Copper-mediated, palladium-catalyzed cross-coupling of 3-iodochromones, thiochromones, and quinolones with Ethyl bromodifluoroacetate

Article abstract of DOI:10.1021/jo400412k

The palladium-catalyzed cross-coupling reaction of 3-iodochromones, thiochromones, and quinolones with ethyl bromodifluoroacetate in the presence of a copper mediator is reported. Under optimized conditions, all reactions worked well and provided difluoro-containing products in moderate to excellent yields.

Full text of DOI:10.1021/jo400412k

Article
pubs.acs.org/joc
Copper-Mediated, Palladium-Catalyzed Cross-Coupling of
3‑Iodochromones, Thiochromones, and Quinolones with Ethyl
Bromodifluoroacetate
Xiaodong Han,†,‡ Zhizhou Yue,‡ Xiaofei Zhang,† Qian He,† and Chunhao Yang*,†
†State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, SIBS, Chinese Academy of Sciences, 555 Zu Chong
Zhi Road, Shanghai 201203, People’s Republic of China
‡Department of Pharmaceutical Engineering, School of Chemical Engineering, Wuhan University of Technology, 205 Luo Shi Road,
Wuhan, Hubei 430070, People’s Republic of China
S
* Supporting Information
ABSTRACT: The palladium-catalyzed cross-coupling reaction of
3-iodochromones, thiochromones, and quinolones with ethyl
bromodifluoroacetate in the presence of a copper mediator is
reported. Under optimized conditions, all reactions worked well
and provided difluoro-containing products in moderate to
excellent yields.
−CF2CO2Et group at the C-3 position of chromone were
fruitless in our study. The copper-mediated cross-coupling of
commercially available BrCF2CO2Et/ClCF2CO2Et reagent with
aryl halide has been well-documented. In 1999, Kumadaki et al.
reported the synthesis of aryldifluoroacetate by BrCF2CO2Et
and aryl iodide in the presence of copper (path D).17 Later, in
2002, Ashwood et al. developed a facile process to achieve 2′-
pyridyldifluoroacetate from 2-halopyridine (path D).18 Re-
cently, Amii et al. described an efficient and simple copper-
catalyzed route (path E).19 Unfortunately, the application of
paths D and E in our study failed, which led us to develop a
novel and convenient method to construct 3-ethoxycarbonyl-
difluoromethyl chromones, -thiochromones, and -quinolones.
In this study, we report an efficient palladium-catalyzed cross-
coupling reaction of 3-iodochromones, thiochromones, and
quinolones with ethyl bromodifluoroacetate in the presence of
copper with moderate to excellent yields.
INTRODUCTION
■
Chromones1 and quinolones2 are important scaffolds of natural
products. These scaffolds are useful building blocks and display
various biological activities, such as anti-inflammatory, anti-
tumor, and antibacterial effects.3 Substituted chromones and
quinolones also play the valuable role of progenitor in
medicinal chemistry.4 Thiochromones, unlike the previously
mentioned abundant chromones and quinolones, have not
been found in natural products, but they display interesting
activities.5
Molecules containing fluorine atom(s) regularly exhibit
beneficial effects in the life science field.6 Recently, compounds
containing a CF2 unit have attracted a considerable amount of
attention, particularly in medicinal chemistry,7 and several
efficient methods for introducing the gem-difluoro unit into
organic compounds have been reported.8 In fact, several drugs
containing gem-difluoro moieties have been approved for sale in
the market, such as pantoprazole,9 gemcitabine,10 lubipro-
stone,11 tafluprost,12 maraviroc,13 and roflumilast14 (Figure 1).
As part of our program to develop novel anticancer agents, we
require a facile route to 3-difluoroacetate-substituted chro-
mones/quinolones. To the best of our knowledge, there are
several reported pathways to prepare alkoxycarbonyldifluoro-
methylated aromatic compounds (Figure 2).
As illustrated in Figure 2, ethoxycarbonyldifluoromethylation
can be achieved by fluorination the carbonyl of oxoarylacetate
esters with a nucleophilic reagent such as SF4 or DAST (path
A). This type of reaction is limited because of the toxic nature
of SF4/DAST and the lack of general available substrates.
Hazardous selenium-containing agents have been adopted as
the starting material in path B.15 Although direct ethoxy-
carbonyldifluoromethylation via an RCF2• radical process has
been reported recently (path C),16 this transformation is not
suitable for our substrates, and attempts to introduce a
RESULTS AND DISCUSSION
■
Initially, 3-iodo-4H-chromen-4-one (1a) was selected as the
template substrate to determine the optimal conditions, and the
outcomes are summarized in Table 1. Surprisingly, reactions in
the presence of copper alone had not occurred, even after 12
additional hours at 125 °C (Table 1, entries 1−3). Considering
the application of palladium in Ullmann cross-coupling for the
synthesis of heteroaromatic compounds,20 we introduced a
palladium catalyst to facilitate this reaction. As expected, 1a
could be converted to 2a with the use of Pd2(dba)3 in 32%
yield (Table 1, entry 4). Motivated by this result, a range of
palladium catalysts were tested. However, only moderate yields
were obtained (entries 4−7). Among all of the tested palladium
Received: February 27, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo400412k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
Figure 1. Several gem-difluoro-containing drugs.
Figure 2. Examples of procedures reported to synthesize aryl difluoroacetates.
catalysts, Pd(dppf)Cl2 provided 2a in less time and higher
yields (entry 7). The solvent was shown to have a marked
impact on the yields, with DMSO providing the best result
(Table 1, entries 7−9). We found that 2 equiv of BrCF2COOEt
was necessary to ensure the completion of the reaction (Table
1, entries 7, 10, and 12). Finally, the effect of the amount of
copper powder was investigated. The results showed that 2
equiv of copper could not lead to the full conversion of the
starting material (SM) 1a, whereas 3 equiv of copper amount
could (Table 1, entries 7 and 13). When the copper content
was increased to 4 or 5 equiv, 2a was obtained in good yield
(entries 14 and 15).
Utilizing these optimized reaction conditions (5 mol % of
Pd(dppf)Cl2, 2 equiv of BrCF2COOEt, 4 equiv of copper
powder, DMSO as solvent at 60 °C), the reactions of various 3-
iodo-substituted chromones, thiochromones, and quinolones
with BrCF2CO2Et were investigated. As depicted in Table 2,
this reaction was compatible with a variety of functional groups,
including electron-donating methyl, methoxy, and aryl groups
as well as electron-withdrawing fluoro and chloro groups. The
effect of the substituent position on the benzene ring was subtle
(Table 2, compound 2b vs 2c; 2e vs 2f; 2i vs 2j; 2k vs 2l). The
yields for different electron-donating groups seem contra-
dictory. Methoxy-substituted substrates provided a good yield
B
dx.doi.org/10.1021/jo400412k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a
Table 1. Optimization of the Reaction Conditions
b
c
entry
catalyst
solvent
1a/BrCF2CO2Et/Cu molar ratio
time (h)
2
yield (%)
1
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
1:1.1:5
1:1.1:5
1:1.1:5
1:2:3
1:2:3
1:2:3
1:2:3
1:2:3
1:2:3
1:1:3
1:1:4
1:1.5:3
1:2:2
1:2:4
nd
nd
nd
d
2
d
3
12
e
4
Pd2(dba)3
4
4
32
37
53
58
40
e
5
Pd(PPh3)4
6
Pd(OAc)2
2
7
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
Pd(dppf)Cl2
2
8
3
e
9
NMP
3.5
2
9
e
e
e
e
10
11
12
13
14
15
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
22
51
54
19
78
76
5
2
4
2
1:2:5
2
a
b
c
1a (0.5 mmol) and solvent (5 mL) were used, 60 °C, under argon atmosphere. Catalyst (0.025 mmol, 0.05 equiv) was employed. Isolated yields.
Reaction was performed at 125 °C. SM was incompletely converted.
d
e
(Table 2, compounds 2b, 2c, 2d, and 2p), whereas methyl
anywhere on the chromones provided lower yields (Table 2,
compound 2e vs 2b; 2f vs 2c; 2g vs 2a; 2o vs 2l). We suspect
that these results may be caused by the less stable palladium
oxidative intermediates of the methyl substrates compared to
the methoxy group. The results for 2g and 2m can also be
explained by the stability of the palladium intermediate. On the
basis of these results, we extended the reaction scope to
thiochromone and aza analogues. Thiochromones and
quinolones also worked well, with good to excellent yields,
except for 2u. Surprisingly, using this method, thiochromones21
showed more favorable reactivity (Table 2, 2q and 2s) than
their oxo, aza analogues, even with methyl substituents (Table
2, 2r and 2q). Finally, this method was exploited in the
modification of a natural product. Graveolinine is a natural
quinolone alkaloid22 isolated from Ruta graveolens L with
interesting antibacterial, spasmolysis, and antitumor activities
(Scheme 1). 3-Iodograveolinine (1v) was prepared following
reported methods23 and then subjected to the previously
determined optimal conditions. The target compound 2v was
obtained in good yield (78%).
A plausible mechanism for the cross-coupling of 3-
iodochromones, thiochromones, quinolones, and BrCF2CO2Et
is depicted in Scheme 2.20a,24 First, if a Pd(II) catalyst is
employed, it may be reduced by copper into an active Pd(0)
species, which then reacts via an oxidative addition into the C−
I bond of compound 1 to form intermediate I. Meanwhile, the
unstable copper ethyl difluoroacetate complex II is formed, and
then intermediate III is generated rapidly via a reaction between
intermediates I and II. Finally, reduction elimination affords the
corresponding products 2, regenerating the Pd(0) catalyst.
In conclusion, we have demonstrated an efficient synthesis of
C-3 ethoxycarbonyldifluoromethylated chromones, thiochro-
mones, and quinolones with functional group compatibility by a
Pd-catalyzed reaction in the presence of copper. This method is
useful for the synthesis of various chromone analogues,
especially for the modification of natural bioactive compounds.
EXPERIMENTAL SECTION
■
1
General Experimental Information. H and 13C NMR spectra
were recorded on a standard spectrometer operating at 300, 400, and
500 MHz (1H 300/400 MHz, 13C 125 MHz). Chemical shifts (δ) are
given in parts per million. The abbreviations of splitting patterns are
described as follows: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, dd = doublet of doublets. SiMe4 (TMS) was used as
internal references in CDCl3 (δ 7.26) for H NMR, and 13C NMR
1
spectra were calibrated with CDCl3 (δ 77.00) or DMSO-d6 (δ 39.97).
High-resolution mass spectra were recorded using the EI method with
a double focusing magnetic mass analyzer. Melting points were
measured uncorrected. Reactions were monitored by thin-layer
chromatography or LC-MS analysis. Column chromatography
(petroleum ether/ethyl acetate) was performed on silica gel (200−
300 mesh). Ethyl bromodifluoroacetate was purchased from
commercial source. Unless otherwise noted, all reactions were run
under argon atmosphere and all solvents are commercially available
without further purification.
Starting Materials. Compound 1f was prepared by the iodination
of 2-methyl-4H-chromen-4-one using the I2/CF3COOAg system
according to a previously reported protocol.25 1g, 1m, 1q, 1r, and
1s were prepared according to a known iodination procedure using the
I2/Ce(NH4)2(NO3)6/CH3CN system.21b 1n was prepared by C-3
lithiation using LDA followed by the addition of iodine according to a
reported method.26 Other chromones were prepared by the addition
of the corresponding substituted o-hydroxyacetophenone with N,N-
dimethylformamide dimethyl acetal (DMFDMA), followed by
cyclization and an iodination process by iodine according to a
reported protocol.27 1q was generated by the iodination of 1-
methylquinolin-4(1H)-one using the I2/Na2CO3 system based on a
previously reported protocol.23b 1r and 1s were prepared from 2-
aminoacetophenone and the corresponding benzoyl chloride accord-
ing to a previously mentioned protocol.23
General Procedure for Preparing Target Compound 2
(Typical Example: 2a). In a two-neck flask, 1a (0.5 mmol) and
Pd(dppf)Cl2 (19 mg, 0.025 mmol, 0.05 equiv) were added. The flask
was capped and then purged under vacuum and filled with argon three
C
dx.doi.org/10.1021/jo400412k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
a b
,
Table 2. Synthesis of 2b−2v via Cross-Coupling Reactions between 1b−1v and BrCF2CO2Et
a
b
Reaction conditions: 1 (0.5 mmol), copper powder (2 mmol), Pd(dppf)CI2 (0.025 mmol, 0.05 equiv) in DMSO at 60 °C, 2 h. Isolated yield.
c
Substrate converted incompletely.
Scheme 1. Preparation of the Graveolinine Ethyldifluoroacetate Derivative
times. BrCF2CO2Et (0.13 mL, 1 mmol) and DMSO (2 mL) were then
added, and the whole mixture was heated to 60 °C. Meanwhile, copper
powder (128 mg, 2 mmol) was added to another two-neck flask under
argon, followed by the addition of DMSO (3 mL). Then, the
suspension was stirred at 60 °C. After 1 h, the substrate solution was
transferred into copper powder suspension rapidly under argon using a
syringe maintaining the temperature around 60 °C. Once the reaction
was complete, at room temperature, ethyl acetate (15 mL) was added.
Aqueous solution of KH2PO4 (1.27 M, 6 mL) was added, then the
mixture was stirred for 10 min. The mixture was filtered through
Celite, the copper salt residue was washed with EtOAc, and the filtrate
was washed with brine and dried over anhydrous Na2SO4. The organic
layer was concentrated and purified on silica gel eluted with PE/
EtOAc to afford product 2a.
Ethyl 2,2-Difluoro-2-(4-oxo-4H-chromen-3-yl)acetate (2a):
White powder (105 mg, 78%); mp 104−105 °C; 1H NMR (300
MHz, CDCl3) δ 8.32 (t, J = 1.2 Hz, 1H), 8.20 (dd, J = 8.0, 1.6 Hz,
1H), 7.74 (td, J = 7.8, 1.7 Hz, 1H), 7.53 (d, J = 8.5 Hz, 1H), 7.47 (t, J
= 7.5 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13
C
=
3
2
NMR (125 MHz, CDCl3) δ 174.6 (t, JCF = 3.1 Hz), 162.7 (t, JCF
3
32.6 Hz), 156.3, 155.1 (t, JCF = 9.7 Hz), 134.8, 126.2, 125.9, 123.9,
D
dx.doi.org/10.1021/jo400412k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
J = 7.9 Hz, 1H), 7.43 (q, J = 7.9 Hz, 2H), 4.41 (q, J = 7.1 Hz, 2H),
2.68 (t, J = 3.4 Hz, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (125
Scheme 2. Mechanism for Copper-Mediated Palladium-
Catalyzed Cross-Coupling Reaction
3
2
MHz, CDCl3) δ 175.4 (t, JCF = 3.5 Hz), 168.3, 163.3 (t, JCF = 32.1
Hz), 155.7, 134.4, 125.8, 125.8, 122.5, 117.8, 116.2 (t, 2JCF = 22.8 Hz),
1
4
112.7 (t, JCF = 249.8 Hz), 63.1, 19.8 (t, JCF = 5.1 Hz), 13.9; HRMS
(EI+) m/z 282.0702 [C14H12F2O4 (M+) requires 282.0704].
Ethyl 2-(2,6-Dimethyl-4-oxo-4H-chromen-3-yl)-2,2-difluoro-
acetate (2h): White solid (86 mg, 58%); mp 105−106 °C; 1H NMR
(300 MHz, CDCl3) δ 7.91 (s, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.35 (d, J
= 8.5 Hz, 1H), 4.41 (q, J = 7.0 Hz, 2H), 2.66 (s, 3H), 2.44 (s, 3H),
1.36 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 175.4 (t, 3JCF
= 3.4 Hz), 168.2, 163.4 (t, 2JCF = 32.0 Hz), 154.0, 135.9, 135.6, 125.1,
122.2, 117.5, 116.0 (t, 2JCF = 22.6 Hz), 112.8 (t, 1JCF = 249.8 Hz), 63.0,
4
21.0, 19.8 (t, JCF = 5.1 Hz), 13.9; HRMS (EI+) m/z 296.0868
[C15H14F2O4 (M+) requires 296.0860].
Ethyl 2,2-Difluoro-2-(7-fluoro-4-oxo-4H-chromen-3-yl)-
1
acetate (2i): White solid (98 mg, 69%); mp 79−80 °C; H NMR
(300 MHz, CDCl3) δ 8.29 (t, J = 1.3 Hz, 1H), 8.25−8.18 (m, 1H),
7.24−7.16 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 173.6 (t, 3JCF = 2.6 Hz), 166.1 (d, 1JCF
= 257.4 Hz), 162.5 (t, 2JCF = 32.3 Hz), 157.4 (d, 3JCF = 13.4 Hz), 155.3
118.9 (t, 2JCF = 22.5 Hz), 118.4, 111.3 (t, 1JCF = 250.6 Hz), 63.4, 13.9;
HRMS (EI+) m/z 268.0544 [C13H10F2O4 (M+) requires 268.0547].
Ethyl 2,2-Difluoro-2-(6-methoxy-4-oxo-4H-chromen-3-yl)-
3
3
2
(t, JCF = 9.7 Hz), 128.5 (d, JCF = 10.7 Hz), 120.7, 119.1 (t, JCF
=
1
22.5 Hz), 115.1 (d, 2JCF = 22.9 Hz), 111.2 (t, JCF = 250.9 Hz), 105.3
2
(d, JCF = 25.6 Hz), 63.5, 13.9; HRMS (EI+) m/z 286.0456
1
acetate (2b): Yellow powder (123 mg, 83%); mp 101−102 °C; H
[C13H9F3O4 (M+) requires 286.0453].
NMR (300 MHz, CDCl3) δ 8.30 (t, J = 1.3 Hz, 1H), 7.54 (d, J = 3.1
Hz, 1H), 7.47 (d, J = 9.2 Hz, 1H), 7.32 (dd, J = 9.2, 3.1 Hz, 1H), 4.39
(q, J = 7.1 Hz, 2H), 3.88 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C NMR
Ethyl 2,2-Difluoro-2-(6-fluoro-4-oxo-4H-chromen-3-yl)-
acetate (2j): Light yellow solid (122 mg, 85%); mp 102−103 °C;
1H NMR (300 MHz, CDCl3) δ 8.32 (t, J = 1.3 Hz, 1H), 7.83 (dd, J =
3
2
(125 MHz, CDCl3) δ 174.5 (t, JCF = 3.0 Hz), 162.7 (t, JCF = 32.5
7.9, 3.0 Hz, 1H), 7.56 (dd, J = 9.2, 4.1 Hz, 1H), 7.50−7.45 (m, 1H),
3
Hz), 157.6, 154.8 (t, JCF = 9.6 Hz), 151.2, 124.8, 124.5, 119.8, 118.1
4.39 (q, J = 7.1 Hz, 2H), 1.39−1.32 (t, J = 7.1 Hz, 3H); 13C NMR
(t, 2JCF = 22.5 Hz), 111.5 (t, 1JCF = 250.3 Hz), 104.8, 63.4, 56.0, 13.9;
HRMS (EI+) m/z 298.0643 [C14H12F2O5 (M+) requires 298.0653].
Ethyl 2,2-Difluoro-2-(7-methoxy-4-oxo-4H-chromen-3-yl)-
3
2
(125 MHz, CDCl3) δ 173.9 (t, JCF = 2.8 Hz), 162.5 (t, JCF = 32.4
Hz), 160.0 (d, 1JCF = 249.1 Hz), 157.9, 155.3 (t, 3JCF = 9.6 Hz), 152.6,
2
3
2
123.0 (d, JCF = 25.5 Hz), 120.7 (d, JCF = 8.2 Hz), 118.3 (t, JCF
=
1
acetate (2c): Light yellow solid (126 mg, 85%); mp 70−71 °C; H
1
2
22.8 Hz), 111.2 (t, JCF = 250.9 Hz), 110.9 (d, JCF = 24.0 Hz), 63.5,
13.9; HRMS (EI+) m/z 286.0448 [C13H9F3O4 (M+) requires
286.0453].
NMR (300 MHz, CDCl3) δ 8.23 (t, J = 1.3 Hz, 1H), 8.09 (d, J = 8.9
Hz, 1H), 7.01 (dd, J = 8.9, 2.3 Hz, 1H), 6.90 (d, J = 2.3 Hz, 1H), 4.38
(q, J = 7.0 Hz, 2H), 3.92 (s, 3H), 1.35 (t, J = 7.0 Hz, 3H); 13C NMR
Ethyl 2-(7-Chloro-4-oxo-4H-chromen-3-yl)-2,2-difluoro-
3
2
(125 MHz, CDCl3) δ 173.8 (t, JCF = 2.8 Hz), 164.8, 162.8 (t, JCF
=
1
acetate (2k): White solid (103 mg, 68%); mp 66−67 °C; H NMR
3
2
32.5 Hz), 158.2, 154.7 (t, JCF = 9.7 Hz), 127.2, 118.8 (t, JCF = 22.3
(300 MHz, CDCl3) δ 8.28 (t, J = 1.4 Hz, 1H), 8.13 (d, J = 8.6 Hz,
1H), 7.56 (d, J = 1.9 Hz, 1H), 7.44 (dd, J = 8.6, 1.9 Hz, 1H), 4.39 (q, J
= 7.1 Hz, 2H), 1.39−1.32 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
1
Hz), 117.6, 115.4, 111.4 (t, JCF = 250.3 Hz), 100.6, 63.4, 56.0, 13.9;
HRMS (EI+) m/z 298.0649 [C14H12F2O5 (M+) requires 298.0653].
Ethyl 2,2-Difluoro-2-(5-methoxy-4-oxo-4H-chromen-3-yl)-
acetate (2d): Yellow solid (109 mg, 73%); mp 98−99 °C; 1H
NMR (300 MHz, CDCl3) δ 8.15 (t, J = 1.2 Hz, 1H), 7.61 (t, J = 8.4
Hz, 1H), 7.06 (d, J = 8.5 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.38 (q, J
= 7.1 Hz, 2H), 3.96 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (125
3
2
CDCl3) δ 173.7 (t, JCF = 3.2 Hz), 162.5 (t, JCF = 32.4 Hz), 156.4,
3
2
155.2 (t, JCF = 9.7 Hz), 141.0, 127.2, 127.1, 122.4, 119.3 (t, JCF
=
1
22.6 Hz), 118.5, 111.1 (t, JCF = 250.9 Hz), 63.5, 13.9; HRMS (EI+)
m/z 302.0160 [C13H9ClF2O4 (M+) requires 302.0157].
3
2
Ethyl 2-(6-Chloro-4-oxo-4H-chromen-3-yl)-2,2-difluoro-
MHz, CDCl3) δ 174.3 (t, JCF = 3.1 Hz), 162.7 (t, JCF = 32.4 Hz),
160.1, 158.3, 153.3 (t, 3JCF = 10.0 Hz), 134.9, 120.1 (t, 2JCF = 22.6 Hz),
114.4, 111.5 (t, 1JCF = 250.3 Hz), 110.1, 107.3, 63.3, 56.6, 13.9; HRMS
(EI+) m/z 298.0644 [C14H12F2O5 (M+) requires 298.0653].
1
acetate (2l): Yellow solid (105 mg, 70%); mp 90−91 °C; H NMR
(400 MHz, CDCl3) δ 8.31 (t, J = 1.2 Hz, 1H), 8.16 (d, J = 2.6 Hz,
1H), 7.69 (dd, J = 8.9, 2.6 Hz, 1H), 7.50 (d, J = 8.9 Hz, 1H), 4.39 (q, J
= 7.2 Hz, 2H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
δ 173.5 (t, 3JCF = 3.0 Hz), 162.5 (t, 2JCF = 32.4 Hz), 155.3 (t, 3JCF = 9.7
Hz), 154.7, 135.0, 132.4, 125.3, 124.8, 120.2, 119.0 (t, 2JCF = 22.7 Hz),
Ethyl 2,2-Difluoro-2-(6-methyl-4-oxo-4H-chromen-3-yl)-
1
acetate (2e): White solid (75 mg, 53%); mp 64−65 °C; H NMR
(400 MHz, CDCl3) δ 8.29 (t, J = 1.2 Hz, 1H), 7.97 (d, J = 1.5 Hz,
1H), 7.54 (dd, J = 8.6, 2.2 Hz, 1H), 7.42(d, J = 8.6 Hz, 1H), 4.38 (q, J
= 7.1 Hz, 2H), 2.46 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (125
1
111.2 (t, JCF = 250.9 Hz), 63.5, 13.9; HRMS (EI+) m/z 302.0184
[C13H9ClF2O4 (M+) requires 302.0157].
3
2
Ethyl 2,2-Difluoro-2-(4-oxo-2-phenyl-4H-chromen-3-yl)-
MHz, CDCl3) δ 174.7 (t, JCF = 3.1 Hz), 162.7 (t, JCF = 32.5 Hz),
155.0 (t, 3JCF = 9.6 Hz), 154.7, 136.4, 135.9, 125.1, 123.5, 118.7 (t, 2JCF
= 22.4 Hz), 118.1, 111.4 (t, 1JCF = 250.2 Hz), 63.4, 21.0, 13.9; HRMS
(EI+) m/z 282.0698 [C14H12F2O4 (M+) requires 282.0704].
1
acetate (2m): White powder (143 mg, 83%); mp 129−130 °C; H
NMR (300 MHz, CDCl3) δ 8.21 (dd, J = 8.0, 1.3 Hz, 1H), 7.78−7.68
(m, 3H), 7.59−7.44 (m, 5H), 4.36 (q, J = 7.1 Hz, 2H), 1.33 (t, J = 7.1
3
Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 176.4 (t, JCF = 2.8 Hz),
Ethyl 2,2-Difluoro-2-(7-methyl-4-oxo-4H-chromen-3-yl)-
acetate (2f): White solid (75 mg, 53%); mp 127−128 °C; 1H
NMR (300 MHz, CDCl3) δ 8.28 (s, 1H), 8.08 (d, J = 8.1 Hz, 1H),
7.31 (d, J = 9.3 Hz, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.51 (s, 3H), 1.36 (t,
2
166.7, 163.3 (t, JCF = 32.4 Hz), 156.0, 134.8, 132.4, 131.3, 129.0,
2
128.2 (3 × ), 126.0, 125.8, 122.6, 118.2, 115.9 (t, JCF = 22.0 Hz),
1
111.8 (t, JCF = 251.5 Hz), 63.0, 13.9; HRMS (EI+) m/z 344.0851
[C19H14F2O4 (M+) requires 344.0860].
3
J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 174.4 (t, JCF = 3.0
2
3
Ethyl 2,2-Difluoro-2-(1-oxo-1H-benzo[f ]chromen-2-yl)-
acetate (2n): White solid (64 mg, 40%); mp 119−120 °C; 1H
NMR (400 MHz, CDCl3) δ 9.91 (d, J = 8.2 Hz, 1H), 8.36 (s, 1H),
8.16 (d, J = 9.1 Hz, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.76 (t, J = 7.4 Hz,
1H), 7.65 (t, J = 7.4 Hz, 1H), 7.56 (d, J = 9.1 Hz, 1H), 4.42 (q, J = 7.1
Hz, 2H), 1.37 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ
176.2 (t, 3JCF = 2.9 Hz), 162.5 (t, 2JCF = 32.6 Hz), 158.2, 155.4 (t, 3JCF
Hz), 162.7 (t, JCF = 32.4 Hz), 156.5, 154.9 (t, JCF = 9.7 Hz), 146.4,
2
1
127.7, 125.6, 121.6, 118.8 (t, JCF = 22.4 Hz), 118.1, 111.4 (t, JCF
=
250.4 Hz), 63.4, 21.9, 13.9; HRMS (EI+) m/z 282.0704 [C14H12F2O4
(M+) requires 282.0704].
Ethyl 2,2-Difluoro-2-(2-methyl-4-oxo-4H-chromen-3-yl)-
acetate (2g): Light yellow powder (61 mg, 43%); mp 88−89 °C;
1H NMR (300 MHz, CDCl3) δ 8.13 (dd, J = 7.9, 1.5 Hz, 1H), 7.69 (t,
E
dx.doi.org/10.1021/jo400412k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
= 9.1 Hz), 137.7, 131.1, 130.3, 129.7, 129.4, 127.8, 126.3, 120.6 (t, 2JCF
= 22.1 Hz), 118.4, 116.5, 112.1 (t, 1JCF = 247.7 Hz), 63.6, 14.2; HRMS
(EI+) m/z 318.0713 [C17H12F2O4 (M+) requires 318.0704].
(d, J = 8.0 Hz, 1H), 7.76 (t, J = 7.9 Hz, 1H), 7.57 (d, J = 8.7 Hz, 1H),
7.47 (t, J = 7.5 Hz, 1H), 6.94 (d, J = 8.3 Hz, 1H), 6.89−6.83 (m, 2H),
6.09 (d, J = 1.4 Hz, 1H), 6.07 (d, J = 1.4 Hz, 1H), 4.35 (q, J = 7.1 Hz,
2H), 3.52 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
Ethyl 2-(6-Chloro-7-methyl-4-oxo-4H-chromen-3-yl)-2,2-di-
fluoroacetate (2o): White powder (101 mg, 64%); mp 120−121
°C; 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 8.14 (s, 1H), 7.42 (s,
1H), 4.39 (q, J = 7.2 Hz, 2H), 2.52 (s, 3H), 1.35 (t, J = 7.2 Hz, 3H);
13C NMR (125 MHz, CDCl3) δ 173.3 (t, 3JCF = 3.1 Hz), 162.5 (t, 2JCF
3
2
CDCl3) δ 175.4 (t, JCF = 2.6 Hz), 164.2 (t, JCF = 32.6 Hz), 153.9,
148.8, 147.9, 141.3, 133.3, 126.8, 126.7, 126.2, 124.8, 122.6, 116.3,
2
1
114.9 (t, JCF = 20.6 Hz), 113.1 (t, JCF = 249.9 Hz), 109.0, 108.6,
101.7, 62.5, 36.9, 14.0; HRMS (EI+) m/z 401.1076 [C21H17F2NO5
(M+) requires 401.1075].
= 32.4 Hz), 155.0 (t, 3JCF = 9.7 Hz), 154.5, 144.3, 133.0, 125.4, 122.8,
120.1, 118.8 (t, 2JCF = 22.5 Hz), 111.2 (t, 1JCF = 250.9 Hz), 63.4, 20.9,
13.8; HRMS (EI+) m/z 316.0313 [C14H11ClF2O4 (M+) requires
316.0314].
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR for all synthesized compounds; 13C NMR spectra for
1g, 1h, 1k, 1n, 1v, and all compounds of 2a−2v. This material
is available free of charge via the Internet at http://pubs.acs.org.
Ethyl 2-(5,7-Dimethoxy-4-oxo-2-phenyl-4H-chromen-3-yl)-
2,2-difluoroacetate (2p): Light yellow solid (258 mg, 84% yield
from 0.76 mmol of 1p); mp 219−220 °C; 1H NMR (300 MHz,
CDCl3) δ 7.65 (d, J = 7.7 Hz, 2H), 7.55−7.44 (m, 3H), 6.47 (d, J = 2.2
Hz, 1H), 6.38 (d, J = 2.1 Hz, 1H), 4.36 (q, J = 7.1 Hz, 2H), 3.93 (s,
3H), 3.87 (s, 3H), 1.33 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
AUTHOR INFORMATION
Corresponding Author
*E-mail: chyang@simm.ac.cn. Fax: +86-21-50806770.
■
3
2
CDCl3) δ 175.0 (t, JCF = 2.9 Hz), 164.9, 164.0, 163.4 (t, JCF = 32.1
Hz), 161.1, 159.6, 132.3, 131.0, 129.0, 128.1 (3×), 116.8 (t, 2JCF = 21.8
Hz), 112.1 (t, 1JCF = 251.0 Hz), 107.8, 96.8, 92.6, 62.8, 56.5, 55.9, 13.9;
HRMS (EI+) m/z 404.1073 [C21H18F2O6 (M+) requires 404.1071].
Ethyl 2,2-Difluoro-2-(2-methyl-4-oxo-4H-thiochromen-3-yl)-
Notes
The authors declare no competing financial interest.
1
acetate (2q): Yellow solid (135 mg, 91%); mp 140−141 °C; H
ACKNOWLEDGMENTS
NMR (400 MHz, CDCl3) δ 8.45−8.39 (d, J = 8.2 Hz, 1H), 7.64 (td, J
= 8.1, 1.5 Hz, 1H), 7.58−7.51 (m, 2H), 4.39 (q, J = 7.1 Hz, 2H), 2.71
(t, J = 4.5 Hz, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz,
■
This work was supported by the “Interdisciplinary Cooperation
Team” Program for Science and Technology Innovation of
Chinese Academy of Science, and the National Natural Science
Foundation of China (21072205) and SIMM1203ZZ-0103.
3
2
CDCl3) δ 178.4 (t, JCF = 3.6 Hz), 163.4 (t, JCF = 32.1 Hz), 155.8,
2
136.5, 132.2, 130.2, 128.9, 128.2, 126.5 (t, JCF = 21.7 Hz), 125.2,
1
4
113.7 (t, JCF = 251.6 Hz), 62.7, 22.1 (t, JCF = 6.4 Hz), 13.9; HRMS
(EI+) m/z 298.0479 [C14H12F2O3S (M+) requires 298.0475].
REFERENCES
■
Ethyl 2-(2,6-Dimethyl-4-oxo-4H-thiochromen-3-yl)-2,2-
difluoroacetate (2r): White solid with pale yellow (111 mg, 71%);
mp 122−123 °C; 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 1H), 7.44 (s,
2H), 4.38 (q, J = 7.1 Hz, 2H), 2.69 (t, J = 4.5 Hz, 3H), 2.45 (s, 3H),
1.35 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 178.5 (t, 3JCF
= 3.5 Hz), 163.5 (t, 2JCF = 32.1 Hz), 155.7, 138.8, 133.6, 133.5, 130.0,
128.6, 126.3 (t, 2JCF = 21.7 Hz), 125.1, 113.8 (t, 1JCF = 251.5 Hz), 62.7,
(1) (a) Saengchantara, S. T.; Wallace, T. W. Nat. Prod. Rep. 1986, 3,
465. (b) Tsao, R.; McCallum, J. Chemistry of Flavonoids. In Fruit and
Vegetable Phytochemicals: Wiley-Blackwell: New York, 2009; p 131.
(2) Michael, J. P. Nat. Prod. Rep. 2008, 25, 166.
(3) (a) Hutter, J. A.; Salman, M.; Stavinoha, W. B.; Satsangi, N.;
Williams, R. F.; Streeper, R. T.; Weintraub, S. T. J. Nat. Prod. 1996, 59,
541. (b) Zhang, F.; Li, L.; Niu, S.; Si, Y.; Guo, L.; Jiang, X.; Che, Y. J.
Nat. Prod. 2012, 75, 230. (c) Simonetti, S. O.; Larghi, E. L.; Bracca, A.
B. J.; Kaufman, T. S. Org. Biomol. Chem 2012, 10, 4124.
(4) (a) Dias, M. M.; Machado, N. F. L.; Marques, M. P. M. Food
Funct. 2011, 2, 595. (b) Legoabe, L. J.; Petzer, A.; Petzer, J. P. Bioorg.
Med. Chem. Lett. 2012, 22, 5480. (c) Gong, L.; Tan, Y.-C.; Boice, G.;
Abbot, S.; McCaleb, K.; Iyer, P.; Zuo, F.; Porto, J. D.; Wong, B.; Jin, S.;
Chang, A.; Tran, P.; Hsieh, G.; Niu, L.; Shao, A.; Reuter, D.; Lukacs,
C. M.; Kammlott, R. U.; Kuglstatter, A.; Goldstein, D. Bioorg. Med.
Chem. Lett. 2012, 22, 7381. (d) Huang, X.; Li, W.; Yang, X.-W.
Fitoterapia 2012, 83, 709.
(5) Nussbaumer, P.; Lehr, P.; Billich, A. J. Med. Chem. 2002, 45,
4310.
(6) Hagmann, W. K. J. Med. Chem. 2008, 51, 4359.
́ ́
(7) (a) Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127,
992. (b) Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013.
(8) (a) Hu, J.; Zhang, W.; Wang, F. Chem. Commun. 2009, 7465.
(b) Ji, Y.; Brueckl, T.; Baxter, R. D.; Fujiwara, Y.; Seiple, I. B.; Su, S.;
Blackmond, D. G.; Baran, P. S. Proc. Natl. Acad. Sci. U.S.A. 2011, 108,
14411. (c) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.;
Dixon, D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am.
Chem. Soc. 2012, 134, 1494. (d) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.;
4
22.2 (t, JCF = 6.3 Hz), 21.4, 14.0; HRMS (EI+) m/z 312.0635
[C15H14F2O3S (M+) requires 312.0632].
Ethyl 2,2-Difluoro-2-(4-oxo-2-phenyl-4H-thiochromen-3-yl)-
1
acetate (2s): White powder (160 mg, 90%); mp 99−100 °C; H
NMR (300 MHz, CDCl3) δ 8.50 (d, J = 8.4 Hz, 1H), 7.72−7.64 (m,
1H), 7.62−7.54 (m, 2H), 7.55−7.41 (m, 5H), 4.35 (q, J = 7.1 Hz,
2H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 179.1
(t, 3JCF = 2.4 Hz), 163.4 (t, 2JCF = 32.0 Hz), 157.6, 137.2, 135.0, 132.5,
130.3, 130.0, 128.9, 128.4, 128.2 (3×), 128.1, 125.9 (t, 2JCF = 20.4 Hz),
1
125.4, 112.6 (t, JCF = 253.4 Hz), 62.7, 13.9; HRMS (EI+) m/z
360.0633 [C19H14F2O3S (M+) requires 360.0632].
Ethyl 2,2-Difluoro-2-(1-methyl-4-oxo-1,4-dihydroquinolin-3-
1
yl)acetate (2t): White solid (112 mg, 80%); mp 143−144 °C; H
NMR (400 MHz, CDCl3) δ 8.42 (dd, J = 8.5, 1.6 Hz, 1H), 7.98 (s,
1H), 7.74 (td, J = 8.8, 1.6 Hz, 1H), 7.45 (dd, J = 8.2, 7.0 Hz, 2H), 4.40
(q, J = 7.1 Hz, 2H), 3.89 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C NMR
3
2
(125 MHz, CDCl3) δ 174.9 (t, JCF = 3.4 Hz), 163.7 (t, JCF = 33.2
Hz), 142.4 (t, 3JCF = 8.4 Hz), 140.4, 133.1, 126.8, 126.8, 124.9, 115.7,
2
1
114.3 (t, JCF = 22.7 Hz), 112.4 (t, JCF = 249.0 Hz), 63.1, 41.4, 14.0;
HRMS (EI+) m/z 281.0860 [C14H13F2NO3 (M+) requires 281.0863].
Ethyl 2,2-Difluoro-2-(1-methyl-4-oxo-2-phenyl-1,4-dihydro-
quinolin-3-yl)acetate (2u): Pale yellow powder (102 mg, 57%); mp
181−182 °C; 1H NMR (300 MHz, CDCl3) δ 8.47 (d, J = 8.0 Hz, 1H),
7.79−7.73 (m, 1H), 7.60−7.35 (m, 7H), 4.35 (q, J = 7.1 Hz, 2H), 3.46
(s, 3H), 1.32 (t, J = 7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ
175.3 (t, 3JCF = 3.1 Hz), 164.2 (t, 2JCF = 32.4 Hz), 154.3, 141.3, 133.4,
133.3, 129.7, 128.6 (3×), 128.3, 126.8, 126.2, 124.7, 116.3, 114.7 (t,
́
Funder, E. D.; Dixon, D. D.; Rodriguez, R. A.; Baxter, R. D.; Herle, B.;
Sach, N.; Collins, M. R.; Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95.
́
(9) Afzelius, L.; Zamora, I.; Masimirembwa, C. M.; Karlen, A.;
Andersson, T. B.; Mecucci, S.; Baroni, M.; Cruciani, G. J. Med. Chem.
2004, 47, 907.
1
2JCF = 21.1 Hz), 113.0 (t, JCF = 250.2 Hz), 62.4, 36.9, 13.9; HRMS
(10) Wu, W.; Sigmond, J.; Peters, G. J.; Borch, R. F. J. Med. Chem.
2007, 50, 3743.
(11) Cuthbert, A. W. Br. J. Pharmacol. 2011, 162, 508.
(12) Matsumura, Y.; Mori, N.; Nakano, T.; Sasakura, H.; Matsugi, T.;
Hara, H.; Morizawa, Y. Tetrahedron Lett. 2004, 45, 1527.
(EI+) m/z 357.1182 [C20H17F2NO3 (M+) requires 357.1176].
Ethyl 2-(2-(Benzo[d][1,3]dioxol-5-yl)-1-methyl-4-oxo-1,4-
dihydroquinolin-3-yl)-2,2-difluoroacetate (2v): Gray white solid
(156 mg, 78%); mp 116−117 °C; 1H NMR (300 MHz, CDCl3) δ 8.45
F
dx.doi.org/10.1021/jo400412k | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
́
(13) Romero-Sanchez, M. C.; Machmach, K.; Gonzalez-Serna, A.;
́
Genebat, M.; Pulido, I.; Garcia-Garcia, M.; Alvarez-Rios, A. I.;
Ferrando-Martinez, S.; Ruiz-Mateos, E.; Leal, M. Antimicrob. Agents
Chemother. 2012, 56, 5858.
(14) Liu, K. K.-C.; Sakya, S. M.; O’Donnell, C. J.; Flick, A. C.; Ding,
H. X. Bioorg. Med. Chem. 2012, 20, 1155.
(15) (a) Murakami, S.; Kim, S.; Ishii, H.; Fuchigami, T. Synlett 2004,
815. (b) Murakami, S.; Ishii, H.; Tajima, T.; Fuchigami, T. Tetrahedron
2006, 62, 3761.
(16) Ohtsuka, Y.; Yamakawa, T. Tetrahedron 2011, 67, 2323.
(17) Sato, K.; Kawata, R.; Ama, F.; Omote, M.; Ando, A.; Kumadaki,
I. Chem. Pharm. Bull. 1999, 47, 1013.
(18) Ashwood, M. S.; Cottrell, I. F.; Cowden, C. J.; Wallace, D. J.;
Davies, A. J.; Kennedy, D. J.; Dolling, U. H. Tetrahedron Lett. 2002, 43,
9271.
(19) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett.
2011, 13, 5560.
(20) (a) Banwell, M. G.; Kelly, B. D.; Kokas, O. J.; Lupton, D. W.
Org. Lett. 2003, 5, 2497. (b) Banwell, M. G.; Lupton, D. W.; Ma, X.;
Renner, J.; Sydnes, M. O. Org. Lett. 2004, 6, 2741. (c) Banwell, M. G.;
Jones, M. T.; Loong, D. T. J.; Lupton, D. W.; Pinkerton, D. M.; Ray, J.
K.; Willis, A. C. Tetrahedron 2010, 66, 9252.
(21) (a) Holshouser, M. H.; Loeffler, L. J.; Hall, I. H. J. Med. Chem.
1981, 24, 853. (b) Zhang, F. J.; Li, Y. L. Synthesis 1993, 565.
(22) An, Z.-Y.; Yan, Y.-Y.; Peng, D.; Ou, T.-M.; Tan, J.-H.; Huang, S.-
L.; An, L.-K.; Gu, L.-Q.; Huang, Z.-S. Eur. J. Med. Chem. 2010, 45,
3895.
(23) (a) Li, L.; Wang, H.-K.; Kuo, S.-C.; Wu, T.-S.; Lednicer, D.; Lin,
C. M.; Hamel, E.; Lee, K.-H. J. Med. Chem. 1994, 37, 1126.
(b) Mphahlele, M. J.; Nwamadi, M. S.; Mabeta, P. J. Heterocycl. Chem.
2006, 43, 255. (c) Mphahlele, M. J. J. Heterocycl. Chem. 2010, 47, 1.
́
(24) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
(25) Tang, G.; Ding, K.; Nikolovska-Coleska, Z.; Yang, C.-Y.; Qiu, S.;
Shangary, S.; Wang, R.; Guo, J.; Gao, W.; Meagher, J.; Stuckey, J.;
Krajewski, K.; Jiang, S.; Roller, P. P.; Wang, S. J. Med. Chem. 2007, 50,
3163.
(26) (a) Costa, A. M. B. S. R. C. S.; Dean, F. M.; Jones, M. A.;
Varma, R. S. J. Chem. Soc., Perkin Trans. 1 1985, 799. (b) Wang, C.-L.;
Li, H.-Q.; Meng, W.-D.; Qing, F.-L. Bioorg. Med. Chem. Lett. 2005, 15,
4456.
(27) Igarashi, Y.; Kumazawa, H.; Ohshima, T.; Satomi, H.;
Terabayashi, S.; Takeda, S.; Aburada, M.; Miyamoto, K.-i. Chem.
Pharm. Bull. 2005, 53, 1088.
G
dx.doi.org/10.1021/jo400412k | J. Org. Chem. XXXX, XXX, XXX−XXX