.86 (d, J = 8.6 Hz, 1 H), 6.35 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 177.8, 162.3 (d, JCF = 250 Hz),
152.7, 142.7, 135.1, 135.0 (d, JCF = 4 Hz), 134.0, 132.2, 131.8 (d,
JCF = 8 Hz), 130.5, 128.5, 126.4, 126.1, 124.1, 117.8, 117.0 (d,
JCF = 23 Hz), 112.8.
MS (EI, 70 eV): m/z (%) = 345 (100), 317 (67).
Anal. Calcd for C22H16FNO2: C, 76.51; H, 4.67. Found: C, 76.39; H,
4.80.
2-(4-Acetylphenyl)-1-(4-chlorophenyl)-4-quinolone (2t)
Yield: 81% (2 h); mp 248–249 °C; white solid.
IR (KBr): 3056, 1690, 1625, 1598, 1490, 1410, 1266, 1017, 832
cm–1.
19F NMR (376 MHz, CDCl3): d = –110.3.
MS (EI, 70 eV): m/z (%) = 349 (100), 321 (88), 285 (23).
1H NMR (400 MHz, CDCl3): d: = 8.42 (d, J = 7.5 Hz, 1 H), 7.80 (d,
J = 7.2 Hz, 2 H), 7.46 (t, J = 7.0 Hz, 1 H), 7.36–7.23 (m, 5 H), 7.16
(d, J = 7.5 Hz, 2 H), 6.86 (d, J = 8.1 Hz, 1 H), 6.35 (s, 1 H), 2.55 (s,
3 H).
Anal. Calcd for C21H13ClFNO: C, 72.11; H, 3.75. Found: C, 71.99;
H, 3.58.
2-(3-Methoxyphenyl)-1-[(4-methoxycarbonyl)phenyl]-4-qui-
nolone (2q)
Yield: 75% (2.5 h); mp 218–219 °C; white solid.
13C NMR (100 MHz, CDCl3): d = 197.2, 177.6, 152.5, 142.4, 139.8,
137.4, 137.0, 135.3, 132.3, 131.3, 130.2, 129.5, 128.1, 126.4, 126.1,
124.2, 117.8, 112.7, 26.6.
IR (KBr): 2953, 1726, 1626, 1598, 1464, 1408, 1280, 1115, 762
cm–1.
MS (EI, 70 eV): m/z (%) = 373 (100), 345 (53), 330 (41).
Anal. Calcd for C23H16ClNO2: C, 73.90; H, 4.31. Found: C, 73.77;
H, 4.09.
1H NMR (400 MHz, CDCl3): d = 8.47 (d, J = 7.9 Hz, 1 H), 8.05 (d,
J = 8.3 Hz, 2 H), 7.46 (t, J = 8.2 Hz, 1 H), 7.36 (t, J = 7.6 Hz, 1 H),
7.29 (d, J = 8.3 Hz, 2 H), 7.09 (t, J = 7.9 Hz, 1 H), 6.84 (d, J = 8.6
Hz, 1 H), 6.76–6.72 (m, 3 H), 6.34 (s, 1 H), 3.92 (s, 3 H), 3.68 (s, 3
H).
13C NMR (100 MHz, CDCl3): d = 177.9, 165.8, 159.1, 153.3, 143.2,
142.2, 136.5, 132.1, 130.9, 130.6, 130.2, 129.3, 126.5, 126.1, 124.0,
121.7, 117.7, 114.9, 114.6, 112.8, 55.3, 52.5.
2-(4-Acetylphenyl)-1-(4-methoxyphenyl)-4-quinolone (2u)
Yield: 70% (2.5 h); mp 236–237 °C.
IR (KBr): 1683, 1624, 1599, 1511, 1462, 1413, 1258, 833, 766
cm–1.
1H NMR (400 MHz, CDCl3): d = 8.46 (d, J = 7.7 Hz, 1 H), 7.79 (d,
J = 8.0 Hz, 2 H), 7.47 (t, J = 7.1 Hz, 1 H), 7.35 (t, J = 7.2 Hz, 1 H),
7.29 (d, J = 7.7 Hz, 2 H), 7.07 (d, J = 8.5 Hz, 2 H), 6.92 (d, J = 8.4
Hz, 1 H), 6.84 (d, J = 8.5 Hz, 2 H), 6.37 (s, 1 H), 3.78 (s, 3 H), 2.55
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 197.3, 177.6, 159.6, 153.1, 142.9,
140.2, 136.7, 132.0, 131.3, 130.8, 129.4, 127.8, 126.1, 126.1, 123.9,
118.0, 114.8, 112.3, 55.4, 26.5.
MS (EI, 70 eV): m/z (%) = 385 (51), 357 (27), 59 (100).
Anal. Calcd for C24H19NO4: C, 74.79; H, 4.97. Found: C, 74.88; H,
4.78.
2-(3-Methoxyphenyl)-1-[3-(trifluoromethyl)phenyl)]-4-qui-
nolone (2r)
Yield: 72% (2.5 h); mp 245–246 °C; white solid.
MS (EI, 70 eV): m/z (%) = 369 (100), 341 (40).
IR (KBr): 3059, 1631, 1599, 1496, 1466, 1408, 1323, 1167, 1120,
752 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.49 (d, J = 8.0 Hz, 1 H), 7.62 (m,
1 H), 7.56–7.48 (m, 3 H), 7.41–7.36 (m, 2 H), 7.11 (t, J = 7.9 Hz, 1
H), 6.84 (d, J = 8.6 Hz, 1 H), 6.74 (t, J = 8.4 Hz, 2 H), 6.67 (s, 1 H),
6.45 (s, 1 H), 3.68 (s, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.9, 159.1, 153.4, 142.3, 139.9,
136.3, 133.5, 132.3, 132.2 (q, JCF = 33 Hz), 130.4, 129.4, 127.3 (q,
JCF = 3 Hz), 126.6, 126.2, 125.8 (q, JCF = 3 Hz), 124.1, 123.2 (q,
JCF = 271 Hz), 121.6, 117.5, 115.0, 114.5, 112.8, 55.3.
Anal. Calcd for C24H19NO3: C, 78.03; H, 5.18. Found: C, 77.87; H,
5.00.
1,2-Disubstituted 4-Quinolones 2j–l; General Procedure
An oven-dried Schlenk tube was charged with the appropriate
1-(2-halophenyl)-2-en-3-amin-1-one 1 (1 equiv), CuI (5 mol%),
DMEDA (5 mol%), t-BuONa (2 equiv), and DMSO (0.1 M). The
tube was sealed and stirred at 80 °C for the period of time indicated
below (and in Tables 2 and 3) for each product 2. The reaction mix-
ture was cooled to r.t., diluted with Et2O, and washed with a sat.
NaCl soln. The organic phase was separated, dried (Na2SO4), fil-
tered, and concentrated under reduced pressure. The residue was
purified by chromatography (silica gel, n-hexane–EtOAc).
19F NMR (376 MHz, CDCl3): d = –62.9.
MS (EI, 70 eV): m/z (%) = 395 (100), 367 (55).
Anal. Calcd for C23H16F3NO2: C, 69.87; H, 4.08. Found: C, 69.69;
H, 3.99.
1-Butyl-2-phenyl-4-quinolone (2j)
Yield: 86% (1 h) from 1j; 89% (3 h) from 1zb; mp 72–73 °C; pale
brown crystals.
1-(4-Fluorophenyl)-2-(3-methoxyphenyl)-4-quinolone (2s)
Yield: 83% (4 h); mp 188–189 °C; white solid.
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York

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R. Bernini et al.
PAPER
72, 2046. (g) Yan, S.; Wu, H.; Wu, N.; Jiang, Y. Synlett
IR (KBr): 2963, 2933, 2874, 1626, 1594, 1483, 1462, 1415, 1302,
1173, 763, 706 cm–1.
2007, 2699.
(3) For some recent references, see: (a) Vohra, R. K.; Bruneau,
C.; Renaud, J.-L. Adv. Synth. Catal. 2006, 348, 2571.
(b) Hu, H.-Y.; Liu, Y.; Ye, M.; Xu, J.-H. Synlett 2006, 1913.
(c) Nishiwaki, N.; Nishimoto, T.; Tamura, M.; Ariga, M.
Synlett 2006, 1437. (d) Pešková, M.; Šimůnek, P.; Bertolasi,
V.; Macháček, V.; Lyčka, A. Organometallics 2006, 25,
2025. (e) Tu, S.; Jiang, B.; Jia, R.-H.; Zhang, J.-Y.; Zhang,
Y.; Yao, C.-S.; Shi, F. Org. Biomol. Chem. 2006, 4, 3664.
(f) Huang, J.; Liang, Y.; Pan, W.; Yang, Y.; Dong, D. Org.
Lett. 2007, 9, 5345. (g) Tu, S.; Li, C.; Li, G.; Cao, L.; Shao,
Q.; Zhou, D.; Jiang, B.; Zhou, J.; Xia, M. J. Comb. Chem.
2007, 9, 1144. (h) Cheng, X.-M.; Liu, X.-M. J. Comb.
Chem. 2007, 9, 906. (i) Cunha, S.; Damasceno, F.; Ferrari, J.
Tetrahedron Lett. 2007, 48, 5795. (j) Xiang, D.; Yang, Y.;
Zhang, R.; Liang, Y.; Pan, W.; Huang, J.; Dong, D. J. Org.
Chem. 2007, 72, 8593.
1H NMR (400 MHz, CDCl3): d = 8.51 (dd, J = 8.0, 1.1 Hz, 1 H),
7.69 (dt, J = 7.7, 1.2 Hz, 1 H), 7.55 (m, 1 H), 7.50–7.48 (m, 3 H),
7.31–7.48 (m, 3 H), 6.24 (s, 1 H), 4.02 (t, J = 7.7 Hz, 2 H), 1.66 (m,
2 H), 1.16 (m, 2 H), 0.75 (t, J = 7.3 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.4, 154.6, 140.7, 136.1, 132.2,
129.4, 128.7, 128.3, 127.4, 127.1, 123.5, 116.3, 112.9, 48.0, 30.8,
19.7, 13.4.
MS (EI, 70 eV): m/z (%) = 277 (56), 234 (100).
Anal. Calcd for C19H19NO: C, 82.28; H, 6.90. Found: C, 82.10; H,
6.97.
1-Benzyl-2-phenyl-4-quinolone (2k)
Yield: 53% (1 h); mp 118–119 °C; white crystals.
IR (KBr): 1626, 1599, 1484, 1416, 1312, 1269, 737, 700 cm–1.
(4) (a) Osuka, A.; Mori, Y.; Suzuki, H. Chem. Lett. 1982, 2031.
(b) Yang, S. C.; Wang Huey, M.; Kuo, C. S.; Chen, L. C.
Heterocycles 1991, 32, 2399. (c) Gravestock, D.; Dovey, M.
C. Synthesis 2003, 523. (d) Gravestock, D.; Dovey, M. C.
Synthesis 2003, 1470.
1H NMR (400 MHz, CDCl3): d = 8.54 (d, J = 7.8 Hz, 1 H), 7.54 (t,
J = 7.1 Hz, 1 H), 7.47–7.25 (m, 10 H), 7.01 (d, J = 7.2 Hz, 3 H),
6.37 (s, 1 H), 5.30 (s, 1 H).
13C NMR (100 MHz, CDCl3): d = 177.7, 155.1, 141.2, 136.4, 135.7,
132.4, 129.7, 129.1, 128.7, 128.2, 127.7, 127.3, 126.9, 125.5, 123.8,
117.3, 113.2, 52.2.
(5) For some selected palladium-catalyzed reactions, see:
(a) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980,
45, 2938. (b) Kasahara, A.; Izumi, T.; Murakami, S.; Yanai,
H.; Takatori, M. Bull. Chem. Soc. Jpn. 1986, 59, 927.
(c) Sakamoto, T.; Nagano, T.; Kondo, Y.; Yamanaka, H.
Synthesis 1990, 215. (d) Michael, J. P.; Chang, S.-F.;
Wilson, C. Tetrahedron Lett. 1993, 34, 8365. (e) Koerber-
Plé, K.; Massiot, G. Synlett 1994, 759. (f) Chen, L.-C.;
Yang, S.-C.; Wang, H.-M. Synthesis 1995, 385. (g)Latham,
E. J.; Stanfoth, S. P. Chem. Commun. 1996, 2253.
(h) Latham, E. J.; Stanfoth, S. P. J. Chem. Soc., Perkin
Trans. 1 1997, 2059. (i) Blache, Y.; Sinibaldi-Troin, M.-E.;
Voldoire, A.; Chavignon, O.; Gramain, J.-C.; Teulade, J.-C.;
Chapat, J.-P. J. Org. Chem. 1997, 62, 8553. (j) Edmonson,
S. D.; Mastracchio, A.; Parmee, E. R. Org. Lett. 2000, 2,
1109. (k) Yamazaki, K.; Kondo, Y. J. Comb. Chem. 2002, 4,
191. (l) Yamazaki, K.; Nakamura, Y.; Kondo, Y. J. Org.
Chem. 2003, 68, 6011. (m) Sorensen, U. S.; Pombo-Villar,
E. Helv. Chim. Acta 2004, 87, 82. (n) Dajka-Halász, B.;
Monsieurs, K.; Éliás, O.; Károlyházy, L.; Tapolcsányi, P.;
Maes, B. U. W.; Riedl, Z.; Hajós, G.; Dommisse, R. A.;
Lemière, G. L. F.; Košmrlj, J.; Mátyus, P. Tetrahedron 2004,
60, 2283. For copper-catalyzed reactions, see ref. 2g. For
gold-catalyzed reactions see: (o) Arcadi, A.; Di Giuseppe,
S.; Marinelli, F.; Rossi, E. Tetrahedron: Asymmetry 2001,
12, 2715. For silver-catalyzed reactions, see: (p) Robinson,
R. S.; Dovey, M. C.; Gravestock, D. Tetrahedron Lett. 2004,
45, 6787.
(6) Cacchi, S.; Fabrizi, G.; Filisti, E. Org. Lett. 2008, 10, 2629.
(7) Pozharskii, A. F.; Soldatenkov, A. T.; Katritzky, A. R.
Heterocycles and Health, In Heterocycles in Life and
Society; John Wiley: Chichester UK, 1997, 135–164.
(8) Nakamura, S.; Kozuka, M.; Bastow, K. F.; Tokuda, H.;
Nishino, H.; Suzuki, M.; Tatsuzaki, J.; Natschke, S. L. M.;
Kuo, S.-C.; Lee, K.-H. Bioorg. Med. Chem. 2005, 13, 4396.
(9) Edmont, D.; Rocher, R.; Plisson, C.; Chenault, J. Bioorg.
Med. Chem. Lett. 2000, 10, 1831.
(10) Osawa, T.; Ohta, H.; Akimoto, K.; Harada, K.; Soga, H.;
Jinno, Y. EP 343574, 1989; Chem. Abstr. 1990, 112,
235197.
(11) (a) 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. (b) Hadjeri, M.; Peiller, E.-L.; Beney, C.; Deka, N.;
MS (EI, 70 eV): m/z (%) = 311 (56), 91 (100).
Anal. Calcd for C22H17NO: C, 84.86; H, 5.50. Found: C, 84.90; H,
5.69.
1-Cyclohexyl-2-phenyl-4-quinolone (2l)
Yield: 36% (2 h); mp 199–200 °C; white crystals.
IR (KBr): 2936, 2852, 1626, 1598, 1484, 1400, 1260, 1169, 764,
704 cm–1.
1H NMR (400 MHz, CDCl3): d = 8.53 (d, J = 8.0 Hz, 1 H), 7.98 (d,
J = 8.8 Hz, 1 H), 7.64 (t, J = 7.1, 1.7 Hz, 1 H), 7.51 (m, 3 H), 7.42–
7.37 (m, 3 H), 6.23 (s, 1 H), 4.17 (m, 1 H), 2.44 (m, 2 H), 1.86 (m,
4 H), 1.63 (m, 1 H), 1.22–1.00 (m, 3 H).
13C NMR (100 MHz, CDCl3): d = 177.3, 155.7, 141.1, 137.4, 130.9,
129.4, 128.8, 128.2, 127.7, 127.2, 123.3, 118.9, 113.4, 63.5, 31.1,
26.5, 25.2.
MS (EI, 70 eV): m/z (%) = 303 (100), 221 (67).
Anal. Calcd for C21H21NO: C, 83.13; H, 6.98. Found: C, 83.00; H,
6.79.
Acknowledgment
The work was carried out in the framework of FIRB 2003 supported
by the Ministero dell’Università e della Ricerca Scientifica e
Tecnologica and by the University ‘La Sapienza’.
References
(1) For recent reviews, see: (a) Elassar, A.-Z. A.; El-Khair, A.
A. Tetrahedron 2003, 59, 8463. (b) Stanovnik, B.; Svete, J.
Chem. Rev. 2004, 104, 2433.
(2) For some recent references, see: (a) Tietcheu, C.; Garcia,
C.; Gardette, D.; Dugat, D.; Gramain, J.-C. J. Heterocycl.
Chem. 2002, 39, 965. (b) White, J. D.; Ihle, D. C. Org. Lett.
2006, 8, 1081. (c) Bellur, E.; Langer, P. Tetrahedron Lett.
2006, 47, 2151. (d) Cruz, M. C.; Jiménez, F.; Delgado, F.;
Tamariz, J. Synlett 2006, 749. (e) Ursic, U.; Bevk, D.; Pirc,
S.; Pezdirc, L.; Stanovnik, B.; Svete, J. Synthesis 2006,
2376. (f) Davis, F. A.; Xu, H.; Zhang, J. J. Org. Chem. 2007,
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York

PAPER
Lawson, M. A.; Dumontet, C.; Boumendjel, A. J. Med.
Copper-Catalyzed Quinolone Synthesis
1219
H.-P. Tetrahedron 1998, 54, 83. (f) Liu, Y.; Yu, C.-Y.;
Wang, M.-X. ARKIVOC 2003, (ii), 146. (g) Ding, D.; Li,
X.; Wang, X.; Du, Y.; Shen, J. Tetrahedron Lett. 2006, 47,
6997. (h) Park, C.-H.; Lee, J.; Jung, H. Y.; Kim, M. J.; Lim,
S. H.; Yeo, H. T.; Choi, E. C.; Yoon, E. J.; Kim, K. W.; Cha,
J. H.; Kim, S.-H.; Chang, D.-J.; Kwon, D.-Y.; Li, F.; Suh,
Y.-G. Bioorg. Med. Chem. 2007, 15, 6517. (i) Al-Hiari, Y.
M.; Al-Mazari, I. S.; Shakya, A. K.; Darwish, R. M.; Abu-
Dahab, R. Molecules 2007, 12, 1240. (j) Zewge, D.; Chen,
C.-y.; Deer, C.; Dormer, P. G.; Hughes, D. L. J. Org. Chem.
2007, 72, 4276. (k) Jones, C. P.; Anderson, K. W.;
Buchwald, S. L. J. Org. Chem. 2007, 72, 7968.
Chem. 2004, 47, 4964. (c) Hradil, P.; Krejcí, P.; Hlavác, J.;
Wiedermannová, I.; Lycka, A.; Bertolasi, V. J. Heterocycl.
Chem. 2004, 41, 375. (d) Lai, Y.-Y.; Hung, L.-J.; Lee, K.-
H.; Xiao, Z.; Bastow, K. F.; Yamori, T.; Kuo, S.-C. Bioorg.
Med. Chem. 2005, 13, 265. (e) Ferlin, M. G.; Chiarelotto,
G.; Gasparotto, V.; Via, L. D.; Pezzi, V.; Barzon, L.; Palu,
G.; Castagliuolo, I. J. Med. Chem. 2005, 48, 3417.
(f) Gasparotto, V.; Castagliuolo, I.; Chiarelotto, G.; Pezzi,
V.; Montanaro, D.; Brun, P.; Palu, G.; Viola, G.; Ferlin, M.
G. J. Med. Chem. 2006, 49, 1910.
(12) Huang, L.-J.; Hsieh, M.-C.; Teng, C.-M.; Lee, K.-H.; Kuo,
S.-C. Bioorg. Med. Chem. 1998, 6, 1657.
(13) (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) Wu, F. X. H.; Nakajima, S.; Or,
Y. S.; Lu, Z.-H.; Sun, Y.; Miao, Z.; Wang, Z. WO
(15) Karpov, A. S.; Muller, T. J. J. Org. Lett. 2003, 5, 3451.
(16) In general, the use of copper catalysts proved superior to that
of palladium catalysts in this reaction. For example, 2a was
isolated in only 25% yield when 1a was subjected to
Pd2(dba)3 (0.025 equiv), P(o-Tol)3 (0.1 equiv), and Cs2CO3
(2 equiv) in toluene at 80 °C for 8 hours.
2005010029, 2005; Chem. Abstr. 2005, 142, 198355.
(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.
(17) Ge, H.; Niphakis, M. J.; Georg, G. I. J. Am. Chem. Soc. 2008,
130, 3708.
(18) The enaminone derivative containing a 4-bromophenyl
substituent (instead of the 2-halophenyl group in1), and with
R1 = n-Bu, R2 = Ph was recovered essentially unchanged
after 8 hours when it was subjected to standard cyclization
conditions.
(19) (a) Evindar, G.; Batey, R. A. Org. Lett. 2003, 5, 133.
(b) Evindar, G.; Batey, R. A. J. Org. Chem. 2006, 71, 1802.
(20) Bell, M. R.; Zalay, A. W.; Oesterlin, R.; Schane, P.; Potts, G.
O. J. Med. Chem. 1970, 13, 664.
(14) For recent reviews, see: (a) Kouznetsov, V. V.; Méndez, L.
Y. V.; Gómez, M. M. Curr. Org. Chem. 2005, 9, 141.
(b) Mitscher, L. A. Chem. Rev. 2005, 105, 559. For other
selected references, see: (c) Glushkov, R. G.; Marchenko,
N. B.; Padeiskaya, E. N.; Shipilova, L. D. Khim.-Farm. Zh.
1990, 24, 24. (d) White, L. A.; Storr, R. C. Tetrahedron
1996, 52, 3117. (e) Clemencin-Le Guillou, C.; Remuzon,
P.; Bouzard, D.; Quirion, J.-C.; Giorgi-Renault, S.; Husson,
Synthesis 2009, No. 7, 1209–1219 © Thieme Stuttgart · New York