Facile synthesis of 2-fluoroindenones via a Knoevenagel condensation/palladium-catalyzed annulation

Article abstract of DOI:10.1016/j.jfluchem.2018.04.009

An efficient synthesis of 2-fluoroindenones was developed starting from simple o-bromo-2-fluroethenones and aldehydes. This domino reaction involved Knoevenagel condensation and intramolecular Heck coupling cyclization. A variety of 2-fluoroindenones were generated in good to excellent yields.

Full text of DOI:10.1016/j.jfluchem.2018.04.009

Accepted Manuscript
Title: Facile synthesis of 2-fluoroindenones via a Knoevenagel
condensation/palladium-catalyzed annulation
Authors: Yue Su, Xiang Fang, Jun Zhou, Yizhen Bian, Xueyan
Yang, Fanhong Wu
PII:
S0022-1139(18)30020-4
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.04.009
FLUOR 9155
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
6-1-2018
14-4-2018
14-4-2018
Please cite this article as: Su Y, Fang X, Zhou J, Bian Y, Yang X, Wu F, Facile synthesis
of 2-fluoroindenones via a Knoevenagel condensation/palladium-catalyzed annulation,
Journal of Fluorine Chemistry (2010), https://doi.org/10.1016/j.jfluchem.2018.04.009
This is a PDF file of an unedited manuscript that has been accepted for publication.
As a service to our customers we are providing this early version of the manuscript.
The manuscript will undergo copyediting, typesetting, and review of the resulting proof
before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that
apply to the journal pertain.

Facile
synthesis
of
2-fluoroindenones
via
a
Knoevenagel
condensation/palladium-catalyzed annulation
Yue Su a, Xiang Fang a,*, Jun Zhou a, Yizhen Bian b, Xueyan Yang a,*, Fanhong Wu c
a Key Laboratory for Advanced Material and Institute of Fine Chemicals, School of Chemistry
and Molecular Engineering, East China University of Science and Technology, 130 Meilong
Road, Shanghai 200237, China
b School of Pharmacy, East China University of Science and Technology, 130 Meilong Road,
Shanghai 200237, China
c School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 100
Haiquan Road, Shanghai 201418, China
e-mail: fangxiang@ecust.edu.cn, yxy@ecust.edu.cn
Graphical abstract
Highlights
 Domino reaction leading to 2-fluoroindenones
 No need of toxic CO gas
 Simple ortho-bromoketones and aldehydes were used
1

Abstract: An efficient synthesis of 2-fluoroindenones was developed starting from
simple o-bromo-2-fluroethenones and aldehydes. This domino reaction involved
Knoevenagel condensation and intramolecular Heck coupling cyclization. A variety of
2-fluoroindenones were generated in good to excellent yields.
Keywords: 2-Fluoroindenones, Domino reaction, Knoevenagel condensation, Intramolecular
Heck cyclization
2

1. Introduction
Indenones are important carbocyclic compounds that are core moieties in a variety
of natural products and biological active molecules [1]. For example, a structural
analogue of indenone A is used as a fluorescent binding agent to estrogen receptors [2]
neo-lignin B was isolated from Virolasebifera plant fruits [3], and compound C is a
structural analogue of the selective COX-2 inhibitor nimesulide [4]. Compound D, as a
hit toward agonists of peroxisome proliferator-activated receptor γ (PPAR γ), has
displayed the most active agonistic activity with an EC50 value of 50 nM (Fig. 1) [5].
,
Figure 1. Compounds containing an indenone core.
On account of their importance, various methods have been developed to access
indenones over the past decades. Although traditional indenone syntheses have largely
[6]
relied upon Friedel-Crafts cyclizations
and the addition of Grignard reagents to
2-substituted indandiones [7], a number of transition-metal-catalyzed annulations of
[8]
alkynes were accomplished using carbon monoxide (CO) as carbonylating agent
,
while annulations of internal alkynes with ortho-bifunctionalized arenes have also
3

been established (Scheme 1, Eq. 1) [9]. In recently years, guided by powerful C-H
[10g]
[10h]
activation technologies, rhodium [10a-10e], rhenium [10f], cobalt
and ruthenium
catalyzed direct annulations of benzoyl chlorides, benzimides, benzamides,
azomethines, arylnitrones and benzaldehydes with alkynes have been established
(Scheme 1, Eq. 2). On the other hand, radical-mediated cyclizations were also
reported (Scheme 1, Eq. 3) [11]
.
Introduction of fluorine atoms has become a crucial strategy in drug design [12]. The
judicious incorporation fluorine atoms or fluorine-containing units on specific
positions of biologically active organic molecules can significantly affect their pKa,
conformation, intrinsic potency, pharmacokinetic properties and membrane
permeability [13]. To the best of our knowledge, there are few 2-fluoroindenone
examples reported in literature [14]. Herein, we describe an efficient domino process
for the synthesis of 2-fluoroindenones starting from o-bromoketones and aldehydes
(Scheme 1, Eq. 4).
4

Scheme 1. Synthetic strategies to indenones
2. Results and discussion
According to a previous method [15], 1-(2-bromoaryl)-2-fluoroethanones 2 were
easily prepared from 1-(2-bromoaryl) ethanones 1 using Selectfluor as fluorination
reagent in methanol (Scheme 2).
5

Scheme 2. Synthesis of 1-(2-bromoaryl)-2-fluoroethanones 2
With substrates 2 in hand, we initially examined the reaction of
1-(2-bromophenyl)-2-fluoroethanone 2a and benzaldehyde 3a. With 1.2 equiv of
K2CO3
in ethanol at room temperature, the Knoevenagel condensation reaction
was carried out in 94% yield. Then, the isolated 4a was subjected to a Pd-catalyzed
intramolecular Heck coupling cyclization. By a careful, systematic examination of
the influence of a variety of catalysts, ligands, bases and solvent, the optimal
intramolecular Heck coupling reaction for the formation of the 2-fluoroindenone
5aa was found to be 10 mol% Pd(OAc)2, 20 mol% BINAP, 2 equiv of K2CO3 at
o
110 C in toluene for 8 hours (92% yield). With these encouraging results, we
performed a condensation reaction and a subsequent intramolecular Heck reaction
in a one-pot manner. However, the overall yield was significant affected by the
different solvents in two steps. To our delight, after evaporating the ethanol under
vacuum after the Knoevenagel condensation step, the desired 2-fluoroindenone 5aa
was obtained in 91% overall yield (Scheme 3).
6

Scheme 3. Step-wise and one-pot synthesis of 2-fluoroindenone 5aa
With these accomplishments, we then investigated the scope of this domino
protocol between various 1-(2-bromoaryl)-2-fluoroethanones 2 and aldehydes 3
(Table 1). Gratifyingly, the reaction was amenable and afforded the 2-fluoroindenones
5aa−5cf in good to excellent yields. Delightfully, the reaction proceeded smoothly
with electron-withdrawing fluorine atom (5ah), as well as electron-donating alkyl
(5ab and 5ag), OMe (5ac and 5ad), N, N-dimethyl (5ae) substituents on the aromatic
ring of benzaldehydes. The reaction was also successful with electron-deactivating (F,
Cl) atoms on the aromatic ring of 1-(2-bromoaryl)-2-fluoroethanones.
Table 1. Scope of domino cyclization synthesis of 2-fluoroindenones 5a,b
7

a Reaction conditions: 1) 1.1 equiv 2, 1 equiv aldehyde 3, 1.2 equiv K2CO3, ethanol (2
mL), rt, 3 h; 2) 10 mol% Pd(OAc)2, 20 mol% BINAP, 2.0 equiv K2CO3, toluene (3
8

mL), 110 oC, 8 h.
b Isolated yield.
3. Conclusion
In summary, we have developed a convenient domino protocol via Knoevenagel
condensation
followed
by
intermolecular
Heck
annulation.
Using
1-(2-bromoaryl)-2-fluoroethanones and aldehydes as readily materials, varieties of
2-fluoroindenones can be achieve in good to excellent yields.
4. Experimental
4.1. General
All reactions were carried out in oven-dried glassware under nitrogen atmosphere.
All commercially available reagents were used without further purification, unless
specified otherwise.
1
13
All new compounds were characterized by H NMR,19F NMR, C NMR and IR
spectroscopy，in addition to high-resolution mass spectroscopy. High-resolution mass
spectra were carried out on a Finnigan GC-MS-4021 spectrometer. 1H (400MHz) and
13C (101MHz) NMR spectra were recorded on a BrukerAM-400 spectrometer with
19
Me4Si as an internal standard. F NMR spectra were obtained on a BrukerAM-400
(376MHz) spectrometer in CDCl3 with CFCl3 as an external standard, in which
downfield shifts were designated as negative. All chemical shifts (δ) were expressed
in parts per million and coupling constants (J) are given in hertz.
9

4.2. General procedure for Domino reaction of 1-(2-bromoaryl)-2-fluoroethanones
and aldehydes
A suspension of 1-(2-bromoaryl)-2-fluroethanones 2 (0.33 mmol, 1.1 equiv),
aldehydes 3 (0.3 mmol, 1 equiv) and K2CO3 (0.36 mmol, 1.2 equiv) in ethanol (2 mL)
was stirred at room temperature for 3 h. When the reaction was completed (monitored
by TLC), the solvent was removed in vacuum. Then, Pd(OAc)2 (0.03 mmol, 10%),
BINAP (0.06 mmol, 20%), K2CO3 (0.6 mmol, 2.0 equiv) in toluene (3 mL) was added,
and the mixture was stirred under N2 atmosphere at 110 oC for 8 h. The crude product
was purified by flash column chromatography on silica gel using petroleum
ether/ethyl acetate as eluent.
4.2.1. 2-fluoro-3-phenyl-inden-1-one(5aa)
1
Yellow solid. m.p.: 85.7-86.7 oC. H NMR (400 MHz, Chloroform-d) δ 7.65 (d, J =
6.4 Hz, 2H), 7.54-7.45 (m, 3H), 7.43 (d, J = 7.6 Hz, 1H), 7.33 (d, J = 7.4 Hz, 1H),
7.25-7.17 (m, 2H). 13C NMR (101 MHz, Chloroform-d) δ 187.41 (d, J = 24.0Hz),
151.41 (d, J = 292.1 Hz), 140.54, 135.54, 134.10, 130.33, 128.97, 128.74, 128.55,
128.25, 126.79, 123.25, 121.73 (d, J = 8.0 Hz). 19F NMR (376 MHz, Chloroform-d) δ
-150.47 (s, 1F). IR (neat, cm-1): 1726, 1631, 1599, 1494, 1446, 960, 690. MS (EI):
m/z(%) 77 (3), 165 (3), 196 (34), 224 (100, M+). HRMS: Calcd. for C15H9FO:
224.0637; found: 224.0639.
10

4.2.2. 3-(2,4-dimethylphenyl)-2-fluoro-inden-1-one(5ab)
Orange solid. m.p.: 95.1-95.4 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.53-7.43 (m,
1H), 7.34 (t, J = 7.5 Hz, 1H), 7.30-7.25 (m, 2H), 7.23 (d, J = 9.6 Hz, 1H), 7.16 (d, J =
7.8 Hz, 1H), 6.92 (d, J = 7.2 Hz, 1H), 2.42 (s, 3H), 2.35 (s, 3H). 13C NMR (101 MHz,
Chloroform-d) δ 186.58 (d, J = 23.1 Hz), 150.17 (d, J = 290.4 Hz), 140.78, 138.93,
135.93, 135.09, 133.24, 130.80, 127.56, 126.78, 125.58, 125.44, 123.68, 121.93,
120.61 (d, J = 7.9 Hz), 20.31, 19.11. 19F NMR (376 MHz, Chloroform-d) δ -144.78 (s,
1F). IR (neat, cm-1): 2924, 1719, 1603, 1530, 1451, 1432, 957, 710. MS (EI): m/z(%)
77 (4), 183 (38), 203 (16), 209 (58), 252 (100, M+). HRMS: Calcd. for C17H13FO:
252.0950; found: 252.0951.
4.2.3. 2-fluoro-3-(4-methoxyphenyl)-inden-1-one(5ac)
Orange solid. m.p.: 150.6-150.8 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.71 (d, J =
8.8 Hz, 2H), 7.48 (d, J = 7.1 Hz, 1H), 7.41 (t, J = 7.3 Hz, 1H), 7.35 (d, J = 7.1 Hz,
13
1H), 7.32-7.24 (m, 1H), 7.12-7.01 (m, 2H), 3.93 (s, 3H). C NMR (101 MHz,
Chloroform-d) δ 186.23 (d, J = 22.1 Hz), 160.17, 149.89 (d, J = 289.1 Hz), 139.43,
134.51, 132.81, 128.98, 127.63, 126.14, 121.95, 120.68 (d, J = 7.9 Hz), 119.96,
113.44, 54.41. 19F NMR (376 MHz, Chloroform-d) δ -151.91 (s, 1F). IR (neat, cm-1):
2922, 1734, 1602, 1514, 1461, 1451, 912, 718. MS (EI): m/z(%) 77 (4), 183 (38), 211
(19), 239 (19), 254 (100, M+). HRMS: Calcd. for C16H11FO2: 254.0743; found:
254.0744.
11

4.2.4. 2-fluoro-3-(2-methoxyphenyl)-inden-1-one(5ad)
o
1
Orange solid. m.p.: 153.8-154.4 C. H NMR (400 MHz, Chloroform-d) δ 7.50-7.37
(m, 3H), 7.31 (d, J = 15.0 Hz, 1H), 7.19 (t, J = 7.0 Hz, 1H), 7.11-7.02 (m, 2H), 6.96
(d, J = 7.3 Hz, 1H), 3.86 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 187.79 (d, J =
22.9 Hz), 157.37, 151.79 (d, J = 292.2 Hz), 141.50, 134.12, 133.55, 131.54, 129.59,
128.27, 126.49, 122.72, 121.93 (d, J = 7.8 Hz), 120.61, 117.39, 111.57, 55.59. 19F
NMR (376 MHz, Chloroform-d) δ -144.24 (s, 1F). IR (neat, cm-1): 2912, 1735, 1604,
1508, 1472, 1450, 928, 709. MS (EI): m/z(%) 77 (4), 183 (38), 211 (19), 239 (19),
254 (100, M+). HRMS: Calcd. for C16H11FO2: 254.0743; found: 254.0744.
4.2.5. 3-(4-(dimethylamino)phenyl)-2-fluoro-inden-1-one(5ae)
o
1
Purplish red solid. m.p.: 110.6 -110.8 C. H NMR (400 MHz, Chloroform-d) δ 7.68
(d, J = 8.9 Hz, 2H), 7.48-7.30 (m, 3H), 7.23 (d, J = 7.5 Hz, 1H), 6.79 (d, J = 9.0 Hz,
2H), 3.07 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 185.94 (d, J = 21.2 Hz),
150.49, 149.24 (d, J = 284.8 Hz), 139.38, 135.46, 132.30, 128.94, 127.39, 126.90,
121.40, 120.82 (d, J = 7.8 Hz), 114.98, 110.67, 39.03. 19F NMR (376 MHz,
Chloroform-d) δ -153.66 (s, 1F). IR (neat, cm-1): 2918, 1707, 1603, 1526, 1484, 1442,
959, 702. MS (EI): m/z(%) 175 (3), 223 (4), 251 (14), 267 (100, M+). HRMS: Calcd.
for C17H14FNO: 267.1059; found: 267.1058.
4.2.6. 2-fluoro-3-(furan-2-yl)-inden-1-one(5af)
12

o
1
Orange solid. m.p.: 168.0-168.5 C. H NMR (400 MHz, Chloroform-d) δ 7.85-7.77
(m, 1H), 7.74 (d, J = 2.2 Hz, 1H), 7.48-7.38 (m, 2H), 7.26 (s, 1H), 7.22-7.17 (m, 1H),
6.69 (dd, J = 3.8, 1.9 Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ 186.14 (d, J =
20.7 Hz), 149.23 (d, J = 293.7 Hz), 145.26, 142.51, 137.99, 134.08, 128.90, 127.20,
125.26, 123.48 (d, J = 7.9 Hz), 122.85, 117.31, 113.14. 19F NMR (376 MHz,
Chloroform-d) δ -144.90 (s, 1F). IR (neat, cm-1): 2962, 2849, 2351, 1724, 1597, 1473,
1420, 803, 743. MS (EI): m/z(%) 157 (33), 221 (3), 214 (100, M+). HRMS: Calcd. for
C13H7FO2: 214.0430; found: 214.0431.
4.2.7. 3-(4-(tert-butyl)phenyl)-2-fluoro-inden-1-one(5ag)
Yellow solid. m.p.: 175.8-176.5 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.64 (d, J =
8.4 Hz, 2H), 7.58-7.51 (m, 2H), 7.47-7.43 (m, 1H), 7.39-7.34 (m, 1H), 7.31 (d, J = 7.0
Hz, 1H), 7.26-7.19 (m, 1H), 1.38 (s, 9H). 13C NMR (101 MHz, Chloroform-d) δ
187.44 (d, J = 22.1 Hz), 153.89, 151.29 (d, J = 291.89 Hz), 140.54, 135.65, 133.96,
128.64, 128.08, 126.97, 125.93, 125.69, 123.09, 121.81 (d, J = 8.0 Hz), 35.03, 31.17.
19F NMR (376 MHz, Chloroform-d) δ -150.93 (s, 1F). IR (neat, cm-1): 2962, 2849,
2351, 1724, 1597, 1473, 1420, 803, 743. MS (EI): m/z(%) 77 (3), 220 (34), 238 (5),
280 (100, M+). HRMS: Calcd. for C19H17FO: 280.1029; found: 280.1263.
4.2.8. 2-fluoro-3-(4-fluorophenyl)-1H-inden-1-one(5ah)
o
1
Orange solid. m.p.: 166.0-166.4 C. H NMR (400 MHz, Chloroform-d) δ 7.73-7.54
(m, 2H), 7.50-7.44 (m, 1H), 7.38 (td, J = 7.6, 7.1, 1.5 Hz, 1H), 7.29-7.20 (m, 2H),
13

13
7.20-7.13 (m, 1H), 6.95 (t, J = 8.6 Hz, 1H). C NMR (101 MHz, Chloroform-d) δ
194.76 (d, J = 18.4 Hz), 161.88 (d, J = 248.7 Hz), 151.00(d, J = 287.8 Hz), 136.30,
131.43 (d, J = 8.2 Hz), 129.06, 127.79, 125.07, 121.53 (d, J = 8.1 Hz), 116.40, 116.18,
19
115.65, 115.44. F NMR (376 MHz, Chloroform-d) δ -108.54 – -108.66 (m, 1F),
-150.51(s, 1F). IR (neat, cm-1): 1738, 1606, 1510, 1479, 1449, 910, 677. MS (EI):
m/z(%) 194 (7), 214 (35), 242 (100, M+). HRMS: Calcd. for C15H8F2O: 242.0544;
found: 242.0543.
4.2.9. 2,5-difluoro-3-(4-methoxyphenyl)-inden-1-one(5bc)
Orange solid. m.p.: 154.9-155.6 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.54 (d, J =
8.8 Hz, 2H), 7.36 (dd, J = 7.9, 5.3 Hz, 1H), 6.97 (d, J = 8.9 Hz, 3H), 6.79 (ddd, J =
8.9, 8.0, 2.2 Hz, 1H), 3.81 (s, 3H). 13C NMR (101 MHz, Chloroform-d) δ 184.51 (d, J
= 22.3 Hz), 165.36 (d, J = 255.1 Hz), 160.31, 150.29 (d, J = 292.5 Hz), 142.88,
132.63 (d, J = 9.3 Hz), 128.80, 123.98 (d, J = 9.9 Hz), 121.86, 119.38, 113.59, 110.26,
54.41. 19F NMR (376 MHz, Chloroform-d) δ -102.01 (td, J = 9.8, 5.5 Hz, 1F),
-148.45(s, 1F). IR (neat, cm-1): 2963, 1713, 1637, 1599, 1510, 1460, 945, 798. MS
(EI): m/z(%) 175 (3), 223 (4), 251 (14), 267 (100, M+). HRMS: Calcd. for C16H10F2O2:
267.1059; found: 267.1058.
4.2.10. 3-(4-(tert-butyl)phenyl)-2,5-difluoro-inden-1-one(5bg)
1
Orange solid. m.p.: 171.9-172.8 oC. H NMR (400 MHz, Chloroform-d) δ 7.84 (m, J
= 9.0, 5.3, 1.5 Hz, 1H), 7.55 (d, J = 8.5 Hz, 1H), 7.47 (d, J = 7.1 Hz, 1H), 7.35 (d, J =
14

8.5 Hz, 2H), 7.05 (t, J = 8.6 Hz, 1H), 6.78 (d, J = 36.8 Hz, 1H), 1.24 (s, 9H). 13C
NMR (101 MHz, Chloroform-d) δ 185.39 (d, J = 22.8 Hz), 162.08 (d, J = 249.4 Hz),
151.78 (d, J = 292.6 Hz), 131.28 (d, J = 8.0 Hz), 130.28, 130.19, 125.48 (d, J = 10.4
Hz), 118.01, 117.78, 116.59, 116.37, 115.96, 115.74, 35.03, 31.17. 19F NMR (376
MHz, Chloroform-d) δ -101.71 – -101.87 (m, 1F), -147.43 (s, 1F). IR (neat, cm-1):
2926, 1707, 1606, 1516, 1480, 1439, 1366, 1359, 940, 701. MS (EI): m/z(%) 77 (3),
220 (34), 238 (5), 298 (100, M+). HRMS: Calcd. for C19H16F2O: 298.1169; found:
298.1170.
4.2.11. 2,5-difluoro-3-(4-fluorophenyl)-inden-1-one(5bh)
Yellow solid. m.p.: 170.0-170.5 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.58 (dd, J
= 8.6, 5.3 Hz, 1H), 7.08-7.02 (m, 2H), 6.91 (t, J = 8.6 Hz, 3H), 6.87-6.83 (m, 1H). 13C
NMR (101 MHz, Chloroform-d) δ 192.54 (d, J = 22.2 Hz), 162.72 (d, J = 253.3 Hz),
162.32 (d, J = 255.8 Hz), 151.93 (d, J = 287.8 Hz), 131.27 (d, J = 8.1 Hz), 128.38 (d,
J = 3.5 Hz), 127.95 (d, J = 10.7 Hz), 118.03, 117.80, 115.97, 115.76, 114.52, 114.29.
19F NMR (376 MHz, Chloroform-d) δ -96.15 (td, J = 9.3, 5.8 Hz, 1F), -112.77 –
-112.87 (m, 1F), -189.88 (s, 1F). IR (neat, cm-1): 1738, 1607, 1511, 1477, 1450, 910,
678. MS (EI): m/z(%), 212 (12), 232 (42), 260 (100, M+). HRMS: Calcd. for
C15H7F3O: 260.0449; found: 260.0451.
4.2.12. 4-chloro-3-(4-(dimethylamino)phenyl)-2-fluoro-inden-1-one(5ce)
15

o
1
Burgundy solid. m.p.: 162.4-163.1 C. H NMR (400 MHz, Chloroform-d) δ
7.65-7.54 (m, 2H), 7.31 (s, 1H), 7.25 (d, J = 3.1 Hz, 1H), 7.19 (s, 1H), 6.79-6.62 (m,
2H), 3.01 (s, 6H). 13C NMR (101 MHz, Chloroform-d) δ 186.29 (d, J = 27.2 Hz),
152.30 (d, J = 280.7 Hz), 151.54, 138.81, 134.50, 132.80, 132.09, 129.63, 129.16,
127.23, 123.02 (d, J = 8.0 Hz), 118.79, 111.80, 40.04. 19F NMR (376 MHz,
Chloroform-d) δ -152.43 (s, 1F). IR (neat, cm-1): 2959, 2918, 1707, 1606, 1526, 1453,
1416, 979, 731. MS (EI): m/z(%) 121 (5), 194 (9), 285 (14), 301 (100, M+). HRMS:
Calcd. for C17H13ClFNO: 303.0670; found: 303.0671.
4.2.13. 4-chloro-2-fluoro-3-(furan-2-yl)-inden-1-one(5cf)
Orange solid. m.p.: 167.5-168.3 oC. 1H NMR (400 MHz, Chloroform-d) δ 7.76 (dd, J
= 4.9, 3.0 Hz, 2H), 7.44-7.38 (m, 2H), 7.22 (d, J = 3.7 Hz, 1H), 6.71 (dd, J = 3.8, 1.9
Hz, 1H). 13C NMR (101 MHz, Chloroform-d) δ186.45 (d, J = 26.6 Hz), 148.61(d, J =
290.88 Hz), 145.62, 135.87, 134.96, 133.10, 129.83, 124.55 (d, J = 8.4 Hz), 123.46,
118.03, 117.92, 113.37, 113.02. 19F NMR (376 MHz, Chloroform-d) δ -143.85 (s, 1F).
IR (neat, cm-1): 2958, 2852, 2361, 1723, 1595, 1462, 1423, 803, 744. MS (EI): m/z(%)
157 (33), 221 (3), 248 (100, M+). HRMS: Calcd. for C13H6ClFO2: 248.0040; found:
248.0041.
Acknowledgment
The authors thank the National Natural Science Foundation of China (No.
21672151) for financial support.
16

References
[1] (a) G.M. Anstead, J.L. Ensign, C.S. Peterson, J.A. Katzenellenbogen, J. Org.
Chem. 54 (1989) 1485-1491;
(b) R.E. McDevitt, M.S. Malamas, E.S. Manas, R.J. Unwalla, Z.B. Xu, C.P. Miller,
H.A. Harris, Bioorg, Med. Chem. Lett. 15 (2005) 3137-3142;
(c) J.H. Ahn, M.S. Shin, S.H. Jung, S.K. Kang, K.R. Kim, S.D. Rhee, W.H. Jung, S.D.
Yang, S.J. Kim, J.R. Woo, J.H. Lee, H.G. Cheon, S.S. Kim, J. Med. Chem. 49 (2006)
4781-4784;
(d) B.V. Ramulu, G. Satyanarayana, RSC. Adv. 5 (2015) 70972-70976.
[2] (a) R.E. McDevitt, M.S. Malamas, E.S. Manas, R.J. Unwalla, Z.B. Xu, C.P. Miller,
H.A. Harris, Bioorg. Med. Chem. Lett. 15 (2005) 3137-3142;
(b) G.M. Anstead, S.R. Wilson, J.A. Katzenellenbogen, J. Med. Chem. 32 (1989)
2163-2171.
[3] (a) L.M.X. Lopes, M. Yoshida, O.R. Gottlieb, Phytochemistry. 23 (1984)
2021-2024;
(b) D.C. Harrowven, N.A. Newman, C.A. Knight, Tetrahedron Lett. 39 (1998)
6757-6760.
[4] C.H. Park, X. Siomboing, S. Yous, B. Gressier, M. Luyckx, P. Chavatte, Eur. J.
Med. Chem. 37 (2002) 461-468.
[5] J.H. Ahn, M.S. Shin, S.H. Jung, S.K. Kang, K.R. Kim, S.D. Rhee, W.H. Jung, S.D.
Yang, S.J. Kim, J.R. Woo, etc. J. Med. Chem. 49 (2006) 4781-4784.
17

[6] (a) M.B. Floyd, G.R.J. Allen, J. Org. Chem. 35 (1970) 2647-2653;
(b) G. Jammaer, H. Martens, G. Hoornaert, Tetrahedron 31 (1975) 2293-2296.
[7] (a) G.M. Anstead, J.L. Ensign, C.S. Peterson, J.A. Katzenellenbogen, J. Org.
Chem. 54 (1989) 1485-1491;
(b) M.-L. Pang, Y. Wang, X.-Q. Feng, Y. Chen, J. Han, J.-B. Meng, Synthesis 11
(2008) 1725-1728.
[8] Y. Harada, J. Nakanishi, H. Fujihara, M. Tobisu, Y. Fukumoto, N. Chatani, J. Am.
Chem. Soc. 129 (2007) 5766-5771.
[9] (a) W. Tao, L.J. Silverberg, A.L. Rheingold, R.F. Heck, Organometallics 8 (1989)
2550-2559;
(b) R.C. Larock, M.J. Doty, J. Org. Chem. 58 (1993) 4579-4583;
(c) R.C. Larock, Q. Tian, A.A. Pletnev, J. Am. Chem. Soc. 121 (1999) 3238-3239;
(d) A.A. Pletnev, Q. Tian, R.C. Larock, J. Org. Chem. 67 (2002) 9276-9287;
(e) H. Tsukamoto, Y. Kondo, Org. Lett. 9 (2007) 4227-4230;
(f) J. Feng, G. Lu, M. Lv, C. Cai, J. Org. Chem. 79 (2014) 10561-10567;
(g) T. Morimoto, K. Yamasaki, A. Hirano, K. Tsutsumi, N. Kagawa, K. Kakiuchi, Y.
Harada, Y. Fukumoto, N. Chatani, T. Nishioka, Org. Lett. 11 (2009) 1777-1780.
[10] (a) K. Kokubo, K. Matsumasa, M. Miura, M. Nomura, J. Org. Chem. 61 (1996)
6941-6946;
(b) B.J. Li, H.Y. Wang, Q.L. Zhu, Z.J. Shi, Angew. Chem. Int. Ed. 51 (2012)
3948-3952;
(c) Z.S. Qi, M. Wang, X.W. Li, Org. Lett. 15 (2013) 5440-5443;
18

(d) Y. Y. Chen, F. Wang, W.C. Zhen, X.W. Li, Adv. Synth. Catal. 355 (2013) 353-359;
(e) S. Chen, J. Yu, Y. Jiang, F. Chen, J. Cheng, Org. Lett. 15 (2013) 4754-4757;
(f) Y. Kuninobu, T. Matsuki, K. Takai, Org. Lett. 12 (2010) 2948-2950;
(g) K. Gao, N. Yoshikai, Chem. Commun. 48 (2012) 4305-4307;
(h) P. Zhao, F. Wang, K. Han, X. Li, Org. Lett. 14 (2012) 5506-5509.
[11] (a) A.V. Vasilyev, S. Walspurger, P. Pale, J. Sommer, Tetrahedron Lett. 45 (2004)
3379-3381;
(b) A.V. Vasilyev, S. Walspurger, M. Haouas, J. Sommer, P. Pale, A.P. Rudenko, Org.
Biomol. Chem. 2 (2004) 3483-3489;
(c) X.Q. Pan, J.P. Zou, G.L. Zhang, W. Zhang, Chem. Commun. 46 (2010),
1721-1723.
[12] (a) X.Y. Yang, T. Wu, R.J. Phipps, F.D. Toste, Chem. Rev. 115 (2015) 826-870;
(b) X.H. Xu, K. Matsuzaki, N. Shibata, Chem. Rev. 115 (2015) 731-764;
(c) P.R. Savoie, J.T. Welch, Chem. Rev. 115 (2015) 1130-1190;
(d) D.O. Hagan, H. Deng, Chem. Rev. 115 (2015) 634-649;
(e) C.F. Ni, M.Y. Hu, J.B. Hu, Chem. Rev. 115 (2015) 765-825.
[13] R.C. Larock, M.J. Doty, S. Cacchi, J. Org. Chem. 58 (1993) 4579-4583.
[14] (a) Y.V. Zonov, V. M. Karpov, V.E. Platonov, J. Fluorine Chem. 128 (2007)
1058-1064;
(b) J.C. Sloop, P.D. Boyle, A.W. Fountain, C. Gomez, J.L. Jackson, W.F. Pearman,
R.D. Schmidt, J. Weyand, Applied Sciences. 2 (2012) 61-99.
[15] J. Liu, J. Chan, C.M. Bryant, P.A. Duspara, E.E. Lee, D. Powell, H. Yang, Z.P.
19

Liu, C. Walpole, E. Roberts, R.A. Batey, Tetrahedron Lett. 53 (2012) 2971-2975.
20