Easy Access to Difluoromethylene-Containing Arene Analogues through Palladium-Catalysed C–H Olefination

Article abstract of DOI:10.1002/ejoc.201600954

An efficient palladium-catalysed ortho-C–H olefination of α,α-difluorophenylacetic acid derivatives using 8-aminoquinoline as a bidentate directing group has been developed. A range of olefinated arenes can thus be synthesized in a concise way. This reaction provides an easy and straightforward route to a panel of difluoromethylated arene analogues in moderate to good yields, with a satisfactory tolerance of common functional groups. Transformation of the products into a variety of other difluoromethylene-containing compounds demonstrates the utility of this method.

Full text of DOI:10.1002/ejoc.201600954

A Journal of
Accepted Article
Title: An Easy Access to Difluoromethylene-Containing Arene Analogues via
Palladium-Catalyzed C−H Olefination
Authors: Changdong Shao; Guangfa Shi; Yanghui Zhang
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An Easy Access to Difluoromethylene-Containing Arene Ana-
logues via Palladium-Catalyzed C−H Olefination
Changdong Shao,[a,b] Guangfa Shi,[a] and Yanghui Zhang *[a,b,c]
Abstract: An efficient palladium-catalyzed ortho C−H olefination of
α,α-difluorophenylacetic acid derivatives using 8-aminoquinoline as
the bidentate directing group has been developed. A range of olefi-
nated arenes can be synthesized in a concise way. This reaction
provides an easy and straightforward access to a panel of difluoro-
methylated arene analogues in moderate to good yields with a satis-
factory tolerance of common functional groups. Transformations of
the products to a variety of other difluoromethylene-containing com-
pounds demonstrated the utility of this method.
Introduction
Organofluorine compounds have found extensive applications in
a wide range of fields owing to their novel and useful proper-
ties.[1] In particular, fluorine substituents are widely present in
pharmaceutical molecules.[2] Currently, there are over 150 fluori-
nated drugs in the market, which make up 20~30% of all phar-
maceuticals and agrochemicals.[3] As such, it is of great im-
portance for chemists and pharmaceutists to develop facile and
efficient methods for fluorine incorporation.[4] A large number of
compounds usually need to be synthesized for high-throughput
drug screening in drug discovery, and these compounds are
often analogues. Currently, the approaches for
Scheme 1. TM-catalyzed 8-aminoquinoline assisted C-H functionalization
reactions.
the synthesis of organofluorine compounds usually involve in-
corporating fluorine substituents into a precursor of each ana-
logue, i.e. one-analogue-at-a-time approach (Figure 1, A). How-
ever, drug discovery requires a synthetic approach that offers a
panel of analogues in a straightforward manner (Figure 1, B).
In the past few decades, C−H functionalization is emerging as
Figure 1. Approaches for the synthesis of difluoromethylated compounds.
a novel and valuable strategy in organic synthesis.[5] In particular,
it provides an easy access to a wide range of analogues. Most
of C−H functionalization reactions rely on the use of directing
[a]
School of Chemical Science and Engineering, Tongji University,
1239 Siping Road, Shanghai 200092, P.R. China
E-mail: zhangyanghui@tongji.edu.cn
Homepage: http://zhangyhgroup.tongji.edu.cn
UNEP-Tongji Institute of Environment for Sustainable Development,
Tongji University,
1239 Siping Road, Shanghai 200092, P.R. China
Shanghai Key Laboratory of Chemical Assessment and Sustainabili-
ty,
groups, because they can solve regioselectivity problems and
accelerate C−H cleavage process.[6] Directed C−H functionaliza-
tion allows for a range of substituents to be introduced into the
substrates, and therefore a number of analogues can be obtai-
ned in a concise way. Thus, we envisaged that fluorine-
containing directing groups would provide an easy access to a
wide range of fluorinated analogues.
[b]
[c]
1239 Siping Road, Shanghai 200092, P.R. China
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/
Recently, the difluoromethylene groups have attracted great
attentions owing to their special biological properties, and
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European Journal of Organic Chemistry
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molecules containing these groups are particularly desirable
building blocks for medicinal chemistry.[1c,1d,7]
On the other hand, among a variety of directing groups, the
bidentate ones have proved to be particularly powerful, and
successfully utilized to enable a range of novel organic trans-
formations.[8] In this context, 8-minoquinoline[9] is particularly
attractive. Chatani and Maiti reported several examples of
Entry
Additive
Oxidant
Solvent
Yield (%)b, c
1
—
BQ
DCE
13
Rh/Ru/Ni-catalyzed C−H alkylation reaction with olefines
[10a-c]
(Scheme 1, a1).
Daugulis and Ackermann demonstrated
2
HOAc
MsOH
PivOH
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
TFA
BQ
DCE
21
Cobalt-catalyzed 8-aminoquinoline-directed annulation reactions
with olefines via a C−H/N−H functionalization process (a2, a3).
3
BQ
DCE
36 (1)
66 (2)
79 (11) [76]d
41 (2)
51 (5)
69 (5)
34 (1)
14
[10d-e]
Cobalt-catalyzed ortho C−H allylation with unactivated
olefines was also reported by Chatani and Maiti (a4). [10f-g] Palla-
4
BQ
DCE
dium-catalyzed C−H functionalization reactions via
a six-
5
BQ
DCE
membered palladium-cycle using phenylacetyl aminoquinoline
as the substrate have also been reported by Chen (b1), Shi (b2),
and Maiti (b3) respectively. [10h-j]
6
AgOAc
Ag2CO3
Cu(OAc)2
K2S2O8
O2
DCE
7
DCE
Inspired by these great reactions, in particularl Maiti’s impres-
sive work (b3), [10j] and our persistent interests in organofluorine
chemistry,[11] we present herein an efficient palladium-catalyzed
Fujiwara-Moritani reaction of α,α-difluorophenylacetic acid deri-
vatives using 8-aminoquinoline as the bidentate directing group.
The directing group can be readily removed under mild conditi-
ons in the presence of the difluoromethylene group, affording
diverse ortho-olefinated α,α-difluorophenylacetic acid derivatives
(c). This reaction provides a new strategy for the synthesis of a
range of difluoromethylene-containing arene analogues.
8
DCE
9
DCE
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
DCE
—
DCE
11
BQ
DMF
DMA
NMP
DMSO
mesitylene
dioxane
MeCN
THF
46 (6)
34 (9)
38
BQ
BQ
Results and Discussion
BQ
60 (4)
10
BQ
We initiated this research project by investigating the C−H olefi-
nation of 2,2-difluoro-2-phenyl-N-(quinolin-8-yl)acetamide (1a)
with n-butyl acrylate (2a). After extensive condition survey, the
reaction formed the desired alkenylated product (3aa) in 13%
yield in the presence of 10 mol % Pd(OAc)2 and 1.2 equivalent
benzoquinone in 1,2-dichloroethane (Table 1, entry 1). The yield
increased slightly to 21% when 1.5 equivalent HOAc was added
(entry 2). Inspired by this result, we screened other acids. Me-
thanesulfonic acid and pivalic acid enhanced the yield to 36%
and 66% respectively (entries 3-4). It should be mentioned that
diolefinated product was formed along with the desired monoole-
finated one in these two reactions. Gratefully, the yield of mono-
substituted product was improved to 79% in the presence of
TFA along with 11% undesired disubstituted byproduct (entry 5).
BQ proved to be the optimal oxidant, whereas other oxidants
such as AgOAc, Ag2CO3, Cu(OAc)2, K2S2O8, and O2 gave lower
yields (entries 6-10), and the yield decreased dramatically in the
absence of BQ (entry 11). The reaction still took place and for-
med the olefinated product in other solvents, including solvents
with a higher boiling point, albeit in lower yields (entries 12-19).
The yield decreased to 45% when 5 mol % Pd(OAc)2 was used
(entry 20) and no
BQ
64 (10)
22
BQ
BQ
40 (2)
45 (2)e
BQ
DCE
f
BQ
DCE
—
BQ
DCE
61 (5)g
31h
BQ
DCE
BQ
DCE
75 (4)i
73 (9)j
BQ
DCE
[a] Reactions conditions: 1a (0.10 mmol), 2a (1.5 equiv.), Pd(OAc)2 (10 mol %),
additive (1.5 equiv.), oxidant (1.2 equiv.), solvent (1.0 mL), 140 oC, air, 6 h. [b]
Yields were determined by 1H NMR using CH2Br2 as the internal standard. [c]
Yields for disubstituted products were in parentheses. [d] Isolated yield was
given in square brackets. [e] Pd(OAc)2 (5 mol %). [f] Without Pd(OAc)2. [g] 130
oC. [h] 120 oC. [i] Under N2. [j] Under O2.
olefinated product was observed in the absence of Pd(OAc)2
(entry 21). The yield was reduced to 61% or 31% when the
reaction were carried out at 130 oC or 120 oC respectively
Table 2. Substrate scope of olefines.[a,b]
Table 1. Optimization of the reaction conditions.[a]
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[a] Reactions conditions: 1 (0.10 mmol), 2a (1.5 equiv.), Pd(OAc)2 (10 mol %),
BQ (1.2 equiv.), TFA (1.5 equiv.), DCE (1.0 mL), 140 oC, air, 6 h. [b] Yields for
disubstituted products showed in parentheses were determined by crude 1H
NMR using CH2Br2 as the internal standard. [c] Isolated yield. [d] 1.1 equiv. 2a
was used.
[a] Reactions conditions: 1a (0.10 mmol), 2 (1.5 equiv.), Pd(OAc)2 (10 mol %),
BQ (1.2 equiv.), TFA (1.5 equiv.), DCE (1.0 mL), 140 oC, air, 6 h. [b] Isolated
yield.
were almost unreactive (2t-v). It should be noted that diolefina-
ted products were not observed for the substrates in Table 2.
Next, the arene scope was examined using n-butyl acrylate
(2a) as the reaction partner. As shown in Table 3, arenes con-
taining a variety of functional groups effectively underwent the
olefination reaction under the standard conditions to form the
corresponding olefinated products. Both electron-donating group,
such as methyl (1b), and electron-withdrawing groups including
carbonyl (1g), cyano (1h), and sulfonyl (1i) group at the para-
position were well-tolerated in the reaction. Fluoro (1d), chloro
(1e), and bromo (1f) groups were intact under the reaction con-
ditions. It should be mentioned that a tiny or small amount of
diolefinated products were formed for the substrate bearing
para-substituents (1b-i). In the presence of meta-substituents
(1j-l), the olefination reaction selectively took place at the less
hindered positions, and diolefinated products were not observed.
The substrates bearing an ortho-substituent, methyl (1m) or
methoxyl (1n) group, were also suitable. The compatibility of
disubstituted substrates was also examined. Thus, 3,5- or 3,4-
disubstituted arene substrates could be efficiently transformed
into the corresponding products 3oa-pa in 77% and 87% yield
respectively. Furthermore, the C−H bond of naphthalene was
also compatible, and the alkenylation reaction occurred selec-
tively at the less hindered position (3qa). Interestingly, when an
oxygen atom was added between the phenyl group and the CF2
group, the reaction still took place, forming mono- and
(entries 22-23). Furthermore, the reaction was insensitive to the
atmosphere and proceeded smoothly under N2, O2, or air (ent-
ries 24-25 ).
With the optimal conditions in hand (Table 1, entry 5), we sur-
veyed the substrate scope of this C–H olefination reaction. First-
ly, we examined the performance of various alkenes under the
optimized conditions. Thus, as shown in Table 2, a range of
styrenes underwent the reaction to form the desired olefinated
products. The halo groups, including F, Cl, and Br, were well
tolerated (2c-g). Styrenes containing other common functional
groups, including methoxy (2i), phenyl (2j), acetoxy (2k), and
ester (2l) groups, were reactive, affording the olefinated pro-
ducts in moderate yields. 2-vinylnaphthalene was also suitable
(2m), and 2-vinylthiophene (2n) underwent the olefination reac-
tion successfully, albeit in a low yield (27%). Considering that
the organophosphorus and organosulfur compounds are exten-
sively exist in pharmaceuticals, agrochemicals, and functional
materials,[12] we then examined two kinds of alkenes that contai-
ning phosphonate (2o) and sulfonyl (2p) group under the optimal
reaction conditions. The reactions formed the desired products
3ao (89%) and 3ap (61%) in good yields. Intriguingly, vinylboro-
nate (2q) selectively underwent the olefination reaction and the
products derived from the reaction of the boronate moiety were
not observed. Unactivated alkenes were also examined, and the
reaction also occurred, albeit in low yields (3ar and 3as). Other
unactivated alkenes bearing a chloro or cyclohexyl group and
vinyl acetate
Table 3. Substrate scope of arenes.[a,b,c]
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High resolution mass spectra were measured on Bruker MicroTOF II ESI-
1
TOF mass spectrometer. H NMR, 13C NMR, and 19F NMR spectra were
recorded on Bruker ARX400 (400 MHz, 101 MHz and 376 MHz, respec-
tively). The 1H chemical shifts are reported in ppm and referenced to
residual protium in the NMR solvent (CDCl3: δ = 7.26 ppm, 6d-DMSO: δ =
2.50 ppm, CD3OD: δ = 3.31 ppm). The 13C chemical shifts are reported in
ppm and referenced to residual protium in the NMR solvent (CDCl3: δ =
77.00 ppm, 6d-DMSO: δ = 39.52 ppm, CD3OD: δ = 49.00 ppm). Coupling
constants (J) are reported in Hertz (Hz). Multiplicities are reported using
the following abbreviations: s = singlet, bs = broad singlet, d = doublet, t
= triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet
of triplets, td = triplet of doublets. Substrates (1a-1q) were synthesized
according to literatures and the rest commercial available chemicals were
used without further purification.
Scheme 2. Late stage transformations.
Typical experimental procedure for 3
diolefinated products in 22% and 51% yield respectivley (3ra).
Furthermore, some mechanistic studies were carried out, and
the outcomes were consistent with the 8-aminoquinoline-
directed C−H activation under palladium catalysis (see ESI).[13]
To demonstrate the synthetic utility of the products obtained
via the C−H alkenylation reaction, compound 3ab was converted
to an aryl difluoroacetic acid. Gratefully, the hydrolysis of 3ab
could take place under mild conditions in the presence of the
A 35 mL sealed tube equipped with a magnetic stir bar was charged with
substrates 1 (0.10 mmol), palladium (II) acetate (10 mol %), 1,4-
benzoquinone (1.2 equiv.), trifluoroacetic acid (1.5 equiv.), alkenes 2 (1.5
equiv.), and 1,2-dichloroethane (1.0 mL) under air. The reaction tube was
sealed with a Teflon® high pressure valve and moved into a preheated oil
bath. After stirring at 140 oC for 6 hours, the reaction mixture was allowed
to cool down to room temperature and diluted with ethyl acetate (10 mL).
The mixture was washed with saturated sodium sulfide (5 mL, once) and
brine (5 mL, twice), dried over anhydrous sodium sulfate and concentrat-
ed in vacuo. The residue was purified by preparative thin layer chroma-
tography (PTLC) to give the corresponding compounds 3.
difluoromethylene
group,
providing
(E)-2,2-difluoro-2-(2-
styrylphenyl)acetic acid (4) in 94% yield. Compound 4 is a ver-
satile intermediate, and can be transformed into a variety of
products containing difluoromethylene groups (Scheme 2). First,
4 was converted to its acyl chloride derivative by reacting with
(COCl)2. The resulting acyl chloride was then allowed to react
with N,O-dimethylhydroxylamine hydrochloride and PhMgBr,
affording aryldifluoroketone derivative 5 as the final product in
81% total yield.[14] Second, the acyl chloride reacted with glycine
methyl ester hydrochloride to form aryldifluoroamide derivative 6
in 93% yield. Third, the reduction of the ester, which was ob-
tained by treating the acyl chloride with methanol, gave ar-
yldifluoroethanol derivative 7 in 96% yield.[15] Finally, the double
bond of 4 could be reduced via hydrogenation to give alkylated
product 8 almost quantitatively (98%).[16]
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)phenyl-
1
)acrylate (3aa): White solid (32.2 mg, 76%). H NMR (400 MHz, CDCl3)
δ 10.97 (s, 1H), 8.86 (d, J = 3.9 Hz, 1H), 8.73 (d, J = 7.5 Hz, 1H), 8.27 (d,
J = 15.8 Hz, 1H), 8.18 (d, J = 8.2 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.65
(d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.1 Hz, 1H), 7.56 – 7.45 (m, 4H), 6.33 (d,
J = 15.8 Hz, 1H), 4.01 (t, J = 6.7 Hz, 2H), 1.51 – 1.39 (m, 2H), 1.35 –
1.19 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
166.10, 161.48 (t, J = 30.5 Hz), 148.74, 141.45 (t, J = 2.8 Hz), 138.58,
136.23, 134.14 (t, J = 2.5 Hz), 132.72, 131.33 (t, J = 23.8 Hz), 131.19,
129.47, 128.12, 127.83, 127.03, 126.94 (t, J = 8.5 Hz), 123.08, 122.30,
121.92, 117.07, 115.46 (t, J = 255.6 Hz), 64.33, 30.43, 18.96, 13.57.
HRMS (ESI-TOF) m/z: calcd. for C24H22F2N2NaO3+: 447.1491 (M + Na) +,
found: 447.1501.
(E)-2,2-difluoro-N-(quinolin-8-yl)-2-(2-styrylphenyl)acetamide (3ab):
White solid (23.2 mg, 58%). H NMR (400 MHz, CDCl3) δ 11.00 (s, 1H),
Conclusions
1
8.80 (dd, J = 4.2, 1.4 Hz, 1H), 8.73 (dd, J = 7.4, 0.9 Hz, 1H), 8.17 (dd, J =
8.3, 1.4 Hz, 1H), 7.83 (d, J = 7.7 Hz, 1H), 7.75 – 7.63 (m, 2H), 7.58 –
7.46 (m, 4H), 7.45 – 7.33 (m, 3H), 7.16 – 7.03 (m, 3H), 6.95 (d, J = 16.0
Hz, 1H). 13C NMR (101 MHz, CDCl3) δ 162.04 (t, J = 30.7 Hz), 148.67,
138.53, 136.85, 136.83 (t, J = 3.0 Hz), 136.25, 132.79, 132.60, 131.08,
130.25 (t, J = 23.4 Hz), 128.31, 127.82, 127.72, 127.44, 127.37, 127.07,
126.70, 126.65 (t, J = 8.8 Hz), 125.35 (t, J = 2.1 Hz), 122.98, 121.84,
117.05, 115.72 (t, J = 255.0 Hz). HRMS (ESI-TOF) m/z: calcd. for
C25H18F2N2NaO+: 423.1279 (M + Na) +, found: 423.1287.
In conclusion, we have successfully developed an efficient pal-
ladium-catalyzed
ortho
C−H
olefination
of
α,α-
difluorophenylacetic acid derivatives using 8-aminoquinoline as
the bidentate directing group. The reaction provides an efficient
and concise manner to gain access to a range of difluoromethyl-
ated arene analogues. The bidentate directing group can be
removed under mild conditions. This strategy for synthesizing
difluoromethylene group-containing compounds would have
application potentials in drug discovery.
(E)-2,2-difluoro-2-(2-(3-fluorostyryl)phenyl)-N-(quinolin-8-yl)acetami-
de (3ac): White solid (26.7 mg, 64%). 1H NMR (400 MHz, CDCl3) δ 11.02
(s, 1H), 8.82 (dd, J = 4.2, 1.5 Hz, 1H), 8.72 (dd, J = 7.5, 1.1 Hz, 1H), 8.16
(dd, J = 8.3, 1.5 Hz, 1H), 7.84 (d, J = 7.7 Hz, 1H), 7.71 – 7.64 (m, 2H),
7.57 – 7.40 (m, 5H), 7.13 – 6.99 (m, 3H), 6.87 (d, J = 16.0 Hz, 1H), 6.83
– 6.76 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 162.83 (d, J = 245.2 Hz),
161.95 (t, J = 30.6 Hz), 148.79, 139.16 (d, J = 7.7 Hz), 138.46, 136.35 (t,
J = 3.0 Hz), 136.23, 132.67, 131.45 (d, J = 2.4 Hz), 131.12, 130.44 (t, J =
23.5 Hz), 129.69 (d, J = 8.4 Hz), 127.81, 127.77, 127.50, 126.99, 126.79
Experimental Section
General Information
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European Journal of Organic Chemistry
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(d, J = 2.4 Hz), 126.69 (t, J = 8.8 Hz), 123.06, 122.68 (d, J = 2.7 Hz),
121.91, 116.98, 115.62 (t, J = 255.0 Hz), 114.50 (d, J = 21.5 Hz), 112.86
(d, J = 21.9 Hz). HRMS (ESI-TOF) m/z: calcd. for C25H17F3N2NaO+:
441.1185 (M + Na) +, found: 441.1200.
137.03 (t, J = 3.0 Hz), 136.19, 134.09, 132.80, 132.59, 131.05, 130.13 (t,
J = 23.4 Hz), 128.99, 127.80, 127.29, 127.23, 127.05, 126.60 (t, J = 8.8
Hz), 126.59, 124.32 (t, J = 2.1 Hz), 122.90, 121.78, 117.01, 115.73 (t, J =
254.7 Hz), 21.15. HRMS (ESI-TOF) m/z: calcd. for C26H20F2N2NaO+:
437.1436 (M + Na) +, found: 437.1455.
(E)-2,2-difluoro-2-(2-(4-fluorostyryl)phenyl)-N-(quinolin-8-yl)acetami-
de (3ad): White solid (32.2 mg, 77%). 1H NMR (400 MHz, CDCl3) δ
10.98 (s, 1H), 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.70 (dd, J = 7.5, 1.2 Hz,
1H), 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.83 (dd, J = 7.8, 0.8 Hz, 1H), 7.66 (d,
J = 7.7 Hz, 1H), 7.61 – 7.46 (m, 5H), 7.42 (t, J = 7.6 Hz, 1H), 7.32 – 7.26
(m, 2H), 6.86 (d, J = 16.0 Hz, 1H), 6.77 – 6.68 (m, 2H). 13C NMR (101
MHz, CDCl3) δ 162.25 (d, J = 247.7 Hz), 162.05 (t, J = 30.6 Hz), 148.65,
138.51, 136.71 (t, J = 3.1 Hz) 136.32, 133.03 (d, J = 3.3 Hz), 132.75,
131.47, 131.11, 130.32 (t, J = 23.4 Hz), 128.17 (d, J = 8.0 Hz), 127.84,
127.50, 127.36, 127.09, 126.60 (t, J = 8.8 Hz), 125.26 (d, J = 2.2 Hz),
123.01, 121.88, 117.04, 115.63 (t, J = 255.3 Hz), 115.17 (d, J = 21.7 Hz).
HRMS (ESI-TOF) m/z: calcd. for C25H17F3N2NaO+: 441.1185 (M + Na) +,
found: 441.1180.
(E)-2,2-difluoro-2-(2-(4-methoxystyryl)phenyl)-N-(quinolin-8-yl)acet-
amide (3ai): White solid (23.2 mg, 54%). 1H NMR (400 MHz, CDCl3) δ
10.98 (s, 1H), 8.82 (dd, J = 4.2, 1.6 Hz, 1H), 8.71 (dd, J = 7.4, 1.2 Hz,
1H), 8.17 (dd, J = 8.3, 1.5 Hz, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.68 (d, J =
7.7 Hz, 1H), 7.57 – 7.46 (m, 5H), 7.39 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 8.9
Hz, 2H), 6.88 (d, J = 16.0 Hz, 1H), 6.58 (d, J = 8.7 Hz, 2H), 3.74 (s, 3H).
13C NMR (101 MHz, CDCl3) δ 162.14 (t, J = 30.8 Hz), 159.28, 148.66,
138.58, 137.14 (t, J = 2.9 Hz), 136.26, 132.86, 132.17, 131.05, 130.05,
129.74, 127.94, 127.85, 127.16, 127.14, 127.09, 126.61 (t, J = 8.9 Hz),
123.17 (t, J = 1.9 Hz), 122.93, 121.82, 117.08, 113.71, 113.23 (t, J =
+
229.5 Hz), 55.19. HRMS (ESI-TOF) m/z: calcd. for C26H20F2N2NaO2
453.1385 (M + Na) +, found: 453.1403.
:
(E)-2-(2-(3-chlorostyryl)phenyl)-2,2-difluoro-N-(quinolin-8-yl)acetami-
de (3ae): White solid (25.6 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 11.00
(s, 1H), 8.81 (d, J = 4.1 Hz, 1H), 8.71 (d, J = 7.5 Hz, 1H), 8.16 (d, J = 8.3
Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.71 – 7.61 (m, 2H), 7.58 – 7.39 (m,
5H), 7.27 (d, J = 7.9 Hz, 1H), 7.20 (d, J = 7.5 Hz, 1H), 7.06 (d, J = 7.9 Hz,
1H), 6.99 (t, J = 7.7 Hz, 1H), 6.83 (d, J = 16.1 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 161.98 (t, J = 30.5 Hz), 148.80, 138.73, 138.50, 136.43 (t,
J = 3.0 Hz), 136.25, 134.33, 132.71, 131.36, 131.14, 130.52 (t, J = 23.6
Hz), 129.45, 127.86, 127.82, 127.63, 127.60, 127.05, 127.02, 126.69 (t, J
= 8.7 Hz), 126.50, 124.81, 123.08, 121.92, 117.01, 115.60 (t, J = 255.0
Hz). HRMS (ESI-TOF) m/z: calcd. for C25H17ClF2N2NaO+: 457.0890 (M +
Na) +, found: 457.0897.
(E)-2-(2-(2-([1,1'-biphenyl]-4-yl)vinyl)phenyl)-2,2-difluoro-N-(quinolin-
8-yl)acetamide (3aj): White solid (24.7 mg, 52%). 1H NMR (400 MHz,
CDCl3) δ 11.01 (s, 1H), 8.81 (dd, J = 4.1, 1.4 Hz, 1H), 8.73 (dd, J = 7.3,
1.2 Hz, 1H), 8.12 (dd, J = 8.2, 1.1 Hz, 1H), 7.85 (d, J = 7.8 Hz, 1H), 7.75
– 7.66 (m, 2H), 7.59 – 7.27 (m, 14H), 6.96 (d, J = 16.0 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ 162.07 (t, J = 30.6 Hz), 148.64, 140.51, 140.32,
138.54, 136.87 (t, J = 3.0 Hz), 136.23, 135.90, 132.79, 132.23, 131.10,
130.32 (t, J = 23.4 Hz), 128.73, 127.80, 127.46, 127.42, 127.29, 127.09,
126.90, 126.78, 126.63 (t, J = 8.8 Hz), 125.44, 122.95, 121.80, 117.04,
115.70 (t,
J = 254.9 Hz). HRMS (ESI-TOF) m/z: calcd. for
C31H22F2N2NaO+: 499.1592 (M + Na) +, found: 499.1606.
(E)-4-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)styryl)phenyl
1
(E)-2-(2-(3-bromostyryl)phenyl)-2,2-difluoro-N-(quinolin-8-yl)acetam-
ide (3af): White solid (26.8 mg, 56%). 1H NMR (400 MHz, CDCl3) δ
11.00 (s, 1H), 8.81 (dd, J = 4.2, 1.6 Hz, 1H), 8.71 (dd, J = 7.5, 1.3 Hz,
1H), 8.16 (dd, J = 8.3, 1.6 Hz, 1H), 7.83 (dd, J = 7.8, 0.9 Hz, 1H), 7.68 –
7.60 (m, 2H), 7.59 – 7.41 (m, 6H), 7.25 (d, J = 8.0 Hz, 1H), 7.21 (d, J =
8.0 Hz, 1H), 6.92 (t, J = 7.9 Hz, 1H), 6.81 (d, J = 16.0 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ 161.97 (t, J = 30.7 Hz), 148.80, 139.01, 138.50,
136.42 (t, J = 3.0 Hz), 136.25, 132.70, 131.26, 131.14, 130.53, 130.52 (t,
J = 23.7Hz), 129.73, 129.50, 127.86, 127.82, 127.61, 127.07, 127.05,
126.67 (t, J = 8.7 Hz), 125.16, 123.08, 122.56, 121.93,117.00, 115.60 (t,
J = 255.1 Hz). HRMS (ESI-TOF) m/z: calcd. for C25H17BrF2N2NaO+:
501.0385 (M + Na) +, found: 501.0369.
acetate (3ak): White solid (31.1 mg, 68%). H NMR (400 MHz, CDCl3) δ
10.96 (s, 1H), 8.77 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 7.5, 1.2 Hz,
1H), 8.15 (dd, J = 8.3, 1.5 Hz, 1H), 7.83 (d, J = 7.2 Hz, 1H), 7.71 – 7.61
(m, 2H), 7.57 – 7.34 (m, 7H), 6.91 (d, J = 16.0 Hz, 1H), 6.85 (d, J = 8.6
Hz, 2H), 2.29 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 169.20, 161.95 (t, J
= 30.8 Hz), 150.11, 148.70, 138.44, 136.65 (t, J = 2.8 Hz), 136.23,
134.64, 132.68, 131.53, 131.08, 130.22 (t, J = 23.5 Hz), 127.78, 127.62,
127.51, 127.39, 127.00, 126.62 (t, J = 8.8 Hz), 125.64, 123.02, 121.86,
121.45, 116.98, 115.67 (t, J = 255.0 Hz), 21.06. HRMS (ESI-TOF) m/z:
calcd. for C27H20F2N2NaO3+: 481.1334 (M + Na) +, found: 481.1341.
Methyl (E)-4-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)styryl-
)benzoate (3al): White solid (23.8 mg, 52%). 1H NMR (400 MHz, CDCl3)
δ 10.98 (s, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.69 (dd, J = 7.5, 1.1 Hz,
1H), 8.15 (dd, J = 8.3, 1.5 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 7.80 – 7.65
(m, 4H), 7.57 – 7.41 (m, 5H), 7.38 (d, J = 8.3 Hz, 2H), 6.92 (d, J = 16.0
Hz, 1H), 3.90 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 166.70, 161.97 (t, J
= 30.6 Hz), 148.71, 141.26, 138.49, 136.34, 136.29, 132.68, 131.58,
131.16, 130.62 (t, J = 23.5 Hz), 129.59, 128.94, 128.12 (t, J = 2.0 Hz),
127.96, 127.84, 127.54, 127.05, 126.68 (t, J = 8.7 Hz), 126.45, 123.09,
121.91, 117.03, 115.58 (t, J = 255.1 Hz), 52.02. HRMS (ESI-TOF) m/z:
calcd. for C27H20F2N2NaO3+: 481.1334 (M + Na) +, found: 481.1347.
(E)-2-(2-(4-bromostyryl)phenyl)-2,2-difluoro-N-(quinolin-8-yl)acetam-
ide (3ag): White solid (24.0 mg, 50%). 1H NMR (400 MHz, CDCl3) δ
10.97 (s, 1H), 8.80 (dd, J = 4.2, 1.6 Hz, 1H), 8.68 (dd, J = 7.6, 1.2 Hz,
1H), 8.18 (dd, J = 8.3, 1.6 Hz, 1H), 7.83 (dd, J = 7.8, 0.9 Hz, 1H), 7.68 –
7.38 (m, 7H), 7.18 – 7.08 (m, 4H), 6.80 (d, J = 16.0 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ 162.02 (t, J = 30.6 Hz), 148.64, 138.48, 136.57 (t, J
= 2.8 Hz), 136.36, 135.74, 132.69, 131.54, 131.30, 131.13, 130.47 (t, J =
23.5 Hz), 128.03, 127.83, 127.69, 127.48, 127.06, 126.60 (t, J = 8.8 Hz),
126.33 (t, J = 1.8 Hz), 123.02, 121.89, 121.49, 117.00, 115.57 (t, J =
255.0 Hz). HRMS (ESI-TOF) m/z: calcd. for C25H17BrF2N2NaO+:
501.0385 (M + Na) +, found: 501.0396.
(E)-2,2-difluoro-2-(2-(2-(naphthalen-2-yl)vinyl)phenyl)-N-(quinolin-8-
yl)acetamide (3am): White solid (27.9 mg, 62%). 1H NMR (400 MHz,
CDCl3) δ 11.03 (s, 1H), 8.79 – 8.67 (m, 2H), 8.07 (dd, J = 8.3, 1.5 Hz,
1H), 7.87 (d, J = 7.8 Hz, 1H), 7.81 – 7.63 (m, 4H), 7.58 – 7.51 (m, 3H),
7.50 – 7.35 (m, 7H), 7.08 (d, J = 16.0 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 162.09 (t, J = 31.4 Hz), 148.62, 138.47, 136.92, 136.12, 134.39,
133.33, 132.96, 132.89, 132.76, 131.11, 130.37 (t, J = 24.1 Hz), 127.96,
127.85, 127.75, 127.47, 127.00, 126.85, 126.64 (t, J = 8.6 Hz), 126.05,
125.86, 125.79, 123.59, 122.95, 121.74, 116.98, 115.69 (t, J = 255.2 Hz).
(E)-2,2-difluoro-2-(2-(4-methylstyryl)phenyl)-N-(quinolin-8-yl)acetam-
ide (3ah): White solid (26.5 mg, 64%). 1H NMR (400 MHz, CDCl3) δ
11.04 (s, 1H), 8.85 (dd, J = 4.2, 1.5 Hz, 1H), 8.78 (d, J = 7.4 Hz, 1H),
8.20 (dd, J = 8.3, 1.4 Hz, 1H), 7.89 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.7
Hz, 1H), 7.68 (d, J = 16.0 Hz, 1H), 7.63 – 7.49 (m, 4H), 7.46 (t, J = 7.5
Hz, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.01 – 6.90 (m, 3H), 2.31 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 162.07 (t, J = 30.7 Hz), 148.63, 138.52, 137.59,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600954
FULL PAPER
HRMS (ESI-TOF) m/z: calcd. for C29H20F2N2NaO+: 473.1436 (M + Na) +,
found: 473.1440.
115.68 (t, J = 254.3 Hz), 33.07, 31.89, 29.56, 29.49, 29.29, 29.09, 28.91,
22.67, 14.10. HRMS (ESI-TOF) m/z: calcd. for C29H34F2N2NaO+:
487.2531 (M + Na) +, found: 487.2514.
(E)-2,2-difluoro-N-(quinolin-8-yl)-2-(2-(2-(thiophen-2-yl)vinyl)phenyl-
1
)acetamide (3an): claret viscous oil (11.0 mg, 27%). H NMR (400 MHz,
(E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)phenyl)allyl
acetate (3as): White solid (13.9 mg, 35%). H NMR (400 MHz, CDCl3) δ
1
CDCl3) δ 10.97 (s, 1H), 8.80 (dd, J = 4.2, 1.4 Hz, 1H), 8.73 (dd, J = 7.4,
1.1 Hz, 1H), 8.16 (dd, J = 8.3, 1.1 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.67
(d, J = 7.8 Hz, 1H), 7.60 – 7.43 (m, 5H), 7.39 (t, J = 7.7 Hz, 1H), 7.11 –
7.00 (m, 2H), 6.98 (d, J = 3.4 Hz, 1H), 6.84 (dd, J = 5.0, 3.6 Hz, 1H). 13C
NMR (101 MHz, CDCl3) δ 161.97 (t, J = 30.8 Hz), 148.64, 142.36, 138.60,
136.45, 136.19, 132.90, 131.07, 130.09 (t, J = 23.5 Hz), 127.81, 127.40,
127.32, 127.13, 127.07, 126.75 (t, J = 8.7 Hz), 126.36, 125.42, 124.90,
124.85 (t, J = 2.4 Hz), 122.94, 121.84, 117.05, 115.72 (t, J = 254.9 Hz).
HRMS (ESI-TOF) m/z: calcd. for C23H16F2N2NaOS+: 429.0844 (M + Na) +,
found: 429.0835.
10.88 (s, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.72 (dd, J = 7.4, 1.2 Hz,
1H), 8.18 (dd, J = 8.3, 1.5 Hz, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.59 (dd, J =
8.3, 1.3 Hz, 1H), 7.57 – 7.44 (m, 4H), 7.40 (t, J = 7.5 Hz, 1H), 7.22 (d, J =
15.7 Hz, 1H), 6.13 (dt, J = 15.6, 6.1 Hz, 1H), 4.58 (dd, J = 6.1, 1.2 Hz,
2H), 1.87 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 170.51, 161.79 (t, J =
30.7 Hz), 148.78, 138.57, 136.29, 135.92 (t, J = 2.8 Hz), 132.73, 131.06,
130.49 (t, J = 2.4 Hz), 130.11 (t, J = 23.6 Hz), 127.98, 127.84, 127.82,
127.57, 127.06, 126.51 (t, J = 8.7 Hz), 123.04, 121.97, 117.05, 115.56 (t,
J
= 254.9 Hz), 64.57, 20.56. HRMS (ESI-TOF) m/z: calcd. for
C22H18F2N2NaO3+: 419.1178 (M + Na) +, found: 419.1189.
Diethyl (E)-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)styryl-
)phosphonate (3ao): Clear viscous oil (41.0 mg, 89%). 1H NMR (400
MHz, CDCl3) δ 10.93 (s, 1H), 8.85 (dd, J = 2.6, 1.6 Hz, 1H), 8.70 (d, J =
7.5 Hz, 1H), 8.17 (d, J = 8.3 Hz, 1H), 8.03 (td, J = 19.7, 1.7 Hz, 1H), 7.75
(d, J = 7.6 Hz, 1H), 7.66 – 7.43 (m, 6H), 6.20 (t, J = 17.9 Hz, 1H), 4.10 –
3.88 (m, 4H), 1.21 (t, J = 7.0 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ
161.40 (t, J = 30.6 Hz), 148.78, 145.26 – 145.06 (m), 138.53, 136.25,
134.98 (d, J = 24.0 Hz), 132.72, 131.29, 130.89 (t, J = 23.9 Hz), 129.45,
128.05, 127.82, 126.97, 126.77 (t, J = 8.4 Hz), 123.12, 121.99, 118.96 (d,
J = 188.7 Hz), 117.00, 115.46 (t, J = 255.5 Hz), 61.98 (d, J = 5.6 Hz),
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-5-me-
thylphenyl)acrylate (3ba): White solid (24.1 mg, 55%). 1H NMR (400
MHz, CDCl3) δ 10.94 (s, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.73 (dd, J =
7.5, 1.2 Hz, 1H), 8.25 (dt, J = 15.8, 2.2 Hz, 1H), 8.18 (dd, J = 8.3, 1.5 Hz,
1H), 7.66 (d, J = 8.0 Hz, 1H), 7.59 (dd, J = 8.3, 1.3 Hz, 1H), 7.56 – 7.43
(m, 3H), 7.28 (d, J = 8.1 Hz, 1H), 6.32 (d, J = 15.7 Hz, 1H), 4.02 (t, J =
6.7 Hz, 2H), 2.40 (s, 3H), 1.52 – 1.37 (m, 2H), 1.35 – 1.19 (m, 2H), 0.83
(t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.19, 161.68 (t, J =
30.7 Hz), 148.73, 141.64 (t, J = 2.7 Hz), 141.44, 138.61, 136.24, 133.97
(t, J = 2.4 Hz), 132.81, 130.19, 128.78, 128.61 (t, J = 24.0 Hz), 127.85,
127.07, 126.98 (t, J = 8.4 Hz), 123.03, 122.00, 121.91, 117.08, 115.66 (t,
J = 255.3 Hz), 64.31, 30.46, 21.21, 18.99, 13.60. HRMS (ESI-TOF) m/z:
calcd. for C25H24F2N2NaO3+: 461.1647 (M + Na) +, found: 461.1648.
16.16 (d,
J
=
6.4 Hz). HRMS (ESI-TOF) m/z: calcd. for
C23H23F2N2NaO4P+: 483.1256 (M + Na) +, found: 483.1267.
(E)-2,2-difluoro-2-(2-(2-(phenylsulfonyl)vinyl)phenyl)-N-(quinolin-8-
yl)acetamide (3ap): White solid (28.3 mg, 61%). 1H NMR (400 MHz,
CDCl3) δ 10.97 (s, 1H), 8.88 (dd, J = 4.2, 1.4 Hz, 1H), 8.68 (d, J = 7.6 Hz,
1H), 8.39 (d, J = 15.2 Hz, 1H), 8.18 (dd, J = 8.3, 1.3 Hz, 1H), 7.88 – 7.83
(m, 2H), 7.81 – 7.74 (m, 1H), 7.61 (d, J = 8.2 Hz, 1H), 7.58 – 7.46 (m,
6H), 7.40 (t, J = 7.8 Hz, 2H), 6.78 (d, J = 15.2 Hz, 1H). 13C NMR (101
MHz, CDCl3) δ 161.08 (t, J = 30.6 Hz), 148.85, 140.36 (t, J = 3.2 Hz),
140.11, 138.44, 136.25, 133.24, 132.53, 132.10, 131.64 (t, J = 24.1 Hz),
131.33, 131.13, 130.30, 129.06, 128.50, 127.79, 127.71, 126.96 (t, J =
Butyl (E)-3-(4-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-[1,1'-
biphenyl]-3-yl)acrylate (3ca): White solid (30.5 mg, 61%). 1H NMR (400
MHz, CDCl3) δ 11.01 (s, 1H), 8.89 (dd, J = 4.2, 1.5 Hz, 1H), 8.76 (dd, J =
7.4, 0.8 Hz, 1H), 8.33 (d, J = 15.8 Hz, 1H), 8.20 (dd, J = 8.3, 1.4 Hz, 1H),
7.91 – 7.81 (m, 2H), 7.69 (d, J = 8.5 Hz, 1H), 7.64 – 7.38 (m, 8H), 6.41 (d,
J = 15.7 Hz, 1H), 4.03 (t, J = 6.7 Hz, 2H), 1.52 – 1.42 (m, 2H), 1.33 –
1.22 (m, 2H), 0.84 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
166.10, 161.56 (t, J = 30.7 Hz), 148.79, 144.22, 141.57, 139.41, 138.66,
136.27, 134.64 (t, J = 2.3 Hz), 132.80, 130.10 (t, J = 24.0 Hz), 128.98,
128.26, 128.07, 127.89, 127.57 (t, J = 8.4 Hz), 127.21, 127.11, 126.95,
8.6 Hz), 126.83, 123.27, 122.04, 116.97, 115.18 (t, J = 256.2 Hz). HRMS
+
(ESI-TOF) m/z: calcd. for C25H18F2N2NaO3S+: 487.0898 (M + Na)
found: 487.0909.
,
123.12, 122.58, 121.96, 117.16, 115.58 (t, J = 255.4 Hz), 64.41, 30.47,
+
19.00, 13.61. HRMS (ESI-TOF) m/z: calcd. for C30H26F2N2NaO3
523.1804 (M + Na) +, found: 523.1826.
:
(E)-2,2-difluoro-N-(quinolin-8-yl)-2-(2-(2-(4,4,5,5-tetramethyl-1,3,2-
dioxaborolan-2-yl)vinyl)phenyl)acetamide (3aq): Clear viscous oil
(18.0 mg, 40%). 1H NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 8.88 (dd, J =
4.2, 1.5 Hz, 1H), 8.75 (dd, J = 7.4, 1.3 Hz, 1H), 8.18 (dd, J = 8.3, 1.5 Hz,
1H), 7.86 (d, J = 18.0 Hz, 1H), 7.77 (d, J = 7.4 Hz, 1H), 7.64 (d, J = 7.7
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-5-fluo-
rophenyl)acrylate (3da): White solid (35.4 mg, 80%). 1H NMR (400 MHz,
CDCl3) δ 10.97 (s, 1H), 8.87 (dd, J = 4.2, 1.5 Hz, 1H), 8.71 (dd, J = 7.5,
1.0 Hz, 1H), 8.25 – 8.15 (m, 2H), 7.78 (dd, J = 8.8, 5.5 Hz, 1H), 7.64 –
7.45 (m, 3H), 7.34 (dd, J = 9.5, 2.2 Hz, 1H), 7.17 (td, J = 8.6, 2.4 Hz, 1H),
6.31 (d, J = 15.7 Hz, 1H), 4.01 (t, J = 6.7 Hz, 2H), 1.50 – 1.40 (m, 2H),
1.32 – 1.20 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 165.74, 163.97 (d, J = 252.0 Hz), 161.28 (t, J = 30.6 Hz), 148.81,
140.23, 138.61, 136.93 (d, J = 8.4 Hz), 136.29, 132.66, 129.41 (q, J = 8.8
Hz), 127.88, 127.52 (dt, J = 24.2, 3.2 Hz), 127.07, 123.41, 123.21,
121.99, 117.14, 116.30 (d, J = 21.8 Hz), 115.15 (t, J = 256.6 Hz), 115.11
(d, J = 23.1 Hz), 64.52, 30.42, 18.97, 13.58. HRMS (ESI-TOF) m/z: calcd.
for C24H21F3N2NaO3+: 465.1396 (M + Na) +, found: 465.1406.
Hz, 1H), 7.61 – 7.38 (m, 5H), 6.05 (d, J = 18.0 Hz, 1H), 0.94 (s, 12H). 13
C
NMR (101 MHz, CDCl3) δ 161.95 (t, J = 30.3 Hz), 148.66, 145.74, 138.74,
137.52 (t, J = 2.6 Hz), 136.18, 132.98, 131.08, 130.31 (t, J = 23.5 Hz),
128.27, 127.90, 127.63, 127.16, 126.40 (t, J = 8.7 Hz), 122.83, 121.86,
117.05, 115.50 (t, J = 254.7 Hz), 83.08, 24.33. HRMS (ESI-TOF) m/z:
calcd. for C25H25BF2N2NaO3+: 473.1823 (M + Na) +, found: 473.1836.
(E)-2-(2-(dodec-1-en-1-yl)phenyl)-2,2-difluoro-N-(quinolin-8-yl)acet-
amide (3ar): Clear oil (14.0 mg, 30%). 1H NMR (400 MHz, CDCl3) δ
10.91 (s, 1H), 8.86 (dd, J = 4.2, 1.6 Hz, 1H), 8.75 (dd, J = 7.4, 1.4 Hz,
1H), 8.18 (dd, J = 8.3, 1.5 Hz, 1H), 7.76 (d, J = 7.8 Hz, 1H), 7.63 – 7.46
(m, 4H), 7.44 (t, J = 7.4 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 15.6
Hz, 1H), 6.04 (dt, J = 15.3, 6.8 Hz, 1H), 1.99 (dd, J = 13.8, 6.8 Hz, 2H),
1.37 – 0.96 (m, 16H), 0.89 (t, J = 7.0 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 162.10 (t, J = 30.6 Hz), 148.67, 138.65, 137.66 (t, J = 3.1 Hz),
136.25, 136.00, 132.91, 130.93, 129.49 (t, J = 23.3 Hz), 127.87, 127.77,
127.13, 126.74, 126.40, 126.31 (t, J = 8.9 Hz), 122.88, 121.88, 117.05,
Butyl (E)-3-(5-chloro-2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)eth-
yl)phenyl)acrylate (3ea): White solid (33.0 mg, 72%). 1H NMR (400
MHz, CDCl3) δ 10.97 (s, 1H), 8.87 (dd, J = 4.2, 1.5 Hz, 1H), 8.70 (dd, J =
7.5, 0.9 Hz, 1H), 8.28 – 8.07 (m, 2H), 7.72 (d, J = 8.5 Hz, 1H), 7.63 –
7.57 (m, 2H), 7.56 – 7.47 (m, 2H), 7.44 (dd, J = 8.4, 1.5 Hz, 1H), 6.32 (d,
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600954
FULL PAPER
J = 15.7 Hz, 1H), 4.01 (t, J = 6.7 Hz, 2H), 1.49 – 1.40 (m, 2H), 1.32 –
1.20 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ
165.68, 161.07 (t, J = 30.4 Hz), 148.78, 140.09 (t, J = 2.7 Hz), 138.55,
137.44, 136.26, 135.98 (t, J = 2.4 Hz), 132.58, 129.82 (t, J = 24.2 Hz),
129.32, 128.44 (t, J = 8.6 Hz), 128.13, 127.83, 127.02, 123.46, 123.21,
121.96, 117.11, 115.07 (t, J = 256.4 Hz), 64.48, 30.39, 18.95, 13.56.
HRMS (ESI-TOF) m/z: calcd. for C24H21ClF2N2NaO3+: 481.1101 (M + Na)
+, found: 481.1092.
MHz, CDCl3) δ 10.97 (s, 1H), 8.85 (d, J = 4.1 Hz, 1H), 8.72 (d, J = 7.3 Hz,
1H), 8.25 (d, J = 15.7 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.63 – 7.43 (m,
5H), 7.30 (d, J = 7.9 Hz, 1H), 6.31 (d, J = 15.7 Hz, 1H), 4.01 (t, J = 6.7 Hz,
2H), 2.40 (s, 3H), 1.48 – 1.39 (m, 2H), 1.31 – 1.19 (m, 2H), 0.82 (t, J =
7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.20, 161.50 (t, J = 30.6
Hz), 148.67, 141.28 (t, J = 2.7 Hz), 139.96, 138.50, 136.17, 132.67,
131.84, 131.12 (t, J = 23.6 Hz), 131.10 (t, J = 2.61 Hz), 127.98, 127.77,
127.47 (t, J = 8.4 Hz), 126.94, 123.02, 121.86, 121.23, 116.98, 115.48 (t,
J = 255.7 Hz), 64.19, 30.39, 21.24, 18.90, 13.51. HRMS (ESI-TOF) m/z:
calcd. for C25H24F2N2NaO3+: 461.1647 (M + Na) +, found: 461.1665.
Butyl (E)-3-(5-bromo-2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)eth-
yl)phenyl)acrylate (3fa): White solid (30.7 mg, 61%). 1H NMR (400 MHz,
CDCl3) δ 10.97 (s, 1H), 8.88 (d, J = 4.1 Hz, 1H), 8.70 (d, J = 7.5 Hz, 1H),
8.17 (dd, J = 20.6, 5.1 Hz, 2H), 7.77 (s, 1H), 7.65 (d, J = 8.5 Hz, 1H),
7.61 (d, J = 8.1 Hz, 2H), 7.57 – 7.48 (m, 2H), 6.32 (d, J = 15.7 Hz, 1H),
4.01 (t, J = 6.7 Hz, 2H), 1.50 – 1.39 (m, 2H), 1.33 – 1.19 (m, 2H), 0.83 (t,
J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.69, 161.06 (t, J = 30.4
Hz), 148.79, 140.03 (t, J = 2.7 Hz), 138.55, 136.33, 136.15 (t, J = 2.3 Hz),
132.58, 132.33, 131.08, 130.32 (t, J = 24.2 Hz), 128.57 (t, J = 8.5 Hz),
127.87, 127.08, 125.73, 123.53, 123.25, 121.99, 117.20, 115.13 (t, J =
256.5 Hz), 64.51, 30.41, 18.97, 13.59. HRMS (ESI-TOF) m/z: calcd. for
C24H21BrF2N2NaO3+: 525.0596 (M + Na) +, found: 525.0617.
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-4-(tri-
fluoromethyl)phenyl)acrylate (3ka): White solid (48.7 mg, 99%). 1H
NMR (400 MHz, CDCl3) δ 11.04 (s, 1H), 8.89 (d, J = 4.2 Hz, 1H), 8.68 (d,
J = 7.5 Hz, 1H), 8.28 – 8.15 (m, 2H), 8.07 (s, 1H), 7.77 (q, J = 8.5 Hz,
2H), 7.61 (d, J = 8.3 Hz, 1H), 7.57 – 7.48 (m, 2H), 6.37 (d, J = 15.8 Hz,
1H), 3.98 (t, J = 6.8 Hz, 2H), 1.49 – 1.33 (m, 2H), 1.30 – 1.16 (m, 2H),
0.81 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.49, 160.76 (t,
J = 30.1 Hz), 148.82, 139.92, 138.54, 137.82, 136.26, 132.47, 132.25 (t,
J = 24.2 Hz), 131.39 (q, J = 33.4 Hz), 128.78, 127.98 (d, J = 3.3 Hz),
127.84, 126.98 (d, J = 0.9 Hz), 124.45, 124.02 (td, J = 8.8, 4.4 Hz),
123.35 (q, J =273.7 Hz ), 123.32, 122.00, 117.12, 114.68 (t, J = 257.1
Hz), 64.55, 30.33, 18.90, 13.50. HRMS (ESI-TOF) m/z: calcd. for
C25H21F5N2NaO3+: 515.1365 (M + Na) +, found: 515.1382.
Butyl (E)-3-(5-acetyl-2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)eth-
yl)phenyl)acrylate (3ga): White solid (37.7 mg, 81%). 1H NMR (400
MHz, CDCl3) δ 11.00 (s, 1H), 8.88 (dd, J = 4.2, 1.5 Hz, 1H), 8.69 (dd, J =
7.5, 0.9 Hz, 1H), 8.30 – 8.14 (m, 3H), 8.03 (d, J = 8.2 Hz, 1H), 7.91 (d, J
= 8.2 Hz, 1H), 7.61 (dd, J = 8.2, 1.0 Hz, 1H), 7.57 – 7.47 (m, 2H), 6.41 (d,
J = 15.7 Hz, 1H), 4.00 (t, J = 6.7 Hz, 2H), 2.65 (s, 3H), 1.49 – 1.38 (m,
2H), 1.32 – 1.19 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 196.68, 165.78, 160.94 (t, J = 30.0 Hz), 148.84, 140.55 (t, J =
2.6 Hz), 139.09, 138.60, 136.30, 135.30 (t, J = 23.9 Hz), 134.90 (t, J =
2.5 Hz), 132.58, 128.86, 127.87, 127.85, 127.55 (t, J = 8.5 Hz), 127.06,
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-4-nit-
rophenyl)acrylate (3la): White solid (21.1 mg, 45%). 1H NMR (400 MHz,
CDCl3) δ 11.07 (s, 1H), 8.91 (dd, J = 4.2, 1.5 Hz, 1H), 8.73 – 8.60 (m,
2H), 8.37 (dd, J = 8.6, 2.0 Hz, 1H), 8.26 – 8.15 (m, 2H), 7.81 (d, J = 8.6
Hz, 1H), 7.63 (d, J = 7.4 Hz, 1H), 7.58 – 7.48 (m, 2H), 6.41 (d, J = 15.8
Hz, 1H), 3.99 (t, J = 6.7 Hz, 2H), 1.47 – 1.35 (m, 2H), 1.31 – 1.15 (m, 2H),
0.81 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.21, 160.41 (t,
J = 29.9 Hz), 148.92, 147.90, 140.55, 139.17, 138.57, 136.33, 133.06 (t,
J = 25.0 Hz), 132.39, 129.42, 127.88, 127.03, 125.89, 125.68, 123.48,
123.59, 123.29, 122.01, 117.17, 115.00 (t, J = 256.7 Hz), 64.50, 30.42,
+
26.75, 18.97, 13.58. HRMS (ESI-TOF) m/z: calcd. for C26H24F2N2NaO4
489.1596 (M + Na) +, found: 489.1598.
:
122.50 (t, J = 9.3 Hz), 122.09, 117.24, 114.27 (t, J = 258.2 Hz), 64.75,
+
30.34, 18.92, 13.54. HRMS (ESI-TOF) m/z: calcd. for C24H21F2N3NaO5
492.1341 (M + Na) +, found: 492.1350.
:
Butyl (E)-3-(5-cyano-2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)eth-
yl)phenyl)acrylate (3ha): White solid (24.2 mg, 54%). 1H NMR (400
MHz, CDCl3) δ 11.02 (s, 1H), 8.89 (dd, J = 4.2, 1.5 Hz, 1H), 8.66 (d, J =
7.6 Hz, 1H), 8.24 – 8.11 (m, 2H), 7.95 – 7.86 (m, 2H), 7.76 (d, J = 8.2 Hz,
1H), 7.62 (d, J = 8.3 Hz, 1H), 7.57 – 7.49 (m, 2H), 6.34 (d, J = 15.8 Hz,
1H), 3.99 (t, J = 6.7 Hz, 2H), 1.48 – 1.37 (m, 2H), 1.31 – 1.18 (m, 2H),
0.82 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.30, 160.46 (t,
J = 29.7 Hz), 148.87, 139.18 (t, J = 2.7 Hz), 138.53, 136.32, 135.76 (t, J
= 2.3 Hz), 135.50 (t, J = 24.1 Hz), 132.37, 131.63, 128.04, 127.95,
127.86, 127.02, 124.68, 123.44, 122.06, 117.25, 117.19, 115.51, 114.50
(t, J = 257.6 Hz) 64.65, 30.34, 18.92, 13.54. HRMS (ESI-TOF) m/z: calcd.
for C25H21F2N3NaO3+: 472.1443 (M + Na) +, found: 472.1441.
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-3-me-
thylphenyl)acrylate (3ma): White solid (27.6 mg, 63%). 1H NMR (400
MHz, CDCl3) δ 10.96 (s, 1H), 8.87 (dd, J = 4.2, 1.5 Hz, 1H), 8.71 (dd, J =
7.5, 1.0 Hz, 1H), 8.32 (dt, J = 15.7, 5.6 Hz, 1H), 8.18 (dd, J = 8.3, 1.5 Hz,
1H), 7.59 (dd, J = 8.2, 1.1 Hz, 1H), 7.57 – 7.47 (m, 2H), 7.39 – 7.32 (m,
2H), 7.29 – 7.24 (m, 1H), 6.19 (d, J = 15.7 Hz, 1H), 4.05 (t, J = 6.7 Hz,
2H), 2.57 (t, J = 3.8 Hz, 3H), 1.57 – 1.46 (m, 2H), 1.36 – 1.24 (m, 2H),
0.86 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.31, 161.70 (t,
J = 30.6 Hz), 148.77, 144.87 (t, J = 4.9 Hz), 138.61, 138.00 (t, J = 3.2 Hz),
136.23, 136.14 (t, J = 3.3 Hz), 133.34, 132.79, 130.45, 129.68 (t, J = 22.1
Hz), 127.85, 127.26, 127.03, 123.04, 121.93, 117.11 (t, J = 257.5 Hz),
117.02, 64.27, 30.51, 21.67 (t, J = 5.3 Hz), 19.02, 13.61. HRMS (ESI-
TOF) m/z: calcd. for C25H24F2N2NaO3+: 461.1647 (M + Na) +, found:
461.1645.
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-5-(me-
thylsulfonyl)phenyl)acrylate (3ia): White solid (38.6 mg, 77%). 1H NMR
(400 MHz, CDCl3) δ 11.04 (s, 1H), 8.89 (dd, J = 4.2, 1.6 Hz, 1H), 8.67
(dd, J = 7.6, 0.9 Hz, 1H), 8.25 – 8.17 (m, 3H), 8.07 – 7.99 (m, 2H), 7.62
(dd, J = 8.3, 1.0 Hz, 1H), 7.57 – 7.49 (m, 2H), 6.43 (d, J = 15.7 Hz, 1H),
4.00 (t, J = 6.7 Hz, 2H), 3.09 (s, 3H), 1.49 – 1.39 (m, 2H), 1.32 – 1.18 (m,
2H), 0.82 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 165.37,
160.53 (t, J = 29.7 Hz), 148.89, 143.32, 139.37 (t, J = 2.7 Hz), 138.53,
136.54, 136.32, 136.05, 132.37, 128.36 (t, J = 8.5 Hz), 127.86, 127.80,
127.07, 127.00, 124.77, 123.46, 122.07, 117.17, 114.58 (t, J = 257.7 Hz),
64.62, 44.33, 30.35, 18.92, 13.54. HRMS (ESI-TOF) m/z: calcd. for
C25H24F2N2NaO5S+: 525.1266 (M + Na) +, found: 525.1277.
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-3-me-
1
thoxyphenyl)acrylate (3na): White solid (22.7 mg, 50%). H NMR (400
MHz, CDCl3) δ 10.90 (s, 1H), 8.88 (dd, J = 4.2, 1.6 Hz, 1H), 8.76 (dd, J =
7.0, 1.8 Hz, 1H), 8.36 (dt, J = 15.7, 5.5 Hz, 1H), 8.20 (dd, J = 8.3, 1.5 Hz,
1H), 7.62 – 7.53 (m, 2H), 7.50 (dd, J = 8.3, 4.2 Hz, 1H), 7.43 (t, J = 8.1
Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.24 (d, J =
15.7 Hz, 1H), 4.21 (t, J = 6.7 Hz, 2H), 3.71 (s, 3H), 1.74 – 1.63 (m, 2H),
1.50 – 1.36 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3)
δ 166.45, 162.67 (t, J = 29.2 Hz), 157.87 (t, J = 5.2 Hz), 148.66, 144.01 (t,
J = 6.0 Hz), 138.75, 137.47, 136.26, 133.44, 132.00, 127.97, 127.19,
122.57, 122.17, 121.95, 121.86, 120.07 (t, J = 23.1 Hz), 116.87, 115.72 (t,
Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-4-me-
thylphenyl)acrylate (3ja): White solid (35.0 mg, 80%). 1H NMR (400
This article is protected by copyright. All rights reserved

European Journal of Organic Chemistry
10.1002/ejoc.201600954
FULL PAPER
J = 255.5 Hz), 112.90, 64.46, 56.41, 30.71, 19.16, 13.72. HRMS (ESI-
TOF) m/z: calcd. for C25H24F2N2NaO4+: 477.1596 (M + Na) +, found:
477.1594.
(t, J = 6.7 Hz, 4H), 1.59 – 1.48 (m, 4H), 1.38 – 1.26 (m, 4H), 0.84 (t, J =
7.4 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 166.26, 156.52 (t, J = 36.4
Hz), 148.87, 145.93, 138.59, 137.95, 136.28, 132.51, 131.06, 128.84,
127.86, 127.51, 127.10, 123.37, 122.01, 121.54, 117.45, 115.09 (t, J =
279.0 Hz), 64.53, 30.53, 19.06, 13.62. HRMS (ESI-TOF) m/z: calcd. for
C31H32F2N2NaO6+: 589.2121 (M + Na) +, found: 589.2116.
Butyl
(E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-4,6-
dimethylphenyl)acrylate (3oa): White solid (34.8 mg, 77%). 1H NMR
(400 MHz, CDCl3) δ 10.92 (s, 1H), 8.85 (d, J = 4.2 Hz, 1H), 8.70 (d, J =
7.3 Hz, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 16.3 Hz, 1H), 7.62 –
7.44 (m, 4H), 7.18 (s, 1H), 5.95 (d, J = 16.3 Hz, 1H), 3.52 (t, J = 6.6 Hz,
2H), 2.38 (s, 3H), 2.25 (s, 3H), 1.18 – 0.96 (m, 4H), 0.74 (t, J = 7.1 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 165.40, 162.02 (t, J = 30.1 Hz),
148.64, 141.66, 138.53, 137.92, 136.75, 136.08, 133.55, 132.74, 131.06
(t, J = 3.5 Hz), 130.83 (t, J = 23.0 Hz), 127.74, 127.06, 126.21, 124.98 (t,
J = 8.5 Hz), 122.83, 121.81, 116.87, 115.20 (t, J = 254.8 Hz), 64.00,
30.04, 21.09, 20.43, 18.78, 13.50. HRMS (ESI-TOF) m/z: calcd. for
C26H26F2N2NaO3+: 475.1804 (M + Na) +, found: 475.1809.
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 21372176), Tongji University 985 Phase III
funds, the Program for Professor of Special Appointment (Eas-
tern Scholar) at Shanghai Institutions of Higher Learning, and
Shanghai Science and Technology Commission (14DZ2261100)
for financial support.
Butyl
(E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethyl)-4,5-
dimethylphenyl)acrylate (3pa): White solid (39.3 mg, 87%). 1H NMR
(400 MHz, CDCl3) δ 10.96 (s, 1H), 8.86 (dd, J = 4.2, 1.5 Hz, 1H), 8.73
(dd, J = 7.5, 1.1 Hz, 1H), 8.23 (d, J = 15.7 Hz, 1H), 8.17 (dd, J = 8.3, 1.5
Hz, 1H), 7.58 (dd, J = 8.2, 1.2 Hz, 1H), 7.55 – 7.46 (m, 3H), 7.43 (s, 1H),
6.31 (d, J = 15.7 Hz, 1H), 4.01 (t, J = 6.7 Hz, 2H), 2.31 (s, 3H), 2.30 (s,
3H), 1.50 – 1.40 (m, 2H), 1.32 – 1.20 (m, 2H), 0.83 (t, J = 7.4 Hz, 3H).
13C NMR (101 MHz, CDCl3) δ 166.32, 161.72 (t, J = 30.9 Hz), 148.68,
141.45 (t, J = 2.7 Hz), 139.99, 138.65, 138.54, 136.19, 132.76, 131.26,
129.20, 128.74 (t, J = 23.7 Hz), 128.05 (t, J = 8.2 Hz), 127.80, 127.00,
122.98, 121.87, 120.99, 117.01, 115.64 (t, J = 255.3 Hz), 64.20, 30.43,
19.65, 19.54, 18.95, 13.55. HRMS (ESI-TOF) m/z: calcd. for
C26H26F2N2NaO3+: 475.1804 (M + Na) +, found: 475.1803.
Keywords: Palladium • C−H activation • Olefination • Difluoro-
methylene • Bidentate directing group • Synthetic Methods
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Butyl (E)-3-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethoxy)phen-
yl)acrylate (3ra-mono): Clear oil (9.7 mg, 22%). 1H NMR (400 MHz,
CDCl3) δ 10.98 (s, 1H), 8.84 (dd, J = 4.2, 1.5 Hz, 1H), 8.78 (dd, J = 7.3,
1.3 Hz, 1H), 8.20 (dd, J = 8.3, 1.4 Hz, 1H), 8.06 (d, J = 16.1 Hz, 1H), 7.71
– 7.55 (m, 3H), 7.54 – 7.39 (m, 3H), 7.31 (t, J = 7.3 Hz, 1H), 6.51 (d, J =
16.1 Hz, 1H), 4.05 (t, J = 6.7 Hz, 2H), 1.54 – 1.40 (m, 2H), 1.34 – 1.17 (m,
2H), 0.80 (t, J = 7.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 166.49,
156.90 (t, J = 36.8 Hz), 148.87, 147.94, 138.55, 137.83, 136.28, 132.53,
131.06, 128.41, 127.94, 127.86, 127.08, 126.68, 123.31, 122.41, 121.99,
121.18, 117.37, 114.82 (t, J = 276.0 Hz), 64.38, 30.49, 19.02, 13.59.
HRMS (ESI-TOF) m/z: calcd. for C24H22F2N2NaO4+: 463.1440 (M + Na) +,
found: 463.1437.
Dibutyl 3,3'-(2-(1,1-difluoro-2-oxo-2-(quinolin-8-ylamino)ethoxy)-1,3-
phenylene)(2E,2'E)-diacrylate (3ra-di): Yellow oil (29 mg, 51%). 1H
NMR (400 MHz, CDCl3) δ 11.03 (s, 1H), 8.85 (dd, J = 4.2, 1.5 Hz, 1H),
8.80 (dd, J = 7.3, 1.2 Hz, 1H), 8.21 (dd, J = 8.3, 1.4 Hz, 1H), 8.09 (d, J =
16.1 Hz, 2H), 7.72 (d, J = 7.8 Hz, 2H), 7.67 – 7.56 (m, 2H), 7.51 (dd, J =
8.3, 4.2 Hz, 1H), 7.39 (t, J = 7.8 Hz, 1H), 6.48 (d, J = 16.1 Hz, 2H), 4.08
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Synthetic Methods*
Changdong Shao, Guangfa Shi,
Yanghui Zhang *
Page 1 – Page 5
An Easy Access to Difluoromethyl-
ene-Containing Arene Analogues via
Palladium-Catalyzed C−H Olefination
An efficient method for the synthesis of ortho-olefinated analogues of α,α-
difluorophenylacetic acid via palladium-catalyzed
C−H olefination using 8-
aminoquinoline as the bidentate directing group has been developed. This reaction
provides an easy and straightforward access to a panel of difluoromethylated arene
analogues.
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