A new general approach to 4-substituted-3-halo-2-quinolones

Article abstract of DOI:10.1016/j.jfluchem.2010.01.008

A general procedure for the preparation of 4-substituted-3-halo-2-quinolones (halo = F, Cl, Br) utilizing 2-halo diethylphosphonoacetic acids (halo = F, Cl, Br) and o-aminophenylketones as the starting materials is described. The title compounds are obtained by an intramolecular Horner-Wadsworth-Emmons olefination of halogen-containing N-acyl-o-aminophenylketones. The transformation process is generally applicable under mild conditions.

Full text of DOI:10.1016/j.jfluchem.2010.01.008

Journal of Fluorine Chemistry 131 (2010) 597–605
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
A new general approach to 4-substituted-3-halo-2-quinolones
*
Shuai Zhao, Yan-hong He, Di Wu, Zhi Guan
School of Chemistry and Chemical Engineering, Southwest University, Chongqing 400715, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
A general procedure for the preparation of 4-substituted-3-halo-2-quinolones (halo = F, Cl, Br) utilizing
2-halo diethylphosphonoacetic acids (halo = F, Cl, Br) and o-aminophenylketones as the starting
materials is described. The title compounds are obtained by an intramolecular Horner–Wadsworth–
Emmons olefination of halogen-containing N-acyl-o-aminophenylketones. The transformation process
is generally applicable under mild conditions.
Received 15 December 2009
Received in revised form 14 January 2010
Accepted 19 January 2010
Available online 25 January 2010
ß 2010 Elsevier B.V. All rights reserved.
Keywords:
2-Quinolones
4-Substituted-3-fluoro-2-quinolones
4-Substituted-3-chloro-2-quinolones
4-Substituted-3-bromo-2-quinolones
Horner–Wadsworth–Emmons olefination
1. Introduction
ular condensation of an N-acyl-o-aminophenylketone. For exam-
ple, the condensation of
a-chloro(or bromo)-aroylacetanilides
The 2-quinolone skeleton, as an important structure unit, usually
presents in a large number of alkaloids and in biologically active
compounds [1–3]. There has been considerable interest in develop-
ing 2-quinolones as anticancer [4], antibacterial [5], antihyperten-
sive agents [6], and inhibitors of the macrophage colony-stimulating
factor-1 receptor (FMS) and p38 Mitogen-activated protein (MAP)
kinase [7,8]. Moreover, 2-quinolones are useful precursors to the
corresponding quinolines and isoquinolines [9].
In recent years, an increasing interest in the synthesis of
functionalized 2-quinolones with promising biological properties
has been observed [10]. Especially, 4-substituted-3-halo-2-quino-
lones have been given more attention, which have been used as
cardiac stimulants [11] and herbicides [12]. However, to the best of
our knowledge, there is no general method for the synthesis of 4-
substituted-3-halo-2-quinolones (halo = F, Cl, Br) reported. Some
examples used direct halogenation of 4-substituted-2-quinolones,
such as the bromination of 4-substituted-2-quinolones with NBS
or bromine dissolved in acetic acid to prepare 4-substituted-3-
bromo-2-quinolones [13]. Some used substitution of 4-substitut-
ed-2-quinolone derivates, such as Rh2 (OAc)4 catalyzed cyclic
diazodicarbonyl compounds with a variety of halides obtaining the
corresponding 4-substituted-3-chloro(or 3-bromo)-2-quinolones
[14]. And the substitution of 3-bromo-4-trifloxy-quinolin-2(1H)-
one with Pd(Cl)2(PPh)3 was used to get 4-substituted-3-bromo-2-
quinolones [15]. A frequently employed method is an intramolec-
with concentrated sulfuric acid giving the corresponding 4-
substituted-3-chloro(or bromo)-2-quinolones [16,17], and the
condensation of 2-chloro-2-(2-fluorobenzoyl) acetanilide with
85% KOH in DMF and H2O giving 3-chloro-4-(2-fluorophenyl)-
2(1H)-quinolinone [18]. Nevertheless, the limitation of methods
reported lies in the difficulty of halogenation due to the difficulty in
controlling their regioselectivity, the strong reaction conditions,
and the side reactions involving polyhalogenation [19]. Other
disadvantages involve the low yields of the reaction, a cumber-
some and lengthy process, migration of substituents (rearrange-
ment), and not readily available starting materials. Therefore, it is
required to develop a general, effective and simple method to
prepare 4-substituted-3-halo-2-quinolones. To pursue the goal, we
adopted the strategy shown in Scheme 1. In order to obtain
compounds 1 with high yields and easily controlled regioselec-
tivity of reactions, an intramolecular Horner–Wadsworth–
Emmons olefination of intermediates 2 was employed. The
phosphonoacetate in molecules of intermediates 2 activated the
carboxamide
a-position, which could be eliminated after cycliza-
tion under basic conditions to produce compounds 1. In this
strategy, halogens were previously introduced into intermediates
2 by the acylation of 2-halo diethylphosphonoacetic acids 3 with o-
aminophenylketones 4, which could overcome the difficulty in
controlling their regioselectivity.
2. Results and discussion
Oneofthestartingmaterials2-halodiethylphosphonoaceticacids
* Corresponding author. Tel.: +86 23 68254091; fax: +86 23 68254091.
E-mail address: guanzhi@swu.edu.cn (Z. Guan).
3 were easily prepared in good yields by the hydrolysis of triethyl 2-
0022-1139/$ – see front matter ß 2010 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2010.01.008

598
S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
Scheme 1. Strategy for the preparation of 4-substituted-3-halo-2-quinolones.
Scheme 2. Preparation of 2-halo diethylphosphonoacetic acids 3.
Scheme 3. Preparation of o-aminophenylketones.
Scheme 4. Preparation of 4-substituted-3-halo-2-quinolones. Reagents and conditions: (a) (COCl)2, CH2Cl2, r.t., 24 h; (b) pyridine, CH2Cl2, 0 8C to r.t., 4.5 h; (c) THF, LiCl, DBU,
r.t., 2 h.
halo phosphonoacetates 7 with1 N NaOH [20]. Triethyl 2-fluoropho-
sphonoacetate 7c was commercially available. However, triethyl 2-
chlorophosphonoacetate 7a and triethyl 2-bromophosphonoacetate
7b were prepared according to literatures [21]. The method is
illustrated in Scheme 2. Triethyl 2,2-dichlorophosphonoacetate 6a
was prepared by the chlorination of triethyl phosphonoacetate 5
using sodium hypochlorite, followed by selective reduction to
convert the dichloro product to the corresponding triethyl 2-
chlorophosphonoacetate 7a with sodium sulfite. In the same way,
triethyl 2,2-dibromophosphonoacetate 6b was prepared by the
bromination of triethyl phosphonoacetate 5 using the freshly
prepared sodium hypobromite, followed by selective reduction to
convert the dibromo product to the corresponding triethyl 2-
bromophosphonoacetate 7b with SnCl2-2H2O.
Another starting materials 4a, 4d–f were purchased from
commercial sources. However, 2-amino-5-chloroacetophenone 4b
and 2-amino-4,5-dimethoxyacetophenone 4c were prepared by
ourselves. The method is illustrated in Scheme 3. 3-Chloroaceto-
phenone 8b was converted to 5-chloro-2-nitroacetophenone 9b by
nitration with fuming HNO3 and concentrated H2SO4 at À20 8C,
whichwasthenreducedbyironpowderinAcOHtoform2-amino-5-
chloroacetophenone 4b [22]. 3,4-Dimethoxyacetophenone 8c was
converted to 4,5-dimethoxy-2-nitroacetophenone 9c by nitration
with fuming HNO3 and AcOH at 0 8C, which was then reduced into2-
amino-4,5-dimethoxyacetophenone 4c by H2 with PtO2/C [23].
The intermediates 2 were prepared by the acylation of
o-aminophenylketones 4a–f with 2-halo diethylphosphonoace-
tic acids 3a–c [8]. The method is illustrated in Scheme 4. In order
to realize this transformation, 3 were first converted into acyl
Table 1
The preparation of intermediates 2a–r using 2-halo diethylphosphonoacetic acids 3
and o-aminophenylketones 4.
Compound
R1
R2
R3
X
Conversion
(%)
Yield (%)
2a
2b
2c
2d
2e
2f
CH3
CH3
CH3
Ph
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
F
98
96
95
74
95
92
95
96
94
69
91
90
98
98
96
65
94
93
94
93
92
70
90
88
91
92
91
65
87
85
92
92
90
62
89
88
Cl
H
OCH3
H
OCH3
H
Ph
Cl
H
Ph
NO2
H
H
2g
2h
2i
CH3
CH3
CH3
Ph
H
Cl
H
OCH3
H
OCH3
H
2j
2k
2l
Ph
Cl
H
Ph
NO2
H
H
2m
2n
2o
2p
2q
2r
CH3
CH3
CH3
Ph
H
Cl
H
F
OCH3
H
OCH3
H
F
F
Ph
Cl
H
F
Ph
NO2
H
F

S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
599
Scheme 5. Proposed mechanism for the reaction of N-acyl-o-aminophenylketones with LiCl and DBU.
Table 2
The yields of 4-substituted-3-halo-2-quinolones 1 via a Horner–Wadsworth–Emmons route.
Entry
R1
R2
R3
X
Purification methodology
mp (8C)
Yield (%)
1a
1b
1c
1d
1e
1f
CH3
CH3
CH3
Ph
H
H
Cl
Cl
Cl
Cl
Cl
Cl
Br
Br
Br
Br
Br
Br
F
Recrystallization
300–302
272–274
250–252
191–193
299–301
221–223
268–269
204–206
227–229
228–230
218–220
202–204
179–181
211–213
266–268
254–256
197–199
188–190
88
95
82
94
95
96
85
88
78
26
18
19
40
38
30
91
92
93
Cl
H
Recrystallization
OCH3
H
OCH3
H
Recrystallization
Recrystallization
Ph
Cl
H
Recrystallization
Ph
NO2
H
H
Recrystallization
1g
1h
1i
CH3
CH3
CH3
Ph
H
Recrystallization
Cl
H
Recrystallization
OCH3
H
OCH3
H
Recrystallization
1j
Column chromatography
Column chromatography
Column chromatography
Column chromatography
Column chromatography
Column chromatography
Recrystallization
1k
1l
Ph
Cl
H
Ph
NO2
H
H
1m
1n
1o
1p
1q
1r
CH3
CH3
CH3
Ph
H
Cl
H
F
OCH3
H
OCH3
H
F
F
Ph
Cl
H
F
Recrystallization
Ph
NO2
H
F
Recrystallization
halide in situ by using (COCl)2 at room temperature, which then
reacted with newly added o-aminophenylketones 4 in the
presence of excessive pyridine to give compounds 2a–r. The
reaction underwent smoothly, and good yields were obtained
except 2-aminodiphenyl methanone 4d as substrate. The results
are shown in Table 1. As can be seen from Table 1, the reaction
was applicable to a variety of o-aminophenylketones 4. The
successful acylation of 4 with 3 was achieved when R1 = alkyl
and aryl, and R2, R3 as electron-donating and electron-
withdrawing groups. In order to test the generality of this
method, we embarked on a systematic study of substituted o-
aminophenylketones 4 and 2-halo diethylphosphonoacetic acids
3 as starting materials.
Compounds 2 were subjected to cyclization under the mildly
basic Masamune–Roush conditions (LiCl/DBU) [24]. As it turned
out, the difference of the halogen and substituents had effect on the
cyclization of the intermediates 2. When X = Cl, all the cyclization
of intermediates 2a–f occurred smoothly to produce the expected
2-quinolones 1a–f in excellent yields (Entries 1a–f, Table 2).
However, in the case of X = Br, when R1 = alkyl, the cyclization
of intermediates 2g–i gave the expected 2-quinolones 1g–i in good
yields, but when R1 = aryl, the reactions were complicated, and the
cyclization of intermediates 2j–l gave 1j–l only in yields of 18–26%.
The expected products were obtained only as the minor products,
and the unexpected byproducts 10 were isolated as the main one.
Interestingly, the contrast results were observed for the cyclization
of intermediates 2 with X = F. When R1 = aryl, the cyclization of
intermediates 2p–r occurred smoothly to produce the expected 2-
quinolones 1p–r in excellent yields, but when R1 = alkyl, the
cyclization of intermediates 2m–o gave 1m–o only in yields of 30–
40%, and a few byproducts were observed.
Based on the above results, we proposed the possible
mechanism of the cyclization (Scheme 5). Two carbanions 2i
and 2ii could be formed under basic conditions. Some unexpected
products could be formed via carbanions 2i by inter- and
intramolecular condensations. Not only can carbanions 2ii give
expected products 1 and uneliminated products 10, but also it can
form unexpected products 11 by intermolecular condensation.
3. Conclusions
The reaction of o-aminophenylketones with 2-halo diethylpho-
sphonoacetic acids provides a general procedure for 4-substituted-
3-halo-2-quinolones from readily available starting materials. The

600
S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
cyclization of halogenated N-acyl-o-aminophenylketones is main-
ly influenced by the halogen. Although some compounds were
obtained in low yields, this new method may be considered as new
halogen-containing substrates for the synthesis of a wide variety of
heterocyclic compounds with potential biological activity. Study of
this reaction and the nature of the products are being continued.
and the solvent was removed in vacuo. The desired product was
isolated by partitioning the crude residue between hexane (20 mL)
and H2O (4 Â 5 mL). The aqueous fractions were combined and re-
extracted with chloroform (3 Â 10 mL). The chloroform extracts
were dried (MgSO4) and evaporated at reduced pressure to provide
pure 7b (1.28 g, 81% yield) as colourless oil. 1H NMR (300 MHz,
2
CDCl3):
d
4.37 ppm (d, JP,H = 14.0, 1H, CHBr), 4.33–4.24 ppm (m,
6H, CH2), 1.40–1.30 ppm (m, 9H, CH3).
4. Experimental
Infrared spectra were measured on a Bruker Tensor 27 IR
spectrophotometer. 1H NMR (300 MHz), 13C NMR (75 MHz), 31P
NMR (121 MHz) and 19F NMR (282 MHz) spectra were recorded on
a Bruker AV-300. The spectra were recorded in CDCl3 and DMSO-d6
4.3. General procedure for the preparation of 2-halo
diethylphosphonoacetic acids 3 [26]
To a solution of sodium hydroxide (0.84 g, 15.0 mmol) in water
(15 mL) was added the triethyl 2-halo phosphonoacetate
(10.0 mmol). The reaction mixture was stirred for 20 h at r.t.
and then washed with CH2Cl2 (2 Â 10 mL), acidified to pH 2 with
10% HCl and extracted with AcOEt (3 Â 15 mL). After drying with
MgSO4, the solvent was evaporated under reduced pressure to give
the acids 3.
as solvent at room temperature. The chemical shifts (d) were given
in ppm, and the coupling constants (J) in Hz. HRMS spectra were
recorded on a high resolution ESI-FTICR and MALDI-FTICR mass
spectrometry. Melting points were determined on a X-4 digital
display micromelting point apparatus and were uncorrected.
4.1. Triethyl 2-chlorophosphonoacetate (7a) [25]
4.3.1. 2-Chloro diethylphosphonoacetic acid (3a)
A solution of 5.25% sodium hypochlorite (31.6 g, 22.3 mmol)
was adjusted to pH 7.1 with approximately 2 mL of 3 N HC1.
Triethyl phosphonoacetate (1.0 g, 4.5 mmol) was added drop-
wise at ice-bath temperature with vigorous stirring. After
complete addition, the ice-bath was removed, and stirring
was continued for an additional 5 min. The turbid solution was
extracted with 5 Â 5 mL of hexane. The combined hexane
extracts were dried (MgSO4), and the solvent was removed in
vacuo at 50 8C to give triethyl 2,2-dichlorophosphonoacetate 6a
(1.18 g, 90% yield) as colourless oil. 6a (1.1 g, 3.8 mmol) was
dissolved in EtOH (7.5 mL), and the resulting solution was
cooled in an ice-bath. A solution of sodium sulfite (1.0 g,
7.7 mmol) in H2O (30 mL) was added with stirring at a rate such
that the temperature could be maintained below 15 8C (15 min).
During addition, the reaction mixture became turbid. After
20 min of further stirring at room temperature, it was extracted
with chloroform (5 Â 10 mL). The chloroform extracts were
dried (MgSO4), and the solvent was removed in vacuo. The crude
mixture was partitioned between hexane (20 mL) and 0.1 M
NaHCO3 (85 mL). The bicarbonate fractions were combined and
re-extracted with chloroform (6 Â 5 mL). The chloroform
extracts were dried (MgSO4), and the solvent was removed in
1.96 g (85% yield), colourless oil. 1H NMR (300 MHz, CDCl3):
4.59 ppm (d, JP,H = 17.2, 1H, CHCl), 4.40–4.20 ppm (m, 4H, CH2),
d
2
1.42–1.37 ppm (m, 6H, CH3).
4.3.2. 2-Bromo diethylphosphonoacetic acid (3b)
2.26 g (82% yield), colourless oil. 1H NMR (300 MHz, DMSO):
d
2
5.01 ppm (d, JP,H = 14.6, 1H, CHBr), 4.19–3.98 ppm (m, 4H, CH2),
1.29–1.20 ppm (m, 6H, CH3).
4.3.3. 2-Fluoro diethylphosphonoacetic acid (3c)
1.67 g (78% yield), colourless oil. 1H NMR (300 MHz, CDCl3):
d
5.26 ppm (dd, 2JP,H = 13.4, 2JF,H = 47.1, 1H, CHF), 4.39–4.26 ppm (m,
4H, CH2), 1.42–1.36 ppm (m, 6H, CH3).
4.3.4. 5-Chloro-2-nitroacetophenone (9b) [22]
To
a rapidly stirred solution fuming HNO3 (8.5 ml) and
concentrated H2SO4 (1.3 ml) at À20 8C was added portionwise
3-chloroacetophenone (2.5 g, 16.2 mmol) over 15 min. The reac-
tion mixture was allowed to warm to À10 8C and stirred for 5 h at
this temperature after which ice-water (40 ml) was added and the
reaction mixture extracted twice with CH2Cl2. The organic layers
were combined, washed five times with water, dried over MgSO4
and concentrated under reduced pressure. The residue was filtered
through a pad of silica (eluting with CH2Cl2/PE, 4:1) to afford a pale
green oil which was recrystallized from Et2O/PE to give 5-chloro-2-
nitroacetophenone (2.52 g, 78% yield), pale yellow crystals, mp 63–
vacuo to give pure 7a (0.85 g, 88% yield) as colourless oil. 1H
2
NMR (300 MHz, CDCl3):
d
4.52 ppm (d, JP,H = 16.2, 1H, CHCl),
4.35–4.23 ppm (m, 6H, CH2), 1.43–1.31 ppm (m, 9H, CH3).
4.2. Triethyl 2-bromophosphonoacetate (7b) [21]
65 8C. IR (KBr):
n
1712, 1565, 1520, 1421, 1340, 1307, 1245, 1105,
8.09 ppm (d, Jo = 8.7, 1H,
863 cmÀ1 1H NMR (300 MHz, CDCl3):
.
d
Triethyl phosphonoacetate (1.2 g, 5.4 mmol) was added over
3 min to the freshly prepared, stirred sodium hypobromite
solution cooled in an ice-salt bath. The temperature was
maintained below 10 8C. When addition was complete, the
mixture was immediately extracted with chloroform
(4 Â 10 mL). The chloroform extracts were washed with water
(2 Â 2 mL) and dried (MgSO4), and the solvent was removed in
vacuo. The residue was partitioned between hexane (40 mL) and
H2O (2 Â 0.5 mL) and the hexane extracts were dried (MgSO4).
Removal of the solvent in vacuo left pure triethyl 2,2-dibromopho-
sphonoacetate 6b (1.78 g, 87% yield) as colourless oil. To 6b (2.0 g,
5.2 mmol) dissolved in EtOH (5 mL) was added with cooling (ice-
bath) a solution of 1.12 g (5.0 mmol) of SnCl2-2H2O in H2O (10 mL).
The temperature was maintained below 10 8C. When addition was
complete (20 min), the reaction mixture was stirred for an
additional 5 min at room temperature and then extracted with
CHCl3 (4 Â 10 mL). The chloroform extracts were dried (MgSO4),
Ar–H), 7.57 ppm (d, Jo = 8.7, 1H, Ar–H), 7.39 ppm (s, 1H, Ar–H),
2.56 ppm (s, 3H, OCH3).
4.3.5. 2-Amino-5-chloroacetophenone (4b) [27]
A mixture of 5-chloro-2-nitroacetophenone (2.2 g, 11.0 mmol),
PtO2 (20 mg) and charcoal (200 mg) in EtOH (40 ml) was rapidly
stirred at r.t. for 4.5 h under 1 atm. of hydrogen. The reaction
mixture was filtered through a pad of celite (the residues washed
with CH2Cl2) and concentrated under reduced pressure. The
residues was filtered through a pad of silica (eluting with CH2Cl2/
PE, 4:1) to afford a pale green oil which was recrystallized from
Et2O/PE to give 2-amino-5-chloroacetophenone (1.35 g, 72% yield),
pale green crystals, mp 63–64 8C. IR (KBr):
1616, 1570, 1546, 1475, 1361, 1222, 1158, 956, 823, 626 cmÀ1. 1H
NMR (300 MHz, CDCl3): 7.67 ppm (s, 1H, Ar–H), 7.22 ppm (d,
n 3455, 3320, 1657,
d
Jo = 8.7, 1H, Ar–H), 6.62 ppm (d, Jo = 8.7, 1H, Ar–H), 6.28 ppm (s, 2H,
NH2), 2.57 ppm (s, 3H, OCH3).

S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
601
4.3.6. 4,5-Dimethoxy-2-nitroacetophenone (9c) [23]
4.4.2. Diethyl (2-acetyl-4-
Fuming nitric acid (6.0 mL, 140 mmol) was added dropwise to a
solution of 3,4-dimethoxyacetophenone (3.6 g, 20.0 mmol) in
AcOH (14 mL) at 0 8C. The reaction mixture was maintained at
0 8C for 10 min and at room temperature for 20 min. Then it was
poured into ice and the separated residue was filtered off and
washed with a water solution of NaHCO3 until pH 7 was reached.
Recrystallization from EtOH–acetone afforded compound 9c
chlorophenylcarbamoyl)chloromethylphosphonate (2b)
0.82 g (93% yield), purified by column chromatography
(dichloromethane:methanol = 90:1), yellow oil. IR (KBr): 3475,
1681, 1664, 1577, 1512, 1397, 1361, 1304, 1258, 1163, 1020, 961,
733 cmÀ1 1H NMR (300 MHz, CDCl3):
12.40 ppm (s, 1H, NH),
n
.
d
8.72 ppm (d, Jo = 9.0 Hz, 1H, Ar–H), 7.88 ppm (d, Jm = 2.1 Hz, 1H,
Ar–H), 7.54 ppm (dd, Jm = 2.1 Hz, Jo = 9.0 Hz, 1H, Ar–H), 4.57 ppm
2
(2.34 g, 52% yield), yellow needles, mp 135–137 8C. IR (KBr):
1702, 1578, 1515, 1464, 1326, 1284, 1225, 1183, 1047, 883,
789 cmÀ1 1H NMR (300 MHz, CDCl3):
7.62 ppm (s, 1H, Ar–H),
n
(d, JP,H = 16.2 Hz, 1H, CHCl), 4.37–4.25 ppm (m, 4H, CH2),
2.68 ppm (s, 3H, COCH3), 1.40–1.35 ppm (m, 6H, CH3). 13C NMR
2
.
d
(75 MHz, CDCl3):
d
201.2, 162.9 ppm (d, JP,C = 1.6 Hz), 138.2,
2
6.76 ppm (s, 1H, Ar–H), 3.99 ppm (s, 6H, OCH3), 2.51 ppm (s, 3H,
OCH3).
134.6, 131.1, 128.4, 123.6, 122.2, 64.7 ppm (d, JP,C = 6.8 Hz),
52.8 ppm (d, 1JP,C = 142.3 Hz), 28.3, 16.3 ppm (d, 3JP,C = 5.8 Hz). 31
P
NMR (121 MHz, CDCl3):
d 6.01 ppm (s, 1P). HRMS-MALDI: m/z
4.3.7. 2-Amino-4,5-dimethoxyacetophenone (4c) [23]
[M+Na]+ calcd for C14H18Cl2NO5PNa: 404.0192; found: 404.0192.
A
mixture of 4,5-dimethoxy-2-nitroacetophenone (2.0 g,
9.0 mmol), iron powder (5.0 g), AcOH (18 mL), water (25 mL),
and AcOEt (5 mL) was stirred under reflux for 6 h. After completion
of the reaction, the mixture was neutralized with NaHCO3 until pH
7 and filtered off. The residue was washed on the filter with AcOEt
(3 Â 40 mL). The organic layer was separated and the water layer
was extracted with AcOEt (3 Â 40 mL). Combined extracts were
dried over anhydrous Na2SO4 and evaporated under reduced
pressure. The residue was recrystallized from AcOEt–hexane
afforded compound 4c (1.19 g, 68% yield), pale yellow solid, mp
4.4.3. Diethyl (2-acetyl-4,5-
dimethoxyphenylcarbamoyl)chloromethylphosphonate (2c)
0.86 g (92% yield), purified by column chromatography (dichlor-
omethane:methanol = 100:1), yellowish solid, mp 83–85 8C. IR
(KBr):
n
3436, 1674, 1658, 1583, 1519, 1451, 1312, 1259, 1165,
1H NMR (300 MHz, CDCl3):
1046, 1019, 970, 948, 777 cmÀ1
.
d
12.79 ppm (s, 1H, NH), 8.49 ppm (s, 1H, Ar–H), 7.30 ppm (s, 1H, Ar–
2
H), 4.59 ppm (d, 1H, JP,H = 16.1 Hz, CHCl), 4.36–4.28 ppm (m, 4H,
CH2), 3.98 ppm (s, 3H, OCH3), 3.93 ppm (s, 3H, OCH3), 2.64 ppm (s,
106–108 8C. IR (KBr):
1454, 1406, 1255, 1210, 1164, 1057, 949, 845, 566 cmÀ1
(300 MHz, CDCl3): 7.10 ppm (s, 1H, Ar–H), 6.26 ppm (s, 2H, NH2),
n
3414, 3299, 1629, 1591, 1540, 1511, 1468,
3H, COCH3), 1.40–1.35 ppm (m, 6H, CH3). 13C NMR (75 MHz, CDCl3):
2
.
1H NMR
d
200.4, 162.6 ppm (d, JP,C = 1.7 Hz), 154.1, 144.0, 136.2, 114.8,
2
d
113.3, 103.4, 64.6 ppm (d, JP,C = 6.7 Hz), 56.1, 56.0, 52.7 ppm (d,
1JP,C = 143.3 Hz), 28.1, 16.2 ppm (d, JP,C = 5.8 Hz). 31P NMR
3
6.11 ppm (s, 1H, Ar–H), 3.88 ppm (s, 3H, OCH3), 3.85 ppm (s, 3H,
OCH3), 2.53 ppm (s, 3H, OCH3).
(121 MHz, CDCl3):
d 11.71 ppm (s, 1P). HRMS-MALDI: m/z
[M+Na]+ calcd for C16H23ClNO7PNa: 430.0793; found: 430.0792.
4.4. General procedure for the preparation of N-acyl-o-
aminophenylketone 2a–r
4.4.4. Diethyl (2-acetophenone-
phenylcarbamoyl)chloromethylphosphonate (2d)
0.66 g (70% yield), purified by column chromatography
To a solution of 2-halo-2-diethylphosphonoacetic acids 3a–c
(2.3 mmol) in dichloromethane (2 mL) was added oxalyl
chloride (0.40 mL, 4.7 mmol) at 25 8C under argon. The mixture
was stirred overnight and then concentrated. The brown oil was
diluted with dichloromethane (5 mL), followed by the addition
of the corresponding o-aminophenylketones 4a–f (2.3 mmol) in
dichloromethane (4 mL). In the case of 4f, it was dissolved with
dichloromethane (30 mL), due to the low solubility. Pyridine
(0.38 mL, 4.7 mmol) was slowly added using a ice-water bath
over 10 min. After stirring for 4.5 h, the reaction mixture was
quenched with 3 N HCl (2 mL) and extracted with CH2Cl2
(4 Â 10 mL). The organic layer was washed with brine (5 mL),
dried (Na2SO4), and evaporated to obtain the corresponding
product which was further purified by column chromatography
(silica gel).
(dichloromethane:methanol = 110:1), yellow oil. IR (KBr):
3485, 3278, 1692, 1641, 1583, 1528, 1448, 1317, 1294, 1269,
1163, 1051, 979, 755, 704 cmÀ1 1H NMR (300 MHz, CDCl3):
n
.
d
11.59 ppm (s, 1H, NH), 8.61 ppm (d, J = 8.7 Hz, 1H, Ar–H), 7.73 ppm
(d, J = 7.4 Hz, 2H, Ar–H), 7.63 ppm (s, 1H, Ar–H), 7.59 ppm (d,
J = 7.5 Hz, 2H, Ar–H), 7.49 ppm (t, J = 7.4 Hz, 2H, Ar–H), 7.16 ppm (t,
J = 7.5 Hz, 1H, Ar–H), 4.59 ppm (d, 2JP,H = 16.1 Hz, 1H, CHCl), 4.36–
4.24 ppm (m, 4H, CH2), 1.40–1.31 ppm (m, 6H, CH3). 13C NMR
2
(75 MHz, CDCl3):
d
198.8, 162.5 ppm (d, JP,C = 1.6 Hz), 139.1,
138.1, 134.0, 133.3, 132.5, 129.9 Â 2, 128.2 Â 2, 124.1, 123.1,
2
1
121.5, 64.6 ppm (d, JP,C = 6.7 Hz), 52.6 ppm (d, JP,C = 142.5 Hz),
16.2 ppm (d, JP,C = 5.8 Hz). 31P NMR (121 MHz, CDCl3):
10.88 ppm (s, 1P). HRMS-MALDI: m/z [M+Na]+ calcd for
19H21ClNO5PNa: 432.0738; found: 432.0744.
d
3
C
4.4.1. Diethyl (2-acetylphenylcarbamoyl)chloromethylphosphonate
(2a)
0.75 g (94% yield), purified by column chromatography
(dichloromethane:methanol = 90:1), yellowish solid, mp 93–
4.4.5. Diethyl (2-acetophenone-4-
chlorophenylcarbamoyl)chloromethylphosphonate (2e)
0.92 g (90% yield), purified by column chromatography
(dichloromethane:methanol = 100:1), yellow oil. IR (KBr):
3427, 3238, 1697, 1663, 1604, 1528, 1482, 1332, 1293, 1274,
1224, 1163, 1043, 955, 697, 534 cmÀ1. 1H NMR (300 MHz, CDCl3):
11.39 ppm (s, 1H, NH), 8.57 ppm (d, J = 9.6 Hz, 1H, Ar–H), 7.74 ppm
(d, J = 7.5 Hz, 2H, Ar–H), 7.64 ppm (t, J = 7.3 Hz, 1H, Ar–H), 7.50–
7.55 ppm (m, 4H, Ar–H), 4.58 ppm (d, JP,H = 16.1 Hz, 1H, CHCl),
4.35–4.23 ppm (m, 4H, CH2), 1.37–1.31 ppm (m, 6H, CH3). 13C NMR
n
96 8C. IR (KBr):
1451, 1368, 1344, 1269, 1207, 1159, 1038, 1018, 869, 532 cmÀ1. 1H
NMR (300 MHz, CDCl3): 12.52 ppm (s, 1H, NH), 8.72 ppm (d,
n 3432, 1682, 1643, 1612, 1595, 1525, 1470,
d
d
J = 8.4 Hz, 1H, Ar–H), 7.93 ppm (d, J = 7.9 Hz, 1H, Ar–H), 7.57 ppm
(t, J = 7.6 Hz, 1H, Ar–H), 7.19 ppm (t, J = 7.6 Hz, 1H, Ar–H), 4.57 ppm
2
2
(d, JP,H = 16.1 Hz, 1H, CHCl), 4.37–4.24 ppm (m, 4H, CH2),
2.68 ppm (s, 3H, COCH3), 1.39–1.34 ppm (m, 6H, CH3). 13C NMR
(75 MHz, CDCl3):
d
197.4, 162.5 ppm (d, JP,C = 1.6 Hz), 137.5,
2
2
(75 MHz, CDCl3):
d
202.3, 162.8 ppm (d, JP,C = 1.7 Hz), 139.7,
137.4, 133.6, 133.0, 132.4, 129.9 Â 2, 128.5 Â 2, 128.4, 125.6,
2
2 1
123.1, 64.7 ppm (d, JP,C = 6.8 Hz), 52.5 ppm (d, JP,C = 142.4 Hz),
135.0, 131.5, 123.4, 122.4, 120.7, 64.6 ppm (d, JP,C = 6.8 Hz),
52.8 ppm (d, 1JP,C = 142.3 Hz), 28.3, 16.3 ppm (d, 3JP,C = 5.8 Hz). 31
NMR (121 MHz, CDCl3):
5.38 ppm (s, 1P). HRMS-ESI: m/z [M+Na]+
calcd for C14H19ClNO5PNa: 370.0582; found: 370.0586.
P
16.2 ppm (d, 3JP,C = 5.8 Hz). 31P NMR (121 MHz, CDCl3):
d 6.04 ppm
d
(s, 1P). HRMS-MALDI: m/z [M+Na]+ calcd for C19H20Cl2NO5PNa:
466.0348; found: 466.0341.

602
S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
4.4.6. Diethyl (2-acetophenone-4-
3JP,C = 5.9 Hz). 31P NMR (121 MHz, CDCl3):
d 9.50 ppm (s, 1P).
nitrophenylcarbamoyl)chloromethylphosphonate (2f)
HRMS-ESI: m/z [M+Na]+ calcd for C16H23BrNO7PNa: 474.0288;
0.92 g (88% yield), purified by column chromatography
found: 474.0280.
(dichloromethane:methanol = 110:1), yellow oil. IR (KBr):
n
3471, 3253, 1704, 1648, 1616, 1582, 1541, 1511, 1446, 1413,
1346, 1262, 1157, 1022, 972, 732 cmÀ1. 1H NMR (300 MHz, CDCl3):
4.4.10. Diethyl (2-acetophenone-
phenylcarbamoyl)bromomethylphosphonate (2j)
0.68 g (65% yield), purified by column chromatography
d
11.84 ppm (s, 1H, NH), 8.88 ppm (d, Jo = 9.2 Hz, 1H, Ar–H),
8.51 ppm (s, 1H, Ar–H), 8.45 ppm (dd, Jm = 2.0 Hz, Jo = 9.2 Hz, 1H,
Ar–H), 7.77–7.67 ppm (m, 3H, Ar–H), 7.56 ppm (t, J = 7.5 Hz, 2H,
Ar–H), 4.64 ppm (d, JP,H = 16.4 Hz, 1H, CHCl), 4.37–4.26 ppm (m,
(dichloromethane:methanol = 110:1), yellow oil. IR (KBr):
3480, 3274, 1693, 1642, 1601, 1583, 1528, 1447, 1317, 1294,
1267, 1162, 1051, 966, 755, 703 cmÀ1. 1H NMR (300 MHz, CDCl3):
n
2
d
4H, CH2), 1.39–1.33 ppm (m, 6H, CH3). 13C NMR (75 MHz, CDCl3):
d
11.44 ppm (s, 1H, NH), 8.57 ppm (d, J = 8.5 Hz, 1H, Ar–H), 7.74 ppm
(d, J = 7.6 Hz, 2H, Ar–H), 7.60–7.57 ppm (m, 3H, Ar–H), 7.49 ppm (t,
J = 7.4 Hz, 2H, Ar–H), 7.16 ppm (t, J = 7.6 Hz, 1H, Ar–H), 4.45 ppm
2
196.9, 163.0 ppm (d, JP,C = 1.6 Hz), 144.2, 141.9, 136.7, 133.4,
129.8 Â 2, 128.6 Â 2, 128.5, 128.2, 123.5, 121.5, 64.8 ppm (d,
2JP,C = 6.9 Hz), 52.5 ppm (d, 1JP,C = 141.8 Hz), 16.1 ppm (d,
2
(d, JP,H = 14.5 Hz, 1H, CHBr), 4.36–4.24 ppm (m, 4H, CH2), 1.40–
3JP,C = 5.8 Hz). 31P NMR (121 MHz, CDCl3):
d
6.20 ppm (s, 1P).
1.31 ppm (m, 6H, CH3). 13C NMR (75 MHz, CDCl3):
d
198.6,
HRMS-ESI: m/z [M+Na]+ calcd for C19H20ClN2O7PNa: 477.0589;
162.5 ppm (d, JP,C = 1.6 Hz), 139.2, 138.1, 133.9, 133.2, 132.6,
129.9 Â 2, 128.2 Â 2, 124.3, 123.1, 121.6, 64.7 ppm (d,
2JP,C = 6.8 Hz), 39.4 ppm (d, 1JP,C = 140.0 Hz), 16.2 ppm (d,
2
found: 477.0585.
4.4.7. Diethyl (2-acetylphenylcarbamoyl)bromomethylphosphonate
(2g)
3JP,C = 5.8 Hz). 31P NMR (121 MHz, CDCl3):
d 10.39 ppm (s, 1P).
HRMS-ESI: m/z [M+Na]+ calcd for C19H21BrNO5PNa: 476.0233;
0.82 g (91% yield), purified by column chromatography
(dichloromethane:methanol = 90:1), yellowish solid, mp 88–
found: 476.0225.
90 8C. IR (KBr):
1258, 1166, 1047, 1018, 968, 948, 775 cmÀ1
CDCl3): 12.43 ppm (s, 1H, NH), 8.71 ppm (d, J = 8.4 Hz, 1H, Ar–H),
n
3426, 1669, 1658, 1583, 1516, 1451, 1311,
4.4.11. Diethyl (2-acetophenone-4-
.
1H NMR (300 MHz,
chlorophenylcarbamoyl)bromomethylphosphonate (2k)
0.98 g (87% yield), purified by column chromatography
d
7.93 ppm (d, J = 7.9 Hz, 1H, Ar–H), 7.58 ppm (t, J = 7.4 Hz, 1H, Ar–
H), 7.19 ppm (t, J = 7.5 Hz, 1H, Ar–H), 4.44 ppm (d, JP,H = 14.5 Hz,
(dichloromethane:methanol = 100:1), yellow oil. IR (KBr):
3432, 3235, 1692, 1662, 1604, 1528, 1481, 1331, 1293, 1274,
1244, 1223, 1163, 1039, 975, 953, 696, 528 cmÀ1 1H NMR
(300 MHz, CDCl3): 11.24 ppm (s, 1H, NH), 8.54 ppm (d,
n
2
1H, CHBr), 4.38–4.25 ppm (m, 4H, CH2), 2.69 ppm (s, 3H, COCH3),
.
1.40–1.35 ppm (t, 6H, CH3). 13C NMR (75 MHz, CDCl3):
d
202.2,
d
162.9, 139.9, 135.0 ppm (d, J = 2.8 Hz), 131.5 ppm (d, J = 2.8 Hz),
123.4 ppm (d, J = 1.8 Hz), 122.5 ppm (d, J = 3.2 Hz), 120.82,
J = 9.6 Hz, 1H, Ar–H), 7.75 ppm (d, J = 7.6 Hz, 2H, Ar–H),
7.65 ppm (t, J = 7.1 Hz, 1H, Ar–H), 7.56–7.50 ppm (m, 4H, Ar–H),
4.44 ppm (d, JP,H = 14.5 Hz, 1H, CHBr), 4.35–4.24 ppm (m, 4H,
2
1
2
64.76 ppm (d, JP,C = 6.8 Hz), 39.8 ppm (d, JP,C = 140.0 Hz),
3
28.4 ppm (d, J = 3.6 Hz), 16.3 ppm (d, JP,C = 5.6 Hz). 31P NMR
CH2), 1.37–1.31 ppm (m, 6H, CH3). 13C NMR (75 MHz, CDCl3):
d
2
(121 MHz, CDCl3):
d
13.39 ppm (s, 1P). HRMS-ESI: m/z [M+Na]+
197.2, 162.5 ppm (d, JP,C = 1.4 Hz), 137.6, 137.3, 133.5, 133.1,
132.3, 129.9 Â 2, 128.5 Â 2, 128.4, 125.8, 123.1, 64.8 ppm (d,
2JP,C = 6.8 Hz), 39.3 ppm (d, 1JP,C = 140.0 Hz), 16.2 ppm (d,
calcd for C14H19BrNO5PNa: 414.0076; found: 414.0081.
4.4.8. Diethyl (2-acetyl-4-
3JP,C = 5.8 Hz). 31P NMR (121 MHz, CDCl3):
d 4.83 ppm (s, 1P).
chlorophenylcarbamoyl)bromomethylphosphonate (2h)
0.90 g (92% yield), purified by column chromatography
HRMS-ESI: m/z [M+Na]+ calcd for C19H20ClBrNO5PNa: 509.9843;
found: 509.9842.
(dichloromethane:methanol = 90:1), yellowish oil. IR (KBr):
3425, 1695, 1652, 1608, 1512, 1397, 1317, 1239, 1167, 1126, 1108,
1051, 1020, 976, 945, 762 cmÀ1 1H NMR (300 MHz, CDCl3):
n
4.4.12. Diethyl (2-acetophenone-4-
.
d
nitrophenylcarbamoyl)bromomethylphosphonate (2l)
0.98 g (85% yield), purified by column chromatography
(dichloromethane:methanol = 110:1), yellow oil. IR (KBr):
3472, 3253, 1702, 1650, 1617, 1582, 1541, 1510, 1412, 1346,
1262, 1157, 1021, 971, 732 cmÀ1 1H NMR (300 MHz, CDCl3):
d
12.30 ppm (s, 1H, NH), 8.70 ppm (d, Jo = 9.0 Hz, 1H, Ar–H),
7.87 ppm (s, 1H, Ar–H), 7.53 ppm (dd, Jm = 1.5 Hz, Jo = 9.0 Hz,
n
2
1H, Ar–H), 4.43 ppm (d, JP,H = 14.6 Hz, 1H, CHBr), 4.37–4.28 ppm
(m, 4H, CH2), 2.68 ppm (s, 3H, COCH3), 1.40–1.35 ppm (m, 6H,
.
CH3). 13C NMR (75 MHz, CDCl3):
d
201.1, 162.9 ppm (d,
11.68 ppm (s, 1H, NH), 8.84 ppm (d, J = 9.2 Hz, 1H, Ar–H), 8.49 ppm
(s, 1H, Ar–H), 8.44 ppm (d, J = 9.4 Hz, 1H, Ar–H), 7.76 ppm (d,
J = 7.7 Hz, 2H, Ar–H), 7.69 ppm (t, J = 7.3 Hz, 1H, Ar–H), 7.55 ppm (t,
J = 7.4 Hz, 2H, Ar–H), 4.48 ppm (d, 2JP,H = 14.7 Hz, 1H, CHBr), 4.34–
2JP,C = 1.7 Hz), 138.4, 134.6, 131.1, 128.4, 123.6, 122.3, 64.8 ppm
(d, 2JP,C = 6.9 Hz), 39.57 ppm (d, 1JP,C = 139.8 Hz), 28.4, 16.3 ppm (d,
3JP,C = 5.8 Hz). 31P NMR (121 MHz, CDCl3):
HRMS-ESI: m/z [M+Na]+ calcd for C14H18ClBrNO5PNa: 447.9687;
d 4.74 ppm (s, 1P).
4.25 ppm (m, 4H, CH2), 1.38–1.31 ppm (m, 6H, CH3). 13C NMR
2
found: 447.9683.
(75 MHz, CDCl3):
d
197.0, 163.2 ppm (d, JP,C = 1.6 Hz), 144.6,
142.0, 136.9, 133.6, 130.0 Â 2, 128.8 Â 2, 128.7, 128.4, 123.7, 121.7,
4.4.9. Diethyl (2-acetyl-4,5-
65.0 ppm (d, 2JP,C = 7.0 Hz), 39.2 ppm (d, 1JP,C = 139.4 Hz), 16.3 ppm
3
dimethoxyphenylcarbamoyl)bromomethylphosphonate (2i)
0.95 g (91% yield), purified by column chromatography
(dichloromethane:methanol = 100:1), yellowish solid, mp 128–
(d, JP,C = 6.1 Hz). 31P NMR (121 MHz, CDCl3):
d
3.61 ppm (s, 1P).
HRMS-ESI: m/z [M+Na]+ calcd for C19H20BrN2O7PNa: 521.0084;
found: 521.0079.
130 8C. IR (KBr):
1367, 1343, 1269, 1206, 1159, 1038, 1018, 980, cmÀ1
(300 MHz, CDCl3): 12.69 ppm (s, 1H, NH), 8.47 ppm (s, 1H, Ar–H),
7.30 ppm (s, 1H, Ar–H), 4.45 ppm (d, JP,H = 14.6 Hz, 1H, CHBr),
4.38–4.26 ppm (m, 4H, CH2), 3.98 ppm (s, 3H, OCH3), 3.92 ppm (s,
n
3426, 1679, 1641, 1612, 1593, 1524, 1469, 1452,
.
1H NMR
4.4.13. Diethyl (2-acetylphenylcarbamoyl)fluoromethylphosphonate
(2m)
0.71 g (92% yield), purified by column chromatography
(dichloromethane:methanol = 90:1), white solid, mp 126–129 8C.
d
2
3H, OCH3), 2.63 ppm (s, 3H, COCH3), 1.39–1.35 ppm (m, 6H, CH3).
IR (KBr):
n 3441, 1688, 1655, 1584, 1526, 1451, 1362, 1314, 1258,
2
13C NMR (75 MHz, CDCl3):
d
200.4, 162.8 ppm (d, JP,C = 1.6 Hz),
1164, 1044, 1017, 981, 959, 766 cmÀ1. 1H NMR (300 MHz, CDCl3):
d
154.3, 144.1, 136.6, 114.9, 113.4, 103.5, 64.7 ppm (d, 2JP,C = 6.8 Hz),
12.51 ppm (s, 1H, NH), 8.77 ppm (d, J = 8.4 Hz, 1H, Ar–H), 7.94 ppm
(d, J = 7.9 Hz, 1H, Ar–H), 7.59 ppm (t, J = 7.6 Hz, 1H, Ar–H),
1
56.3, 56.2, 39.9 ppm (d, JP,C = 140.8 Hz), 28.2, 16.3 ppm (d,

S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
603
2
7.21 ppm (t, J = 7.6 Hz, 1H, Ar–H), 5.27 ppm (dd, JP,H = 11.4 Hz,
2JF,H = 46.5 Hz, 1H, CHF), 4.37–4.24 ppm (m, 4H, CH2), 2.68 ppm (s,
3H, COCH3), 1.41–1.35 ppm (m, 6H, CH3). 13C NMR (75 MHz,
(d, J = 5.8 Hz). 19F NMR (282 MHz, CDCl3):
d
À203.7 ppm (dd,
2JH,F = 47.1 Hz, 2JP,F = 71.3 Hz, 1F, CHF). 31P NMR (121 MHz, CDCl3):
2
d
5.09 ppm (d, JF,P = 71.3 Hz, 1P). HRMS-MALDI: m/z [M+Na]+
CDCl3):
d
202.4, 163.5 ppm (dd, 2JP,C = 1.0 Hz, 2JF,C = 16.8 Hz), 139.3,
calcd for C19H21FNO5PNa: 416.1034; found: 416.1036.
135.0 ppm (d, J = 3.3 Hz), 131.6 ppm (d, J = 3.2 Hz), 123.5 ppm (d,
J = 2.5 Hz), 122.4, 120.9, 87.0 ppm (dd, 1JP,C = 158.8 Hz,
1JF,C = 201.2 Hz), 64.2 ppm (d, J1 = 2.5 Hz, J2 = 6.3 Hz), 28.3 ppm
(d, J = 4.6 Hz), 16.3 ppm (dd, J1 = 1.5 Hz, J2 = 5.8 Hz). 19F NMR
4.4.17. Diethyl (2-acetophenone-4-
chlorophenylcarbamoyl)fluoromethylphosphonate (2q)
0.89 g (89% yield), purified by column chromatography
(dichloromethane:methanol = 100:1), yellow oil. IR (KBr):
3485, 3291, 1703, 1646, 1597, 1579, 1516, 1446, 1397, 1289,
1258, 1162, 1019, 975, 948, 702 cmÀ1. 1H NMR (300 MHz, CDCl3):
(282 MHz, CDCl3):
d
À204.1 ppm (dd, 2JH,F = 46.5 Hz, 2JP,F = 71.9 Hz,
n
1F, CHF). 31P NMR (121 MHz, CDCl3):
d 9.79 ppm (d, JF = 71.9 Hz,
1P). HRMS-ESI: m/z [M+Na]+ calcd for C14H19FNO5PNa: 354.0877;
d
found: 354.0874.
11.42 ppm (s, 1H, NH), 8.67 ppm (d, J = 9.6 Hz, 1H, Ar–H), 7.75 ppm
(d, J = 7.4 Hz, 2H, Ar–H), 7.67 ppm (t, J = 7.4 Hz, 1H, Ar–H), 7.59–
7.52 ppm (m, 4H, Ar–H), 5.29 ppm (dd, 2JP,H = 11.4 Hz,
2JF,H = 46.8 Hz, 1H, CHF), 4.35–4.25 ppm (m, 4H, CH2), 1.41–
4.4.14. Diethyl (2-acetyl-4-
chlorophenylcarbamoyl)fluoromethylphosphonate (2n)
0.79 g (92% yield), purified by column chromatography
(dichloromethane:methanol = 90:1), white solid, mp 125–127 8C.
1.35 ppm (m, 6H, CH3). 13C NMR (75 MHz, CDCl3):
d 197.6,
2
163.2 ppm (d, JF,C = 16.8 Hz), 137.4, 137.2, 133.7, 133.0, 132.6,
129.8 Â 2, 128.4 Â 2, 128.3, 125.2, 123.1, 86.8 ppm (dd,
1JP,C = 158.9 Hz, 1JF,C = 200.9 Hz), 64.3 ppm (dd, J1 = 2.6 Hz,
J2 = 6.3 Hz), 16.3 ppm (d, J = 5.7 Hz). 19F NMR (282 MHz, CDCl3):
IR (KBr):
1226, 1166, 1112, 1069, 1043, 1013, 973, 954, 761 cmÀ1
(300 MHz, CDCl3): 12.40 ppm (s, 1H, NH), 8.78 ppm (d, Jo = 9.0 Hz,
n
3444, 1689, 1659, 1577, 1513, 1397, 1310, 1290, 1257,
.
1H NMR
d
2
2
1H, Ar–H), 7.90 ppm (d, Jm = 2.0 Hz, 1H, Ar–H), 7.56 ppm (dd,
d
À204.6 ppm (dd, JH,F = 46.8 Hz, JP,F = 70.5 Hz, CHF). HRMS-ESI:
2
Jm = 2.0 Hz, Jo = 9.0 Hz, 1H, Ar–H), 5.28 ppm (dd, JP,H = 11.5 Hz,
m/z [M+Na]+ calcd for C19H20ClFNO5PNa: 450.0644; found:
2JF,H = 46.8 Hz, 1H, CHF), 4.36–4.28 ppm (m, 4H, CH2), 2.69 ppm (s,
450.0642.
3H, COCH3), 1.43–1.37 ppm (m, 6H, CH3). 13C NMR (75 MHz,
CDCl3):
d
201.3, 163.5 ppm (d, 2JF,C = 16.9 Hz), 137.7, 134.6, 131.1,
4.4.18. Diethyl (2-acetophenone-4-
128.4, 123.4, 122.3, 86.8 ppm (dd, 1JP,C = 158.9 Hz, 1JF,C = 201.0 Hz),
64.3 ppm (dd, J1 = 2.2 Hz, J2 = 6.4 Hz,), 28.3, 16.3 ppm (dd,
nitrophenylcarbamoyl)fluoromethylphosphonate (2r)
0.90 g (88% yield), purified by column chromatography
(dichloromethane:methanol = 110:1), white solid, mp 101–
J1 = 1.2 Hz, J2 = 5.8 Hz). 19F NMR (282 MHz, CDCl3):
d
2
2
À205.5 ppm (dd, JH,F = 46.8 Hz, JP,F = 71.9 Hz, 1F, CHF). HRMS-
ESI: m/z [M+Na]+ calcd for C14H18ClFNO5PNa: 388.0487; found:
388.0489.
103 8C. IR (KBr):
n 3443, 1706, 1641, 1617, 1581, 1543, 1510,
1351, 1254, 1156, 1100, 1021, cmÀ1. 1H NMR (300 MHz, CDCl3):
d
11.88 ppm (s, 1H, NH), 8.97 ppm (d, Jo = 9.2 Hz, 1H, Ar–H),
8.55 ppm (d, Jm = 2.3 Hz, 1H, Ar–H), 8.48 ppm (dd, Jm = 2.3 Hz,
Jo = 9.2 Hz, 1H, Ar–H), 7.76 ppm (d, J = 7.6 Hz, 2H, Ar–H), 7.70 ppm
(d, J = 7.2 Hz, 1H, Ar–H), 7.58 ppm (t, J = 7.5 Hz, 2H, Ar–H),
4.4.15. Diethyl (2-acetyl-4,5-
dimethoxyphenylcarbamoyl)fluoromethylphosphonate (2o)
0.82 g (90% yield), purified by column chromatography
(dichloromethane:methanol = 100:1), yellowish solid, mp 75–
77 8C. IR (KBr):
1369, 1345, 1269, 1209, 1160, 1067, 1046, 1019 cmÀ1
(300 MHz, CDCl3): 12.77 ppm (s, 1H, NH), 8.51 ppm (s, 1H, Ar–H),
2
2
5.34 ppm (dd, JP,H = 11.8 Hz, JF,H = 46.5 Hz, 1H, CHF), 4.37–
4.27 ppm (m, 4H, CH2), 1.43–1.37 ppm (m, 6H, CH3). 13C NMR
(75 MHz, CDCl3):
2
n
3445, 1683, 1643, 1613, 1592, 1528, 1406,
d
197.4, 164.0 ppm (d, JF,C = 16.4 Hz), 144.1,
.
1H NMR
142.1, 136.9, 133.6, 129.9 Â 2, 128.9 Â 2, 128.8, 128.6, 123.3,
1 1
121.7, 86.9 ppm (dd, JP,C = 158.6 Hz, JF,C = 200.7 Hz), 64.5 ppm
(dd, J1 = 2.3 Hz, J2 = 6.4 Hz), 16.3 ppm (d, J = 5.6 Hz). 19F NMR
d
7.30 ppm (s, 1H, Ar–H), 5.26 ppm (dd, 2JP,H = 11.2 Hz,
2JF,H = 46.8 Hz, 1H, CHF), 4.34–4.26 ppm (m, 4H, CH2), 3.98 ppm
(s, 3H, OCH3), 3.92 ppm (s, 3H, OCH3), 2.63 ppm (s, 3H, COCH3),
(282 MHz, CDCl3):
d
À204.4 ppm (dd, 2JH,F = 46.5 Hz, 2JP,F = 70.8 Hz,
1 F, CHF). HRMS-ESI: m/z [M+Na]+ calcd for C19H20FN2O7PNa:
1.41–1.34 ppm (m, 6H, CH3). 13C NMR (75 MHz, CDCl3):
d
200.7,
461.0884; found: 461.0881.
2
163.5 ppm (d, JF,C = 17.4 Hz), 154.3, 144.2, 136.0, 114.9, 113.4,
1
1
103.7, 86.9 ppm (dd, JP,C = 159.2 Hz, JF,C = 201.6 Hz), 64.3 ppm
4.5. General procedure for the preparation of the halogenated
(dd, J1 = 2.2 Hz, J2 = 6.6 Hz), 56.3 Â 2, 28.3, 16.4 ppm (d, J = 5.6 Hz).
2-quinolones 1a–r
2
19F NMR (282 MHz, CDCl3):
d
À204.6 ppm (dd, JH,F = 46.8 Hz,
2JP,F = 70.5 Hz, 1F, CHF). 31P NMR (121 MHz, CDCl3):
2JF,P = 70.5 Hz, 1P). HRMS-MALDI: m/z [M+Na]+ calcd for
16H23FNO7PNa: 414.1088; found: 414.1085.
d
6.06 ppm (d,
In a round-bottomed flask under argon, LiCl (0.13 g, 3 mmol)
and N-acyl-o-aminophenylketones 2a–r (1 mmol) was suspended
in THF (4 mL). DBU (0.45 mL, 3 mmol) was slowly added for 10 min
at r.t., then the mixture was stirred for 2 h. The volatiles were
evaporated, the residue was taken up in ethyl acetate, and washed
with 3 N HCl and satd NaHCO3. After drying (Na2SO4) and
evaporation of the solvent, the corresponding compound was
isolated from the residue by column chromatography or recrys-
tallization.
C
4.4.16. Diethyl (2-acetophenone-
phenylcarbamoyl)fluoromethylphosphonate (2p)
0.57 g (62% yield), purified by column chromatography
(dichloromethane:methanol = 110:1), yellow oil. IR (KBr):
3481, 3286, 1696, 1641, 1584, 1523, 1450, 1296, 1267, 1163,
1018, 978, 923, 755, 733, 703, 644 cmÀ1 1H NMR (300 MHz,
CDCl3): 11.60 ppm (s, 1H, NH), 8.67 ppm (d, J = 8.6 Hz, 1H, Ar–H),
n
.
d
4.5.1. 3-Chloro-4-methyl-2-quinolone (1a) [28]
7.72 ppm (d, J = 7.5 Hz, 2H, Ar–H), 7.61 ppm (t, 3H, J = 6.9 Hz, Ar–
H), 7.49 ppm (t, 2H, J = 7.5 Hz, Ar–H), 7.17 ppm (t, 1H, J = 7.3 Hz,
Ar–H), 5.28 ppm (dd, 2JP,H = 11.3 Hz, 2JF,H = 47.1 Hz, 1H, CHF), 4.34–
4.26 ppm (m, 4H, CH2), 1.39–1.33 ppm (m, 6H, CH3). 13C NMR
170.4 mg (88% yield), recrystallized from ethanol, white solid;
mp 300–302 8C. IR (KBr):
n
3421, 1667, 1606, 1504, 1434, 1381,
12.21 ppm (s, 1H,
746, 633 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
d
NH), 7.83 ppm (d, J = 8.1 Hz, 1H, Ar–H), 7.56 ppm (t, J = 7.6 Hz, 1H,
Ar–H), 7.36 ppm (d, J = 8.1 Hz, 1H, Ar–H), 7.28 ppm (t, J = 7.6 Hz,
1H, Ar–H), 2.60 ppm (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6):
d
157.1, 144.3, 136.6, 130.6, 125.3, 125.1, 122.6, 119.2, 115.7,
16.3 ppm.
(75 MHz, CDCl3):
d
199.1, 163.3 ppm (dd, 2JP,C = 1.0 Hz,
2JF,C = 16.7 Hz), 138.9, 138.2, 134.2, 133.6, 132.6, 129.9 Â 2,
1
128.3 Â 2, 123.9, 123.2, 121.7, 86.9 ppm (dd, JP,C = 158.8 Hz,
1JF,C = 201.0 Hz), 64.3 ppm (dd, J1 = 2.0 Hz, J2 = 6.4 Hz), 16.4 ppm

604
S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
4.5.2. 3,6-Dichloro-4-methyl-2-quinolone (1b) [16(c)]
7.87 ppm (s, 1H, Ar–H), 7.60 ppm (dd, Jm = 1.6 Hz, Jo = 8.7 Hz, 1H,
Ar–H), 7.35 ppm (d, Jo = 8.8 Hz, 1H, Ar–H), 2.63 ppm (s, 3H, CH3).
216.7 mg (95% yield), recrystallized from ethanol, white solid;
mp 272–274 8C. IR (KBr):
n
3445, 1648, 1603, 1487, 1409, 1146,
12.31 ppm (s, 1H,
13C NMR (75 MHz, DMSO-d6):
d 157.0, 146.2, 135.8, 130.5, 126.4,
1098, 629 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
d
124.6, 120.6, 120.3, 117.4, 19.6 ppm.
NH), 7.86 ppm (s, 1H, Ar–H), 7.60 ppm (d, Jo = 8.8 Hz, 1H, Ar–H),
7.36 ppm (d, Jo = 8.7 Hz, 1H, Ar–H), 2.59 ppm (s, 3H, CH3). 13C NMR
4.5.9. 3-Bromo-6,7-dimethoxy-4-methyl-2-quinolone (1i)
(75 MHz, DMSO-d6):
d
156.8, 143.2, 135.4, 130.3, 126.5, 126.4,
232.5 mg (78% yield), recrystallized from ethanol, white solid,
124.4, 120.3, 117.4, 16.2 ppm.
mp 227–229 8C. IR (KBr):
n
3443, 1654, 1514, 1410, 1258, 1230,
11.97 ppm (s,
1207, 1169 cmÀ1 1H NMR (300 MHz, DMSO-d6):
.
d
4.5.3. 3-Chloro-6,7-dimethoxy-4-methyl-2-quinolone (1c)
1H, NH), 7.20 ppm (s, 1H, Ar–H), 6.88 ppm (s, 1H, Ar–H), 3.84 ppm
(s, 3H, OCH3), 3.82 ppm (s, 3H, OCH3), 2.63 ppm (s, 3H, CH3). 13C
208.0 mg (82% yield), recrystallized from ethanol, white solid,
mp 250–252 8C. IR (KBr):
1230, 1205, 1169, 1103, 1035 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
12.00 ppm (s, 1H, NH), 7.17 ppm (s, 1H, Ar–H), 6.88 ppm (s, 1H,
Ar–H), 3.84 ppm (s, 3H, OCH3), 3.82 ppm (s, 3H, OCH3), 2.57 ppm
(s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6):
157.2, 152.1, 145.4,
n
3424, 1655, 1625, 1514, 1414, 1261,
NMR (75 MHz, DMSO-d6): d 158.1, 152.9, 147.4, 146.0, 133.7,
117.0, 113.3, 107.4, 98.7, 56.8, 56.5, 20.8 ppm. HRMS-ESI: m/z
[M+Na]+ calcd for C12H12BrNO3Na: 319.9893; found: 319.9889.
d
d
4.5.10. 3-Bromo-4-phenyl-2-quinolinone (1j) [17(a)]
144.0, 132.5, 122.5, 112.5, 106.6, 98.1, 56.2, 55.9, 16.7 ppm. HRMS-
ESI: m/z [M+Na]+ calcd for C12H12ClNO3Na: 276.0398; found:
276.0401.
78.0 mg (26% yield), purified by column chromatography
(dichloromethane:methanol = 30:1), white solid, mp 228–230 8C.
IR (KBr):
(300 MHz, DMSO-d6):
n .
3444, 1656, 1604, 1110, 1056, 758, 598 cmÀ1 1H NMR
d
11–12 ppm (br.s, 1H, NH), 7.59–7.52 ppm
4.5.4. 3-Chloro-4-phenyl-2-quinolinone (1d)
(m, 4H, Ar–H), 7.36 ppm (s, 1H, Ar–H), 7.31 ppm (d, J = 7.6 Hz, 2H,
Ar–H), 7.14 ppm (s, 1H, Ar–H), 7.13 ppm (s, 1H, Ar–H). 13C NMR
240.4 mg (94% yield), recrystallized from ethanol, white solid,
mp 191–193 8C. IR (KBr):
n
3423, 1658, 1611, 1597, 1437, 1072,
12.45 ppm (s, 1H,
(75 MHz, DMSO-d6):
128.5 Â 2, 127.2, 123.0, 120.8, 117.9, 116.6 ppm.
d
160.3, 152.7, 137.3, 137.1, 130.8, 128.7 Â 2,
750, 631 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
d
NH), 7.61–7.53 ppm (m, 4H, Ar–H), 7.42 ppm (d, J = 8.1 Hz, 1H, Ar–
H), 7.36 ppm (s, 1H, Ar–H), 7.34 ppm (s, 1H, Ar–H), 7.14 ppm (t,
J = 7.7 Hz, 1H, Ar–H), 6.95 ppm (d, J = 8.0 Hz, 1H, Ar–H). 13C NMR
4.5.11. 3-Bromo-6-chloro-4-phenyl-2-quinolone (1k)
60.2 mg (18% yield), purified by column chromatography
(dichloromethane:methanol = 30:1), white solid, mp 218–220 8C.
(75 MHz, DMSO-d6):
d
162.4, 153.1, 142.2, 139.8, 135.7, 133.8 Â 2,
133.7, 133.6 Â 2, 131.6, 129.8, 127.5, 124.5, 120.6 ppm. HRMS-ESI:
IR (KBr):
(300 MHz, DMSO-d6):
n .
3442, 1665, 1056, 1028, 1008, 823, 761 cmÀ1 1H NMR
m/z [M+Na]+ calcd for C15H10ClNONa: 278.0343; found: 278.0345.
d
12.55 ppm (s, 1H, NH), 7.62–7.53 ppm (m,
4H, Ar–H), 7.42 ppm (d, J = 8.8 Hz, 1H, Ar–H). 7.32 ppm (d,
J = 6.8 Hz, 2H, Ar–H), 6.80 ppm (s, 1H, Ar–H). 13C NMR (75 MHz,
4.5.5. 3,6-Dichloro-4-phenyl-2-quinolone (1e) [16(d)]
275.6 mg (95% yield), recrystallized from ethanol, white solid,
DMSO-d6):
d
157.4, 150.0, 136.5, 136.4, 130.7, 129.0 Â 2, 128.9,
mp 299–301 8C. IR (KBr):
n
3420, 1656, 1480, 1407, 1070, 706,
12.56 ppm (s, 1H, NH),
128.2 Â 2, 126.2, 125.4, 120.9, 120.4, 117.6 ppm. HRMS-ESI: m/z
642 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
d
[M+Na]+ calcd for C15H9BrClNONa: 355.9448; found: 355.9444.
7.58–7.50 ppm (m, 4H, Ar–H), 7.39 ppm (d, J = 8.8 Hz, 1H, Ar–H),
7.31 ppm (d, J = 6.8 Hz, 2H, Ar–H), 6.80 ppm (d, J = 1.4 Hz, 1H, Ar–
4.5.12. 3-Bromo-6-nitro-4-phenyl-2-quinolone (1l)
H). 13C NMR (75 MHz, DMSO-d6):
d
157.1, 146.8, 136.0, 134.2,
65.6 mg (19% yield), purified by column chromatography
(dichloromethane:methanol = 30:1), white solid, mp 202–204 8C.
130.4, 128.9, 128.9 Â 2, 128.5 Â 2, 126.4, 126.3, 125.1, 120.7,
117.6 ppm.
IR (KBr):
(300 MHz, DMSO-d6):
n .
3440, 1669, 1058, 1028, 823, 761, 624 cmÀ1 1H NMR
d
12.97 ppm (s, 1H, NH), 8.39 ppm (dd,
4.5.6. 3-Chloro-6-nitro-4-phenyl-2-quinolone (1f)
Jm = 2.2 Hz, Jo = 9.0 Hz, 1H, Ar–H), 7.74 ppm (d, Jm = 2.1 Hz, 1H, Ar–
H), 7.67–7.60 ppm (m, 3H, Ar–H), 7.56 ppm (d, Jo = 9.1 Hz, 1H, Ar–
H), 7.40 ppm (d, J = 6.5 Hz, 2H, Ar–H). 13C NMR (75 MHz, DMSO-
288.7 mg (96% yield), recrystallized from ethanol, white solid,
mp 221–223 8C. IR (KBr):
n
3423, 1655, 1606, 1529, 1486, 1334,
13.01 ppm (s, 1H,
1066, 652 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
d
d6):
d
157.7, 150.7, 142.0, 141.7, 135.9, 129.2, 129.0 Â 2, 128.4 Â 2,
NH), 8.40 ppm (dd, Jm = 2.2 Hz, Jo = 9.0 Hz, 1H, Ar–H), 7.77 ppm (d,
Jm = 2.1 Hz, 1H, Ar–H), 7.67–7.56 ppm (m, 4H, Ar–H), 7.43 ppm (d,
J = 6.7 Hz, 2H, Ar–H). 13C NMR (75 MHz, DMSO-d6):
125.4, 122.7, 121.1, 119.4, 116.8 ppm. HRMS-ESI: m/z [M+Na]+
calcd for C15H9BrN2O3Na: 366.9689; found: 366.9682.
d 157.5, 147.5,
141.8, 141.5, 133.7, 129.4, 129.1 Â 2, 128.7 Â 2, 127.1, 125.2,
4.5.13. 3-Fluoro-4-methyl-2-quinolone (1m)
122.5, 119.3, 116.9 ppm. HRMS-ESI: m/z [M+Na]+ calcd for
70.9 mg (40% yield), purified by column chromatography
(dichloromethane:methanol = 30:1), white solid, mp 179–181 8C.
C
15H9ClN2O3Na: 323.0194; found: 323.0197.
IR (KBr):
NMR (300 MHz, DMSO-d6):
n
3444, 1666, 1629, 1577, 1437, 1204, 749, 698 cmÀ1. 1H
4.5.7. 3-Bromo-4-methyl-2-quinolone (1g) [13(b)]
d 12.15 ppm (s, 1H, NH), 7.70 ppm (d,
202.4 mg (85% yield), recrystallized from ethanol, white solid,
J = 7.3 Hz, 1H, Ar–H), 7.46 ppm (d, J = 6.9 Hz, 1H, Ar–H), 7.32 ppm
(d, J = 7.8 Hz, 1H, Ar–H), 7.25 ppm (d, J = 6.4 Hz, 1H, Ar–H),
mp 268–269 8C. IR (KBr):
n
3440, 1649, 1602, 1502, 1432, 1004,
12.16 ppm (s, 1H,
749, 618 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
d
2.35 ppm (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6):
d
2
1
NH), 7.82 ppm (d, J = 8.1 Hz, 1H, Ar–H), 7.55 ppm (t, J = 7.7 Hz, 1H,
Ar–H), 7.34 ppm (d, J = 8.1 Hz, 1H, Ar–H), 7.24 ppm (t, J = 7.7 Hz,
155.4 ppm (d, JF,C = 28.2 Hz), 148.6 ppm (d, JF,C = 243.6 Hz),
2
135.6, 129.6 ppm (d, J = 2.0 Hz), 127.7 ppm (d, JF,C = 12.8 Hz),
1H, Ar–H), 2.63 ppm (s, 3H, CH3). 13C NMR (75 MHz, DMSO-d6):
d
125.1 ppm (d, J = 6.4 Hz), 122.8, 119.3 ppm (d, J = 4.5 Hz), 115.8,
3
157.6, 147.5, 137.3, 131.1, 125.8, 122.8, 119.6, 119.5, 115.9,
10.1 ppm (d, JF,C = 4.4 Hz). 19F NMR (282 MHz, DMSO-d6):
d
19.9 ppm (d, J = 1.6 Hz).
À133.1 ppm (s, 1F, CF).
4.5.8. 3-Bromo-6-chloro-4-methyl-2-quinolone (1h) [29]
4.5.14. 6-Chloro-3-fluoro-4-methyl-2-quinolone (1n)
239.8 mg (88% yield), recrystallized from ethanol, white solid,
80.4 mg (38% yield), purified by column chromatography
mp 204–206 8C. IR (KBr):
n
3450, 1648, 1602, 1486, 1142, 1097,
12.29 ppm (s, 1H, NH),
(dichloromethane:methanol = 30:1), white solid, mp 211–213 8C.
625 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
d
IR (KBr): n
3445, 1664, 1631, 1574, 1492, 1422, 1202, 645 cmÀ1. 1H

S. Zhao et al. / Journal of Fluorine Chemistry 131 (2010) 597–605
605
NMR (300 MHz, DMSO-d6):
d
12.29 ppm (s, 1H, NH), 7.76 ppm (s,
Acknowledgements
1H, Ar–H), 7.54 ppm (d, Jo = 8.8 Hz, 1H, Ar–H), 7.33 ppm (d,
Jo = 8.8 Hz, 1H, Ar–H), 2.36 ppm (s, J = 2.6 Hz, 3H, CH3). 13C NMR
Financial support from 2007 select project in scientific and
technological activities for returned scholars of The State Personnel
Ministry and the scientific research foundation for the returned
overseas Chinese scholars of The State Education Ministry and
Natural Science Foundation Project of CQ CSTC of 2009BA5051.
(75 MHz, DMSO-d6): d
154.8 ppm (d, 2JF,C = 28.3 Hz), 148.8 ppm (d,
1JF,C = 245.2 Hz), 134.0 ppm (d, J = 2.0 Hz), 129.3 ppm (d,
2
J = 2.5 Hz), 126.8 ppm (d, JF,C = 13.7 Hz), 126.7, 124.0 ppm (d,
J = 6.5 Hz), 120.5 ppm (d, J = 5.1 Hz), 117.3, 9.8 ppm (d,
3JF,C = 4.2 Hz). 19F NMR (282 MHz, DMSO-d6):
d
À129.93 ppm (s,
1F, CF). HRMS-ESI: m/z [M+Na]+ calcd for C10H7ClFNONa:
Appendix A. Supplementary data
234.0092; found: 234.0093.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.jfluchem.2010.01.008.
4.5.15. 3-Fluoro-6,7-dimethoxy-4-methyl-2-quinolone (1o)
71.8 mg (30% yield), purified by column chromatography
(dichloromethane:methanol = 30:1), white solid, mp 266–268 8C.
IR (KBr):
1H NMR (300 MHz, DMSO-d6):
n .
3422, 1657, 1623, 1516, 1423, 1271, 1215, 1169, cmÀ1
References
d
11.96 ppm (s, 1H, NH), 7.11 ppm
[1] C. Ito, M. Itoigawa, A. Furukawa, T. Hirano, T. Murata, N. Kaneda, Y. Hisada, K.
Okuda, H. Furukawa, J. Nat. Product. 67 (2004) 1800–1803.
[2] K. Chen, S.C. Kuo, M.C. Hsieh, A. Mauger, C.M. Lin, E. Hamel, K.H. Lee, J. Med. Chem.
40 (1997) 2266–2275.
[3] L.J. Huang, M.C. Hsieh, C.M. Teng, K.H. Lee, S.C. Kuo, Bioorg. Med. Chem. 6 (1998)
1657–1662.
[4] P. Ferrer, C. Avendan˜o, M. So¨llhuber, Liebigs Ann. (1995) 1895–1899.
[5] L.A. Mitsher, R.M. Zavod, P.V. Devasthale, D.T.W. Chu, P.N. Sharma, A.G. Pernet,
Chemtech 21 (1991) 50–56.
[6] D.V. Kadnikov, R.C. Larock, J. Org. Chem. 69 (2004) 6772–6780.
[7] M.J. Wall, J. Chen, S. Meegalla, S.K. Ballentine, K.J. Wilson, R.L. DesJarlais, C.
Schubert, M.A. Chaikin, C. Crysler, I.P. Petrounia, R.R. Donatelli, E.J. Yurkow, L.
Boczon, M. Mazzulla, M.R. Player, R.J. Patch, C.L. Manthey, C. Molloy, B. Tomczuk,
C.R. Illig, Bioorg. Med. Chem. Lett. 18 (2008) 2097–2102.
(s, 1H, Ar–H), 6.89 ppm (s, 1H, Ar–H), 3.84 ppm (s, 3H, OCH3),
3.80 ppm (s, 3H, OCH3), 2.50 ppm (s, 3H, CH3). 13C NMR (75 MHz,
2
DMSO-d6):
d
154.7 ppm (d, JF,C = 28.1 Hz), 150.8 ppm (d,
J = 2.5 Hz), 147.1 ppm (d, 1JF,C = 239.1 Hz), 145.3, 130.4,
127.6 ppm (d, 2JF,C = 14.2 Hz), 111.7 ppm (d, J = 4.2 Hz),
105.9 ppm (d, J = 5.6 Hz), 98.0, 55.9, 55.5, 10.1 ppm (d,
3JF,C = 4.6 Hz). 19F NMR (282 MHz, DMSO-d6):
1F, CF). HRMS-ESI: m/z [M+Na]+ calcd for C12H12FNO3Na:
d
À136.6 ppm (s,
260.0693; found: 260.0686.
4.5.16. 3-Fluoro-4-phenyl-2-quinolinone (1p)
[8] R.J. Cvetovich, R.A. Reamer, L. DiMichele, J.Y.L. Chung, J.R. Chilenski, J. Org. Chem.
71 (2006) 8610–8613.
217.7 mg (91% yield), recrystallized from ethanol, white solid,
[9] (a) C.Y. Chen, F.R. Chang, W.B. Pan, Y.C. Wu, Phytochemistry 56 (2001) 753–757;
(b) M. Nagarajan, A. Morrell, B.C. Fort, M.R. Meckley, S. Anthony, G. Kohlhagen, Y.
Pommier, M. Cushman, J. Med. Chem. 47 (2004) 5561–5651;
(c) A.L. Ruchelman, P.J. Houghton, N. Zhou, A. Liu, L.F. Liu, E.J. Lavoie, J. Med. Chem.
48 (2005) 792–804.
mp 254–256 8C. IR (KBr):
701 cmÀ1. 1H NMR (300 MHz, DMSO-d6):
7.59–7.50 ppm (m, 4H, Ar–H), 7.46–7.41 ppm (m, 3H, Ar–H), 7.21–
7.14 ppm (m, 2H, Ar–H). 13C NMR (75 MHz, DMSO–d6):
n
3444, 1669, 1617, 1568, 1283, 755,
d
12.45 ppm (s, 1H, NH),
d
[10] (a) P. Hewawasam, W. Fan, J. Knipe, S.L. Moon, C.G. Boissard, V.K. Gribkoff, J.E.
Starret, Bioorg. Med. Chem. Lett. 12 (2002) 1779–1783;
2
1
155.3 ppm (d, JF,C = 28.0 Hz), 147.0 ppm (d, JF,C = 246.6 Hz),
2
135.7 ppm (d, J = 2.0 Hz), 131.5 ppm (d, JF,C = 12.8 Hz), 130.1,
(b) P.R. Angibaud, M.G. Venet, W. Filliers, R. Broeckx, Y.A. Ligny, P. Muller, V.S.
Poncelet, D.W. End, Eur. J. Org. Chem. (2004) 479–486;
129.5 ppm (d, J = 2.6 Hz), 129.4, 129.3, 129.0, 128.8 Â 2, 125.9 ppm
(c) P. Hewawasam, W. Fan, D.A. Cook, K.S. Newberry, C.G. Boissard, V.K. Gribkoff,
J. Starret, N.J. Lodge, Bioorg. Med. Chem. Lett. 14 (2004) 4479–4482;
(d) A. Cappelli, G.P. Mohr, A. Gallelli, M. Rizzo, M. Anzini, S. Vomero, L. Mennuni, F.
Ferrari, F. Makovec, M.C. Menziani, P.G.D. Benedetti, G. Giorgi, J. Med. Chem. 47
(2004) 2574–2586.
(d, J = 6.5 Hz), 122.6, 118.6 ppm (d, J = 2.8 Hz), 115.7. 19F NMR
(282 MHz, DMSO-d6):
d
À130.9 ppm (s, 1F, CF). HRMS-ESI: m/z
[M+Na]+ calcd for C15H10FNONa: 262.0639; found: 262.0643.
[11] D.A. Roberts, S.F. Campbell, Faming Zhuanli Shenqing Gongkai Shuomingshu. CN
85100796 (1986).
4.5.17. 6-Chloro-3-fluoro-4-phenyl-2-quinolone (1q)
[12] G. Theodoridis, PCT Int. Appl. US 4909829 (1987).
[13] (a) B. Riegel, G.R. Lappin, C.J. Albisetti, B.H. Adelson, R.M. Dodson, L.G. Ginger, R.H.
Baker, J. Am. Chem. Soc. 68 (1946) 1229–1232;
251.8 mg (92% yield), recrystallized from ethanol, white solid,
mp 197–199 8C. IR (KBr):
n
.
3445, 1661, 1620, 1569, 1484, 1414,
1H NMR (300 MHz, DMSO-d6):
11–
1271, 1203, 700, 664 cmÀ1
d
(b) D.J. Cook, R.E. Bowen, P. Sorter, E. Daniels, J. Org. Chem. 26 (1961) 4949–4955.
[14] Y.R. Lee, B.S. Cho, H.J. Kwon, Tetrahedron 59 (2003) 9333–9347.
[15] (a) J. Wu, L. Zhang, X.Y. Sun, J. Comb. Chem. 9 (2007) 811–817;
(b) Z.Y. Wang, B. Wang, J. Wu, Chem. Lett. 34 (2005) 550–551.
[16] (a) B. Staskun, J. Org. Chem. 39 (1974) 3494–3497;
(b) J.L.C. Marais, B. Staskun, J. Org. Chem. 50 (1985) 4652–4655;
(c) P.C. Meltzer, B. Staskun, Tetrahedron 33 (1977) 2965–2967;
(d) A.J. Hodgkinso, B. Staskun, J. Org. Chem. 34 (1969) 1709–1713.
[17] (a) A.S. Shawali, M.I. Ali, A.A. Fahmi, Bull. Chem. Soc. Jpn. 46 (1973) 1798–1800;
(b) B. Staskun, P.C. Meltzer, Tetrahedron 33 (1977) 2429–2432.
[18] M. Anzini, A. Cappelli, S. Vomero, G. Giorgi, T. Langer, M. Hamon, N. Merahi, B.M.
Emerit, A. Cagnotto, M. Skorupska, T. Mennini, J.C. Pinto, J. Med. Chem. 38 (1995)
2692–2704.
14 ppm (br.s, 1H, NH), 7.61–7.55 ppm (m, 4H, Ar–H), 7.47–
7.42 ppm (m, 3H, Ar–H), 7.04 ppm (s, 1H, Ar–H). 13C NMR (75 MHz,
2
DMSO-d6):
d
155.1 ppm (d, JF,C = 28.0 Hz), 147.7 ppm (d,
1JF,C = 249.0 Hz), 134.5 ppm (d, J = 3.4 Hz), 130.5 ppm (d,
2JF,C = 13.8 Hz), 129.5, 129.4 ppm (d, J = 2.6 Hz), 129.3 Â 3,
129.0 Â 2, 126.6, 124.6 ppm (d, J = 6.5 Hz), 120.1 ppm (d,
J = 3.4 Hz), 117.7 ppm. 19F NMR (282 MHz, DMSO-d6):
d
À127.56 ppm (s, 1F, CF). HRMS-MALDI: m/z [M+Na]+ calcd for
C
15H9ClFNONa: 296.0249; found: 296.0256.
´
˜
[19] M. Fernandez, E. Cuesta, C. Avendano, Synthesis 11 (1995) 1362–1364.
[20] S. Sano, R. Teranishi, Y. Nagao, Tetrahedron Lett. 43 (2002) 9183–9186.
[21] C.E. McKenna, L.A. Khawli, J. Org. Chem. 51 (1986) 5467–5471.
[22] A.G. Meyer, K.N. Winzenberg, D.G. Sawutz, A.J. Liepa, PCT Int. Appl. US
2006063841 (2006).
4.5.18. 3-Fluoro-6-nitro-4-phenyl-2-quinolone (1r)
264.3 mg (93% yield), recrystallized from ethanol, white solid,
mp 188–190 8C. IR (KBr):
1380, 1336, 1272, 1206, 832, 731 cmÀ1. 1H NMR (300 MHz, DMSO-
d6): 8.30 ppm (d, J = 8.9 Hz, 1H, Ar–H), 7.95 ppm (s, 1H, Ar–H),
7.64–7.62 ppm (m, 3H, Ar–H), 7.54–7.49 ppm (m, 3H, Ar–H). 13C
NMR (75 MHz, DMSO-d6):
155.6 ppm (d, 2JF,C = 28.0 Hz), 148.0 (d,
n 3443, 1666, 1629, 1575, 1535, 1487,
[23] A.V. Butin, S.K. Smirnov, T.A. Stroganova, W. Bender, G.D. Krapivin, Tetrahedron
63 (2007) 474–491.
[24] (a) A. Ianni, S.R. Waldvogel, Synthesis 13 (2006) 2103–2112;
(b) J.U. Peters, T. Capuano, S. Weber, S. Kritter, M. Sa¨gesser, Tetrahedron Lett. 49
(2008) 4029–4032.
[25] M.P. Teulade, P. Savignac, J. Organomet. Chem. 287 (1985) 145–156.
[26] (a) P. Coutrot, A. Ghribi, Synthesis 8 (1986) 661–664;
(b) P. Coutrot, C. Crison, J. Organomet. Chem. 332 (1987) 1–18.
[27] B. Gabriele, R. Mancuso, G. Salerno, G. Ruffolo, P. Plastina, J. Org. Chem. 72 (2007)
6873–6877.
[28] C. Bulow, E. King, Justus Liebigs Annalen der Chemie 439 (1924) 211–220.
[29] M.I. Ali, M.A.A. State, N.M. Hassan, Indian J. Chem., Sect. B: Org. Chem. Incl. Med.
Chem. 11 (1973) 4–6.
d
d
1JF,C = 250.6 Hz), 142.0, 140.3 ppm (d, J = 1.7 Hz), 131.0 ppm (d,
2JF,C = 13.9 Hz), 129.7, 129.5 Â 2, 129.1 Â 2, 129.1, 124.2 ppm (d,
J = 2.2 Hz), 121.9 ppm (d, J = 7.0 Hz), 118.7 ppm (d, J = 3.8 Hz),
117.0 ppm. 19F NMR (282 MHz, DMSO-d6):
d
À127.0 ppm (s, 1F,
CF). HRMS-ESI: m/z [M+Na]+ calcd for C15H9FN2O3Na: 307.0489;
found: 307.0493.