Palladium-Catalyzed Heck-Type Difluoroalkylation of Alkenes with Functionalized Difluoromethyl Bromides

Article abstract of DOI:10.1055/s-0035-1560457

An efficient method for the synthesis of difluoroalkylated alkenes through palladium-catalyzed Heck-type reaction with functionalized difluoromethyl bromides has been developed. The advantages of this protocol are its synthetic simplicity, excellent funct

Full text of DOI:10.1055/s-0035-1560457

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2015, 47, 2912–2923
2912
feature
F. Zhang et al.
Feature
Synthesis
Palladium-Catalyzed Heck-Type Difluoroalkylation of Alkenes
with Functionalized Difluoromethyl Bromides
Feng Zhang
PdCl2(MeCN)2 (10 mol%)
Xantphos (20 mol%)
R2
R2
Qiao-Qiao Min
Xingang Zhang*
CF2R4
BrCF2R4
R1
+
R1
K2CO3, 1,4-dioxane, 80 °C
R3
R3
Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345
Lingling Road, Shanghai 200032, P. R. of China
xgzhang@mail.sioc.ac.cn
R4 = CO2Et, CONR5R6, Ar, HetAr
29 examples, up to 90% yield
Received: 02.07.2015
Accepted after revision: 27.07.2015
Published online: 17.08.2015
veloped by Shibuya.6 Recently, the copper-mediated difluo-
romethylation of iodoalkenes with nucleophilic difluoro-
methylated reagents (i.e., TMSCF2H or n-Bu3SnCF2H) were
also reported by Hartwig and Prakash, respectively.7 De-
spite the importance of these methods, such processes suf-
fer from the use of stoichiometric amount of transition
metal, and/or the requirement of multiple steps for the
preparation of alkenyl halides. Using functionalized difluo-
roakyl halides as electrophiles to access α,α-difluorometh-
ylene alkenes is an alternative strategy. In 2000, a nickel-
catalyzed ethoxycarbonyldifluoromethylation of vinylzirco-
niums with bromodifluoroacetate was developed by
Schwaebe.8 However, the yields were low to moderate, and
additional steps had to be used for the preparation of vinyl-
zirconiums. Other strategies, including stepwise procedures
of addition of free fluoroalkyl radicals to alkenes, followed
by base-assisted elimination have also been demonstrated.9
From the point view of synthetic simplicity and envi-
ronmentally benign processes, a transition-metal-catalyzed
difluoroalkylation of alkenes through Heck-type reaction
from readily and commercially available difluoroalkyl ha-
lides (RCF2–X) would be an attractive and straightforward
alternative. Although transition-metal-catalyzed Heck-type
reactions between alkenes and alkyl halides are estab-
lished,10 similar fluoroalkylation of alkenes with RCF2–X
that are catalyzed by transition metal have remained un-
derdeveloped, and represent a great challenge. Recently, a
Pd-mediated Heck-type reaction of [(bromodifluorometh-
yl)sulfonyl]benzene was reported by Reutrakul.11 However,
the high loading of palladium salt (35 mol%) and low yields
of this reaction significantly restrict its widespread syn-
thetic applications. Therefore, it is highly desirable to devel-
op new strategies and efficient catalytic system to address
these crucial issues. Very recently, we reported the first ex-
ample of Pd-catalyzed fluoroalkylation of alkenes with fluo-
roalkyl bromides.12,13 As part of our continued efforts in this
DOI: 10.1055/s-0035-1560457; Art ID: ss-2015-e0411-fa
Abstract An efficient method for the synthesis of difluoroalkylated
alkenes through palladium-catalyzed Heck-type reaction with function-
alized difluoromethyl bromides has been developed. The advantages of
this protocol are its synthetic simplicity, excellent functional group
compatibility, and efficient late-stage difluoroalkylation of biologically
relevant molecules, thus paving a new way for application in drug dis-
covery and development. Mechanistic studies revealed that the free di-
fluoroalkyl radicals, initiated by a [Pd(0)Ln] via a single-electron-transfer
(SET) pathway, were involved in the Heck-type catalytic cycle.
Key words alkenes, difluoroalkylation, functionalized difluoromethyl
bromides, Heck-type reaction, palladium
Alkenes are an important structural motif in organic
chemistry, and found in a wide range of natural products
and functional materials.1 Owning to the unique properties
of difluoromethylene group CF2, which can increase the di-
pole moments, enhance the acidity of its neighboring
group, and change the molecular conformation,2 the re-
placement of CH2 with its difluorinated counterpart CF2 at
an allylic position could lead to the development of inter-
esting molecules with applications in the life and material
sciences. Although, considerable efforts have been devoted
to the fluoroalkylation of aromatic compounds over the
past few years,3 efficient strategies for the synthesis of α,α-
difluoromethylene alkenes are less studied.4
Usually, such difluoroalkylated alkenes can be prepared
through cross-coupling of difluoroalkylmetal species with
alkenyl halides. In 1986, Kobayashi reported the first exam-
ple of the reaction of iododifluoroacetate-copper with alke-
nyl halides under mild reaction conditions, but stoichio-
metric amount of copper was required.5 Later on, a copper-
catalyzed coupling reaction of [(diethoxyphosphinyl)di-
fluoromethyl]zinc bromide with alkenyl bromides was de-
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F. Zhang et al.
Feature
Synthesis
area,14 we herein describe a general and efficient method
for the Pd-catalyzed Heck type difluoroalkylation of alkenes
with functionalized difluoroalkyl bromides. The reaction
proceeds under mild reaction conditions with excellent
functional groups compatibility, and paves the way for effi-
cient synthesis of a wide range of difluoroalkylated alkenes.
Our initial studies were focused on the palladium-cata-
lyzed coupling reaction of ethyl bromodifluoroacetae (1a)
with styrene (2a) (Table 1). To our delight, a 41% yield (de-
termined by 19F NMR analysis) of the desired product 3a
was observed when the reaction was conducted with
Pd(OAc)2 (10 mol%), Xantphos (20 mol%), and Cs2CO3 (2.0
equiv) in 1,4-dioxane at 80 °C (Table 1, entry 1). It was
found that the reaction was very sensitive to the phosphine
ligands. Among the tested ligands, only bidentate ligand
Xantphos could promote the reaction.15 The choice of the
solvent is also crucial for the reaction efficiency. 1,4-Diox-
ane was the optimal reaction medium; polar solvents, such
as DMSO and DMF, failed to provide 3a. To improve the re-
action efficiency further, different bases and palladium pre-
catalysts were investigated (entries 2–8), and an optimal
yield (75% upon isolation) was obtained when the reaction
was carried out in the presence of PdCl2(MeCN)2 (10 mol%),
Xantphos (20 mol%), and K2CO3 (2.0 equiv) (entry 6) while
Pd(0) catalysts, such as Pd(PPh3)4 and Pd2(dba)3 afforded
lower yields (entries 7, 8). Diminished yields were also ob-
served either by reducing the loading amount of Xantphos
or PdCl2(MeCN)2 (entries 9, 10). However, neither product
nor other by-products were observed without the base or
the ligand, thus demonstrating the essential role of
Pd(0)/Xantphos in the catalytic cycle (entries 11, 12).
Biographical Sketches
Feng Zhang was born in Sich-
uan, China (1985). He received
his B.S. degree from Southwest
University in 2010, and ob-
tained his Ph.D. degree in 2015
from Shanghai Institute of Or-
ganic Chemistry (SIOC), Chinese
Academy of Science (CAS) un-
der the supervision of Prof.
Xingang Zhang. He is currently
a research assistant at the Key
Laboratory of Organofluorine
Chemistry, SIOC, CAS. His re-
search interest is focused on the
transition-metal-catalyzed fluo-
roalkylation reactions.
Qiao-Qiao Min was born in
Hubei, China (1984). He re-
ceived his B.S. degree from
Wuhan University in 2008, and
obtained his M.S. degree as a
joint student of Wuhan Univer-
sity and Shanghai Institute of
Organic Chemistry (SIOC), Chi-
nese Academy of Science (CAS)
in 2010 under the supervision
of Prof. Haibing Zhou and Prof.
Xingang Zhang. He is currently
a research assistant of the Key
Laboratory of Organofluorine
Chemistry, SIOC, CAS. His re-
search interest is focused on the
transition-metal-catalyzed C–F/
C–Rf (Rf, fluoroalkyl and polyflu-
oroaryl group) bond formation
and mechanistic studies.
Xingang Zhang is a research
professor in Shanghai Institute
of Organic Chemistry (SIOC),
Chinese Academy of Sciences
(CAS). He was born in Xinjiang,
China (1975). He graduated in
1998 from Sichuan University
and received a Ph.D. in 2003 at
Shanghai Institute of Organic
Chemistry (SIOC), Chinese
Academy of Sciences (CAS). Af-
ter his postdoctoral work at the
University of Illinois at Urbana
Champaign (UIUC) guided by
Prof. Wilfred A. van der Donk,
he joined the faculty team of
focused on organofluorine
chemistry and chemical biology.
He received the Thieme Chem-
istry Journal Award 2014, the
National Science Fund for Dis-
tinguished Young Scholars
2014, and the 2015 RSC Fluo-
rine Chemistry Prize.
SIOC as
a research associate
professor in 2008, and became
research professor in 2012. His
current research interests are
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F. Zhang et al.
Feature
Synthesis
Table 1 Representative Results for Optimization of Pd-Catalyzed
Heck-Type Reactions of Ethyl Bromodifluoroacetate (1a) with Styrene
(2a)a
It was also possible to carry out the reaction with
branched alkenes (Scheme 2). Good yields were obtained,
when 1,2-dihydronaphthalene (2n) and 1H-indene (2o)
were examined (3n and 3o). It is noteworthy that chrome-
none and quinolinone proceeded smoothly with difluoro-
acetyl group exclusively installed at the C3 position (3p and
3q). In light of the importance of chromenone and quinoli-
none in the discovery of biologically interesting mole-
cules,16 this transformation may have potential applications
in the drug discovery and development. Additionally, the
successful ethoxycarbonyldifluoromethylation of dihydro-
pyrane opens the possibility of the application of this
method for the synthesis of glycomimetics for carbohy-
drate-based bioactive molecule studies (3r).17 In the case of
1,1-diphenylethylene (2s), a mixture of adduct 3s and re-
ductive Heck-type product 3s′ was obtained. As for termi-
nal branched alkenes bearing an alkyl group, the solely
double bond migrated products 3t and 3u were obtained,
thus providing an alternative strategy to prepare difluoroal-
kylated allylic compounds.
To further demonstrate the generality of this method,
different functionalized difluoromethyl bromides were also
explored (Scheme 3). High yields were obtained for bromo-
difluoroacetamide 1b (4a–c). Phenylalanine derivative bro-
modifluoroamide 1c also afforded the fluorinated alkene in
good yield with an excellent functional group tolerance
(4d). This is noteworthy as we can rapidly access such a
valuable building block for fluorinated amino acids based
biologically active peptides and protein engineering stud-
ies.18 Furthermore, bromodifluoromethylarene and 2-bro-
modifluoromethylbenzooxazole were also suitable sub-
strates, providing the corresponding Heck-type products 4e
and 4f in good yields.
The usefulness of this protocol can also be featured by
the late-stage difluoroalkylation of bioactive molecules. As
illustrated in Scheme 4, difluoroalkylated alkenes 6 and 7
can be rapidly accessed by reaction of estrone derived
alkene 5 with 1a and 1c, respectively, thus offering a useful
instrument to prepare diversified fluorinated bioactive
molecules from one key structure.
To gain some mechanistic insight into the present reac-
tion, radical inhibition experiments were performed
(Scheme 5). It was found that when a reaction mixture of 1a
and 2a in the presence of PdCl2(MeCN)2 (10 mol%), Xant-
phos (20 mol%), and K2CO3 in 1,4-dioxane was treated with
an ET scavenger 1,4-dinitrobenzene19 or a radical inhibitor
hydroquinone, the yield of 3a was significantly decreased,
thus implying that a SET pathway via an ethoxycarbonyldi-
fluoromethyl radical, was involved in the catalytic cycle.
[Pd] (x mol%)
Xantphos (y mol%)
CF2CO2Et
BrCF2CO2Et
+
Ph
Ph
base (2.0 equiv)
1,4-dioxane, 80 °C
1a
2a
3a
Entry
[Pd] (x mol%)
Base
Xantphos (y
mol%)
Yield (%)b
1
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PdCl2 (10)
Cs2CO3
20
20
20
20
20
20
20
20
10
10
20
none
41
2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
none
64
3
65
4
PdCl2(PPh3)2 (10)
PdCl2(dppf) (10)
PdCl2(MeCN)2 (10)
Pd(PPh3)4 (10)
53
5
61
6
76 (75)
31
7
8
Pd2(dba)3 (5)
36
9
PdCl2(MeCN)2 (10)
PdCl2(MeCN)2 (5)
PdCl2(MeCN)2 (10)
PdCl2(MeCN)2 (10)
23
10
11
12
49
NR
NR
K2CO3
a Reaction conditions: 1a (0.6 mmol, 2.0 equiv), 2a (0.3 mmol, 1.0 equiv),
1,4-dioxane (2 mL), 24 h. For details of the optimization, see the Support-
ing Information.
b Determined by 19F NMR using fluorobenzene as internal standard. The
isolated yield is shown in parentheses.
To ascertain the substrate scope of this method, a vari-
ety of styrene derivatives was examined with ethyl bromo-
difluoroacetate (1a) (Scheme 1). Many versatile functional
groups, such as ester, aldehyde, and nitrile showed good tol-
erance to the reaction (3h–j). Importantly, the heterocycle
thiazole, was also applicable and provided the correspond-
ing product in a synthetic useful yield (3k). In the case of
indole derivative 2m, moderate yield of 3m was obtained
along with a small amount of 3m′ with second ethoxycar-
bonyldifluoromethyl group installed at C2 position (3m and
3m′). We reasoned that the formation of 3m′ can be as-
cribed to the reaction of indole ring with free ethoxycar-
bonyldifluoromethyl radical that was generated by
Pd/Xantphos/base with 1a. Enamide was also a suitable
substrate, and provided ethoxycarbonyldifluoromethylated
alkene with even higher yield (3l). It should be mentioned
that the 1-gram-scale reaction of 2e also underwent
smoothly and provided 3e in good yield, thus highlighting
the reliability of the current process.
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2915
F. Zhang et al.
Feature
Synthesis
PdCl2(MeCN)2 (10 mol%)
Xantphos (20 mol%)
CF2CO2Et
R1
R1
BrCF2CO2Et
+
K2CO3 (2.0 equiv)
1,4-dioxane, 80 °C
1a
2
3
CF2CO2Et
CF2CO2Et
CF2CO2Et
t-Bu
3a, 75%
3b, 70%
3c, 86%
CF2CO2Et
CF2CO2Et
CF2CO2Et
Me
Ph2N
MeO
Me
3d, 73%
3e, 87%, (66%)b
CF2CO2Et
3f, 51%
CF2CO2Et
CF2CO2Et
MeO2C
NC
F
3i, 61%a
3h, 70%a
3g, 65%
Me
O
OHC
CF2CO2Et
CF2CO2Et
CF2CO2Et
N
N
S
3j, 46%a
3k, 43%
3l, 90%
CF2CO2Et
CF2CO2Et
EtO2CF2C
N
N
Me
Me
3m, 54%
3m', 14%
Scheme 1 Pd-catalyzed ethoxycarbonyldifluoromethylation of linear alkenes with ethyl bromodifluoroacetate (1a). Reagents and conditions (unless
otherwise specified): 1a (0.6 mmol, 2.0 equiv), 2 (0.3 mmol, 1.0 equiv), 1,4-dioxane (2 mL), 24 h. All reported yields are isolated yields. a Molecular
sieves (3Å ) were used. b The reaction was carried out on a 1-gram-scale.
PdCl2(MeCN)2 (10 mol%)
R2
R2
Xantphos (20 mol%)
CF2CO2Et
R1
R1
BrCF2CO2Et
+
K2CO3 (2.0 equiv)
dioxane, 80 °C
R3
R3
1a
2
3
CF2CO2Et
CF2CO2Et
N
O
O
O
CF2CO2Et
CF2CO2Et
3n, 76%
3p, 66%
3q, 69%
3o, 68%
CF2CO2Et
CF2CO2Et
CF2CO2Et
CF2CO2Et
CF2CO2Et
Ph
Ph
O
Ph
Ph
Ph
3t, 72%
3r, 74%
3s, 42%
3s', 35%
3u, 43%
Scheme 2 Pd-catalyzed ethoxycarbonyldifluoromethylation of branched alkenes with ethyl bromodifluoroacetate (1a). Reagents and conditions (unless
otherwise specified): 1a (0.6 mmol, 2.0 equiv), 2 (0.3 mmol, 1.0 equiv), 1,4-dioxane (2 mL), 24 h. All reported yields are isolated yields.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2912–2923

2916
F. Zhang et al.
Feature
Synthesis
PdCl2(MeCN)2 (10 mol%)
Xantphos (20 mol%)
CF2R
R1
R1
BrCF2R
+
K2CO3 (2.0 equiv)
1,4-dioxane, 80 °C
4
1
2
O
O
CF2C
N
O
CF2C
N
O
MeO
4a, 81%
4b, 85%
O
CO2Me
CF2C
N
O
F
F
HN
MeO2C
O
OMe
4c, 70%
4d, 75%
O
F
F
F
F
O
N
N
MeO2C
Ph
4e, 65%a
4f, 78%
Scheme 3 Pd-catalyzed Heck-type reaction of functionalized difluoromethyl bromides with alkenes. Reagents and conditions (unless otherwise speci-
fied): 1 (0.6 mmol, 2.0 equiv), 2 (0.3 mmol, 1.0 equiv), 1,4-dioxane (2 mL), 24 h. All reported yields are isolated yields. a Molecular sieves (3 Å) were
used.
O
O
PdCl2(MeCN)2 (10 mol%)
Xantphos (20 mol%)
H
H
H
H
BrCF2CO2Et
(a)
+
K2CO3, 1,4-dioxane, 80 °C
H
H
1a
EtO2CF2C
5
6, 63%
O
O
H
H
PdCl2(MeCN)2 (10 mol%)
Xantphos (20 mol%)
H
H
CO2Me
NHCOCF2Br
F
H
Ph
+
(b)
H
F
K2CO3, 1,4-dioxane, 80 °C
MeO2C
N
O
1c
5
H
7, 73%
Scheme 4 Synthesis of fluorinated biologically relevant active compounds
PdCl2(MeCN)2 (10 mol%)
To further probe that a free fluoroalkyl radical existed in
the reaction, a radical clock experiment was conducted. As
illustrated in Scheme 6 (a), compound 9 (44% yield) instead
of Heck-type product 10 was obtained when compound 820
was treated with 1a under the standard conditions. This
finding suggested that a free ethoxycarbonyldifluoromethyl
radical was produced in the reaction,20 and the formation of
the radical species VI from V was faster than the generation
of key intermediate palladium complex VIII. Additionally, it
has been demonstrated that the formation of iodine atom
transfer fluoroalkylated adducts between the alkenes and
fluoroalkyl iodides could be promoted by Pd(PPh3)4 without
reformation of alkenes.21 However, when styrene was treat-
Xantphos (20 mol%)
CF2CO2Et
BrCF CO Et
+
Ph
2
2
Ph
additive
3a
1a
2a
K2CO3 (2.0 equiv)
1,4-dioxane, 80 °C
additive
3a, yield (%)
none
76
27
1,4-dinitrobenzene (0.2 equiv)
hydroquinone (0.2 equiv)
20
Scheme 5 Inhibition experiments for Pd-catalyzed cross-coupling of
1a with 2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2912–2923

2917
F. Zhang et al.
Feature
Synthesis
ed with 1a in the presence of Pd(PPh3)4 and Xantphos with-
out the base, no benzyl bromide 11 was detected by GC
[Scheme 6 (b)]. Instead, fluorinated alkene 3a was observed
in 9% yield (determined by 19F NMR). This finding is in sharp
contrast to the result shown in Table 1 entry 7, because if
the possibility that the formation of fluorinated alkenes via
sequential bromine atom transfer radical addition to
alkenes, followed by base-assisted elimination of the result-
ing benzyl bromides is feasible, some compound 11 should
be observed in the absence of base. Thus, such a two-step-
wise process for the formation of difluoroalkylated alkenes
can be excluded.
Rf–X
Rf = CF2R
base
[Pd(0)Ln]
1
[XPd(I)Ln]
Rf
HPd(Ln)X
I
II
Pd(Ln)X
Rf
Rf
R1
Rf
R1
R1
3 and 4
R1
IV
III
2
[XPd(I)Ln]
II
On the basis of these preliminary studies, a plausible
mechanism was proposed as shown in Scheme 7. The reac-
tion was initiated by a single-electron-transfer (SET) path-
way from [Pd(0)Ln] to difluoroalkyl halides.21 The resulting
difluoroalkyl radicals I subsequently reacted with alkenes 2
to generate new radical intermediate III, which then recom-
bined with [XPd(I)Ln] II to form the key palladium species
[(alkyl)Pd(II)LnX] IV. Finally, a β-hydride elimination afford-
ed fluoroalkylated alkenes 3 and 4.
Scheme 7 Proposed reaction mechanism
In conclusion, we have demonstrated an efficient meth-
od for the synthesis of difluoroalkylated alkenes through
Pd-catalyzed Heck-type reaction with functionalized difluo-
romethyl bromides. The reaction allowed difluoroalkylation
of a variety of alkenes under mild reaction conditions with
excellent functional group compatibility. This protocol fea-
tures synthetic simplicity and can be used for the late stage
CF2CO2Et
PdCl2(MeCN)2 (10 mol%)
Xantphos (20 mol%)
(a)
BrCF2CO2Et
+
K2CO3 (2.0 equiv)
1,4-dioxane, 80 °C
Ph
1a
9, 44% yield
8
[Pd(0)Ln]
Ph
fast
[XPd(I)Ln]
8
RF2C
+
CF2R
I
V
RF2C
RF2C
VI
VII
[XPd(I)Ln]
slow
Ph
RF2C
EtO2CF2C
Ph
Pd(II)XLn
VIII
10
CF2CO2Et
3a, 9%
Ph
Pd(PPh3)4 (10 mol%)
(determined by 19F NMR)
Xantphos (20 mol%)
+
BrCF2CO2Et
(b)
Ph
Br
1,4-dioxane, 80 °C
2a
1a
CF2CO2Et
Ph
11 (not detected by GC)
Scheme 6 Experiments for mechanistic studies
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2912–2923

2918
F. Zhang et al.
Feature
Synthesis
difluoroalkylation in the synthesis of biologically relevant
molecules, thus providing a facile route for application in
drug discovery and development. Mechanistic studies re-
vealed that the free fluoroalkyl radicals initiated by a
[Pd(0)Ln] via SET pathway was involved in the Heck-type
catalytic cycle, and the bidentate ligand Xantphos is essen-
tial for the reaction. We believe that such transition-metal-
promoted SET pathway would prompt further research in
the area of fluoroalkylation.
1H NMR (400 MHz, CDCl3): δ = 7.84–7.82 (m, 4 H), 7.60 (d, J = 8.8 Hz, 1
H), 7.51–7.49 (m, 2 H), 7.25–7.22 (m, 1 H), 6.35 (dt, J = 16.4, 11.6 Hz, 1
H), 4.30 (q, J = 7.2 Hz, 2 H), 1.31 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.9 (t, J = 34.94 Hz), 136.9 (t, J =
9.4 Hz), 133.8, 133.2, 131.5 (t, J = 1.3 Hz), 128.7 (t, J = 1.2 Hz), 128.6,
128.3, 127.7, 126.9, 126.6, 123.2, 119.0 (t, J = 25.01 Hz), 112.8 (t, J =
248.7 Hz), 63.1, 13.9.
19F NMR (376 MHz, CDCl3): δ = –103.12 (dd, J = 11.2, 1.1 Hz, 2 F).
MS (EI): m/z (%) = 276 (M+).
HRMS: m/z [M]+ calcd for C16H14F2O2: 276.0962; found: 276.0966.
Ethyl (E)-4-(4-tert-Butylphenyl)-2,2-difluorobut-3-enoate (3c)
All reagents were used as received from commercial sources, unless
specified otherwise. All reagents were weighed and handled in air,
and refilled with an inert atmosphere of N2 at r.t. Anhydrous K2CO3
and 3Å MS were purchased from Aldrich and Alfa, respectively. DMF
and DMSO were distilled under reduced pressure from CaH2. 1,4-Di-
oxane, toluene, and xylene were distilled from sodium and benzophe-
none immediately before use. Petroleum ether (PE) used refers to the
hydrocarbon mixture with a boiling range of 60–90 °C. 1H NMR and
13C NMR spectra were recorded on a Bruker AM 400 and AM 500
spectrometer. 19F NMR spectra were recorded on a Bruker AM 400
spectrometer (CFCl3 as an external standard and low field is positive).
Chemical shifts (δ) are reported in ppm, and coupling constants (J)
are given in hertz (Hz). Standard abbreviations were used to denote
the multiplicities. NMR yield was determined by 19F NMR using fluo-
robenzene as an internal standard before workup of the reaction.
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); 72 mg (86%); colorless oil.
IR (film): 2963, 1755, 1604, 1514 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.40 (s, 4 H), 6.98 (dt, J = 16.4, 2.4 Hz, 1
H), 6.19 (dt, J = 16.4, 11.6 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 1.36 (t, J =
7.2 Hz, 3 H), 1.33 (s, 9 H).
13C NMR (125.7 MHz, CDCl3): δ = 164.0 (t, J = 35.1 Hz), 153.1, 136.6 (t,
J = 9.4 Hz), 131.4, 127.2, 125.8, 118.0 (t, J = 25.3 Hz), 112.9 (t, J = 248.3
Hz), 63.0, 34.8, 31.2, 14.0.
19F NMR (376 MHz, CDCl3): δ = –103.2 (dd, J = 11.6, 2.2 Hz, 2 F).
MS (EI): m/z (%) = 282 (M+).
HRMS: m/z [M]+ calcd for C16H20F2O2: 282.1431; found: 282.1430.
Ethyl (E)-4-(3,4-Dimethylphenyl)-2,2-difluorobut-3-enoate (3d)
Pd-Catalyzed Heck-Type Reaction of Functionalized Difluoro-
methyl Bromides with Alkenes; General Procedure
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 56 mg (73%); colorless oil.
To a 25 mL Schlenk tube were added PdCl2(MeCN)2 (10 mol%) and
Xantphos (20 mol%) under air, followed by anhydrous K2CO3 (powder,
2.0 equiv). The mixture was then evacuated and backfilled with N2 (3
times). Functionalized difluoromethyl bromide 1 (2 equiv), alkene 2
(0.3 mmol), and freshly distilled 1,4-dioxane (2 mL) were added sub-
sequently. The reaction mixture was heated to 80 °C (oil bath). After
stirring for 24 h, the mixture was cooled to r.t., diluted with EtOAc,
and filtered over a pad of Celite. The filtrate was concentrated and the
residue was purified by silica gel chromatography (PE–EtOAc, 10:1) to
give the corresponding product.
IR (film): 2923, 1759, 1593 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.22 (s, 1 H), 7.19 (d, J = 8.0 Hz, 1 H),
7.13 (d, J = 8.0 Hz, 1 H), 7.02 (dt, J = 16.4, 2.4 Hz, 1 H), 6.24 (dt, J = 16.4,
11.6 Hz, 1 H), 4.35 (q, J = 7.2 Hz, 2 H), 2.27 (m, 6 H), 1.36 (t, J = 7.2 Hz,
3 H).
13C NMR (125.7 MHz, CDCl3): δ = 164.0 (t, J = 35.3 Hz), 138.5, 137.0,
136.8 (t, J = 9.4 Hz), 131.7, 130.0, 128.6, 124.9, 117.5 (t, J = 25.01 Hz),
112.9 (t, J = 248.2 Hz), 63.0, 19.7, 19.6, 13.9.
19F NMR (376 MHz, CDCl3): δ = –103.0 (dd, J = 11.2, 1.9 Hz, 2 F).
MS (EI): m/z (%) = 254 (M+).
Ethyl (E)-2,2-Difluoro-4-phenylbut-3-enoate (3a)
HRMS: m/z [M]+ calcd for C14H16F2O2: 254.1118; found: 254.1121.
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 51 mg (75%); colorless oil. This compound is known in
the literature.8
1H NMR (400 MHz, CDCl3): δ = 7.46–7.44 (m, 2 H), 7.40–7.36 (m, 3 H),
7.08 (dt, J = 16.4, 2.4 Hz, 1 H), 6.31 (dt, J = 16.4, 11.2 Hz, 1 H), 4.35 (q,
J = 7.2 Hz, 2 H), 1.36 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.9 (t, J = 34.8 Hz), 136.8 (t, J = 9.4
Hz), 134.1, 129.6, 128.8, 127.4, 118.9 (t, J = 25.0 Hz), 112.7 (t, J = 248.5
Hz), 63.1, 14.0.
Ethyl (E)-2,2-Difluoro-4-(4-methoxyphenyl)but-3-enoate (3e)
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 67 mg (87%); colorless oil.
IR (film): 2926, 1766, 1607, 1514 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38 (d, J = 8.4 Hz, 2 H), 7.01 (dt, J =
16.4, 2.4 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.15 (dt, J = 16.4, 11.2 Hz, 1
H), 4.34 (q, J = 7.6 Hz, 2 H), 3.82 (s, 3 H), 1.35 (t, J = 7.6 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 164.1 (t, J = 35.3 Hz), 160.7, 136.2 (t,
J = 9.5 Hz), 128.8, 126.8, 116.3 (t, J = 25.0 Hz), 114.2, 112.9 (t, J = 248.2
Hz), 63.0, 55.3, 13.9.
19F NMR (376 MHz, CDCl3): δ = –103.3 (dd, J = 11.2, 2.2 Hz, 2 F).
Ethyl (E)-2,2-Difluoro-4-(naphthalen-2-yl)but-3-enoate (3b)
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 58 mg (70%); colorless oil.
19F NMR (376 MHz, CDCl3): δ = –102.7 (d, J = 10.8 Hz, 2 F).
MS (EI): m/z (%) = 256 (M+).
HRMS: m/z [M]+ calcd for C13H14F2O3: 256.0911; found: 256.0912.
IR (film): 2984, 1766, 1653 cm–1
.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2912–2923

2919
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Feature
Synthesis
Ethyl (E)-4-[4-(Diphenylamino)phenyl]-2,2-difluorobut-3-enoate
(3f)
1H NMR (400 MHz, CDCl3): δ = 7.66 (d, J = 8.4 Hz, 2 H), 7.54 (d, J = 8.4
Hz, 2 H), 7.08 (dt, J = 16.4, 2.4 Hz, 1 H), 6.41 (dt, J = 16.4, 11.6 Hz, 1 H),
4.35 (q, J = 6.8 Hz, 2 H), 1.36 (t, J = 6.8 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.4 (t, J = 34.3 Hz), 138.4, 134.9 (t,
J = 9.4 Hz), 132.6, 127.9, 122.5 (t, J = 25.1 Hz), 118.3, 113.0, 112.1 (t, J =
249.5 Hz), 63.4, 13.9.
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 60 mg (51%); colorless oil.
IR (film): 3034, 1766, 1592, 1492 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.23–7.17 (m, 7 H), 7.04–6.99 (m, 6 H),
6.95–6.92 (m, 2 H), 6.90 (dt, J = 16.2, 2.4 Hz, 1 H), 6.07 (dt, J = 16.2,
11.4 Hz, 1 H), 4.26 (q, J = 6.9 Hz, 2 H), 1.28 (t, J = 6.9 Hz, 3 H).
19F NMR (376 MHz, CDCl3): δ = –103.9 (dd, J = 10.9, 2.2 Hz, 2 F).
MS (EI): m/z (%) = 251 (M+).
13C NMR (100 MHz, CDCl3): δ = 163.6 (t, J = 35.1 Hz), 148.7, 146.6,
135.7 (t, J = 9.4 Hz), 128.9, 127.9, 126.9, 124.5, 123.2, 121.8, 115.9 (t,
J = 25.0 Hz), 112.5 (t, J = 246.7 Hz), 63.5, 13.5.
19F NMR (282 MHz, CDCl3): δ = –103.1 (d, J = 11.8 Hz, 2 F).
MS (EI): m/z (%) = 393 (M+).
HRMS: m/z [M]+ calcd for C13H11F2NO2: 251.0758; found: 251.0757.
Ethyl (E)-2,2-Difluoro-4-(3-formylphenyl)but-3-enoate (3j)
Molecular sieves 3 Å (100 mg) were used. The product was purified by
silica gel chromatography (PE–EtOAc, 8:1); yield: 35 mg (46%); color-
les oil.
HRMS: m/z [M]+ calcd for C24H21F2NO2: 393.1540; found: 393.1538.
IR (film): 2925, 2851, 1764, 1699, 1659 cm–1
.
Ethyl (E)-2,2-Difluoro-4-(4-fluorophenyl)but-3-enoate (3g)
1H NMR (400 MHz, CDCl3): δ = 10.03 (s, 1 H), 7.96 (s, 1 H), 7.86 (d, J =
7.6 Hz, 1 H), 7.69 (d, J = 7.6 Hz, 1 H), 7.56 (t, J = 7.6 Hz, 1 H), 7.13 (dt,
J = 16.0, 2.4 Hz, 1 H), 6.41 (dt, J = 16.0, 11.6 Hz, 1 H), 4.35 (q, J = 7.2 Hz,
2 H), 1.36 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 191.1, 163.6 (t, J = 34.3 Hz), 136.9,
135.4 (t, J = 9.3 Hz), 135.1, 133.1, 130.7, 129.6, 128.1, 120.8 (t, J = 25.0
Hz), 121.3 (t, J = 247.4 Hz), 63.2, 13.9.
19F NMR (376 MHz, CDCl3): δ = –103.6 (dd, J = 11.2, 2.3 Hz, 2 F).
MS (EI): m/z (%) = 254 (M+).
HRMS: m/z [M]+ calcd for C13H12F2O3: 254.0755; found: 254.0758.
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 48 mg (65%); colorless oil.
IR (film): 2927, 1762, 1606, 1511 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.41 (m, 2 H), 7.08–7.03 (m, 2 H),
7.02 (m, 1 H), 7.19 (dt, J = 16.0, 2.4 Hz, 1 H), 6.22 (dt, J = 16.0, 11.2 Hz,
1 H), 4.35 (q, J = 7.2 Hz, 2 H), 1.36 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.8 (t, J = 34.9 Hz), 163.4 (d, J =
250.0 Hz), 135.5 (t, J = 9.5 Hz), 130.3 (d, J = 3.4 Hz), 129.2 (d, J = 8.4
Hz), 118.6 (td, J = 25.0, 2.2 Hz), 115.9 (d, J = 21.8 Hz), 112.6 (t, J = 248.5
Hz), 63.1, 13.9.
19F NMR (376 MHz, CDCl3): δ = –103.2 (d, J = 11.2 Hz, 2 F), –110.92 (m,
Ethyl (E)-2,2-Difluoro-4-(4-methylthiazol-5-yl)but-3-enoate (3k)
1 F).
The product was purified by silica gel chromatography (PE–EtOAc,
3:1), yield: 32 mg (43%); colorless oil.
MS (EI): m/z (%) = 244 (M+).
IR (film): 2919, 1732, 1463 cm–1
.
HRMS: m/z [M]+ calcd for C12H11F3O2: 244.0711; found: 244.0712.
1H NMR (400 MHz, CDCl3): δ = 8.65 (s, 1 H), 7.19 (dt, J = 16.0, 2.0 Hz, 1
H), 6.02 (dt, J = 16.0, 11.2 Hz, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 2.50 (s, 3
H), 1.35 (t, J = 7.2 Hz, 3 H).
Methyl (E)-4-(4-Ethoxy-3,3-difluoro-4-oxobut-1-en-1-yl)benzo-
ate (3h)
13C NMR (125.7 MHz, CDCl3): δ = 163.5 (t, J = 34.6 Hz), 154.1, 151.9,
127.4, 126.4 (t, J = 10.1 Hz), 120.3 (t, J = 25.2 Hz), 112.1 (t, J = 249.2
Hz), 63.2, 15.4, 13.9.
Molecular sieves 3 Å (100 mg) were used. The product was purified by
silica gel chromatography (PE–EtOAc, 10:1); yield: 60 mg (70%); col-
orless oil.
IR (film): 2954, 1768, 1723, 1657 cm–1
.
19F NMR (376 MHz, CDCl3): δ = –103.2 (dd, J = 11.6, 1.1 Hz, 2 F).
MS (EI): m/z (%) = 247 (M+).
HRMS: m/z [M]+ calcd for C10H11F2NO2S: 247.0479; found: 247.0483.
1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.4
Hz, 2 H), 7.10 (dt, J = 16.8, 2.4 Hz, 1 H), 6.39 (dt, J = 16.8, 11.2 Hz, 1 H),
4.35 (q, J = 7.2 Hz, 2 H), 3.91 (s, 3 H), 1.36 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 166.4, 163.6 (t, J = 34.5 Hz), 138.3,
135.7 (t, J = 9.4 Hz), 130.9, 130.1, 127.3, 121.2 (t, J = 25.0 Hz), 112.3 (t,
J = 249.0 Hz), 63.2, 52.2, 13.9.
19F NMR (376 MHz, CDCl3): δ = –103.7 (dd, J = 10.8, 2.6 Hz, 2 F).
MS (EI): m/z (%) = 284 (M+).
Ethyl (E)-2,2-Difluoro-4-(2-oxopyrrolidin-1-yl)but-3-enoate (3l)
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 63 mg (90%); colorless oil.
IR (film): 2986, 1766, 1724, 1659 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.55 (m, 1 H), 5.06 (dt, J = 14.4 Hz, J =
11.2 Hz, 1 H), 4.32 (q, J = 7.2 Hz, 2 H), 3.53 (t, J = 7.2 Hz, 2 H), 2.53 (t,
J = 8.0 Hz, 2 H), 2.16 (m, 2 H), 1.34 (t, J = 7.2 Hz, 3 H).
HRMS: m/z [M]+ calcd for C14H14F2O4: 284.0860; found: 284.0863.
Ethyl (E)-4-(4-Cyanophenyl)-2,2-difluorobut-3-enoate (3i)
13C NMR (125.7 MHz, CDCl3): δ = 173.9, 163.4 (t, J = 35.4 Hz), 130.3 (t,
J = 10.4 Hz), 112.9 (d, J = 282.1 Hz), 101.1 (t, J = 26.2 Hz), 63.0, 44.8,
30.8, 17.3, 13.9.
19F NMR (376 MHz, CDCl3): δ = –100.0 (d, J = 10.9 Hz, 2 F).
MS (EI): m/z (%) = 233 (M+).
Molecular sieves 3 Å (100 mg) were used. The product was purified by
silica gel chromatography (PE–EtOAc, 10:1); yield: 46 mg (61%); col-
orless oil.
IR (film): 2986, 2229, 1766, 1658 cm–1
.
HRMS: m/z [M]+ calcd for C10H13F2NO3: 233.0863; found: 233.0860.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2912–2923

2920
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Feature
Synthesis
Ethyl (E)-2,2-Difluoro-4-(1-methyl-1H-indol-5-yl)but-3-enoate
(3m) and Ethyl (E)-4-[3-(2-Ethoxy-1,1-difluoro-2-oxoethyl)-1-
methyl-1H-indol-5-yl]-2,2-difluorobut-3-enoate (3m′)
IR (film): 2963, 1766, 1462 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.50 (d, J = 6.8 Hz, 1 H), 7.48 (d, J = 6.8
Hz, 1 H), 7.35–7.28 (m, 2 H), 7.23 (m, 1 H), 4.36 (q, J = 7.2 Hz, 2 H),
3.63 (s, 3 H), 1.36 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.7 (t, J = 34.8 Hz), 143.4, 142.3 (t,
J = 0.9 Hz), 137.8 (t, J = 26.6 Hz), 134.3 (t, J = 7.5 Hz), 126.9, 126.7,
124.1, 122.6, 112.7 (t, J = 247.5 Hz), 63.2, 37.4 (t, J = 2.4 Hz), 14.0.
A mixture of 3m and 3m′ (52 mg) as a colorless oil was purified by
silica gel chromatography (PE–EtOAc, 3:1); 3m/3m′ = 3.9:1, deter-
mined by 19F NMR spectroscopy; 3m, 54%; 3m′, 14%. The mixture was
further purified by preparative HPLC (column: ODS HYPERSIL (250 ×
10 mm Φ 5 μm); flow rate: 4.5 mL/min; temperature: 25 °C; wave-
length: UV 220 nm, MeCN–H2O (v/v) = 70:30; time: 10 min) to give
pure 3m and 3m′.
19F NMR (376 MHz, CDCl3): δ = –100.58 (d, J = 1.5 Hz, 2 F).
MS (EI): m/z (%) = 238 (M+).
HRMS: m/z [M]+ calcd for C13H12F2O2: 238.0805; found: 238.0802.
3m
IR (film): 2916, 1766, 1652, 1543 cm–1
.
Ethyl 2,2-Difluoro-2-(2-oxo-2H-chromen-4-yl)acetate (3p)
1H NMR (400 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.37 (dd, J = 8.6, 1.6 Hz, 1
H), 7.30 (d, J = 8.6 Hz, 1 H), 7.19 (dt, J = 16.0, 2.4 Hz, 1 H), 7.06 (d, J =
2.8 Hz, 1 H), 6.50 (dd, J = 3.2, 0.8 Hz, 1 H), 6.25 (dt, J = 16.0, 11.6 Hz, 1
H), 4.35 (q, J = 7.2 Hz, 2 H), 3.80 (s, 3 H), 1.37 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 164.3 (t, J = 35.1 Hz), 138.3 (t, J = 9.4
Hz), 137.4, 129.9, 128.6, 125.7, 121.4, 120.5, 115.4 (t, J = 24.9 Hz),
113.3 (t, J = 246.8 Hz), 109.7, 101.8, 63.0, 33.0, 14.0.
19F NMR (375 MHz, CDCl3): δ = –102.3 (dd, J = 11.3, 2.6 Hz, 2 F).
MS (EI): m/z (%) = 279 (M+).
HRMS: m/z [M]+ calcd for C14H14F2O2: 279.1071; found: 279.1073.
The product was purified by silica gel chromatography (PE–EtOAc,
6:1); yield: 53 mg (66%); colorless oil.
IR (film): 2923, 1778, 1737, 1637, 1601 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.17 (s, 1 H), 7.66–7.61 (m, 2 H), 7.39–
7.35 (m, 2 H), 4.38 (q, J = 7.2 Hz, 2 H), 1.34 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 162.2 (t, J = 32.6 Hz), 157.9 (t, J = 4.6
Hz), 154.2, 141.9 (t, J = 7.1 Hz), 133.7, 129.2, 125.2, 121.2 (t, J = 25.5
Hz), 117.5, 117.0, 110.5 (t, J = 250.8 Hz), 63.6, 13.8.
19F NMR (376 MHz, CDCl3): δ = –106.2 (s, 2 F).
MS (EI): m/z (%) = 268 (M+).
HRMS: m/z [M]+ calcd for C13H10F2O4: 268.0547; found: 268.0545.
3m′
IR (film): 2913, 1760, 1682, 1614 cm–1
.
Ethyl 2,2-Difluoro-2-(1-methyl-2-oxo-1,2-dihydroquinolin-4-
yl)acetate (3q)
1H NMR (400 MHz, CDCl3): δ = 7.69 (s, 1 H), 7.47 (d, J = 8.8 Hz, 1 H),
7.35 (d, J = 8.8 Hz, 1 H), 7.17 (dt, J = 16.0, 2.4 Hz, 1 H), 6.80 (s, 1 H),
6.26 (dt, J = 16.0, 11.6 Hz, 1 H), 4.42 (q, J = 7.2 Hz, 2 H), 4.36 (q, J = 7.2
Hz, 2 H), 3.88 (s, 3 H), 1.38 (t, J = 7.2 Hz, 3 H), 1.37 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 164.2 (t, J = 35.1 Hz), 163.0 (t, J =
34.1 Hz), 139.4, 137.5 (t, J = 9.4 Hz), 130.5 (t, J = 29.0 Hz), 126.9, 126.2,
122.8, 122.3, 116.6 (t, J = 24.8 Hz), 113.0 (t, J = 248.3 Hz), 111.0 (t, J =
248.8 Hz), 110.3, 105.3 (t, J = 6.2 Hz), 63.7, 63.0, 31.4, 14.0, 13.9.
19F NMR (375 MHz, CDCl3): δ = –98.7 (s, 2 F), –102.6 (dd, J = 11.6, 2.2
Hz, 2 F).
MS (EI): m/z (%) = 401 (M+).
HRMS: m/z [M]+ calcd for C19H19F4NO4: 401.1250; found: 401.1245.
The product was purified by silica gel chromatography (PE–EtOAc,
2:1); yield: 58 mg (69%); colorless oil.
IR (film): 2988, 1777, 1659, 1598 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 8.13 (s, 1 H), 7.67 (m, 2 H), 7.39 (d, J =
9.0 Hz, 1 H), 7.31 (t, J = 7.2 Hz, 1 H), 4.38 (q, J = 7.2 Hz, 2 H), 3.70 (s, 3
H), 1.34 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 162.7 (t, J = 32.6 Hz), 158.9 (t, J = 4.4
Hz), 140.0, 137.0 (t, J = 7.0 Hz), 131.9, 129.7, 124.5 (t, J = 24.3 Hz),
122.4, 118.5, 113.9, 110.9 (t, J = 247.6 Hz), 62.6, 28.9, 13.4.
19F NMR (376 MHz, CDCl3): δ = –107.0 (s, 2 F).
MS (EI): m/z (%) = 281 (M+).
HRMS: m/z [M]+ calcd for C14H13F2NO3: 281.0863; found: 281.0861.
Ethyl 2-(3,4-Dihydronaphthalen-2-yl)-2,2-difluoroacetate (3n)
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 57 mg (76%); colorless oil.
Ethyl 2-(3,4-Dihydro-2H-pyran-5-yl)-2,2-difluoroacetate (3r)
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 46 mg (74%); colorless oil. This compound is known in
the literature.9b
1H NMR (400 MHz, CDCl3): δ = 6.82 (s, 1 H), 4.31 (q, J = 6.8 Hz, 2 H),
3.99 (t, J = 5.2 Hz, 2 H), 2.12 (t, J = 5.2 Hz, 2 H), 1.88 (m, 2 H), 1.33 (t, J =
6.8 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 164.0 (t, J = 35.9 Hz), 146.3 (t, J =
11.0 Hz), 114.2 (t, J = 248.1 Hz), 105.8 (t, J = 0.3 Hz), 65.9, 62.7, 21.0,
17.8 (t, J = 2.5 Hz), 13.9.
19F NMR (376 MHz, CDCl3): δ = –104.8 (d, J = 0.7 Hz, 2 F).
MS (EI): m/z (%) = 206 (M+).
IR (film): 2984, 1763, 1652, 1455 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.22–7.17 (m, 2 H), 7.15–7.13 (m, 2 H),
6.87 (s, 1 H), 4.35 (q, J = 6.8 Hz, 2 H), 2.88 (t, J = 8.4 Hz, 2 H), 2.44 (td,
J = 8.4, 1.2 Hz, 2 H), 1.35 (t, J = 6.8 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.8 (t, J = 35.1 Hz), 135.4, 131.8,
130.5 (t, J = 23.6 Hz), 128.8, 128.6 (t, J = 9.1 Hz), 127.7, 127.5, 126.8,
113.6 (t, J = 249.7 Hz), 63.0, 27.3, 21.2 (t, J = 2.9 Hz), 13.9.
19F NMR (376 MHz, CDCl3): δ = –107.2 (s, 2 F).
MS (EI): m/z (%) = 252 (M+).
HRMS: m/z [M]+ calcd for C14H14F2O2: 252.0962; found: 252.0960.
HRMS: m/z [M]+ calcd for C9H12F2O3: 206.0755; found: 206.0760.
Ethyl 2,2-Difluoro-2-(1H-inden-2-yl)acetate (3o)
The product was purified by silica gel chromatography (PE–EtOAc,
8:1); yield: 48 mg (68%); colorless oil.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2912–2923

2921
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Feature
Synthesis
Ethyl 2,2-Difluoro-4,4-diphenylbut-3-enoate (3s) and Ethyl 2,2-Di-
fluoro-4,4-diphenylbutanoate (3s′)
1H NMR (400 MHz, CDCl3): δ = 7.46–7.44 (m, 2 H), 7.39–7.33 (m, 3 H),
7.10 (dt, J = 16.4, 2.4 Hz, 1 H), 6.44 (dt, J = 16.4, 11.2 Hz, 1 H), 3.74–
3.98 (m, 8 H).
13C NMR (100 MHz, CDCl3): δ = 162.0 (t, J = 30.4 Hz), 135.7 (t, J = 9.8
Hz), 134.0 (t, J = 1.1 Hz), 129.5, 128.8, 127.4, 119.9 (t, J = 24.3 Hz),
115.2 (t, J = 249.3 Hz), 66.7, 66.6, 46.6 (t, J = 5.4 Hz), 43.4.
19F NMR (376 MHz, CDCl3): δ = –95.1 (dd, J = 10.7, 2.2 Hz, 2 F).
MS (EI): m/z (%) = 267 (M+).
HRMS: m/z [M]+ calcd for C14H15F2NO2: 267.1071; found: 267.1075.
A mixture of 3s and 3s′ (70 mg, 3s/3s′ = 1.2:1, determined by 19F NMR
spectroscopy; 3s, 42%; 3s′, 35%) as a colorless oil was purified by silica
gel chromatography (PE–EtOAc, 10:1). The mixture was further puri-
fied by preparative HPLC (column: ODS HYPERSIL (250 × 10 mm Φ 5
μm); flow rate: 4.0 mL/min; temperature: 25 °C; wavelength: UV 220
nm, MeCN–H2O (v/v) = 70:30; time: 20 min) to give pure 3s and 3s′.
The compounds 3s and 3s′ are both known in the literature.9b
3s
1H NMR (300 MHz, CDCl3): δ = 7.38–7.30 (m, 6 H), 7.27–7.25 (m, 2 H),
7.21–7.19 (m, 2 H), 6.27 (t, J = 12.0 Hz, 1 H), 3.89 (q, J = 7.2 Hz, 2 H),
1.16 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.4 (t, J = 34.1 Hz), 150.9 (t, J = 9.6
Hz), 140.4, 137.1, 129.8 (t, J = 2.0 Hz), 129.0, 128.5, 128.3, 127.9,
127.8, 119.4 (t, J = 28.4 Hz), 112.5 (t, J = 245.2 Hz), 62.7, 13.6.
(E)-2,2-Difluoro-4-(4-methoxyphenyl)-1-morpholinobut-3-en-1-
one (4b)
The product was purified by silica gel chromatography (PE–EtOAc,
5:1); yield: 76 mg (85%); colorless oil.
IR (film): 2985, 1742, 1447, 1373 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.4 Hz, 2 H), 6.93 (dt, J =
16.4, 2.4 Hz, 1 H), 6.89 (d, J = 8.4 Hz, 2 H), 6.29 (dt, J = 16.4, 10.8 Hz, 1
H), 3.82 (s, 3 H), 3.73–3.66 (m, 8 H).
19F NMR (282 MHz, CDCl3): δ = –91.2 (d, J = 17.7 Hz, 2 F).
13C NMR (100 MHz, CDCl3): δ = 162.2 (t, J = 30.4 Hz), 160.4, 135.3 (t,
J = 9.7 Hz), 128.8, 126.8, 117.4 (t, J = 24.4 Hz), 115.5 (t, J = 247.0 Hz),
114.2, 66.7, 66.7, 55.3, 46.7 (t, J = 4.9 Hz), 43.4.
19F NMR (376 MHz, CDCl3): δ = –94.3 (dd, J = 10.9, 1.5 Hz, 2 F).
MS (EI): m/z (%) = 297 (M+).
3s′
1H NMR (400 MHz, CDCl3): δ = 7.30–7.24 (m, 8 H), 7.27–7.17 (m, 2 H),
7.21–7.19 (m, 2 H), 4.27 (t, J = 7.2 Hz, 1 H), 3.82 (q, J = 7.2 Hz, 2 H),
2.94 (td, J = 15.2, 7.2 Hz, 2 H), 1.16 (t, J = 7.2 Hz, 3 H).
19F NMR (375 MHz, CDCl3): δ = –103.5 (t, J = 15.3 Hz, 2 F).
HRMS: m/z [M]+ calcd for C15H17F2NO3: 297.1177; found: 297.1179.
Ethyl 2,2-Difluoro-4-phenylpent-4-enoate (3t)
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); 52 mg (72%); colorless oil. This compound is known in the lit-
erature.9b
Methyl (E)-4-(3,3-Difluoro-4-morpholino-4-oxobut-1-en-1-
yl)benzoate (4c)
The product was purified by silica gel chromatography (PE–EtOAc,
5:1); yield: 68 mg (70%); colorless oil.
IR (film): 2963, 1770, 1625, 1493 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.38–7.26 (m, 5 H), 5.50 (s, 1 H), 5.31
(s, 1 H), 4.04 (q, J = 7.2 Hz, 2 H), 2.50 (s, 3 H), 3.30 (t, J = 16.0 Hz, 2 H),
1.20 (t, J = 7.2 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.4
Hz, 2 H), 7.02 (m, 1 H), 6.56 (dt, J = 16.4, 11.2 Hz, 1 H), 3.91 (s, 3 H),
3.72–3.69 (m, 8 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.7 (t, J = 35.1 Hz), 140.1, 138.8 (t,
J = 3.5 Hz), 128.3, 127.9, 126.3, 119.2, 115.1 (t, J = 252.3 Hz), 62.7, 40.3
(t, J = 24.1 Hz), 13.5.
13C NMR (125.7 MHz, CDCl3): δ = 166.4, 161.7 (t, J = 31.04 Hz), 138.5,
134.2 (t, J = 9.8 Hz), 130.7, 130.0, 127.3, 122.4 (t, J = 23.8 Hz), 115.1 (t,
J = 250.8 Hz), 66.7, 52.2, 46.5 (t, J = 5.0 Hz), 43.4.
19F NMR (376 MHz, CDCl3): δ = –96.0 (d, J = 11.2 Hz, 2 F).
MS (EI): m/z (%) = 325 (M+).
19F NMR (376 MHz, CDCl3): δ = –103.4 (t, J = 15.0 Hz, 2 F).
Ethyl 2,2-Difluoro-3-(1H-inden-3-yl)propanoate (3u)
HRMS: m/z [M]+ calcd for C16H17F2NO4: 325.1126; found: 325.1125.
The product was purified by silica gel chromatography (PE–EtOAc,
10:1); yield: 33 mg (43%); colorless oil.
Methyl (S,E)-2-[2,2-Difluoro-4-(4-methoxyphenyl)but-3-enami-
do]-3-phenylpropanoate (4d)
IR (film): 2984, 1768, 1601, 1462 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.46 (d, J = 7.2 Hz, 1 H), 7.39 (d, J = 7.2
Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.22 (td, J = 7.6, 0.8 Hz, 1 H), 6.48 (s, 1
H), 4.23 (q, J = 6.8 Hz, 2 H), 3.39 (t, J = 16.8 Hz, 2 H), 3.39 (s, 2 H), 1.23
(t, J = 6.8 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 163.9 (t, J = 36.5 Hz), 144.4, 143.7,
134.0, 133.9 (t, J = 4.4 Hz), 126.2, 125.0, 123.8, 119.1, 115.4 (t, J =
252.0 Hz), 62.8, 38.2, 33.1 (t, J = 24.8 Hz), 13.8.
19F NMR (376 MHz, CDCl3): δ = –103.2 (t, J = 16.1 Hz, 2 F).
MS (EI): m/z (%) = 252 (M+).
HRMS: m/z [M]+ calcd for C14H14F2O2: 252.0962; found: 252.0963.
The product was purified by silica gel chromatography (PE–EtOAc,
3:1); yield: 87 mg (75%); colorless oil.
IR (film): 2955, 2925, 1748, 1740, 1604, 1514 cm–1
.
1H NMR (300 MHz, CDCl3): δ = 7.27 (d, J = 8.7 Hz, 2 H), 7.15–7.14 (m, 3
H), 7.00–6.97 (m, 2 H), 6.86 (dt, J = 16.5, 2.1 Hz, 1 H), 6.80–6.78 (m, 3
H), 6.06 (dt, J = 16.5, 11.4 Hz, 1 H), 4.82 (dd, J = 13.5, 6.0 Hz, 1 H), 3.73
(s, 3 H), 3.67 (s, 3 H), 3.16 (dd, J = 14.1, 5.7 Hz, 1 H), 3.05 (dd, J = 14.1,
5.7 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 170.5, 163.1 (t, J = 31.3 Hz), 160.3,
135.8 (t, J = 9.6 Hz), 134.7, 128.8, 128.5, 128.2, 126.9, 126.4, 115.9 (t,
J = 25.0 Hz), 113.9 (t, J = 247.4 Hz), 113.7, 54.8, 52.7, 52.1, 37.0.
(E)-2,2-Difluoro-1-morpholino-4-phenylbut-3-en-1-one (4a)
19F NMR (282 MHz, CDCl3): δ = –102.89 (d, J = 11.5 Hz, 2 F).
MS (EI): m/z (%) = 389 (M+).
HRMS: m/z [M]+ calcd for C21H21F2NO4: 389.1439; found: 389.1436.
The product was purified by silica gel chromatography (PE–EtOAc,
5:1); yield: 65 mg (81%); colorless oil.
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2922
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Feature
Synthesis
Methyl (E)-4-[3-([1,1′-Biphenyl]-4-yl)-3,3-difluoroprop-1-en-1-
IR (ATR, film): 2931, 2552, 1739, 1704, 1531 cm–1
.
yl]benzoate (4e)
1H NMR (400 MHz, CDCl3): δ = 7.29–7.19 (m, 5 H), 7.16 (s, 1 H), 7.07
(d, J = 7.6 Hz, 1 H), 7.06 (d, J = 7.6 Hz, 1 H), 6.95 (dt, J = 16.4, 2.4 Hz, 1
H), 6.86 (br, 1 H), 6.24 (dt, J = 16.4, 11.6 Hz, 1 H), 4.90 (dd, J = 7.2, 6.0
Hz, 1 H), 3.76 (s, 3 H), 3.23 (dd, J = 14.4, 5.4 Hz, 1 H), 3.14 (dd, J = 14.4,
5.4 Hz, 1 H), 2.92 (dd, J = 8.8, 4.0 Hz, 2 H), 2.51 (m, 1 H), 2.43–2.41 (m,
1 H), 2.32–2.28 (m, 1 H), 2.19–2.11 (m, 1 H), 2.10–2.01 (m, 2 H), 1.98–
1.95 (m, 1 H), 1.66–1.59 (m, 2 H), 1.56–1.47 (m, 3 H), 1.45–1.42 (m, 1
H), 0.91 (s, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 220.6, 170.9, 163.4 (t, J = 31.42 Hz),
141.6, 137.0, 136.5 (t, J = 9.4 Hz), 135.1, 131.7, 129.3, 128.7, 128.1,
127.4, 125.8, 124.9, 118.0 (t, J = 25.1 Hz), 114.2 (t, J = 249.3 Hz), 53.2,
52.6, 50.5, 47.9, 44.5, 38.0, 37.5, 35.8, 31.6, 29.3, 26.4, 25.6, 21.6, 13.8.
Molecular sieves 3Å (100 mg) were used. The product was purified by
silica gel chromatography (PE–EtOAc, 10:1); yield: 71 mg (65%);
white solid; mp 81–84 °C.
1H NMR (400 MHz, CDCl3): δ = 8.04 (d, J = 8.4 Hz, 2 H), 7.65 (m, 6 H),
7.49 (m, 4 H), 7.40 (m, 1 H), 6.94 (dt, J = 16.4, 2.4 Hz, 1 H), 6.59 (dt, J =
16.4, 10.0 Hz, 1 H), 3.93 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.5, 143.1, 140.1, 139.1, 135.2 (t, J =
28.0 Hz), 133.2 (t, J = 9.2 Hz), 130.4, 130.1, 128.9, 127.9, 127.3, 127.2,
127.2, 126.7 (t, J = 29.7 Hz), 126.0 (t, J = 5.3 Hz), 119.7 (t, J = 237.1 Hz),
52.2.
19F NMR (375 MHz, CDCl3): δ = –91.2 (dd, J = 9.7, 0.8 Hz, 2 F).
MS (ESI): m/z (%) = 364 (M+).
19F NMR (376 MHz, CDCl3): δ = –103.8 (d, J = 7.1 Hz, 2 F).
MS (EI): m/z (%) = 535 (M+).
HRMS: m/z [M]+ calcd for C32H35F2NO4: 535.2534; found: 535.2538.
HRMS: m/z [M]+calcd for C23H18F2O2: 364.1275; found: 364.1272.
(E)-1-[3-(Benzo[d]oxazol-2-yl)-3,3-difluoroprop-1-en-1-yl]pyrro-
lidin-2-one (4f)
Ethyl 3-(3,4-Dihydronaphthalen-1-yl)-2,2-difluoropropanoate (9)
To a 25 mL Schlenk tube were added PdCl2(MeCN)2 (8 mg, 0.03 mmol,
10 mol%) and Xantphos (35 mg, 0.06 mmol, 20 mol%) under air, fol-
lowed by anhydrous K2CO3 (powder, 2.0 equiv). The mixture was then
evacuated and backfilled with N2 (3 times). Ethyl bromodifluoroace-
tate (1a; 122 mg, 0.6 mmol, 2 equiv), alkene 8 (43 mg, 0.3 mmol) and
fresh distilled 1,4-dioxane (2 mL) were added subsequently. The reac-
tion mixture was heated to 80 °C (oil bath). After stirring for 24 h, the
mixture was cooled to r.t. The mixture was diluted with EtOAc and fil-
tered over a pad of Celite. The filtrate was concentrated, and the resi-
due was purified by silica gel chromatography (PE–EtOAc, 10:1) to af-
ford compound 9; yield: 35 mg (44%); colorless oil.
The product was purified by silica gel chromatography (PE–EtOAc,
1:1); yield: 65 mg (78%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 7.81 (d, J = 7.6 Hz, 1 H), 7.68 (dt, J =
14.4, 2.0 Hz, 1 H), 7.61 (d, J = 7.6 Hz, 1 H), 7.45 (td, J = 7.6, 1.2 Hz, 1 H),
7.40 (td, J = 7.6, 1.2 Hz, 1 H), 5.41 (dt, J = 14.4, 10.4 Hz, 1 H), 3.61 (t, J =
7.2 Hz, 2 H), 2.53 (t, J = 8.4 Hz, 2 H), 2.16 (m, 2 H).
13C NMR (125.7 MHz, CDCl3): δ = 173.9, 158.2 (t, J = 36.7 Hz), 150.7,
139.9, 130.4 (t, J = 10.0 Hz), 126.8, 125.3, 121.3, 113.8 (t, J = 238.9 Hz),
111.4, 101.8 (t, J = 26.0 Hz), 44.9, 30.9, 17.4.
19F NMR (375 MHz, CDCl3): δ = –90.7 (dd, J = 10.9, 1.9 Hz, 2 F).
MS (EI): m/z (%) = 278 (M+).
IR (film): 2937, 1763, 1604, 1466 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.25–7.23 (m, 1 H), 7.21–7.18 (m, 1 H),
7.15–7.12 (m, 2 H), 6.08 (t, J = 4.4 Hz, 2 H), 4.14 (q, J = 7.2 Hz, 2 H),
3.24 (t, J = 8.4 Hz, 2 H), 2.74 (t, J = 8.4 Hz, 2 H), 2.28 (td, J = 8.4, 4.4 Hz,
2 H), 1.21 (t, J = 7.2 Hz, 3 H).
13C NMR (125.7 MHz, CDCl3): δ = 164.1 (t, J = 32.4 Hz), 136.3, 133.8,
131.6, 127.6, 127.3 (t, J = 4.4 Hz), 127.1, 126.3, 122.8, 115.5 (t, J =
252.1 Hz), 62.7, 37.3 (t, J = 24.1 Hz), 28.0, 23.2, 13.7.
HRMS: m/z [M]+ calcd for C14H12F2NO2: 278.0867; found: 278.0866.
Ethyl (E)-2,2-Difluoro-4-[(8R,9S,13S,14S)-13-methyl-17-oxo-
7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopenta[a]phenan-
thren-3-yl]but-3-enoate (6)
The product was purified by silica gel chromatography (PE–EtOAc,
5:1); yield: 76 mg (63%); white solid, mp 150–154 °C.
19F NMR (376 MHz, CDCl3): δ = –103.3 (t, J = 15.7 Hz, 2 F).
MS (EI): m/z (%) = 266 (M+).
HRMS: m/z [M]+ calcd for C15H16F2O2: 266.1118; found: 266.1116.
IR (film): 2931, 1766, 1739 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30 (d, J = 8.0 Hz, 1 H), 7.23 (d, J = 8.0
Hz, 1 H), 7.18 (s, 1 H), 7.01 (dt, J = 16.4, 2.8 Hz, 1 H), 6.25 (dt, J = 16.4,
11.6 Hz, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 2.92 (m, 2 H), 2.51 (dd, J = 14.1,
8.8 Hz, 1 H), 2.42–2.40 (m, 1 H), 2.31 (m, 1 H), 2.18–2.11 (m, 1 H),
2.09–2.01 (m, 2 H), 1.97–1.95 (m, 1 H), 1.65–1.58 (m, 2 H), 1.55–1.47
(m, 3 H), 1.43–1.42 (m, 1 H), 1.35 (t, J = 7.2 Hz, 3 H), 0.91 (s, 3 H).
Acknowledgment
13C NMR (125.7 MHz, CDCl3): δ = 220.6, 164.0 (t, J = 35.1 Hz), 141.7,
137.1, 136.6 (t, J = 9.3 Hz), 131.7, 128.1, 125.9, 124.8, 118.1 (t, J =
25.01 Hz), 112.8 (t, J = 248.3 Hz), 63.1, 50.5, 47.9, 44.5, 38.0, 35.8, 31.6,
29.3, 26.3, 25.7, 21.6, 14.0, 13.8.
This work was financially supported by the National Basic Research
Program of China (973 Program) (Nos. 2012CB821600 and
2015CB931900), the NSFC (21425208, 21421002, 21172242 and
21332010), and SIOC.
19F NMR (376 MHz, CDCl3): δ = –103.1 (d, J = 11.7 Hz, 2 F).
MS (EI): m/z (%) = 402 (M+).
HRMS: m/z [M]+ calcd for C24H28F2O3: 402.2007; found: 402.2008.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560457.
S
u
p
p
o
nrtIo
g
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
Methyl (R)-2-{(E)-2,2-Difluoro-4-[(8R,9S,13S,14S)-13-methyl-17-
oxo-7,8,9,11,12,13,14,15,16,17-decahydro-6H-cyclopen-
ta[a]phenanthren-3-yl]but-3-enamido}-3-phenylpropanoate (7)
The product was purified by silica gel chromatography (PE–EtOAc,
2:1); yield: 118 mg (73%); white solid; mp 104–108 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2015, 47, 2912–2923

2923
F. Zhang et al.
Feature
Synthesis
References
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