4-Aryl-2-quinolones via a domino heck reaction/cyclization process

Article abstract of DOI:10.3987/com-06-s(o)30

The reaction of methyl β-(o-acetamidophenyl)acrylates with aryl iodides in the presence of Pd(OAc)₂ and KOAc in DMF at 120 °C affords 4-aryl-2-quinolones in allowable to good yields.

Full text of DOI:10.3987/com-06-s(o)30

HETEROCYCLES, Vol. 69, 2006
99
HETEROCYCLES, Vol. 69, 2006, pp. 99 - 105. © The Japan Institute of Heterocyclic Chemistry
Received, 29th June, 2006, Accepted, 19th September, 2006, Published online, 22nd September, 2006. COM-06-S(O)30
4-ARYL-2-QUINOLONES
VIA
A
DOMINO
HECK
REACTION/CYCLIZATION PROCESS
Roberta Bernini,a Sandro Cacchi,b* Giancarlo Fabrizi,b* and Alessio
Sferrazzaa
a Department A.B.A.C., University della Tuscia, and University Consortium “La
Chimica per l’Ambiente”, Via S. Camillo De Lellis, 01100 Viterbo, Italy
b
Department of Studies of Chemistry and Technology of Biologically Active
Substances, University “La Sapienza”, P. le A. Moro 5, 00185 Rome, Italy
Abstract – The reaction of methyl β-(o-acetamidophenyl)acrylates with aryl
iodides in the presence of Pd(OAc)2 and KOAc in DMF at 120 °C affords
4-aryl-2-quinolones in allowable to good yields.
During our studies on the Heck reaction of β-substituted α,β-unsaturated carbonyl compounds we have
found that an appropriate choice of reaction conditions may favor the formation of vinylic substitution
products with the original β-substituent on the same side of the carbon-carbon double bond as the
carbonyl group.1 Because of this, β-substituted α,β-unsaturated carbonyl compounds containing a
nucleophile at the ortho position of the β substituent can give rise to cyclization reactions following the
vinylic substitution step and the whole process can be used as a useful tool for the preparation of cyclic
derivatives. We have taken advantage of this synthetic strategy to develop new syntheses of quinolines,2
coumarins,2,3 butenolides4 and cardenolides.1c Since many 2-quinolones show interesting biological
activities5 - including tipifarnid, a 4-aryl-2-quinolone derivative which exhibits anticancer activity6 - and
are also useful synthetic intermediates,7 it appeared of interest to us to explore the preparation of
4-aryl-2-quinolones from readily available methyl β-arylacrylates containing a nitrogen nucleophile in the
ortho position of the β-substituent through a domino Heck/cyclization reaction (Scheme 1).
Herein we report the results of this study.
p-Iodoanisole and methyl β-(o-aminophenyl)acrylate (1a) were initially selected as the model system and
the first attempt was carried out in the presence of 0.05 equiv of Pd(OAc)2 as the source of Pd(0) using a
molten Bu4NOAc/Bu4NBr mixture as the reaction medium at 100 °C.
This paper is dedicated to Dr. Satoshi Omura on the occasion of his 70th birthday.

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HETEROCYCLES, Vol. 69, 2006
O
NHE Ar
OMe
R
ArI
R
NHE
O
OMe
3
1
2
E = H (1a); MeCO (1b)
Ar
R
N
H
O
4
Scheme 1
These conditions were successfully used by us in the diastereoselective synthesis of β,β-diarylacrylates
from cinnamate esters and aryl iodides1d (subsequently extended to aryl bromides by Calò et al.8) and in
the formation of coumarins from 3-(o-hydroxyaryl)acrylate esters and aryl iodides or bromides.3
Unfortunately, no formation of the desired 4-substituted quinolone product was observed, the main
product being the parent quinolone (5) (Scheme 2), most probably derived from 1a via an E/Z
isomerization/cyclization reaction which is faster than the desired Heck/cyclization reaction.
O
OMe
N
H
O
NH2
5 (30%)
1a
Scheme 2
Surmising that the easy E/Z isomerization might be favored by the presence of the free, strongly
electron-donating amino group, we switched to the acetyl derivative (1b) (prepared in 80% overall
isolated yield from commercially available o-iodoaniline via acetylation and palladium-catalyzed vinylic
substitution with methyl acrylate) as the olefin partner. Indeed, subjecting 1b to the same conditions used
for 1a led to the isolation of the free NH quinolone derivative (4a), but only in 15% yield (Table 1, Entry
1). No evidence of 5 or its N-acetyl derivative was attained in this case. We next conducted the model
reaction in DMF in the presence of mixtures of KOAc and Bu4NCl (Table 1, Entry 2) or KOAc and KCl
(Table 1, Entry 3) and found that the quinolone product could be isolated in 45 and 40% yield,
respectively. By omitting chloride salts, 4a was isolated in 36% yield with Bu4NOAc (Table 1, Entry 4)
and 50% yield in the presence of KOAc (Table 1, Entry 5) suggesting that chloride source is unnecessary
for this transformation. An increase of the reaction temperature to 120 °C resulted in the formation of 4a
in 39% yield with Bu4NOAc (Table 1, Entry 6) and in a satisfactory 60% yield by using KOAc (Table 1,

HETEROCYCLES, Vol. 69, 2006
101
Entry 7). A further increase of temperature caused a drop in the yield of 4a (Table 1, Entry 8). This
reaction was subsequently carried out using other solvents such as NMP and DMA. NMP gave a slightly
lower yield (Table 1, Entry 9) whereas with DMA the yield was only moderate (Table 1, Entry 10).
Lower yields were also obtained when NaOAc was used instead of KOAc (Table 1, Entries 11 and 12).
Interestingly, a result comparable to that obtained with KOAc at 120 °C was obtained when the reaction
was carried out in Et3N at 100 °C (Table 1, Entry 13). These conditions, however, proved unsatisfactory
when they were applied to other aryl iodides (see Table 2, footnote c).
Table 1. Bases, Additives, Solvents, and Temperature in the Reaction of Methyl
β-(o-Acetamidophenyl)acrylate (1b) with p-Iodoanisole.a
Entry
Base
Additive
Solvent
Temperature
(°C)
Time
(h)
Yield %
of (4a)b
15
1
Bu4NOAc (2.1 equiv),
Bu4NBr (1.5 equiv)
DMF
100
15
2
3
KOAc
Bu4NCl (1 equiv)
100
100
100
100
120
120
140
120
120
120
120
100
100
120
48
24
24
48
24
48
48
48
48
48
48
24
48
24
45
40
36
50
39
60
52
57
33
30
45
59
30
55
KOAc
KCl (1 equiv)
DMF
DMF
DMF
DMF
DMF
DMF
NMP
DMA
NMP
DMF
4
Bu4NOAc
KOAc
−
−
−
−
−
−
−
−
−
−
−
−
5
6
Bu4NOAc
KOAc
7
8
KOAc
9
KOAc
10
11
12
13
14
15
KOAc
NaOAc
NaOAc
Et3N (5 equiv)
Et3N (2 equiv)
Bu3N (5 equiv)
−
DMF
−
aUnless otherwise stated, reactions were carried out on a 0.4 mmol scale in 1.5 mL of solvent using 1 equiv of (1b), 1.5
b
equiv of p-iodoanisole, 2 equiv of acetate base and 0.05 equiv of Pd(OAc)2 under argon. Yields are given for isolated
products.
In conclusion, the “optimal” reaction conditions for this domino reaction utilize 0.05 equiv of Pd(OAc)2
and 2 equiv of KOAc in DMF at 120 °C. No evidence of the vinylic substitution intermediate (3a) was
attained by monitoring the reaction mixture by TLC or HPLC, suggesting that under these conditions the
Heck reaction is followed by a fast cyclization step. Formation of 3a was observed at lower reaction
temperatures. At 80 °C (48 h) it was isolated in 25% yield along with 8% of 4a and a 30% yield of the
recovered 1b. Decreasing further the reaction temperature to 60 °C led to the isolation of 3a in 30% yield

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HETEROCYCLES, Vol. 69, 2006
after 48 h. The quinolone derivative (4a) was not formed and the starting material was recovered in 50%
yield.
The results obtained subjecting a variety of aryl iodides and methyl β-(o-acetamidoaryl)acrylates to the
optimal conditions are shown in Table 2.
Table 2. Synthesis of 4-Aryl-2-quinolones (4) from Methyl β-(o-Acetamidoaryl)acrylates (1)
and Aryl Iodides (2) through a Domino Heck/Cyclization Reaction.a
Entry
Aryl Iodide (2)
Time (h) Yield % of (4)b
Methyl β-(o-Acetamidophenyl)acrylate (1)
CO2Me
1
p-MeO-C6H4-I
48
60
4a
NHCOMe
1b
2
3
4
1b
1b
1b
p-Me-C6H4-I
m-MeO-C6H4-I
o-MeO-C6H4-I
Me
24
24
24
62
62
−
4b
4c
5
1b
I
48
80
4d
Me
6
7
1b
1b
1b
1b
1b
1b
1b
1b
p-MeCONH-C6H4-I
m-Me-C6H4-I
PhI
48
24
24
24
48
24
24
48
55c
61
51
11
30
65
51
−
4e
4f
8
4g
4h
4i
9
o-F-C6H4-I
10
11
12
13
m-F-C6H4-I
p-F-C6H4-I
4j
p-Cl-C6H4-I
m-CHO-C6H4-I
4k
O
O
14
1b
24
53
4l
I
15
16
1b
1b
p-MeCO-C6H4-I
48
48
−
O
O
52
4m
4n
I
Me
Me
Me
CO2Me
NHCOMe
17
p-MeO-C6H4-I
24
62
Cl
1c
1d
18
19
1c
p-Me-C6H4-I
24
48
55
59
4o
4p
CO2Me
p-MeO-C6H4-I
NHCOMe
Me

HETEROCYCLES, Vol. 69, 2006
103
20
21
1d
1d
p-Me-C6H4-I
p-F-C6H4-I
48
48
55
48
4q
4r
Me
CO2Me
22
p-MeO-C6H4-I
48
40
4s
NHCOMe
NO2
1e
CO2Me
NHCOMe
23
24
1e
p-Me-C6H4-I
48
48
42
41
4t
MeCO
p-MeO-C6H4-I
4u
1f
aReactions were carried out on a 0.4 mmol scale in 1.5 mL of DMF using 1 equiv of (1), 1.5 equiv of aryl iodide,
b
2 equiv of KOAc and 0.05 equiv of Pd(OAc)2 under argon at 120 °C. Yields are given for isolated products.
cCompound (4e) was isolated only in 10% yield when the reaction was carried out in Et3N, according to the
conditions shown in Table 1, Entry 13.
4-Aryl-2-quinolones were isolated in allowable to good yields with a variety of methyl
β-(o-acetamidoaryl)acrylates and aryl iodides. p-Iodobenzaldehyde and p-iodoacetophenone did not
afford the corresponding 2-quinolone products under our standard conditions (Table 2, Entries 13 and 15).
However, appropriately protected aldehydic and ketonic aryl iodides gave the desired products in
satisfactory yields (Table 2, Entries 14 and 16).
In conclusion, we have developed a new straightforward approach to 4-aryl-2-quinolones from readily
available starting materials using a phosphine free palladium-based catalyst system which may represent
a convenient alternative to known olefine-based9 palladium-catalyzed syntheses of this class of
compounds.
ACKNOWLEDGEMENTS
Work carried out in the framework of the National Project "Stereoselezione in Sintesi Organica.
Metodologie ed Applicazioni" supported by Ministero dell’Istruzione, dell’Università e della Ricerca
(MIUR). The authors are also greatly indebted to the University “La Sapienza” for financial support of
this research.
EXPERIMENTAL
Melting points were determined with a Büchi B-545 apparatus and are uncorrected. All of the reagents,
catalysts, and solvents are commercially available and were used as purchased, without further
purification. Reaction products were purified on axially compressed columns, packed with SiO2 25-40
µm (Macherey Nagel), connected to a Gilson solvent delivery system and to a Gilson refractive index
1
13
detector, and eluting with n-hexane/AcOEt mixtures. H NMR (400 MHz), C NMR (100.6 MHz) and
19F NMR (376.5 MHz) spectra were recorded with a Bruker Avance 400 spectrometer using TMS as shift

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HETEROCYCLES, Vol. 69, 2006
reference. EI (70 EV) mass spectra were recorded with a Varian Saturn 2100T GC/MS apparatus. IR
spectra were recorded with a Jasco FT/IR 430 spectrometer.
Typical Procedure for the Synthesis of Methyl β-(o-Acetamidophenyl)acrylates (1). Preparation of
1b.To a stirred solution of N-(2-iodophenyl)acetamide (2.05 g, 7.85 mmol), methyl acrylate (2.12 mL,
23.56 mmol), KOAc (0.77 g, 7.85 mmol), K2CO3 (1.35 g, 9.81 mmol) at 80 °C in DMF (8 mL),
Pd(OAc)2 (0.044 g, 0.196 mmol) was added. The mixture was stirred for 1 h. After cooling, the mixture
was diluted with AcOEt and washed with water. The organic layer was dried over Na2SO4 and
concentrated under reduced pressure. The residue was purified by chromatography (silica gel; 30/70 v/v
n-hexane/AcOEt) to give 1.55 g (90 % yield) of 1b: mp 137-138 °C; IR (KBr) 3275, 1723, 1658 cm-1; 1H
NMR (CDCl3) δ 7.83 (d, J = 15.8 Hz, 1H), 7.73 (m, 1H), 7.55 (m, 1H), 7.48 (bs, 1H), 7.39 (m, 1H), 7.21
13
(m, 1H), 6.40 (d, J = 15.8 Hz, 1H), 3.81 (s, 3H), 2.24 (s, 3H); C NMR (CDCl3) δ 168.4, 166.6, 139.1,
135.4, 130.3, 127.2, 126.6, 125.4, 124.8, 119.7, 51.3, 23.6; MS m/z (relative intensity) 146 (100 %), 118
(94 %), 117 (95%) 219 (M+ 23 %).
Typical Procedure for the Synthesis of 4-Aryl-2-quinolones (4). Preparation of (4a). To a stirred
solution of methyl β-(o-acetamidophenyl)acrylate (0.088 g, 0.40 mmol), p-iodoanisole (0.140 g, 0.60
mmol), KOAc (0.078 g, 0.8 mmol) at 120 °C in DMF (1.5 mL), Pd(OAc)2 (0.0045 g, 0.020 mmol) was
added. The mixture was stirred for 48 h After cooling, the mixture was diluted with AcOEt and washed
with water. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by chromatography (silica gel, 35 g; 25/75 v/v n-hexane/AcOEt) to give 0.061 g
1
(60 % yield) of 4a: mp 196-198 °C; IR (KBr) 3131, 1672 cm-1; H NMR (CDCl3) δ 12.83 (bs, 1H),
7.64-7.62 (m, 1H), 7.57-7.51 (m, 2H), 7.45-7.43 (m, 2H), 7.20-7.18 (m, 1H), 7.06 (m, 2H), 6.35 (s, 1H),
13
3.91 (s, 3H); C NMR (CDCl3) δ 164.4, 160.2, 153.2, 139.1, 130.7, 130.3, 129.5, 126.8, 122.5, 120.6,
119.8, 116.8, 114.2, 55.6; MS m/z (relative intensity) 251 (M+, 100 %), 252 (40 %), 236 (30%) 208
(50 %).
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