Rh-catalyzed allylic C-F bond activation: The stereoselective synthesis of trisubstituted monofluoroalkenes and a mechanism study

Article abstract of DOI:10.1039/c3ob42038h

Rhodium-catalyzed allylic C-F bond activation via oxidative addition was found to be a promising approach for the conversion of allylic difluoro-homoallylic alcohols into trisubstituted monofluoroalkenes in good yields with excellent stereoselectivity. The mechanism study shows that C-F bond activation via oxidative addition is involved and PPh₃ is responsible for the excellent stereoselectivity. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3ob42038h

Organic &
Biomolecular Chemistry
View Article Online
View Journal | View Issue
PAPER
Rh-catalyzed allylic C–F bond activation:
the stereoselective synthesis of trisubstituted
monofluoroalkenes and a mechanism study†
Cite this: Org. Biomol. Chem., 2014,
12, 581
He Zhang,a Jin-Hong Lin,a Ji-Chang Xiao*a and Yu-Cheng Gub
Received 17th September 2013,
Accepted 12th November 2013
Rhodium-catalyzed allylic C–F bond activation via oxidative addition was found to be a promising
approach for the conversion of allylic difluoro-homoallylic alcohols into trisubstituted monofluoroalkenes
in good yields with excellent stereoselectivity. The mechanism study shows that C–F bond activation via
oxidative addition is involved and PPh3 is responsible for the excellent stereoselectivity.
DOI: 10.1039/c3ob42038h
www.rsc.org/obc
Introduction
The chemical inertness of the C–F bond makes the chemistry
of C–F bond activation a specialized field and an area of
research that has received a great deal of interest and atten-
tion.1 Outstanding progress has been made recently in the
development of novel methods for activation of the C–F bond
catalyzed by transition metals, which could activate the C–F
bond under mild conditions and further functionalize sub-
strates.2 Research into transition metal-catalyzed Csp2–F bond
activation has been intensively studied2a–f while Csp3–F bond
activation needs much more exploration.2g–r In the investi-
gation of transition metal-catalyzed Csp3–F bond activation,
the chemical properties of the C–F bond were well studied but
most of these methods led to non-fluorinated products2g–l, p or
resulted in low chemoselectivity.2m,n The selective Csp3–F
bond activation catalyzed by transition metals remains chal-
lenging, and has the potential to be a highly efficient approach
for the construction of unique partially fluorinated molecules
which cannot be easily obtained by other methods.
Scheme 1 This work.
monofluoroalkenes were obtained utilizing Pd-catalyzed reduc-
tive defluorination.2q Paquin et al. found that C–F bond acti-
vation followed by a coupling reaction can give functionalized
fluoroalkenes.2o Selective allylic Csp3–F bond activation is a
promising method for the synthesis of functionalized mono-
fluoroalkenes under mild conditions but stereoselectivity is an
issue that remains to be addressed.5
We have reported that disubstituted monofluoroalkenes
can be synthesized with excellent stereoselectivity by a coup-
ling reaction.6 However, in the synthesis of trisubstituted
monofluoroalkenes, the same approach gave the required pro-
ducts with only moderate to good stereoselectivity. Herein we
report the allylic Csp3–F bond activation catalyzed by rhodium
via oxidative addition for the first time and the application of
this method to the highly stereoselective conversion of allylic
difluoro-homoallylic alcohols into trisubstituted monofluo-
roalkenes, carbonyl group substituted monofluoroalkenes,
which is a class of useful intermediate for the synthesis of bio-
logically active substances (Scheme 1).7
As an important class of fluorinated molecules, monofluo-
roalkenes have found potential applications in materials
science and medicinal chemistry.3 As a result, considerable
effort has been directed towards their synthesis.4 Recently,
Fujii et al. and Paquin et al. independently reported that
monofluoroalkenes can be synthesized through selective allylic
Csp3–F bond activation catalyzed by palladium. In Fujii’s case,
Results and discussion
Screening of reaction conditions
aKey Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: jchxiao@sioc.ac.cn; Tel: (+86)21-5492-5430
Allylic difluoro-homoallylic alcohols could be easily prepared
from the reaction of aldehyde with 3-bromo-3,3-difluoro-
propene in the presence of indium (Scheme 2).8
2,2-Difluoro-1-phenylbut-3-en-1-ol (1a) was used as the sub-
strate for the screening of reaction conditions because of its
bSyngenta, Jealott’s Hill International Research Centre, Bracknell, Berkshire
RG42 6EY, UK
†Electronic supplementary information (ESI) available. CCDC 929445. For ESI
and crystallographic data in CIF or other electronic format see DOI:
10.1039/c3ob42038h
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 581–588 | 581

View Article Online
Paper
Organic & Biomolecular Chemistry
presence of PPh3 will be discussed in the Mechanism study
section.
The purity of the Rh(PPh3)3Cl used in all the experiments
described above was 98%. In order to exclude the possibility
that the reaction might be catalyzed by impurities in the cata-
lyst, 99.99% pure Rh(PPh3)3Cl was used in an additional experi-
ment. The result was almost the same, which is compelling
evidence that it is, indeed, Rh(PPh3)3Cl catalyses the reaction
(entry 13). Other ligands (PCy3 or 2,2′-bipyridyl) were
also screened but the results were worse (entries 14–15). So
the optimal conditions for the reaction are DMF–dioxane as
cosolvents, Rh(PPh3)3Cl as a catalyst and 4 Å MS and PPh3 as
additives (entry 9).
Scheme 2 Preparation of substrates.
straightforward preparation and purification. In our initial
attempts, no reaction was observed in the presence of different
bases but in the absence of a transition metal catalyst (Table 1,
entries 1–3). With CH3CN as a solvent and at 70 °C, even the
use of Pd(PPh3)4 or Rh(PPh3)3Cl as a catalyst led to none of the
required products (entries 4 and 5).
However, to our delight, when the reaction was performed
at 120 °C in DMF, 19F NMR showed that only a single com-
pound was formed, and this was determined to be the desired
product (entry 6). On addition of PPh3, as well as 4 Å MS to
remove traces of water from the DMF, the yield increased to
81% (entry 7). When dioxane was used as a solvent, stereo-
selectivity and yield were both lower (entry 8). With dioxane as
a cosolvent in DMF, a better result was obtained (entry 9). It
was also found that Rh(PPh3)3Cl was necessary for the reaction
(entry 10).
Since 4 Å MS and PPh3 together were shown to have a sig-
nificant positive effect on the reaction, it was worth determin-
ing the role of each reagent. When 4 Å MS was used without
PPh3, the selectivity dropped sharply (entry 11). On the other
hand, without the 4 Å MS, the yield lowered dramatically
(entry 12). We believe that the 4 Å MS not only acts as a drying
agent, but also absorbs the HF generated, driving the reaction
forward. The reason for the improvement in selectivity in the
Reaction scope
With these optimized conditions in hand, we investigated the
scope of substrates that could be accommodated and, as
shown in Scheme 3, found that the reaction could tolerate
various functional groups. Substrates with electron-withdraw-
ing groups were converted smoothly into the products with
excellent stereoselectivity and good yields (2b–2d, 2h–2i). No
negative effect was observed here when Cl or F was contained
(2e–2f). However, with Br present in the substrate, much of the
unreacted starting material (>40%) remained and the isolated
yield was much lower (53%). This might stem from the oxi-
dative addition of the catalyst to the C–Br bond competing
with the required reaction (2g).9
Surprisingly, in the case of substrates substituted by the
electron-donating groups, the stereoselectivity of reactions was
very low, even though the yields were still good to excellent
Table 1 Optimization of Rh(I)-catalyzed allylic C–F activationa
Entry
Catalyst
Additive
Solvent
Z/Eb
Yieldb (%)
1c
2c
3
—
—
—
DBU
CH3CN
CH3CN
DMF
CH3CN
CH3CN
DMF
DMF
Dioxane
DMF–dioxane
DMF–dioxane
DMF–dioxane
DMF–dioxane
DMF–dioxane
DMF–dioxane
DMF–dioxane
—
—
—
—
NR
NR
NR
NR
NR
25
81
76
87
—
72
16
87
78
31
NaOBut
Cs2CO3
—
—
—
PPh3 + 4 Å MS
PPh3 + 4 Å MS
PPh3 + 4 Å MS
PPh3 + 4 Å MS
4 Å MS
4c
5c
6
Pd(PPh3)4
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
—
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
Rh(PPh3)3Cl
—
ND
30/1
12/1
20/1
—
5/1
—
20/1
50/1
7/1
7
8
9
10
11
12
13d
14
15
PPh3
PPh3 + 4 Å MS
PCy3 + 4 Å MS
2,2′-Bipyridyl + 4 Å MS
a Conditions: a mixture of 1a (0.5 mmol), a catalyst (0.025 mmol), an additive and a solvent (2 mL) in a sealed tube was stirred at 120 °C; in
entries 1–3, 1 equiv. of each additive was used; in the other entries, 4 Å MS was used on a 100 mg scale and PPh3 or other additives were used on
a 0.1 mmol scale. ND = not determined, NR = no reaction. b Determined by 19F NMR. c The reaction was performed at 70 °C, reaction time was
16 h. d The purity of the Rh(PPh3)3Cl used is 99.99%.
582 | Org. Biomol. Chem., 2014, 12, 581–588
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
Scheme 4 Possible pathways of the reaction.
Scheme 3 Reaction scope. Isolated yields; the Z/E ratios and the yield
in parentheses shown were determined by 19F NMR.
Scheme 5 Evidence to exclude path 1.
by β-H elimination and rearrangement could also afford the
expected product (path 2).12
The possibility via path 1 was excluded by deuterium-label-
ing experiments.13 When the hydroxy was deuterated, the con-
version proceeded well but only afforded non-deuterated
product, without any sign of the deuterated product
(Scheme 5, eqn (1)). Surprisingly, when the benzyl proton was
replaced with deuterium in the substrate, the reaction gave
two deuterated products, with deuterium locating at terminal
methyl and double bond respectively (eqn (2)). The deuterated
results clearly demonstrate that dehydrogenation of alcohol is
not involved in the reaction, otherwise the deuterated sub-
strates 1p and 1s should give the same deuterated products.
Furthermore, the failure to reduce activated alkene 3 of the
standard reaction system suggests that RhH2(III) is not gene-
rated, which also means path 1 may not be involved (eqn (3)).11
Based on the above results, we propose that the mechanism
involves Csp3–F bond activation and β-hydride elimination as
illustrated in Scheme 6. Take 1p as the example. The oxidative
addition of the C–F bond to Rh(PPh3)3Cl generates a rhodium
complex I. The subsequent β-D elimination requires Rh(III) and
D in the syn position. Due to the eclipsed conformation (I), the
2-substituted group on phenyl shows strong steric hindrance
and leads to a sluggish reaction. That is why 2j and 2k were
obtained in low yields. The generated intermediate II would
readily undergo insertion of a double bond into a Rh(III)–D
bond, proceeding in two different routes to give intermediates
III and III′. β-H elimination of intermediate III′ followed by re-
insertion affords intermediate III″. Finally, isomerization and
Fig. 1 X-ray structure of 2e.
(2h–2i). The reaction is quite sensitive to steric effects. When
the 2-position of the phenyl group was substituted, almost no
reaction was observed (2j–2k). For example, the 2-EtO-phenyl-
substituted substrate reacted very sluggishly, even when the
temperature was increased to 140 °C, and the 19F NMR yield
was so low that the stereoselectivity was not determined.
For the naphthyl and heteroaromatic substrates, the desired
product was the major product and the stereoselectivity was
still quite good (2m). But for the aliphatic substrates, an
isomer of the desired product (2nA, 2nB) was obtained and
this is explained in the ESI.†
The structure of the product 2e was determined by single
crystal X-ray diffraction (Fig. 1).10 Other structures were sur-
mised by analogy.
Mechanism study
The transformation might proceed via two different pathways,
involving dehydrogenation of alcohol (path 1, Scheme 4) or
C–F bond activation via oxidative addition (path 2), respecti-
vely. The coordination of alcohol to Rh(I) followed by dehydro-
genation, insertion of a terminal double bond into a Rh–H
bond and β-F elimination would give the final product
(path 1).2r,11 On the other hand, C–F bond activation followed
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 581–588 | 583

View Article Online
Paper
Organic & Biomolecular Chemistry
Scheme 8 PPh3 mediated isomerization of the alkene.
(monitored by 19F NMR at 0.5 h, 3 h, and 6 h) led to Z-2h as
the major isomer. Under the same conditions but starting
with Z-2h, only 3% isomerized to E-2h. These results indicate
that the stereoselectivity is determined by the electrophilicity
of the double bond towards PPh3.
Scheme 6 Proposed mechanism.
Conclusions
In conclusion, rhodium-catalyzed allylic Csp3–F bond acti-
vation via oxidative addition was reported for the first time
and found to be an efficient approach for the conversion of
allylic difluoro-homoallylic alcohols into trisubstituted mono-
fluoroalkenes in good yields with excellent stereoselectivity.
The careful study of the mechanism shows that C–F bond acti-
vation via oxidative addition is involved and PPh3 is respon-
sible for the excellent stereoselectivity. The application of C–F
bond activation to the synthesis of other important fluori-
nated molecules is in progress.
Scheme 7 Proposed mechanism for the isomerization.
β-H elimination of III and III″ lead to deuterated products 2q
and 2r respectively, and F(H)Rh(III).14 The reductive elimin-
ation of F(H)Rh(III) generates catalyst Rh(I) and HF, which is
absorbed by 4 Å MS.
Experimental
General information
Reagents and solvents were purchased from commercial
sources and used as received. Molecular sieves (4 Å, powder)
were dried under vacuum at 220 °C and stored in a glove box
before use. Tetramethylsilane or residual proton signals were
used as internal standards for 1H NMR, 13C NMR and 19F
With regard to the excellent stereoselectivity, we believe
PPh3 plays an important role.15 The carbon–carbon double
bond in the product is sufficiently electron deficient to be
attacked by PPh3 to give intermediate V (Scheme 7). Two sig-
nificant conformations of intermediate V can be identified,
conformations a and b, and the former is favoured over the
latter for steric reasons. The elimination of PPh3 from confor-
mer a affords the desired product in the Z-configuration. In
the case of substrates with an electron-donating group on the
benzene ring, the double bond is less readily attacked by PPh3
because it is not sufficiently electron deficient, leading to a
larger proportion of E-stereoisomeric products.
NMR spectra. Data for H NMR, 13C NMR and 19F NMR were
recorded as follows: chemical shift (δ, ppm), multiplicity (s =
singlet, d = doublet, t = triplet, m = multiplet or unresolved,
brs = broad singlet, coupling constant(s) in Hz, integration).
1
General experimental procedure for the synthesis of
3,3-difluoropropene derivatives
In order to support our hypothesis for the role of PPh3 in
these reactions, further evidence was collected (Scheme 8).
When a solution of E-2h in DMF–dioxane was kept at 120 °C
for 3 h in the absence of PPh3, only very low levels of isomeri-
zation were observed (determined by 19F NMR). In a parallel
experiment but with the addition of PPh3, isomerization
Compounds 1a–1o were synthesized using the method
reported by Masayuki Kirihara et al.8
2,2-Difluoro-1-phenylbut-3-en-1-ol (1a). 71% yield. Colorless
liquid. 1H NMR (300 MHz, CDCl3) δ 7.48–7.31 (m, 5H),
5.95–5.75 (m, 1H), 5.59 (d, J = 17.4 Hz, 1H), 5.46 (d, J = 11.0
Hz, 1H), 4.91 (td, J = 9.7, 4.0 Hz, 1H), 2.50 (d, J = 4.0 Hz, 1H);
584 | Org. Biomol. Chem., 2014, 12, 581–588
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
19F NMR (282 MHz, CDCl3) δ −107.87 (dt, J = 247.2, 10.5 Hz, 11.0 Hz, 1H), 4.90 (t, J = 8.5 Hz, 1H), 2.58–1.23 (brs, 1H); 19F
1F), −108.95–−109.99 (m, 1F). NMR (282 MHz, CDCl3) δ −107.58 (dt, J = 247.5, 10.2 Hz, 1F),
Methyl 3-(2,2-difluoro-1-hydroxybut-3-en-1-yl)benzoate (1b). −108.74 to −110.72 (m, 1F).
1
43% yield. Colorless liquid. H NMR (400 MHz, CDCl3) δ 8.06
1-(3-Bromophenyl)-2,2-difluorobut-3-en-1-ol (1g). 75% yield.
(s, 1H), 7.94 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.7 Hz, 1H), 7.37 (t, Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.54 (s, 1H), 7.45
J = 7.7 Hz, 1H), 5.99–5.78 (m, 1H), 5.53 (d, J = 17.4 Hz, 1H), (d, J = 7.8 Hz, 1H), 7.29 (d, J = 7.8 Hz, 1H), 7.18 (t, J = 7.8 Hz,
5.42 (d, J = 11.1 Hz, 1H), 4.95 (t, J = 9.6 Hz, 1H), 4.27 (brs, 1H), 1H), 5.87–5.71 (m, 1H), 5.55 (d, J = 17.4 Hz, 1H), 5.44 (d, J =
3.84 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 167.06 (s), 136.99 11.1 Hz, 1H), 4.78 (t, J = 9.5 Hz, 1H), 3.32 (s, 1H); 13C NMR
(s), 132.20 (s), 129.53 (s), 129.44 (s), 129.18 (t, J = 25.6 Hz), (101 MHz, CDCl3) δ138.17 (m), 131.67 (s), 130.53 (s), 129.64 (s),
128.66 (s), 127.98 (s), 121.38 (t, J = 9.2 Hz), 119.25 (t, J = 244.6 128.88 (t, J = 25.6 Hz), 126.26 (s), 122.12 (s), 121.93 (t, J =
Hz), 74.97 (t, J = 30.1 Hz), 52.00 (s); 19F NMR (282 MHz, CDCl3) 9.0 Hz), 119.23 (t, J = 244.8 Hz), 74.96 (t, J = 29.3 Hz); 19F NMR
δ −107.30 (dt, J = 247.9, 9.6 Hz, 1F), −109.27 to −110.38 (m, (282 MHz, CDCl3) δ −107.35 (dt, J = 248.0, 10.2 Hz, 1F),
1F); IR (neat) ν = 3466, 2955, 1723, 1449, 1293, 1203, 995, −108.81 to −110.36 (m, 1F); IR (neat) ν = 3440, 1573, 1421,
747 cm−1; HRMS(ESI) calcd for C12H12F2NaO3 [M + Na]+ 1192, 1073, 997, 955, 777 cm−1
265.06467; found 265.06525.
C10H9BrF2O [M]+ 262.0; found 262.0. Anal. calcd for
2,2-Difluoro-1-(4-(methylsulfonyl)phenyl)but-3-en-1-ol (1c). C10H9BrF2O: C, 45.65; H,3.45; found C, 45.60; H, 3.78.
; GCMS(EI) calcd for
1
67% yield. White solid. H NMR (400 MHz, CDCl3) δ 7.81 (d,
1-(4-(Benzyloxy)phenyl)-2,2-difluorobut-3-en-1-ol (1h). 41%
1
J = 8.2 Hz, 2H), 7.60 (d, J = 8.2 Hz, 2H), 5.96–5.81 (m, 1H), 5.57 yield. White solid. H NMR (400 MHz, CDCl3) δ 7.51–7.24 (m,
(d, J = 17.4 Hz, 1H), 5.48 (d, J = 11.1 Hz, 1H), 5.00 (t, J = 9.5 Hz, 7H), 7.08–6.86 (m, 2H), 5.93–5.74 (m, 1H), 5.59 (d, J = 17.4 Hz,
1H), 3.93 (brs, 1H), 3.03 (s, 3H); 13C NMR (101 MHz, CDCl3) 1H), 5.45 (d, J = 11.1 Hz, 1H), 5.05 (s, 2H), 4.81 (t, J = 9.7 Hz,
δ 142.83 (s), 139.89 (s), 129.00 (t, J = 25.6 Hz), 128.70 (s), 1H), 2.58 (brs, 1H); 13C NMR (101 MHz, CDCl3) δ 159.09 (s),
126.74 (s), 121.88 (t, J = 9.2 Hz), 119.07 (t, J = 244.4 Hz), 74.63 136.80 (s), 129.54 (t, J = 25.6 Hz), 128.89 (s), 128.57 (s), 128.45 (s),
(t, J = 30.6 Hz), 44.21 (s); 19F NMR (282 MHz, CDCl3) δ −106.08 128.00 (s), 127.46 (s), 121.46 (t, J = 9.1 Hz), 119.62 (t, J =
(dt, J = 248.5, 9.5 Hz), −110.73 (dt, J = 248.5, 9.5 Hz); IR (neat) 245.4 Hz), 114.54 (s), 75.49 (t, J = 29.9 Hz), 70.00 (s); 19F NMR
ν = 3472, 2930, 1601, 1420, 1304, 1149, 959, 766 cm−1; HRMS- (282 MHz, CDCl3) δ −108.56 (dt, J = 246.6, 10.7 Hz, 1F),
(ESI) calcd for C11H12F2NaO3S [M + Na]+ 285.03674; found −109.48 to −110.73 (m, 1F); IR (neat) ν = 3437, 2904, 1614,
285.03689.
1513, 1244, 1175, 1066, 993 cm−1
; HRMS(EI) calcd for
2,2-Difluoro-1-(3-(trifluoromethyl)phenyl)but-3-en-1-ol (1d). C17H16F2O2 [M]+ 290.1118; found 290.1115.
1
51% yield. Colorless liquid. H NMR (400 MHz, CDCl3) δ 7.68
1-(4-(Dimethylamino)phenyl)-2,2-difluorobut-3-en-1-ol (1i).
(s, 1H), 7.64–7.51 (m, 2H), 7.44 (t, J = 7.8 Hz, 1H), 5.92–5.72 75% yield. Yellow liquid. 1H NMR (400 MHz, CDCl3)
(m, 1H), 5.54 (d, J = 17.4 Hz, 1H), 5.45 (d, J = 11.1 Hz, 1H), 4.91 δ 7.37–7.12 (m, 2H), 6.70 (d, J = 8.8 Hz, 2H), 5.95–5.78 (m, 1H),
(t, J = 9.3 Hz, 1H), 3.66–2.78 (brs, 1H); 13C NMR (101 MHz, 5.73–5.51 (m, 1H), 5.44 (d, J = 11.1 Hz, 1H), 4.77 (t, J = 10.0 Hz,
CDCl3) δ 137.04 (s), 131.07 (s), 130.61 (q, J = 32.5 Hz), 128.88 (t, 1H), 2.95 (s, 6H), 2.49 (brs, 1H); 13C NMR (101 MHz, CDCl3) δ
J = 26.8 Hz), 128.64 (s), 125.48 (q, J = 4.0 Hz), 124.49 (m), 150.70 (s), 129.89 (t, J = 25.8 Hz), 128.49 (s), 123.72 (s), 121.11
124.03 (q, J = 272.0 Hz), 122.10 (m), 119.38 (t, J = 244.9 Hz), (t, J = 9.2 Hz), 119.75 (t, J = 244.1 Hz), 112.00 (s), 75.76 (t, J =
75.28 (t, J = 30.3 Hz); 19F NMR (282 MHz, CDCl3) δ −63.07 (s, 29.6 Hz), 40.44 (s); 19F NMR (376 MHz, CDCl3) δ −108.21 (dt,
3F), −107.58 (dt, J = 248.2, 11.3 Hz, 1F), −108.89 to −116.93 J = 245.2, 10.6 Hz, 1F), −109.41 (dt, J = 245.1, 10.4 Hz, 1F); IR
(m, 1F); IR (neat) ν = 3441, 1422, 1330, 1167, 1130, 1103, 1075, (neat) ν = 3420, 2890, 1616, 1525, 1354, 1163, 1064, 992 cm−1
;
997 cm−1; LRMS(ESI) calcd for C11H9F5NaO [M + Na]+ 275.0; HRMS(EI) calcd for C12H15F2NO [M]+ 227.1122; found
found 275.0. Anal. calcd for C11H9F5O: C, 52.39; H, 3.60; found 227.1126.
C, 52.26; H, 3.83.
1-(2-Chlorophenyl)-2,2-difluorobut-3-en-1-ol (1j). 45% yield.
2,2-Difluoro-1-(4-fluorophenyl)but-3-en-1-ol (1e). 68% yield. Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.59 (d, J =
Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.38–7.30 (m, 7.5 Hz, 1H), 7.39–7.20 (m, 3H), 5.99–5.83 m, 1H), 5.58 (d, J =
2H), 7.01 (t, J = 8.7 Hz, 2H), 5.88–5.72 (m, 1H), 5.53 (d, J = 17.3 Hz, 1H), 5.50–5.38 (m, 2H), 2.85 (brs, 1H); 13C NMR
17.4 Hz, 1H), 5.43 (d, J = 11.1 Hz, 1H), 4.82 (t, J = 9.5 Hz, 1H), (101 MHz, CDCl3) δ 133.87 (t, J = 2.0 Hz), 133.62 (s), 129.81 (s),
3.04 (brs, 1H); 13C NMR (101 MHz, CDCl3) δ 162.87 (d, J = 129.39 (t, J = 25.8 Hz), 129.37 (m), 129.30 (s), 126.81 (s), 121.66
247.1 Hz), 131.81 (s), 129.39 (d, J = 8.1 Hz), 129.15 (t, J = (t, J = 9.3 Hz), 119.49 (t, J = 245.6 Hz), 71.38 (t, J = 29.5 Hz);
25.7 Hz), 121.74 (t, J = 9.2 Hz), 119.46 (t, J = 244.2 Hz), 115.05 19F NMR (376 MHz, CDCl3) δ −109.44 (dt, J = 244.8, 10.6 Hz,
(d, J = 21.5 Hz), 75.16 (t, J = 30.3 Hz); 19F NMR (282 MHz, 1F), −110.17 (dt, J = 244.8, 11.3 Hz, 1F); IR (neat) ν = 3452,
CDCl3) δ −108.52 (dd, J = 245.3, 10.4 Hz, 1F), −109.59 1443, 1421, 1134, 1071, 1035, 995, 753 cm−1; GCMS(EI) calcd
to −110.89 (m, 1F), −113.26 to −114.08 (m, 1F); IR (neat) ν = for C10H9ClF2O [M]+ 218.0; found 218.1. Anal. calcd for
3441, 1607, 1513, 1422, 1228, 1159, 1068, 995 cm−1; HRMS(EI) C10H9ClF2O: C, 54.94; H, 4.15; found C, 54.83; H, 4.26.
calcd for C10H9F3O [M]+ 202.0605; found 206.0604.
1-(2-Ethoxyphenyl)-2,2-difluorobut-3-en-1-ol (1k). 71% yield.
1-(4-Chlorophenyl)-2,2-difluorobut-3-en-1-ol (1f). 77% yield. Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 7.37–7.30 (m,
Colorless liquid. 1H NMR (300 MHz, CDCl3) δ 7.42–7.30 (m, 1H), 7.29–7.18 (m, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.83 (d, J =
4H), 5.93–5.73 (m, 1H), 5.58 (d, J = 17.3 Hz, 1H), 5.48 (d, J = 8.3 Hz, 1H), 5.99–5.83 (m, 1H), 5.56 (d, J = 17.4 Hz, 1H), 5.37
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 581–588 | 585

View Article Online
Paper
Organic & Biomolecular Chemistry
(d, J = 11.1 Hz, 1H), 5.11–5.25 (m, 1H), 4.09–3.64 (m, 3H), 1.36
(Z)-2-Fluoro-1-phenylbut-2-en-1-one (2a). 59% yield. Color-
(t, J = 6.4 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 156.57 (s), less liquid. 1H NMR (400 MHz, CDCl3) δ 7.86–7.72 (m, 2H),
130.35 (t, J = 25.9 Hz), 129.47 (s), 129.38 (s), 124.22 (s), 120.42 7.62–7.51 (m, 1H), 7.51–7.39 (m, 2H), 6.09 (dq, J = 33.8, 7.3 Hz,
(s), 120.31 (t, J = 9.1 Hz), 120.22 (t, J = 248.9 Hz), 111.71 (s), 1H), 1.89 (dd, J = 7.3, 2.9 Hz, 3H); 13C NMR (101 MHz, CDCl3)
71.33–71.11 (m), 63.84 (s), 14.51 (s); 19F NMR (282 MHz, δ 187.39 (d, J = 27.8 Hz), 155.96 (d, J = 260.2 Hz), 136.17 (s),
CDCl3) δ −109.47 (dt, J = 251.0, 11.3 Hz, 1F), −110.58 (dt, J = 132.65 (s), 129.11 (d, J = 3.5 Hz), 128.28 (s), 119.39 (d, J = 13.4
244.2, 12.1 Hz, 1F); IR (neat) ν = 3449, 2983, 1589, 1495, 1420, Hz), 10.05 (d, J = 5.1 Hz); 19F NMR (376 MHz, CDCl3) δ −125.37
1122, 1046, 755 cm−1; HRMS(EI) calcd for C12H14F2O2 [M]+ (d, J = 33.4 Hz); IR (neat) ν = 3066, 1724, 1670, 1449, 1276,
228.0962; found 228.0961.
1168, 1001, 716 cm−1; HRMS(EI) calcd for C10H9FO [M]+
2,2-Difluoro-1-(naphthalen-2-yl)but-3-en-1-ol (1l). 58% yield. 164.0637; found 164.0636.
White solid. 1H NMR (400 MHz, CDCl3) δ 7.93–7.76 (m, 4H),
(Z)-Methyl 3-(2-fluorobut-2-enoyl)benzoate (2b). 85% yield.
7.60–7.43 (m, 3H), 5.99–5.76 (m, 1H), 5.66–5.52 (m, 1H), 5.44 Colorless liquid. 1H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 8.23
(d, J = 11.1 Hz, 1H), 5.06 (t, J = 9.5 Hz, 1H), 2.45 (brs, 1H); 13C (d, J = 7.8 Hz, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.56 (t, J = 7.8 Hz,
NMR (101 MHz, CDCl3) δ 133.53–133.36 (m), 132.87 (s), 129.36 1H), 6.14 (dq, J = 33.7, 7.3 Hz, 1H), 3.95 (s, 3H), 1.92 (dd, J =
(t, J = 25.6 Hz), 128.15 (s), 127.88 (s), 127.64 (s), 127.09 (s), 7.3, 2.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 186.24 (d, J =
126.39 (s), 126.23 (s), 124.99 (s), 121.64 (t, J = 9.2 Hz), 119.70 (t, 28.7 Hz), 165.92 (s), 155.75 (d, J = 260.4 Hz), 136.33 (s), 133.37
J = 244.9 Hz), 76.00(t, J = 29.3 Hz); 19F NMR (376 MHz, CDCl3) (s), 133.19 (d, J = 3.6 Hz), 130.32 (s), 130.09 (d, J = 4.1 Hz),
δ −107.59 (dt, J = 246.8, 10.4 Hz, 1F), −108.48 to −109.27 (m, 128.56 (s), 119.64 (d, J = 13.3 Hz), 52.28 (s), 10.06 (d, J =
1F); IR (neat) ν = 3442, 2892, 1509, 1420, 1206, 1068, 994, 5.0 Hz); 19F NMR (376 MHz, CDCl3) δ −125.49 (d, J = 34.4 Hz);
804 cm−1; HRMS(EI) calcd for C14H12F2O [M]+ 234.0856; found IR (neat) ν = 2953, 1726, 1700, 1437, 1303, 1211, 1081,
234.0859.
732 cm−1; HRMS(EI) calcd for C12H11FO3 [M]+ 222.0692; found
1-(Benzo[b]thiophen-3-yl)-2,2-difluorobut-3-en-1-ol
(1m). 222.0690.
67% yield. Yellow liquid. 1H NMR (400 MHz, CDCl3) δ
(Z)-2-Fluoro-1-(4-(methylsulfonyl)phenyl)but-2-en-1-one (2c).
1
7.86–7.73 (m, 2H), 7.48 (s, 1H), 7.39–7.24 (m, 2H), 5.98–5.78 73% yield. Yellow solid. H NMR (400 MHz, CDCl3) δ 8.05 (d, J
(m, 1H), 5.67–5.52 (m, 1H), 5.46–5.32 (m, 1H), 5.20 (t, J = 9.5 = 8.0 Hz, 2H), 7.96 (d, J = 8.0 Hz, 2H), 6.17 (dq, J = 33.5, 7.3 Hz,
Hz, 1H), 2.97 (brs, 1H); 13C NMR (101 MHz, CDCl3) δ 140.25 1H), 3.10 (s, 3H), 1.93 (dd, J = 7.3, 2.6 Hz, 3H); 13C NMR
(s), 137.66 (s), 131.48 (s), 129.48 (t, J = 25.6 Hz), 126.26 (s), (101 MHz, CDCl3) δ 185.90 (d, J = 29.4 Hz), 155.57 (d, J = 260.1
124.61 (s), 124.32 (s), 122.75 (s), 122.59 (s), 121.80 (t, J = 9.2 Hz), 143.69 (s), 140.64 (s), 129.88 (d, J = 3.8 Hz), 127.45 (s),
Hz), 119.71 (t, J = 244.9 Hz), 71.32 (t, J = 31.2 Hz); 19F NMR 120.89 (d, J = 13.0 Hz), 44.24 (s), 10.27 (d, J = 4.9 Hz); 19F NMR
(376 MHz, CDCl3) δ −106.83 (dt, J = 247.1, 10.2 Hz, 1F), (376 MHz, CDCl3) δ −126.05 (d, J = 33.4 Hz); IR (neat) ν = 2921,
−107.90 to −108.86 (m, 1F); IR (neat) ν = 3449, 1427, 1143, 1690, 1399, 1291, 1152, 1085, 750 cm−1; HRMS(EI) calcd for
1099, 1065, 993, 958, 767 cm−1 LRMS(ESI) calcd for C11H11FO3S [M]+ 242.0413; found 242.0408.
C12H10F2OS [M + Na]+ 263.0; found 263.0. Anal. calcd for
C12H10F2OS: C, 59.99; H, 4.20; found C, 59.91; H, 4.57.
(Z)-2-Fluoro-1-(3-(trifluoromethyl)phenyl)but-2-en-1-one (2d).
57% yield. Colorless liquid. H NMR (400 MHz, CDCl3) δ 8.07
1
4,4-Difluoro-1-phenylhex-5-en-3-ol (1n). 34% yield. Colorless (s, 1H), 8.00 (d, J = 7.8 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.61 (t,
liquid. 1H NMR (400 MHz, CDCl3) δ 7.32–7.26 (m, 2H), J = 7.8 Hz, 1H), 6.17 (dq, J = 33.5, 7.3 Hz, 1H), 1.92 (dd, J = 7.3,
7.23–7.11 (m, 3H), 6.04–5.84 (m, 1H), 5.76–5.60 (m, 1H), 5.53 2.8 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 185.77 (d, J = 29.3
(d, J = 11.1 Hz, 1H), 3.82–3.72 (m, 1H), 2.97–2.87 (m, 1H), Hz), 155.83 (d, J = 260.7 Hz), 136.68 (s), 132.37 (d, J = 4.2 Hz),
2.80–2.64 (m, 1H), 1.98–1.85 (m, 2H), 1.84–1.68 (m, 1H); 19F 131.02 (q, J = 33.2 Hz), 129.20 (q, J = 3.6 Hz), 129.04 (s),
NMR (376 MHz, CDCl3) δ −108.31 to −109.18 (m, 1F), −111.75 126.16–125.94 (m), 123.54 (d, J = 272.6 Hz), 119.82 (d, J = 13.2
to −112.58 (m, 1F).
Hz), 10.18 (d, J = 5.0 Hz); 19F NMR (376 MHz, CDCl3) δ −62.90
(s, 3F), −125.55 (d, J = 33.4 Hz, 1F); IR (neat) ν = 2928, 1674,
1645, 1437, 1265, 1164, 1131, 750 cm−1; HRMS(EI) calcd for
C11H8F4O [M]+ 232.0511; found 232.0506.
General experimental procedure for the synthesis of α-fluoro-
α,β-unsaturated ketone derivatives
(Z)-2-Fluoro-1-(4-fluorophenyl)but-2-en-1-one
(2e). 77%
1
In a glove box, Rh(PPh3)3Cl (19.6 mg, 0.025 mmol), PPh3 yield. White solid. H NMR (400 MHz, CDCl3) δ 7.97–7.77 (m,
(26.2 mg, 0.2 mmol) and 4 Å MS (100 mg) were added to a 2H), 7.13 (t, J = 8.6 Hz, 2H), 6.12 (dq, J = 33.9, 7.3 Hz, 1H), 1.89
sealed tube, then DMF (1.5 mL) and dioxane (0.5 mL) were (dd, J = 7.3, 2.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 185.54
added. Compound 1 (0.5 mmol) was added to the mixture. (d, J = 28.9 Hz), 165.48 (d, J = 254.8 Hz), 156.03 (d, J = 261.2
The tube was sealed and the mixture was stirred at 120 °C for Hz), 132.27 (d, J = 2.4 Hz), 131.91 (dd, J = 9.2, 4.6 Hz), 118.65
3 h. The stereoselectivity was determined by 19F NMR before (d, J = 13.3 Hz), 115.53 (d, J = 21.9 Hz), 10.00 (d, J = 5.2 Hz); 19
F
the reaction was quenched with water (30 mL). The mixture NMR (376 MHz, CDCl3) δ −105.09 to −105.21 (m, 1F), −124.74
was extracted with 50 mL Et2O. The Et2O solution was washed (d, J = 34.0 Hz, 1F); IR (neat) ν = 1667, 1648, 1603, 1336, 1169,
with brine (20 mL × 3), and then dried over Na2SO4. The 1088, 847 cm−1; HRMS(EI) calcd for C10H8F2O [M]+ 182.0543;
solvent was removed under reduced pressure and the residue found 182.0546; Anal. calcd for C10H8F2O: C, 65.93; H, 4.43;
was purified by flash chromatography to afford the product 2.
found C, 66.20; H, 4.58.
586 | Org. Biomol. Chem., 2014, 12, 581–588
This journal is © The Royal Society of Chemistry 2014

View Article Online
Organic & Biomolecular Chemistry
Paper
(Z)-1-(4-Chlorophenyl)-2-fluorobut-2-en-1-one
(2f). 71% 9.1, 2.0 Hz, 2H), 6.65 (d, J = 9.1 Hz, 2H), 5.81 (dq, J = 22.9,
yield. Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.78 (d, J = 8.3 7.7 Hz, 1H), 3.06 (s, 6H), 1.86 (dd, J = 7.7, 2.8 Hz, 3H);
Hz, 2H), 7.44 (d, J = 8.3 Hz, 2H), 6.12 (dq, J = 33.7, 7.3 Hz, 1H), 13C NMR (101 MHz, CDCl3) δ 185.65 (d, J = 31.9 Hz), 155.02 (d,
1.90 (dd, J = 7.3, 2.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ J = 257.7 Hz), 153.65 (s), 131.86 (d, J = 5.3 Hz), 123.60 (d, J =
185.86 (d, J = 29.3 Hz), 155.87 (d, J = 260.8 Hz), 139.19 (s), 3.5 Hz), 113.10 (d, J = 20.2 Hz), 110.54 (s), 39.89 (s), 11.14 (d,
134.29 (s), 130.63 (d, J = 4.3 Hz), 128.64 (s), 119.14 (d, J = 13.1 J = 7.1 Hz); 19F NMR (376 MHz, CDCl3) δ −110.27 (d, J =
Hz), 10.07 (d, J = 5.1 Hz); 19F NMR (376 MHz, CDCl3) δ −125.12 22.8 Hz); IR (neat) ν = 2920, 1594, 1548, 1437, 1374, 1350,
(d, J = 33.8 Hz); IR (neat) ν = 2925, 1670, 1588, 1402, 1283, 1259, 1191 cm−1
;
HRMS(EI) calcd for C12H14NFO [M]+
1093, 929, 755 cm−1; HRMS(EI) calcd for C10H8ClFO [M]+ 207.1059; found 207.1056.
198.0248; found 198.0247.
(Z)-2-Fluoro-1-(naphthalen-2-yl)but-2-en-1-one
(2g). 53% yield. Colorless oil. H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H),
(2l). 87%
1
(Z)-1-(3-Bromophenyl)-2-fluorobut-2-en-1-one
1
yield. Colorless oil. H NMR (400 MHz, CDCl3) δ 7.94–7.90 (m, 7.94–7.78 (m, 4H), 7.54 (dt, J = 18.8, 7.3 Hz, 2H), 6.14 (dq, J =
1H), 7.75–7.67 (m, 2H), 7.34 (t, J = 7.9 Hz, 1H), 6.13 (dq, J = 33.9, 7.3 Hz, 1H), 1.90 (dd, J = 7.3, 2.8 Hz, 3H); 13C NMR
33.6, 7.3 Hz, 1H), 1.91 (dd, J = 7.3, 2.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 187.08 (d, J = 27.9 Hz), 156.15 (d, J =
(101 MHz, CDCl3) δ 185.71 (d, J = 28.8 Hz), 155.73 (d, J = 260.6 260.8 Hz), 135.20 (s), 133.30 (s), 132.08 (s), 130.73 (d, J =
Hz), 137.88 (s), 135.59 (s), 132.03 (d, J = 4.0 Hz), 129.92 (s), 4.9 Hz), 129.29 (s), 128.36 (s), 128.19 (s), 127.66 (s), 126.76 (s),
127.70 (d, J = 4.1 Hz), 122.52 (s), 119.83 (d, J = 13.3 Hz), 10.17 124.88 (d, J = 2.8 Hz), 119.04 (d, J = 13.4 Hz), 10.04 (d, J =
(d, J = 5.0 Hz); 19F NMR (376 MHz, CDCl3) δ −125.48 (d, J = 33. 5.1 Hz); 19F NMR (376 MHz, CDCl3) δ −124.64 (d, J = 34.0 Hz);
6 Hz); IR (neat) ν = 2913, 1670, 1645, 1560, 1284, 1266, IR (neat) ν = 3060, 1665, 1627, 1281, 1001, 820, 774 cm−1
743 cm−1; HRMS(EI) calcd for C10H8BrFO [M]+ 241.9743; HRMS(EI) calcd for C14H11FO [M]+ 214.0794; found 214.0796;
;
found 241.9741.
(Z)-1-(4-(Benzyloxy)phenyl)-2-fluorobut-2-en-1-one
62% yield. Colorless oil. H NMR (400 MHz, CDCl3) δ 7.85 (d,
Anal. calcd for C14H11FO: C, 78.49; H, 5.18; found C,78.60;
(Z-2h). H, 5.24.
(Z)-1-(Benzo[b]thiophen-3-yl)-2-fluorobut-2-en-1-one
1
(2m).
J = 7.8 Hz, 2H), 7.49–7.28 (m, 5H), 7.00 (d, J = 8.8 Hz, 2H), 6.06 52% yield. Colorless oil. 1H NMR (400 MHz, CDCl3) δ
(dq, J = 34.2, 7.3 Hz, 1H), 5.11 (s, 2H), 1.86 (dd, J = 7.3, 2.8 Hz, 8.57–8.51 (m, 1H), 8.37 (d, J = 2.0 Hz, 1H), 7.87–7.84 (m, 1H),
3H); 13C NMR (101 MHz, CDCl3) δ 185.60 (d, J = 28.3 Hz), 7.51–7.44 (m, 1H), 7.43–7.37 (m, 1H), 6.23 (dq, J = 34.3, 7.3 Hz,
162.52 (s), 156.29 (d, J = 261.6 Hz), 136.00 (s), 131.72 (d, J = 1H), 1.88 (dd, J = 7.3, 2.9 Hz, 3H); 13C NMR (101 MHz, CDCl3)
4.7 Hz), 128.81 (s), 128.61 (s), 128.17 (s), 127.40 (s), 117.54 (d, δ 180.17 (d, J = 29.3 Hz), 156.67 (d, J = 262.8 Hz), 139.23 (s),
J = 13.5 Hz), 114.42 (s), 70.04 (s), 9.93 (d, J = 5.2 Hz); 19F NMR 137.82 (d, J = 14.3 Hz), 137.26 (s), 132.17 (d, J = 1.9 Hz), 125.65
(376 MHz, CDCl3) δ −124.03 (d, J = 34.1 Hz); IR (neat) ν = 1646, (s), 125.51 (s), 124.93 (s), 122.17 (s), 116.82 (d, J = 13.5 Hz),
1603, 1259, 1163, 933, 838, 762 cm−1; HRMS(EI) calcd for 9.93 (d, J = 5.4 Hz); 19F NMR (376 MHz, CDCl3) δ −125.07 (d,
C17H15FO2 [M]+ 270.1056; found 270.1053.
J = 34.3 Hz); IR (neat) ν = 1647, 1628, 1490, 1459, 1422, 1233,
(E)-1-(4-(Benzyloxy)phenyl)-2-fluorobut-2-en-1-one
(E-2h). 768 cm−1; HRMS(EI) calcd for C12H9FOS [M]+ 220.0358; found
12% yield. Colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.91 (dd, 220.0361.
J = 8.9, 2.0 Hz, 2H), 7.46–7.29 (m, 5H), 7.01 (d, J = 8.9 Hz, 2H),
(Z)-4-Fluoro-1-phenylhex-4-en-3-one (2nA). 53% yield. Color-
5.91 (dq, J = 23.0, 7.7 Hz, 1H), 5.12 (s, 2H), 1.91 (dd, J = 7.7, less oil. Contaminated with 10% 2nB. 1H NMR (400 MHz,
2.9 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 186.49 (d, J = CDCl3) δ 7.31–7.24 (m, 2H), 7.22–7.15 (m, 3H), 6.08 (dq, J =
33.6 Hz), 162.90 (s), 154.53 (d, J = 256.8 Hz), 136.03 (s), 131.85 34.1, 7.3 Hz, 1H), 2.98–2.88 (m, 4H), 1.77 (dd, J = 7.3, 2.9 Hz,
(d, J = 5.8 Hz), 129.16 (d, J = 4.2 Hz), 128.65 (s), 128.22 (s), 3H); 13C NMR (101 MHz, CDCl3) δ 192.78 (d, J = 31.0 Hz),
127.43 (s), 115.57 (d, J = 20.0 Hz), 114.54 (d, J = 0.9 Hz), 70.11 155.90 (d, J = 260.4 Hz), 140.71 (s), 128.49 (s), 128.34 (s),
(s), 11.31 (d, J = 6.8 Hz); 19F NMR (376 MHz, CDCl3) δ −111.71 126.18 (s), 114.36 (d, J = 13.1 Hz), 39.45 (s), 29.36 (s), 9.67 (d,
(d, J = 22.7 Hz); IR (neat) ν = 1674, 1599, 1509, 1252, 1169, J = 5.0 Hz); 19F NMR (376 MHz, CDCl3) δ −130.56 (d, J = 34.1
1096, 770 cm−1; HRMS(EI) calcd for C17H15FO2 [M]+ 270.1056; Hz); IR (neat) ν = 2925, 1660, 1454, 1300, 1199, 1119, 1002,
found 270.1055.
700 cm−1; HRMS(EI) calcd for C12H13OF [M]+ 192.0950; found
(Z)-1-(4-(Dimethylamino)phenyl)-2-fluorobut-2-en-1-one (Z-2i). 192.0951.
1
48% yield. Yellow oil. H NMR (400 MHz, CDCl3) δ 7.85 (d, J =
8.8 Hz, 2H), 6.63 (d, J = 8.8 Hz, 2H), 6.01 (dq, J = 35.2, 7.3 Hz,
1H), 3.04 (s, 6H), 1.85 (dd, J = 7.3, 2.9 Hz, 3H); 13C NMR
(101 MHz, CDCl3) δ 184.63 (d, J = 27.9 Hz), 156.86 (d, J =
Acknowledgements
263.0 Hz), 153.39 (s), 131.84 (d, J = 5.3 Hz), 123.10 (s), 115.30
(d, J = 13.6 Hz), 110.45 (s), 39.84 (s), 9.71 (d, J = 5.5 Hz); 19F We thank the National Natural Science Foundation (21032006,
NMR (376 MHz, CDCl3) δ −122.77 (d, J = 34.6 Hz); IR (neat) ν = 21172240), the 973 Program of China (2012CBA01200), the
2919, 1630, 1593, 1414, 1328, 1294, 1156, 996 cm−1; HRMS(EI) Chinese Academy of Sciences and the Syngenta PhD Student-
calcd for C12H14NFO [M]+ 207.1059; found 207.1057.
ship Award for financial support. We thank Dr John Clough of
(E)-1-(4-(Dimethylamino)phenyl)-2-fluorobut-2-en-1-one (E-2i). Syngenta at Jealott’s Hill International Research Centre for
45% yield. Yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.87 (dd, J = proof reading of the manuscript.
This journal is © The Royal Society of Chemistry 2014
Org. Biomol. Chem., 2014, 12, 581–588 | 587

View Article Online
Paper
Organic & Biomolecular Chemistry
3 (a) F. Babudri, G. M. Farinola, F. Naso and R. Ragni, Chem.
Commun., 2007, 1003; (b) S. Couve-Bonnaire, D. Cahard
and X. Pannecoucke, Org. Biomol. Chem., 2007, 5, 1151;
(c) F. Babudri, A. Cardone, G. M. Farinola, C. Martinelli,
R. Mendichi, F. Naso and M. Striccoli, Eur. J. Org. Chem.,
2008, 1977; (d) A. Choudhary and R. T. Raines, Chem-
BioChem, 2011, 12, 1801.
4 For recent reviews, please see: (a) G. Landelle, M. Bergeron,
M. O. Turcotte-Savard and J.-F. Paquin, Chem. Soc. Rev.,
2011, 40, 2867; (b) H. Yanai and T. Taguchi, Eur. J. Org.
Chem., 2011, 5939; (c) S. Hara, Top. Curr. Chem., 2012, 327,
59. For recent examples, please see: (d) X. Lin, F. Zheng
and F.-L. Qing, J. Org. Chem., 2012, 77, 8696; (e) L. Debien,
B. Quiclet-Sire and S. S. Zard, Org. Lett., 2012, 14, 5118;
(f) M. Bergeron, D. Guyader and J.-F. Paquin, Org. Lett.,
2012, 14, 5888; (g) C. Schneider, D. Masi, S. Couve-
Bonnaire, X. Pannecoucke and C. Hoarau, Angew. Chem.,
Int. Ed., 2013, 52, 3246; (h) A. Macé, F. Tripoteau, Q. Zhao,
E. Gayon, E. Vrancken, J.-M. Campagne and B. Carboni,
Org. Lett., 2013, 15, 906; (i) F. Larnaud, J. Malassis,
E. Pfund, B. Linclau and T. Lequeux, Org. Lett., 2013, 15,
2450.
Notes and references
1 (a) H. Amii and K. Uneyama, Chem. Rev., 2009, 109, 2119;
(b) R. P. Hughes, Eur. J. Inorg. Chem., 2009, 4591;
(c) A. Nova, R. Mas-Ballesté and A. Lledós, Organometallics,
2012, 31, 1245; (d) W. Rauf, A. Hazari, V. Gouverneur and
J. M. Brown, Pure Appl. Chem., 2010, 82, 1415; (e) A. D. Sun
and J. A. Love, Dalton Trans., 2010, 39, 10362; (f) T. Braun
and F. Wehmeier, Eur. J. Inorg. Chem., 2011, 613;
(g) E. Clot, O. Eisenstein, N. Jasim, S. A. Macgregor,
J. E. Mcgrady and R. N. Perutz, Acc. Chem. Res., 2011, 44,
333; (h) M. F. Kuehnel, D. Lentz and T. Braun, Angew.
Chem., Int. Ed., 2013, 52, 3328.
2 For recent examples, please see: (a) T. Braun,
M. A. Salomon, K. Altenhoner, M. Teltewskoi and S. Hinze,
Angew. Chem., Int. Ed., 2009, 48, 1818; (b) Y. Laot, L. Petit
and S. Zard, Org. Lett., 2010, 12, 3426; (c) M. Teltewskoi,
J. A. Panetier, S. A. Macgregor and T. Braun, Angew. Chem.,
Int. Ed., 2010, 49, 3947; (d) M. Takachi, Y. Kita, M. Tobisu,
Y. Fukumoto and N. Chatani, Angew. Chem., Int. Ed., 2010,
49, 8717; (e) M. Ohashi, T. Kambara, T. Hatanaka, H. Saijo,
R. Doi and S. Ogoshi, J. Am. Chem. Soc., 2011, 133, 3256;
(f) H. Lv, J.-H. Zhan, Y.-B. Cai, Y.-B. Yu, B. Wang and
J.-L. Zhang, J. Am. Chem. Soc., 2012, 134, 16216;
(g) E. Benedetto, M. Keita, M. Tredwell, C. Hollingworth,
J. M. Brown and V. Gouverneur, Organometallics, 2012, 31,
1408; (h) B. M. Kraft, R. J. Lachicotte and W. D. Jones,
J. Am. Chem. Soc., 2000, 122, 8559; (i) J. Choi, D. Y. Wang,
S. Kundu, Y. Choliy, T. J. Emge, K. Krogh-Jespersen and
A. S. Goldman, Science, 2011, 332, 1545; ( j) G. Blessley,
P. Holden, M. Walker, J. M. Brown and V. Gouverneur, Org.
Lett., 2012, 14, 2754; (k) A. Hazari, V. Gouverneur and
J. M. Brown, Angew. Chem., Int. Ed., 2009, 48, 1296;
(l) L. Hintermann, F. Läng, P. Maire and A. Togni,
5 J.-F. Paquin, Synlett, 2011, 289.
6 H. Zhang, C.-B. Zhou, Q.-Y. Chen, J.-C. Xiao and R. Hong,
Org. Lett., 2011, 13, 560.
7 (a) W. Chang, R. T. Mosley, S. Bansal, M. Keilman,
A. M. Lam, P. A. Furman, M. J. Otto and M. J. Sofia, Bioorg.
Med. Chem. Lett., 2012, 22, 2938; (b) T. Takagaki, T. Bando
and H. Sugiyama, J. Am. Chem. Soc., 2012, 134, 13074.
8 M. Kirihara, T. Takuwa, S. Takizawa, T. Momose and
H. Nemoto, Tetrahedron, 2000, 56, 8275.
9 N. S. Townsend, A. B. Chaplin, M. A. Naser,
A. L. Thompson, N. H. Rees, S. A. Macgregor and
A. S. Weller, Chem.–Eur. J., 2010, 16, 8376.
Eur. J. Inorg. Chem., 2006, 1397; (m) B. M. Kraft and 10 The structure of the product 2e was determined by single
W. D. Jones, J. Am. Chem. Soc., 2002, 124, 8681;
(n) M. F. Kuehnel, P. Holstein, M. Kliche, J. Kruger,
crystal X-ray diffraction (see ESI†). Summary of Data CCDC
929445.
S. Matthies, D. Nitsch, J. Schutt, M. Sparenberg and 11 C.-H. Jun, C.-W. Huh and S.-J. Na, Angew. Chem., Int. Ed.,
D. Lentz, Chem.–Eur. J., 2012, 18, 10701; (o) X. Pigeon, 1998, 37, 145.
M. Bergeron, F. Barabé, P. Dubé, H. N. Frost and 12 C. Pubill-Ulldemolins, M. Poyatos, C. Bo and E. Fernandez,
J.-F. Paquin, Angew. Chem., Int. Ed., 2010, 49, 1123; Dalton Trans., 2013, 42, 746.
(p) T. Stahl, H. F. T. Klare and M. Oestreich, J. Am. Chem. 13 L. Verbit, Synthesis, 1972, 254.
Soc., 2013, 135, 1248; (q) T. Narumi, K. Tomita, 14 P. A. Evans and J. D. Nelson, J. Am. Chem. Soc., 1998, 120,
E. Inokuchi, K. Kobayashi, S. Oishi, H. Ohno and N. Fujii,
Org. Lett., 2007, 9, 3465; (r) T. Miura, Y. Ito and 15 D. Basavaiah and G. Veeraraghavaiah, Chem. Soc. Rev.,
M. Murakami, Chem. Lett., 2008, 37, 1006. 2012, 41, 68.
5581.
588 | Org. Biomol. Chem., 2014, 12, 581–588
This journal is © The Royal Society of Chemistry 2014