Suzuki-Miyaura coupling reactions of iodo(difluoroenol) derivatives, fluorinated building blocks accessible at near-ambient temperatures

Article abstract of DOI:10.1021/jo3011705

A recently developed method for the near-ambient generation of difluorovinylzinc reagents has facilitated the preparation of 1-(N,N-diethylcarbamoyloxy)-2,2-difluoro-1-iodoethene and 2,2-difluoro-1-iodo-1- (2′-methoxyethoxymethoxy)ethene. The utility of these reagents has been investigated in Suzuki-Miyaura couplings with a range of potassium trifluoroborate coupling partners, with the scope of successful couplings proving wide. Deiodinated species appeared as significant side products, but a solvent change from i-PrOH to t-BuOH suppressed the pathway to these species and improved coupling yields.

Full text of DOI:10.1021/jo3011705

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Suzuki−Miyaura Coupling Reactions of Iodo(difluoroenol)
Derivatives, Fluorinated Building Blocks Accessible at Near-Ambient
Temperatures
Peter G. Wilson,† Jonathan M. Percy,*,† Joanna M. Redmond,‡ and Adam W. McCarter†
†WestCHEM Department of Pure and Applied Chemistry, University of Strathclyde, Thomas Graham Building, 295 Cathedral Street,
Glasgow G1 1XL, U.K.
‡Respiratory TA, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage SG1 2NY, U.K.
S
* Supporting Information
ABSTRACT: A recently developed method for the near-
ambient generation of difluorovinylzinc reagents has facilitated
the preparation of 1-(N,N-diethylcarbamoyloxy)-2,2-difluoro-
1 - i o d o e t h e n e a n d 2 , 2 - d i fl u o r o - 1 - i o d o - 1 - ( 2 ′ -
methoxyethoxymethoxy)ethene. The utility of these reagents
has been investigated in Suzuki−Miyaura couplings with a
range of potassium trifluoroborate coupling partners, with the
scope of successful couplings proving wide. Deiodinated species appeared as significant side products, but a solvent change from
i-PrOH to t-BuOH suppressed the pathway to these species and improved coupling yields.
Scheme 1. Applications of Building Blocks Derived from
Trifluoroethanol
INTRODUCTION
■
Modern synthetic organic chemistry is subject to an expanding
range of pressures which constrain the starting materials it can
use and the range of reaction conditions it can deploy. While
the use of low-temperature conditions can deliver high
selectivity, cryogenic methods are expensive when carried out
on a large scale, and reactions which avoid their use are often
preferred. It follows that there is considerable interest in
carrying out many of the important reactions of synthetic
organic chemistry at, or close to, ambient temperatures.
The synthesis of selectively difluorinated molecules is an area
of high current activity; recent achievements include new
methods for the difluoromethylation of arenes1 and hetero-
arenes2 and novel difluoroenolate chemistry described by Colby
et al.3 which installs a difluoromethylene unit. There are many
strategies for the synthesis of difluorinated molecules from
building blocks, small commercial molecules which already
contain the required fluorine atoms.4 Trifluoroethanol 1a is an
extremely versatile starting material for the synthesis of a wide
range of selectively fluorinated molecules. Protection, followed
by dehydrofluorination/metalation begins to transform this
bulk chemical into valuable organometallic intermediates.5−9 In
our hands, this approach has been exploited in coupling10−12
and cycloaddition13−15 reactions, and rearrangement/ring-
closing metathesis sequences16−22 (Scheme 1) to afford
analogues of a range of saccharide, cyclitol, and azasugar
natural products including 2−5.
utilizing trifluoroborate 6 published by Katz and co-workers23
as extremely important and welcome (Figure 1).
Figure 1. Katz and co-workers’ potassium trifluoroborate.
Trifluoroborate 6 was prepared and used in Suzuki−Miyaura
couplings;23 although a low-temperature procedure was still
required to prepare 6, the avoidance of tin reagents was a
significant development. We have recently developed a
sequence in which dehydrofluorination/metalation chemistry
of 1b and 1c can be carried out at close to ambient temperature
Our work relied on the use of low reaction temperatures,
typically −78 °C, though in the case of 1d, a reaction
temperature of −100 °C was required.16 In some cases,
organotin chemistry was used to deliver these difluoroalkenol
units into coupling reactions, so we saw the methodology
Received: June 6, 2012
© XXXX American Chemical Society
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and followed by a Negishi coupling reaction (Scheme 2).24−26
We were able to use the intermediate organozinc reagents in
Negishi coupling reactions to prepare a range of difluorinated
alkene products, in high yields in some cases.
Scheme 2. Generation and Negishi Coupling of Vinylzinc
Reagent 7
However, there were limitations to Negishi and Suzuki−
Miyaura methods, particularly with π-electron-deficient aryl
bromides. In some cases, HF addition was observed after
product formation, while in other cases coupling was
unsuccessful. We sought a method that would avoid low-
temperature conditions entirely, tolerate a wider range of
coupling partners, and use storable fluorinated intermediates. In
this paper, we wish to report complementary Suzuki−Miyaura
reactions of iodides 8a and 8b, which can be prepared at ice-
bath temperature (Scheme 3).
Figure 2. Potassium trifluoroborate coupling partners.
The coupling conditions were based initially on those
reported by Molander31 with a modest excess of boron reagent
(1.2 equivalents), (Ph3P)2PdCl2 (2 mol %) precatalyst, and
Cs2CO3 in a toluene/water mixture (2.7:1 v/v); the more
stable Pd(II) catalyst was found to be as effective as Pd(PPh3)4.
The excess reagent was required to convert the iodides 8a and
8b completely due to difficulty of separating unreacted iodide
from the products (Scheme 4).
Scheme 3. Ice-Bath Temperature Synthesis of Iodides 8a and
8b
Scheme 4. Suzuki−Miyaura Coupling of Iodides 8a and 8b
RESULTS AND DISCUSSION
■
We prepared 5 g batches of known27 8b by this method; 2.5
equiv of LDA was added dropwise to a solution of 1c and
ZnCl2 in THF at 0 °C to afford zinc species 7. A solution of I2
in THF was then added via syringe to quench vinylzinc 7; after
workup, the crude iodide was purified by filtration through a
plug of silica followed by Kugelrohr distillation to afford iodide
8b in 71% yield. The preparation of iodide 8a was less efficient,
with 50% the highest yield obtained (for a 3 g batch). The same
procedure was observed, but a short contact time between the
zinc reagent and iodine was essential for this yield; times of 1 h
and longer significantly reduced the yield of iodide 8a (cf.
25%). Addition of DMPU cosolvent was necessary for a
respectable yield of 8a; the urea cosolvent ensures full
conversion of 1b to the organozinc intermediate.24 Both
iodides were found to be stable after purification and could be
stored under N2 in the refrigerator without decomposition (3
months). Discoloration of the materials was observed when
they were stored at room temperature.
Full conversion of the iodide occurred over 2 h at 90 °C with
a number of electron-rich potassium aryltrifluoroborates,
producing products in good to excellent yields (Table 1;
entries 2, 12, and 14). Not all borates coupled successfully
under these conditions, with solubility appearing to be limiting
in some cases, prompting a search for more general conditions.
To improve borate solubility, more polar solvents were
investigated; alcohols were chosen as relatively sustainable
candidates.35 The 3-nitrophenyl borate 9n was chosen to
optimize the reaction conditions as products 10an and 10bn
are difficult compounds to generate in good yield (as we24 and
others23,26 have found in previous work). Borate 9n, iodide 8b,
Cs2CO3 (3 equiv), and (Ph3P)2PdCl2 (2 mol %) dissolved fully
in an alcohol (n-PrOH, i-PrOH, or t-BuOH)/water (2.7:1)
mixture at 90 °C. Iodide 8b was consumed completely in all
alcoholic solvent systems, but differing ratios of side products
were observed in each case. When n-PrOH was used, addition,
addition/elimination, and reduced species 11, 12, and 13 were
generated in a 4:1:10 ratio (Figure 3). Changing to i-PrOH
removed addition and addition/elimination products 11 and
12, but 13 was now the major product. Only a small reduction
in the amount of 13 produced was observed when the i-PrOH
was degassed by using the freeze−pump−thaw method.
We chose potassium trifluoroborate coupling partners to
probe the scope of our iodide species in Suzuki−Miyaura
coupling because of the reported superior stability and efficacy
of these reagents over the more traditional boronic acids,
exemplified by the wide range of couplings performed by
Molander and co-workers.28−32 These stable salts were
generated in moderate to excellent (51−99%) yields from the
boronic acids following literature procedures (Figure 2).33,34
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Table 1. Scope of Suzuki−Miyaura Coupling of 8a and 8b with Potassium Trifluoroborate Salts*
*
Method 1: (Ph3P)2PdCl2 (2 mol %), Cs2CO3 (3 equiv), potassium trifluoroborate (1.2 equiv), toluene/H2O (2.7:1), 90 °C. Method 2:
(Ph3P)2PdCl2 (2 mol %), Cs2CO3 (3 equiv), potassium trifluoroborate (1.2 equiv), i-PrOH/H2O (freeze−pump−thaw) (2.7:1) 90 °C. Method 3:
a
(Ph3P)2PdCl2 (2 mol %), Cs2CO3 (3 equiv), potassium trifluoroborate (1.2 equiv), t-BuOH/H2O (2.7:1), 90 °C. Estimated yield: product
contaminated with ∼1% of 13 and ∼1% of 8a. Estimated yield: product contaminated with ∼5% of 13 and ∼4% of 8b.
b
In the former, iodide is displaced by generic boronic acid 16,
formed in situ from the trifluoroborate36 before transmetalation
in a monophosphine cycle.37 In the latter, alcohol coordination
is followed by elimination38 of HI followed by β-hydride
elimination39 to form an hydridopalladium complex; reductive
elimination then releases 13. Similar reactions were reported by
Helquist during the palladium-catalyzed dehalogenation of
arenes40 and Buchwald and co-workers41 in palladium-catalyzed
ether formation. Suzuki couplings carried out in solvents which
lack protons α-to oxygen should therefore be free from
formation of 13, with t-BuOH the obvious choice of solvent.
On substitution of i-PrOH with t-BuOH, the coupling of
nitroborate 9n now proceeded without formation of 13.
Figure 3. Side products arising from the Suzuki−Miyaura coupling.
Deiodinated 13 could arise from reductive elimination from a
palladium hydride complex such as 20, itself produced from β-
hydride elimination of palladium alkoxide 19 (Scheme 5). We
show key intermediate 15 which partitions between the
Suzuki−Miyaura coupling pathway and the reductive pathway.
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particular note as only ∼10% of 10bd could be isolated using
our Negishi procedure. Styrenes bearing an electron-with-
drawing group generally required the optimized t-BuOH
conditions and were generated more smoothly and in higher
yield than in the complementary Negishi protocol (entries 15−
26). Aldehydes 10am and 10bm, generated in 67% and 90%
yield, are exciting because they could not be generated at all
using the Negishi coupling method, and the formyl group is a
potential locus for diversity generation. Entries 25 and 26 show
formation of the reactive nitro congeners in good yield.
Pleasingly, iodides 8a and 8b coupled with heteroaryl borates
(entries 27−35) to afford species which were inaccessible via
the Negishi protocol. Entry 33 is of interest; borate 9r is a
relatively stable species that is effective in coupling reactions,43
and the pyridine product 10br contains an activated
difluoroalkenyl group, so its stability is pleasing. We also tried
to prepare 2-pyridyl trifluoroborate 23 from 2-bromopyr-
idine44,45 and from commercial 24 (treatment with KHF2 in
aqueous methanol)33,34 but were unsuccessful on both
occasions (Figure 4). A potential alternative coupling partner
is Burke’s MIDA boronate 25,46 but we were unable to secure
this species via the published procedure.47
Scheme 5. Proposed Catalytic Cycle for Generation of 13
However, it was necessary to keep the reaction time as short as
possible as HF addition product 14 was produced (due to the
strong electron-withdrawing effect of the nitro group). This HF
addition product was previously observed during our Negishi
coupling work24 and arises from LiF formed during the
generation of difluorovinylzinc reagent 7. Fluoride is also
formed from the trifluoroborate salts (vide infra), and HF
addition may therefore be a consequence of their use. However,
HF addition to afford adducts such as 14 only occurs when the
ring is strongly activated by the nitro group. After 18 h, styrene
10bn and 14 were formed in a 5:1 ratio, with a yield of 55% of
10bn. Shortening the reaction time to 4 h resulted in an
improved yield of 75% of 10bn. A similar trend was observed
when coupling 9n with 8a. A yield of 39% of 10an was
improved to 61% after reducing the reaction time from 18 to 4
h.
Figure 4. 2-Pyridyl borate 23 and boronate precursors 24 and 25.
These simple coupling conditions reached their limit of
effectiveness when nonaromatic borate coupling partners are
introduced. Vinyl borate 9t coupled with both iodides, but the
products were very difficult to separate from unreacted starting
material and side products because of their similar Rf ’s and
boiling points. Coupling of alkynyl and alkyl borates has failed
to date under these conditions, but efforts to couple sp and sp3
borates to 8a and 8b are ongoing in our laboratory.
The β-hydride pathway to 13 was confirmed by carrying out
the coupling of 8b and borate 9n in 1-deuterio-1-cyclohexanol
21 (Scheme 6).42
Scheme 6. Probing the Origin of Product 13
A precatalyst loading as low as 0.05 mol % of (Ph3P)2PdCl2
was tolerated in the coupling of 9g; a yield of 80% of 10bg was
obtained. Lowering the catalyst loading to 0.025 mol % resulted
in lower (40%) conversion to 10bg.48
A larger (5 mmol) scale coupling of iodide 8b under the
optimized conditions afforded 10bm in 82% yield after
chromatography, further enhancing the utility of this Suzuki−
Miyaura coupling protocol.
Product 10bn and deuterated species 22 were produced in a
∼3:1 ratio; the 19F NMR chemical shifts of 22 were distinct
from those of 13, and one of the fluorine nuclei showed a
splitting pattern consistent with the spin quantum number of
deuterium (I = 1) (see the Supporting Information for the
spectrum). The same reaction performed in cyclohexanol
produced 10bn and reduced species 13 in a ∼4:1 ratio,
suggesting strongly that there is no primary kinetic isotope
effect on the reaction. Neither β-hydride elimination nor
reductive elimination is likely to be the rate-determining step
for the side reaction. The different proportions of 13 and 22
may arise from the partitioning of 15 between the two ligand
exchange steps in Scheme 5.
Suzuki−Miyaura coupling reactions can use a range of boron
reagents; boronic acids are currently most readily available from
commercial sources, but the range of available potassium
trifluoroborate salts is growing. These reagents are easy to
prepare from the boronic acids, and they enjoy the distinct
advantages32 of higher integrity and stability over the boronic
acids, which can be supplied as complex mixtures (of
monomers, dimers, and trimers) and can deborylate on storage
and in reactions.44 Trifluoroborates are structurally unambig-
uous (making reaction stoichiometries easier to control and
reproduce) and nonhygroscopic. They release active boron
reagent slowly into solution,49 which can prevent buildup and
decomposition of boronic acids. We therefore prioritized the
potassium trifluoroborates as coupling partners for our
relatively valuable iodide species 8a and 8b. However, we
have also examined a selection of freshly purchased boronic
acids in Suzuki−Miyaura couplings with iodide 8b (Table 2).
The scope of the Suzuki coupling was investigated (Table 1).
Several results improved significantly upon our recently
published Negishi methodology.24 All electron-rich borates
coupled in good yield with substituents tolerated in all positions
of the benzene ring (entries 1−12). Entries 5 and 6 are of
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received unless otherwise stated. 1-(N,N-diethylcarbamoyloxy)-2,2,2-
trifluoroethane was prepared according to the method of Howarth,52
and 1-(2′-methoxyethoxymethoxy)-2,2,2-trifluoroethane was prepared
according to the method of Patel.53 Iodide 8b was prepared according
to the method of Percy.24 All trifluoroborates were generated from the
commercial boronic acids using the methods of Vedejs33 and
Molander34 (see the Supporting Information for characterization).
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-iodoethene (8a).
n-Butyllithium (26.09 mL, 2.3 M, 60 mmol) was added dropwise to
a solution of diisopropylamine (8.43 mL, 60 mmol) in THF (20 mL)
at 0 °C and the reaction stirred for 30 min at this temperature. The
freshly prepared LDA was added dropwise via cannula to a solution of
acetal 1b (3.76 g, 20 mmol), ZnCl2 (3.0 g, 22 mmol), and 1,3-
dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (10 mL) in THF (40
mL) at 0 °C. The yellow solution was stirred at 0 °C for 1 h and then
1 h further at room temperature. A solution of iodine (5.08 g in 25 mL
THF) was then added via syringe (a slight exotherm was observed, ca.
10 °C) and the orange solution stirred for 10 min. The solution was
quenched with aqueous ammonium chloride (60 mL) and extracted
with diethyl ether (2 × 100 mL). The organic extracts were combined,
washed with saturated sodium sulfite solution (100 mL), dried
(MgSO4) and concentrated under reduced pressure. The brown
residue was washed through a pad of silica (10% diethyl ether in
hexane), concentrated under reduced pressure, and distilled
(Kugelrohr, 70 °C/2 mbar) to afford iodide 8a (2.96 g, 50%) as a
colorless oil: Rf (40% diethyl ether in hexane) 0.39; IR νmax(film)/
cm−1 2937, 2894, 2829, 1774, 1735, 1457, 1285, 1181, 1155, 1101,
1075, 1026, 963, 911, 847; 1H NMR (400 MHz, CDCl3) δ (ppm) 4.88
(s, 2 H), 3.85−3.82 (m, 2 H), 3.61−3.58 (m, 2 H), 3.42 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 152.2 (dd, JC−F 296.4, 278.8), 96.0
(t, JC−F 3.1), 71.0, 68.6, 58.4; 19F NMR (376 MHz, CDCl3) δ (ppm)
−89.7 (d, J 49.2, 1 F), −100.6 (d, J 49.2, 1 F); LRMS (CI) m/z 262
[M−CH3O]+; GC (98%) tR 8.01 min. Compound decomposed before
accurate mass spectrometric measurements could be carried out off-
site.
Table 2. Scope of Suzuki−Miyaura Coupling of 8a and 8b
with Selected Boronic Acids
entry
boronic acid
product
yield (%)
1
2
3
4
5
6
7
8
4-OMe
10ba
10bh
10bl
83
92
74
60
75
0
4-CF3
3-CN
3-formyl
3-NO2
10bm
10bn
10bo
10bp
10bq
3-pyridyl
6′-Br-3-pyridyl
4-isoquinolyl
25
5
Entries 1−5 show that the boronic acids are also effective
coupling partners; entry 5 shows that the HF addition side
reaction is avoided with this most activated substrate but the
method gives a poor yield for entry 7 and fails entirely for
entries 6 and 8 (all boronic acids which deborylate relatively
easily50). It follows that the substrate scope is wider with the
potassium trifluoroborates, and we would recommend these as
the boron reagents, particularly if value has been added through
synthesis.
In conclusion, we have generated iodo(difluoroenol)
derivatives in useful, synthetic amounts using near-ambient
temperature conditions. Higher yields of these species were
obtained when contact time between the iodide products and
iodine was restricted. General conditions for the Suzuki−
Miyaura coupling of these species with potassium aryl- and
heteroaryltrifluoroborates and boronic acids at low palladium
catalyst loading were identified. These protocols yielded
product in moderate to excellent yield, overcoming a limitation
in scope described in previous publications and signaling a
further advance in the coupling of useful difluorovinyl units.51
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-iodoethene (8b). A
solution of iodine (2.54 g, 10 mmol in 10 mL of THF) was added
dropwise to alkenylzinc reagent 7 (40 mL of a 0.25 M solution in
THF) at 15 °C. The reaction mixture was stirred at this temperature
overnight. The reaction mixture was quenched with saturated aqueous
ammonium chloride (30 mL) and extracted with diethyl ether (2 × 40
mL). The organic extracts were combined, washed with saturated
sodium sulfite solution (40 mL), dried (MgSO4), and concentrated
under reduced pressure to a brown oil. Distillation afforded iodide 8b
(2.17 g, 71%) as a pale yellow oil: bp 50 °C/2 mmHg (Kugelrohr); 1H
NMR (400 MHz, CDCl3) δ (ppm) 3.39−3.25 (m, 4 H), 1.19 (br t, J
6.9, 6 H); 13C NMR (400 MHz, CDCl3) δ (ppm) 153.8(dd, JC−F
280.0, 297.7), 151.3, 60.7 (dd, JC−F 58.2, 27.4), 42.9, 42.0, 14.2, 13.2;
19F NMR (400 MHz, CDCl3) δ (ppm) −84.9 (d, J 42.3, 1 F), −98.5
EXPERIMENTAL SECTION
■
General Experimental Methods. All NMR spectra were
recorded on a 400 MHz spectrometer. 1H and 13C NMR spectra
were recorded using the deuterated solvent as the lock and the residual
solvent as the internal reference. 19F NMR spectra were recorded
relative to chlorotrifluoromethane as the external standard. The
multiplicities of the spectroscopic data are presented in the following
manner: s = singlet, d = doublet, t = triplet, q = quartet and m =
multiplet. Homocouplings (H−H, F−F) are given in hertz and
specified by J; the nuclei involved in heteronuclear couplings are
defined with the observed nucleus given first. HRMS measurements
were performed using an instrument with an ion trap. GC−MS spectra
were obtained on an instrument fitted with a DB5-type column (30 m
× 0.25 μm) running a 70−320 °C temperature program, ramp rate 20
°C min−1 with helium carrier gas flow at 1 cm3 min−1. LC−MS
measurements (ESI) were recorded on an instrument fitted with a C18
column (50 mm × 2.1 mm i.d. 1.7 μm packing diameter) running at
40 °C. Thin-layer chromatography was performed on precoated
aluminum-backed silica gel plates, and visualization was achieved using
potassium permanganate staining and UV detection at 254 nm.
Column chromatography was performed on silica gel (40−63 μm)
using a semi-automated system. IR spectra were recorded on an ATR
IR spectrometer. Melting points are uncorrected. Phase separation was
accomplished with proprietary fritted phase separators. Hexane was
distilled before chromatography. All other materials were used as
(d, J 42.3, 1 F). These data are consistent with those reported by Percy
and co-workers.52
General Coupling Procedure 1. 2,2-Difluoro-1-(2′-methoxye-
thoxymethoxy)-1-(4″-chlorophenyl)ethene (10ag). A mixture of
potassium trifluoroborate 9g (89 mg, 0.41 mmol), iodide 8a (100
mg, 0.34 mmol), cesium carbonate (332 mg, 1.0 mmol), and
bis(triphenylphosphino)palladium dichloride (4.8 mg, 0.0068 mmol)
was taken up in a mixture of toluene (0.75 mL) and H2O (0.275 mL).
The reaction mixture was stirred at 90 °C for 2 h. The reaction
mixture was then cooled to room temperature and partitioned
between DCM (10 mL) and H2O (10 mL). The organic phase was
separated and dried by passing through a hydrophobic frit. The solvent
was removed under reduced pressure, and the residue was purified by
flash column chromatography on silica (10% diethyl ether in hexane)
to afford styrene 10ag (68 mg, 72%) as a colorless oil: Rf (40% diethyl
1
ether in hexane) 0.44; H NMR (400 MHz, CDCl3) δ (ppm) 7.44−
7.35 (m, 4 H), 4.87 (s, 2 H), 3.88−3.84 (m, 2 H), 3.59−3.54 (m, 2 H),
3.39 (s, 3 H); 13C NMR (100 MHz, CDCl3) 155.0 (app t, JC−F 290.3),
133.6, 128.3, 128.0 (br d, JC−F 5.8), 127.5 (dd, JC−F 6.0, 3.4), 114.5
(dd, JC−F 35.3, 19.2), 95.0 (t, JC−F 3.0), 71.1, 68.1, 58.5; 19F NMR (376
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MHz, CDCl3) δ (ppm) −97.0 (d, J 54.5, 1 F), −105.4 (d, J 54.5, 1 F).
These data were consistent with those reported previously.20
289.4, 281.5), 131.2, 130.4, 119.9, 117.5 (br s), 111.7 (dd, JC−F 42.0,
19.8), 110.7, 93.6, 71.1, 67.4, 58.5, 55.2; 19F NMR (376 MHz, CDCl3)
δ (ppm) −100.1 (d, J 60.1, 1 F), −107.7 (d, J 60.1, 1 F); HRMS (NSI)
m/z calcd for C13H20F2NO4 [M + NH4]+ 292.1355, found 292.1358;
LRMS m/z (CI) 275 [M + H]+; GC (98%) tR 11.32 min.
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(4″-thioanisoyl)-
ethene (10ad). Prepared from 8a (50 mg, 0.17 mmol) and 9d (47 mg,
0.20 mmol) using general procedure 3 to afford 10ad (37 mg, 62%) as
a pale yellow oil: Rf (40% diethyl ether in hexane) 0.28; IR νmax(film)/
cm−1 2887, 2820, 1730, 1495, 1262, 1178, 1096, 1077, 980, 945, 824;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.41−7.37 (m, 2 H), 7.29−7.25
(m, 2 H), 4.89 (s, 2 H), 3.89−3.86 (m, 2 H), 3.60−3.56 (m, 2 H), 3.40
(s, 3 H), 2.51 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 154.9
(app t, JC−F 289.1), 138.6, 126.6 (dd, JC−F 5.7, 3.4), 126.0 (br d, JC−F
6.6), 125.8, 114.8 (dd, JC−F 35.0, 18.5), 94.9 (t, JC−F 3.0), 71.1, 68.0,
58.5, 15.0; 19F NMR (400 MHz, CDCl3) δ (ppm) −98.0 (d, J 56.9, 1
F), −106.4 (d, J 56.9, 1 F); HRMS (NSI) m/z calcd for
C13H20F2NO3S [M + NH4]+ 308.1127, found 308.1128; LRMS m/z
(CI) 319 [M + C2H5]+; GC (98%) tR 12.94 min.
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(2″-methylphenyl)-
ethene (10ae). Prepared from 8a (50 mg, 0.17 mmol) and 9e (40 mg,
0.20 mmol) using general procedure 3 to afford 10ae (50 mg, 95%) as
a pale yellow oil: Rf (40% diethyl ether in hexane) 0.38; 1H NMR (400
MHz, CDCl3) δ (ppm) 7.36−7.19 (m, 4 H), 4.73 (d, JH−F 0.9, 2 H),
3.83−3.79 (m, 2 H), 3.57−3.54 (m, 2 H), 3.40 (s, 3 H), 2.37 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ (ppm) 153.7 (dd, JC−F 289.9, 280.5),
General Coupling Procedure 2. 2,2-Difluoro-1-(2′-methoxye-
thoxymethoxy)-1-(3″-formylphenyl)ethene (10am). A mixture of
potassium trifluoroborate 9m (43 mg, 0.2 mmol), iodide 8a (50 mg,
0.17 mmol), cesium carbonate (166 mg, 0.51 mmol) and bis-
(triphenylphosphino)palladium dichloride (2.4 mg, 0.0034 mmol) was
taken up in a mixture of degassed (3 x freeze−pump−thaw cycle) iso-
propanol (0.750 mL) and H2O (0.275 mL). The reaction mixture was
stirred at 90 °C for 2 h. The reaction mixture was then cooled to room
temperature and partitioned between DCM (5 mL) and H2O (5 mL).
The organic phase was separated and dried by passing through a
hydrophobic frit. The solvent was removed under reduced pressure
and the residue was purified by flash column chromatography on silica
(10% diethyl ether in hexane) to afford styrene 10am (31 mg, 67%) as
a colorless oil; Rf (40% diethyl ether in hexane) 0.13; IR νmax(film)/
cm−1 2924, 2893, 2738, 1698, 1293, 1146, 1070, 1021, 1008, 850, 799,
734, 693; 1H NMR (400 MHz, CDCl3) δ (ppm) 10.05 (s, 1 H), 8.00
(br s, 1 H), 7.85 (dd, J 7.7, 1.23, 1 H), 7.78 - 7.73 (m, 1 H), 7.58 (t, J
7.7, 1 H), 4.92 (br s, 2 H), 3.9−3.87 (m, 2 H), 3.59−3.55 (m, 2 H),
3.39 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 191.3, 155.3
(app t, JC−F 291.5), 136.2, 131.8 (dd, JC−F 6.3, 3.2), 130.9 (br d, JC−F
6.5), 128.8, 128.7, 127.5 (dd, JC−F 6.0, 3.8), 114.4 (dd, JC−F 34.8, 19.2),
95.3 (t, JC−F 3.0), 71.0, 68.2, 58.5; 19F NMR (376 MHz, CDCl3) δ
(ppm) −95.7 (d, J 52.6, 1 F), −104.6 (d, J 52.6, 1 F); HRMS (NSI)
m/z calcd for C13H18F2NO4 [M + NH4]+ 290.1204, Found 290.1202;
LRMS (CI) m/z 301 [M + C2H5]+; GC (98%) tR 12.02 min.
137.5 (d, JC−F 2.7), 130.2 (t, JC−F 2.7), 129.9, 129.0, 127.5, 125.2, 113.8
(dd, JC−F 42.1, 17.7), 92.8, 71.1, 67.3, 58.5, 18.9; 19F NMR (376 MHz,
CDCl3) δ (ppm) −102.2 (d, J 63.6, 1 F), −109.2 (d, J 63.6, 1 F).
These data were consistent with those reported previously.24
General coupling procedure 3. 2,2-Difluoro-1-(2′-methoxye-
thoxymethoxy)-1-(4″-methoxyphenyl)ethene (10aa). A mixture of
potassium trifluoroborate 9a (27 mg, 0.13 mmol), iodide 8a (31 mg,
0.11 mmol), cesium carbonate (103 mg, 0.32 mmol), and
bis(triphenylphosphino)palladium dichloride (1.5 mg, 0.0021 mmol)
was taken up in a mixture of tert-butyl alcohol (0.750 mL) and H2O
(0.275 mL). The reaction mixture was stirred at 90 °C for 18 h, cooled
to room temperature, and partitioned between DCM (5 mL) and H2O
(5 mL). The organic phase was separated and dried by passing
through a hydrophobic frit. The solvent was removed under reduced
pressure, and the residue was purified by flash column chromatography
on silica (10% diethyl ether in hexane) to afford styrene 10aa (30 mg,
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(4″-tert-
butylphenyl)ethene (10af). Prepared from 8a (50 mg, 0.17 mmol)
and 9f (49 mg, 0.20 mmol) using general procedure 3 to afford 10af
(61 mg, 99%) as a colorless oil: Rf (40% diethyl ether in hexane) 0.47;
IR νmax(film)/cm−1 2960, 2882, 1722, 1465, 1260, 1154, 1109, 975,
945, 837, 740; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.42 (br s, 4 H),
4.89 (s, 2 H), 3.90−3.87 (m, 2 H), 3.60−3.56 (m, 2 H), 3.40 (s, 3 H),
1.35 (s, 9 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 154.9 (app t,
JC−F 288.4), 150.9, 126.4 (br d, JC−F 6.1), 126.0 (dd, JC−F 5.5, 3.5),
125.0, 115.1 (dd, JC−F 35.5, 18.3), 94.8 (t, JC−F 3.0), 71.1, 68.0, 58.5,
34.1, 30.7; 19F NMR (376 MHz, CDCl3) δ (ppm) −98.7 (d, J 58.0, 1
F), −107.1 (d, J 58.0, 1 F); HRMS (NSI) m/z calcd for C16H26F2NO3
[M + NH4]+ 318.1875, found 318.1880; LRMS m/z (CI) 301 [M +
H]+; GC (98%) tR 12.25 min.
1
87%) as a pale yellow oil: Rf (40% diethyl ether in hexane) 0.30; H
NMR (400 MHz, CDCl3) δ (ppm) 7.42−7.38 (m, 2 H), 6.95−6.91
(m, 2 H), 4.88 (s, 2 H), 3.89−3.86 (m, 2 H), 3.84 (s, 3 H), 3.60−3.57
(m, 2 H), 3.40 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 159.1,
154.6 (app t, JC−F 287.7), 127.9 (dd, JC−F 5.2, 3.6), 121.5 (br d, JC−F
6.0), 114.8 (dd, JC−F 36.5, 18.6), 113.5, 94.6 (t, JC−F 2.8), 71.1, 67.9,
58.5, 54.8; 19F NMR (376 MHz, CDCl3) δ (ppm) −99.9 (d, J 61.4, 1
F), −108.5 (d, J 61.4, 1 F). These data were consistent with those
reported previously.24
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(4″-
trifluoromethylphenyl)ethene (10ah). Prepared from 8a (50 mg, 0.17
mmol) and 9h (51 mg, 0.20 mmol) using general procedure 1 (90 °C,
18 h) to afford 10ah (47 mg, 88%) as a pale yellow oil: Rf (40% diethyl
ether in hexane) 0.31; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.67 (br
d, J 8.6, 2 H), 7.61 (br d, J 8.6, 2 H), 4.90 (s, 2 H), 3.89−3.85 (m, 2
H), 3.58−3.54 (m, 2 H), 3.39 (s, 3 H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 155.0 (app t, JC−F 291.9), 133.4 (br d, JC−F 6.4), 129.7 (q,
JC−F 32.5), 126.3 (dd, JC−F 6.5, 3.5), 125.0 (q, JC−F 3.0), 123.4 (q, JC−F
271.8), 114.5 (dd, JC−F 34.2, 19.3), 95.4 (t, JC−F 3.0), 71.0, 68.2, 58.5;
19F NMR (376 MHz, CDCl3) δ (ppm) −62.8 (s, 3 F), −94.9 (d, J
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(3″-
methoxyphenyl)ethene (10ab). Prepared from 8a (50 mg, 0.17
mmol) and 9b (44 mg, 0.20 mmol) using general procedure 3 to
afford 10ab (53 mg, 95%) as a pale yellow oil: Rf (40% diethyl ether in
1
hexane) 0.28; H NMR (400 MHz, CDCl3) δ (ppm) 7.31 (t, J 8.0, 1
H), 7.08 (dq, J 7.8, J 1.3, 1 H), 7.04−7.02 (m, 1 H), 6.88 (br dd, J 8.3,
J 2.5, 1 H), 4.90 (s, 2 H), 3.90−3.86 (m, 2 H), 3.83 (s, 3 H), 3.60−
3.56 (m, 2 H), 3.40 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm)
159.2, 155.1 (app t, JC−F 289.9), 130.8 (br d, JC−F 6.1), 129.1, 118.8
(dd, JC−F 5.9, 3.4), 115.0 (dd, JC−F 35.4, 18.4), 113.5, 111.8 (dd, JC−F
5.6, 3.4), 94.9 (t, JC−F 3.1), 71.1, 68.0, 58.5, 54.8; 19F NMR (376 MHz,
CDCl3) δ (ppm) −97.6 (d, J 55.6, 1 F), −105.7 (d, J 55.6, 1 F). These
data were consistent with those reported previously.24
50.0, 1 F), −103.6 (d, J 50.0, 1 F). These data were consistent with
those reported previously.24
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(3″-
trifluoromethylphenyl)ethene (10aj). Prepared from 8a (50 mg, 0.17
mmol) and 9j (51 mg, 0.20 mmol) using general procedure 3 to afford
10aj (40 mg, 78%) as a pale yellow oil: Rf (40% diethyl ether in
hexane) 0.17; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.76 (br s, 1 H),
7.68 (br d, J 7.8, 1 H), 7.59 (br d, J 7.8, 1 H), 7.53 (t, J 7.8, 1 H), 4.92
(s, 2 H), 3.90−3.86 (m, 2 H), 3.58−3.55 (m, 2 H), 3.40 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 155.0 (app t, JC−F 291.3), 130.7
(br d, JC−F 6.4), 130.6 (q, JC−F 32.6), 129.3 (br d, JC−F 4.0), 128.6,
124.4 (d, JC−F 3.5), 123.4 (q, JC−F 272.6), 123.1−122.8 (m), 114.4 (dd,
JC−F 34.6, 19.3), 95.4 (t, JC−F 3.2), 71.0, 68.2, 58.5; NMR 19F (376
MHz, CDCl3) δ (ppm) −62.8 (s, 3 F) −95.7 (d, J 51.9, 1 F), −104.5
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(2″-
methoxyphenyl)ethene (10ac). Prepared from 8a (50 mg, 0.17
mmol) and 9c (44 mg, 0.20 mmol) using general procedure 1 to afford
10ac (52 mg, 93%) as a pale yellow oil: Rf (40% diethyl ether in
hexane) 0.28; IR νmax(film)/cm−1 2977, 2939, 2842, 1724, 1497, 1422,
1
1264, 1142, 982, 755; H NMR (400 MHz, CDCl3) δ (ppm) 7.41−
7.32 (m, 2 H), 6.99 (dt, J 7.5, J 0.8, 1 H), 6.95 (d, J 8.2, 1 H), 4.80 (s, 2
H), 3.87 (s, 3 H), 3.83−3.79 (m, 2 H), 3.57−3.53 (m, 2 H), 3.39 (s, 3
H); 13C NMR (100 MHz, CDCl3) δ (ppm) 157.4, 154.0 (dd, JC−F
F
dx.doi.org/10.1021/jo3011705 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(d, J 51.9, 1 F). These data were consistent with those reported
previously.24
2,2-Difluoro-1-(2′-methoxy-ethoxymethoxy)-1-(6″-bromo-3-pyr-
idyl) ethene (10aq). Prepared from 8a (50 mg, 0.17 mmol) and 9q
(54 mg, 0.20 mmol) using general procedure 3 to afford 10aq (21 mg,
32%) as a yellow oil. Rf (40% diethyl ether in hexane) 0.23; IR
νmax(film)/cm−1 2930, 2885, 2820, 1724, 1457, 1271, 1155, 1088, 975,
936, 837; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.49 (d, J 2.5, 1 H),
7.65 (ddd, J 8.4, J 2.5, JH−F 0.9, 1 H), 7.52 (d, J 8.4, 1 H), 4.92 (s, 2 H),
3.88−3.85 (m, 2 H), 3.58−3.54 (m, 2 H), 3.39 (s, 3 H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 155.3 (app t, JC−F 292.5), 147.7 (dd, JC−F
6.8, 3.5), 141.2, 135.8 (dd, JC−F 6.5, 3.2), 127.5, 125.6 (br d, JC−F 6.6),
112.6 (dd, JC−F 35.8, 20.3), 95.7 (t, JC−F 3.1), 71.1, 68.4, 58.7; 19F
NMR (376 MHz, CDCl3) δ (ppm) −94.0 (d, J 50.2, 1 F), −103.6 (d, J
50.2, 1 F); HRMS (NSI) m/z calcd for C11H13BrF2NO3 [M + H]+
324.0041, found 324.0049; LRMS m/z (CI) 352 [M + C2H5]+; GC
(98%) tR 12.34 min..
2,2-Difluoro-1-(2′-methoxy-ethoxymethoxy)-1-(3-benzothio-
phenyl) ethene (10as). Prepared from 8a (50 mg, 0.17 mmol) and 9s
(49 mg, 0.20 mmol) using general procedure 3 to afford 10as (35 mg,
57%) as a yellow oil. Rf (40% diethyl ether in hexane) 0.36; IR
νmax(film)/cm−1 3103, 2926, 2889, 2822, 1745, 1457, 1429, 1284,
1224, 1114, 1096, 1079, 958, 913, 831, 760, 734; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.98−7.94 (m, 1 H), 7.91−7.87 (m, 1 H), 7.59 (s, 1
H), 7.46−7.38 (m, 2 H), 4.82 (d, JH−F 0.8, 2 H), 3.86−3.83 (m, 2 H),
3.57−3.53 (m, 2 H), 3.39 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 154.9 (dd, JC−F 290.5, 284.5), 139.4, 137.0 (d, JC−F 3.2), 127.6
(t, JC−F 3.9), 124.3, 124.2, 123.9 (dd, JC−F 5.3), 122.7, 122.2, 110.8 (dd,
JC−F 39.9, 19.3), 93.9 (t, JC−F 2.6), 71.1, 67.7, 58.6; 19F NMR (376
MHz, CDCl3) δ (ppm) −99.5 (d, J 57.3, 1 F), −107.2 (d, J 57.3, 1 F);
HRMS (NSI) m/z calcd for C14H18F2NO3S [M + H]+ 318.0970,
found 318.0974; LRMS m/z (CI) 329 [M + C2H5]+; GC (98%) tR
12.98 min.
1,1-Difluoro-2-(2′-methoxy-ethoxymethoxy)-1,3-butadiene
(10at). Prepared from 8a (549 mg, 1.87 mmol) and 9t (300 mg, 2.24
mmol) using general procedure 3 to afford 10at (97 mg, 27%) as a
colorless oil after Kugelrohr distillation (100 mbar, 95 °C). Rf (40%
diethyl ether in hexane) 0.31; IR νmax(film)/cm−1 2975, 2935, 2889,
1744, 1455, 1366, 1244, 1192, 1162, 1086, 1045, 1024, 983, 896, 849;
1H NMR (400 MHz, CDCl3) δ (ppm) 6.25 (dddd, J 17.3, 11.1, JH−F
3.7, 1.6, 1 H), 5.43 (br d, J 17.3, 1 H), 5.21−5.17 (m, including app d,
J 11.2, 1 H), 4.95 (s, 2 H), 3.90−3.87 (m, 2 H), 3.61−3.58 (m, 2 H),
3.42 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 154.7 (app t,
JC−F 293.5), 123.9 (d, JC−F 4.7), 115.2 (dd, JC−F 35.8, 17.3), 113.3 (dd,
JC−F 11.9, 4.4), 95.7 (t, JC−F 3.0), 71.1, 68.1, 58.5; 19F NMR (376
MHz, CDCl3) δ (ppm) −98.1 (d, J 54.5, 1 F), −106.6 (dd, J 54.5, JF−H
2.7, 1 F); HRMS (APCI) m/z calcd for C8H16F2NO3 [M + NH4]+
212.1093, found 212.1092; LRMS m/z (CI) 195 [M + H]+; GC
(98%) tR 10.48 min.
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(4″-cyanophenyl)-
ethene (10ak). Prepared from 8a (50 mg, 0.17 mmol) and 9k (43 mg,
0.20 mmol) using general procedure 3 to afford 10ak (27 mg, 59%) as
a pale yellow oil: Rf (40% diethyl ether in hexane) 0.16; 1H NMR (400
MHz, CDCl3) δ (ppm) 7.69 (d, J 8.5, 2 H), 7.60 (d, J 8.5, 2 H), 4.91
(s, 2 H), 3.89−3.86 (m, 2 H), 3.58−3.55 (m, 2 H), 3.40 (s, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 155.6 (app t, JC−F 293.8), 134.6
(br d, JC−F 6.8), 131.8, 126.4 (dd, JC−F 7.0, 3.4), 117.9, 114.4 (dd, JC−F
33.7, 19.5), 111.2, 95.6, 71.0, 68.3, 58.6; 19F NMR (376 MHz, CDCl3)
δ (ppm) −93.1 (d, J 45.5, 1 F), −101.5 (d, J 45.5, 1 F). These data
were consistent with those reported previously.24
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(3″-cyanophenyl)-
ethene (10al). Prepared from 8a (50 mg, 0.17 mmol) and 9k (43 mg,
0.20 mmol) using general procedure 3 to afford 10ak (25 mg, 55%) as
a pale yellow oil: Rf (40% diethyl ether in hexane) 0.17; 1H NMR (400
MHz, CDCl3) δ (ppm) 7.80−7.79 (m, 1 H), 7.74−7.71 (m, 1 H), 7.61
(dt, J 7.8, J 1.3, 1 H), 7.52 (t, J 7.8, 1 H), 4.91 (s, 2 H), 3.90−3.86 (m,
2 H), 3.59−3.55 (m, 2 H), 3.40 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 155.4 (app t, JC−F 292.0), 131.4 (dd, JC−F 6.3, 2.2),
131.1, 130.2 (dd, JC−F 6.8, 3.3), 129.6 (dd, JC−F 6.2, 3.9), 129.0, 117.8,
113.9 (dd, JC−F 34.5, 19.8), 112.6, 95.5 (t, JC−F 3.1), 71.0, 68.3, 58.6;
19F NMR (376 MHz, CDCl3) δ (ppm) −94.5 (d, J 50.2, 1 F), −103.5
(d, J 50.2, 1 F). These data were consistent with those reported
previously.24
2,2-Difluoro-1-(2′-methoxyethoxymethoxy)-1-(3″-nitrophenyl)-
ethene (10an). Prepared from 8a (50 mg, 0.17 mmol) and 9n (47 mg,
0.20 mmol) using general procedure 3 (90 °C, 3 h) to afford 10an (30
mg, 61%) as a colorless oil: Rf (40% diethyl ether in hexane) 0.23; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.37 (app t, J 2.0, 1 H), 8.18 (dd, J
8.0, J 2.0, 1 H), 7.82 (m, including app d, J 8.0, 1 H), 7.59 (app t, J 8.0,
1 H), 4.95 (s, 2 H), 3.92−3.88 (m, 2 H), 3.59−3.55 (m, 2 H), 3.39 (s,
3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 155.5 (app t, JC−F
292.6), 148.1, 131.9 (dd, JC−F 6.5, 2.1), 131.7 (dd, JC−F 6.9, 3.2), 129.1,
122.4, 120.9 (dd, JC−F 6.0, 3.7), 114.1 (dd, JC−F 34.1, 19.5), 95.7 (t,
JC−F 3.0), 71.0, 68.3, 58.5; 19F NMR (376 MHz, CDCl3) δ (ppm)
−94.1 (d, J 49.0, 1 F), −103.0 (d, J 49.0, 1 F). These data were
consistent with those reported previously.24
2,2-Difluoro-1-(2′-methoxy-ethoxymethoxy)-1-(3-pyridyl) ethene
(10ao). Prepared from 8a (50 mg, 0.17 mmol) and 9o (38 mg, 0.20
mmol) using general procedure 3 to afford 10ao (27 mg, 54%) as a
yellow oil. Rf (70% diethyl ether in hexane) 0.19; IR νmax(film)/cm−1
2934, 2885, 1731, 1567, 1418, 1267, 1153, 1125, 1099, 1077, 978, 937,
849, 812, 711; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.73 (br s, 1 H),
8.55 (br d, J 4.8, 1 H), 7.79−7.75 (m, 1 H), 7.32 (dd, J 8.1, 4.8, 1 H),
4.90 (s, 2 H), 3.87−3.84 (m, 2 H), 3.56−3.53 (m, 2 H), 3.38 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ (ppm) 155.7 (app t, JC−F 291.8),
1-(N,N-diethylcarbamoyloxy)-2,2-difluoro-1-(4′-methoxyphenyl)
ethene (10ba). Prepared from 8b (137 mg, 0.45 mmol) and 9a (107
mg, 0.5 mmol) using general procedure 1 (90 °C for 1 h) to afford
10ba (103 mg, 80%) as a pale yellow oil. Rf (40% diethyl ether in
hexane) 0.32; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.37 (d, J 8.9, 2
H), 6.93 (d, J 8.9, 2 H), 3.84 (s, 3 H), 3.46 (q, J 6.9, 2 H), 3.38 (q, J
6.9, 2 H), 1.27 (t, J 6.9, 3 H), 1.20 (t, J 6.9, 3 H); 13C NMR (100
MHz, CDCl3) δ (ppm) 158.9, 154.1 (app t, JC−F 288.1), 152.5, 126.6
(dd, JC−F 6.0, 3.3), 122.1 (br d, JC−F 6.3), 113.6, 111.7 (dd, JC−F 38.9,
19.5), 54.8, 42.0, 41.4, 13.7, 12.7; 19F NMR (376 MHz, CDCl3) δ
(ppm) −95.9 (d, J 54.5, 1 F), −106.0 (d, J 54.5, 1 F). These data were
consistent with those reported previously24
149.2, 147.9 (dd, JC−F 6.7, 3.5), 134.0 (dd, JC−F 6.2, 3.3), 126.4 (d, JC−F
6.8), 123.3, 113.6 (dd, JC−F 36.3, 19.7), 95.8 (t, JC−F 3.1), 71.5, 68.7,
59.0; 19F NMR (400 MHz, CDCl3) δ (ppm) −95.3 (d, J 52.8, 1 F),
−105.0 (d, J 52.8, 1 F); HRMS (NSI) m/z calcd for C11H13F2NO3
[M]+ 245.0858, found 245.0854; LRMS m/z (CI) 274 [M + C2H5]+;
GC (98%) tR 10.77 min.
2,2-Difluoro-1-(2′-methoxy-ethoxymethoxy)-1-(4-isoquinolyl)
ethene (10ap). Prepared from 8a (50 mg, 0.17 mmol) and 9p (48 mg,
0.20 mmol) using general procedure 3 to afford 10ap (19 mg, 32%) as
a pale yellow oil. Rf (70% diethyl ether in hexane) 0.22; IR νmax(film)/
cm−1 2932, 2895, 2822, 1752, 1504, 1279, 1193, 1166, 1150, 960, 761,
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(3′-methoxyphenyl)-
ethene (10bb). Prepared from 8b (50 mg, 0.17 mmol) and 9b (42 mg,
0.2 mmol) using general procedure 2 to afford 10bb (33 mg, 59%) as a
1
749; H NMR (400 MHz, CDCl3) δ (ppm) 9.30 (s, 1 H), 8.60 (s, 1
H), 8.12 (br d, J 8.4, 1 H), 8.04 (br d, J 8.4, 1 H), 7.81−7.77 (m, 1 H),
7.71−7.66 (m, 1 H), 4.80 (d, JH−F 0.7, 2 H), 3.82−3.79 (m, 2 H),
3.53−3.50 (m, 2 H), 3.38 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 155.0 (dd, JC−F 292.1, 283.5), 153.7, 144.5 (t, JC−F 3.1), 133.9
(d, JC−F 3.1), 130.7, 127.9, 127.6, 127.2, 123.8, 119.7, 111.3 (dd, JC−F
40.8, 21.5), 93.6, 71.0, 67.6, 58.5; 19F NMR (376 MHz, CDCl3) δ
(ppm) −98.4 (d, J 57.3, 1 F), −107.1 (d, J 57.3, 1 F); HRMS (NSI)
m/z calcd for C15H16F2NO3 [M + H]+ 296.1093, found 296.1096;
LRMS m/z (CI) 324 [M + C2H5]+; GC (98%) tR 13.19 min.
1
pale yellow oil: Rf (40% diethyl ether in hexane) 0.35; H NMR (400
MHz, CDCl3) δ (ppm) 7.31 (app t, J 8.1, 1 H), 7.06−7.03 (m, 1 H),
6.98 (br s, 1 H), 6.87 (dd, J 8.1, J 2.5, 1 H), 3.47 (q, J 7.1, 2 H), 3.40
(q, J 7.1, 2 H), 1.29 (t, J 7.1, 3 H), 1.20 (t, J 7.1, 3 H); 13C NMR (100
MHz, CDCl3) δ (ppm) 159.1, 154.5 (app t, JC−F 290.3), 152.4, 131.1
(d, JC−F 6.6), 129.1, 117.4 (dd, JC−F 6.7, 3.5), 113.2, 111.8 (dd, JC−F
37.8, 19.1), 110.8 (dd, JC−F 6.7, 3.6), 54.7, 42.1, 41.5, 13.7, 12.8; 19F
NMR (376 MHz, CDCl3) δ (ppm) −93.4 (d, J 48.3, 1 F), −103.1 (d, J
G
dx.doi.org/10.1021/jo3011705 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
48.3, 1 F). These data were consistent with those reported
previously.24
(90 °C for 18 h) to afford 10bh (94 mg, 88%) as a colorless oil: Rf
(40% diethyl ether in hexane) 0.43; H NMR (400 MHz, CDCl3) δ
1
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(2′-methoxyphenyl)-
ethene (10bc). Prepared from 8b (50 mg, 0.17 mmol) and 9c (42 mg,
0.2 mmol) using general procedure 2 to afford 10bc (33 mg, 59%) as a
yellow oil: Rf (40% diethyl ether in hexane) 0.31; IR νmax(film)/cm−1
(ppm) 7.66 (d, J 8.4, 2 H), 7.55 (d, J 8.4, 2 H), 3.49 (q, J 7.2, 2 H),
3.38 (q, J 7.2, 2 H), 1.30 (t, J 7.1, 3 H), 1.21 (t, J 7.1, 3 H); 13C NMR
(100 MHz, CDCl3) δ (ppm) 154.8 (app t, JC−F 292.6), 152.2, 133.5
(br d, JC−F 6.9), 129.5 (q, JC−F 32.5), 125.0−125.2 (m, includes signals
for 2(Ar)C−H), 123.4 (q, JC−F 272.6), 111.2 (dd, JC−F 37.8, 19.9),
42.2, 41.6, 13.7, 12.7; 19F NMR (376 MHz, CDCl3) δ (ppm) −62.9 (s,
3 F), −91.1 (d, J 43.1, 1 F), −101.3 (d, J 43.1, 1 F). These data were
consistent with those reported previously.24
1 -( N , N - D i e t h y l c a r b a m o y l o x y ) - 2 , 2 - d ifl uo ro-1 -( 3′ -
trifluoromethylphenyl)ethene (10bj). Prepared from 8b (50 mg, 0.17
mmol) and 9j (50 mg, 0.2 mmol) using general procedure 2 to afford
10bj (32 mg, 60%) as a pale yellow oil: Rf (40% diethyl ether in
hexane) 0.40; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.68 (br s, 1 H),
7.63 (br d, J 7.7, 1 H), 7.58 (br d, J 7.7, 1 H), 7.53 (t, J 7.7, 1 H), 3.49
(q, J 7.2, 2 H), 3.39 (q, J 7.2, 2 H), 1.30 (t, J 7.1, 3 H), 1.21 (t, J 7.1, 3
H); 13C NMR (100 MHz, CDCl3) δ (ppm) 154.7 (app t, JC−F 291.0),
152.1, 130.8 (br d, JC−F 6.9), 130.6 (q, JC−F 32.6), 128.6, 128.1 (dd,
JC−F 7.0, 3.0), 124.3 (d, JC−F 3.14), 123.2 (q, JC−F 271.2), 121.5−121.8
(m), 111.1 (dd, JC−F 37.3, 19.5), 42.2, 41.6, 13.6, 12.7; 19F NMR (376
MHz, CDCl3) δ (ppm) −63.9 (s, 3 F), −91.7 (d, J 45.3, 1 F), −102.1
(d, J 45.3, 1 F). These data were consistent with those reported
previously.24
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4′-cyanophenyl)-
ethene (10bk). Prepared from 8b (50 mg, 0.33 mmol) and 9k (101
mg, 0.4 mmol) using general procedure 1 (90 °C for 18 h) to afford
10bk (57 mg, 62%) as a pale yellow solid: Rf (40% diethyl ether in
hexane) 0.18; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (br d, J 8.3
2 H), 7.53 (br d, J 8.3 2 H), 3.48 (q, J 7.2, 2 H), 3.38 (q, J 7.2, 2 H),
1.29 (t, J 7.2, 3 H), 1.20 (t, J 7.2, 3 H); 13C NMR (100 MHz, CDCl3)
δ (ppm) 154.9 (app t, JC−F 294.0), 152.0, 134.5 (br d, JC−F 7.4), 131.8,
125.2 (dd, JC−F 7.4, 3.7), 117.9, 111.2 (dd, JC−F 37.4, 20.3), 111.1, 42.3,
41.6, 13.7, 12.7; 19F NMR (376 MHz, CDCl3) δ (ppm) −89.3 (d, J
39.1, 1 F), −99.3 (d, J 39.1, 1 F). These data were consistent with
those reported previously.24
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(3′-cyanophenyl)-
ethene (10bl). Prepared from 8b (50 mg, 0.17 mmol) and 9l (41 mg,
0.2 mmol) using general procedure 2 to afford 10bl (28 mg, 61%) as a
yellow oil: Rf (40% diethyl ether in hexane) 0.15; 1H NMR (400 MHz,
CDCl3) δ (ppm) 7.69 (br d, J 1.1, 1 H), 7.67−7.66 (m, 1 H), 7.60
(app br d, J 7.7, 1 H), 7.52 (app t, J 7.7, 1 H), 3.47 (q, J 7.1, 2 H), 3.40
(q, J 7.1, 2 H), 1.29 (t, J 7.1, 3 H), 1.21 (t, J 7.1, 3 H); 13C NMR (100
MHz, CDCl3) δ (ppm) 154.7 (app t, JC−F 291.7), 152.1, 131.4 (br d,
JC−F 7.0), 131.0, 129.1−129.0 (m), 128.4 (dd, JC−F 6.3, 4.0), 117.9,
112.6, 110.6 (dd, JC−F 37.8, 20.2), 42.3, 41.6, 13.7, 12.7; 19F NMR
(376 MHz, CDCl3) δ (ppm) −90.7 (d, J 42.6, 1 F), −101.2 (d, J 42.6,
1 F). These data were consistent with those reported previously.24
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(3′-formylphenyl)-
ethene (10bm). Prepared from 8b (50 mg, 0.17 mmol) and 9m (42
mg, 0.2 mmol) using general procedure 2 to afford 10bm (42 mg,
90%) as a pale yellow oil: Rf (40% diethyl ether in hexane) 0.17; IR
νmax(film)/cm−1 2979, 2941, 1728, 1689, 1424, 1267, 1187, 1142,
1012, 796, 753, 689; 1H NMR (400 MHz, CDCl3) δ (ppm) 10.04 (s, 1
H), 7.93 (br s, 1 H), 7.83 (app br d, J 7.7, 1 H), 7.72−7.69 (m, 1 H),
7.58 (app t, J 7.7, 1 H), 3.49 (q, J 7.1, 2 H), 3.38 (q, J 7.1, 2 H), 1.30
(t, J 7.0, 3 H), 1.20 (t, J 7.0, 3 H); 13C NMR (100 MHz, CDCl3) δ
(ppm) 191.2, 154.7 (app t, JC−F 292.4), 152.2, 136.2, 131.1 (d, JC−F
6.7), 130.6 (dd, JC−F 7.0, 3.4), 128.9, 128.7, 126.1 (dd, JC−F 6.3, 3.9),
111.2 (dd, JC−F 38.1, 19.8), 42.2, 41.6, 13.7, 12.7; 19F NMR (376 MHz,
CDCl3) δ (ppm) −91.8 (d, J 45.3, 1 F), −102.2 (d, J 45.3, 1 F);
HRMS (NSI) m/z calcd for C14H19F2N2O3 [M + NH4]+ 301.1358,
found 301.1360; LRMS m/z (CI) 284 [M + H]+; GC (98%) tR 12.40
min.
1
2977, 2939, 2842, 1724, 1497, 1437, 1422, 1264, 1142, 982, 755; H
NMR (400 MHz, CDCl3) δ (ppm) 7.42 (d, J 7.6, 1 H), 7.38−7.33 (m,
1 H), 6.99 (dt, J 7.6, J 0.9, 1 H), 6.94 (d, J 8.4, 1 H), 3.88 (s, 3 H),
3.41−3.29 (m, 4 H), 1.23−1.12 (m, 6 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 156.8 (d, JC−F 2.4), 154.0 (dd, JC−F 290.1, 284.4),
152.7, 130.3 (t, JC−F 3.0), 130.1, 119.9, 118.4 (br d, JC−F 4.6), 110.7,
108.5 (dd, JC−F 45.1, 20.6), 55.1, 41.9, 41.4, 13.5, 12.8; 19F NMR (376
MHz, CDCl3) δ (ppm) −96.2 (d, J 49.9, 1 F), −104.6 (d, J 49.9, 1 F);
HRMS (NSI) m/z calcd for C14H18F2NO3 [M + H]+ 286.1249, found
286.1253; LRMS m/z (CI) 314 [M + C2H5]+; GC (98%) tR 11.70
min.
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4′-thioanisoyl)-
ethene (10bd). Prepared from 8b (101 mg, 0.33 mmol) and 9d (91
mg, 0.4 mmol) using general procedure 1 to afford 10bd (92 mg, 93%)
as a pale yellow oil: Rf (40% diethyl ether in hexane) 0.21; IR
νmax(film)/cm−1 3014, 2947, 1724, 1442, 1166, 1116, 1096, 982, 812,
798, 755; 1H NMR (400 MHz, CDCl3) δ (ppm) 7.35 (d, J 8.4, 2 H),
7.27 (d, J 8.4, 2 H), 3.46 (q, J 6.9, 2 H), 3.37 (q, J 6.9, 2 H), 2.50 (s, 3
H), 1.28 (t, J 6.9, 3 H), 1.20 (t, J 6.9, 3 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 154.3 (app t, JC−F 290.7), 152.4, 138.4, 126.4 (d, JC−F
6.6), 125.9, 125.4 (dd, JC−F 6.4, 3.6), 111.7 (dd, JC−F 38.4, 19.4), 42.1,
41.5, 15.1, 13.7, 12.8; 19F NMR (376 MHz, CDCl3) δ (ppm) −94.1
(d, J 49.9, 1 F), −104.0 (d, J 49.9, 1 F); HRMS (NSI) m/z calcd for
C14H18F2NO2S [M + H]+ 302.1021 found, 302.1025; LRMS m/z (CI)
302 [M + H]+; GC (98%) tR 13.42 min.
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(2′-methylphenyl)-
ethene (10be). Prepared from 8b (101 mg, 0.33 mmol) and 9e (78
mg, 0.4 mmol) using general procedure 1 to afford 10be (83 mg, 93%)
1
as a pale yellow oil: Rf (40% diethyl ether in hexane) 0.50; H NMR
(400 MHz, CDCl3) δ (ppm) 7.42 (br d, J 7.5, 1 H), 7.31−7.19 (m, 3
H), 3.41−3.25 (m, 4 H), 1.23−1.09 (m, 6 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 154.1 (dd, JC−F 290.0, 282.6), 153.0, 137.8, 130.4,
130.1, 129.3, 129.1 (d, JC−F 4.6), 125.7, 111.1 (dd, JC−F 46.1, 18.8),
42.4, 41.8, 19.5, 14.1, 13.2; 19F NMR (376 MHz, CDCl3) δ (ppm)
−97.4 (d, J 53.9, 1 F), −106.2 (d, J 53.9, 1 F). These data were
consistent with those reported previously.24
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4′-tert-
butylphenyl)ethene (10bf). Prepared from 8b (101 mg, 0.33 mmol)
and 9f (95 mg, 0.4 mmol) using general procedure 1 to afford 10bf
(68 mg, 66%) as a colorless oil: Rf (40% diethyl ether in hexane) 0.25;
IR νmax(film)/cm−1 2965, 2872, 1727, 1474, 1420, 1265, 1146, 982,
1
948, 927, 844, 825, 784, 754; H NMR (400 MHz, CDCl3) δ (ppm)
7.43 (d, J 8.5, 2 H), 7.37 (d, J 8.5, 2 H), 3.47 (q, J 7.1, 2 H), 3.39 (q, J
7.1, 2 H), 1.34 (s, 9 H), 1.29 (t, J 6.9, 3 H), 1.21 (t, J 6.9, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 154.4 (app t, JC−F 289.3), 152.5,
150.7, 126.8 (d, JC−F 6.7), 125.0, 124.7 (dd, JC−F 6.4, 3.4), 111.9 (dd,
JC−F 38.6, 19.1), 42.1, 41.5, 34.1, 30.7, 13.6, 12.8; 19F NMR (376 MHz,
CDCl3) δ (ppm) −97.4 (d, J 53.9, 1 F), −106.2 (d, J 53.9, 1 F);
HRMS (NSI) m/z calcd for C17H24F2NO2 [M + H]+ 312.1770, found:
312.1771; LRMS m/z (CI) 312 [M + H]+; GC (98%) tR 12.70 min.
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4′-chlorophenyl)-
ethene (10bg). Prepared from 8b (101 mg, 0.33 mmol) and 9g (87
mg, 0.4 mmol) using general procedure 1 to afford 10bg (84 mg, 88%)
as a colorless oil: Rf (40% diethyl ether in hexane) 0.39; 1H NMR (400
MHz, CDCl3) δ (ppm) 7.37 (s, 4 H), 3.46 (q, J 7.0, 2 H), 3.38 (q, J
7.0, 2 H), 1.34 (s, 9 H), 1.28 (t, J 7.1, 3 H), 1.20 (t, J 7.1, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 154.4 (app t, JC−F 291.1), 152.3,
133.5, 128.3 (d, JC−F 5.5), 128.3, 126.3 (dd, JC−F 6.7, 3.5), 111.3 (dd,
JC−F 38.7, 20.1), 42.2, 41.5, 13.7, 12.8; 19F NMR (376 MHz, CDCl3) δ
(ppm) −93.1 (d, J 47.7, 1 F), −103.1 (d, J 47.7, 1 F). These data were
consistent with those reported previously.24
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(3′-nitrophenyl)-
ethene (10bn). Prepared from 8b (50 mg, 0.17 mmol) and 9n (45 mg,
0.2 mmol) using general procedure 3 (90 °C for 4 h) to afford 10bn
(37 mg, 75%) as a pale yellow oil: Rf (40% diethyl ether in hexane)
0.31; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.29 (t, J 2.0, 1 H), 8.18
(dd, J 8.2, J 2.0, 1 H), 7.80−7.77 (m, 1 H), 7.60 (t, J 8.2, 1 H), 3.51 (q,
1 - (N, N-D iethy lcar bam oyl oxy) -2 , 2-di flu oro -1 - (4′ -
trifluoromethylphenyl)ethene (10bh). Prepared from 8b (101 mg,
0.33 mmol) and 9h (100 mg, 0.4 mmol) using general procedure 1
H
dx.doi.org/10.1021/jo3011705 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
J 7.1, 2 H), 3.39 (q, J 7.1, 2 H), 1.32 (t, J 7.2, 3 H), 1.22 (t, J 7.2, 3 H);
13C NMR (100 MHz, CDCl3) δ (ppm) 154.9 (app t, JC−F 293.2),
152.0, 148.0, 131.9 (br d, JC−F 7.3), 130.6 (dd, JC−F 8.1, 3.5), 129.2,
122.3, 119.8 (dd, JC−F 5.9, 4.4), 110.7 (dd, JC−F 37.5, 20.5), 42.3, 41.6,
13.7, 12.7; 19F NMR (376 MHz, CDCl3) δ (ppm) −90.3 (d, J 42.2, 1
F), −100.7 (d, J 42.2, 1 F). These data were consistent with those
reported previously.24
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(3-pyridyl)ethene
(10bo). Prepared from 8b (50 mg, 0.17 mmol) and 9o (37 mg, 0.2
mmol) using general procedure 2 (90 °C for 3 h) to afford 10bo (26
mg, 61%) as a colorless oil: Rf (60% diethyl ether in hexane) 0.12; IR
νmax(film)/cm−1 2980, 2939, 1737, 1411, 1275, 1150, 82, 706; 1H
NMR (400 MHz, CDCl3) δ (ppm) 8.67 (d, J 2.2, 1 H), 8.53 (dd, J 4.8,
1.4, 1 H), 7.75−7.70 (m, 1 H), 7.31 (ddd, J 8.1, J 4.8, 0.7, 1 H), 3.44
(q, J 6.9, 2 H), 3.35 (q, J 7.0, 2 H), 1.26 (t, J 7.1, 3 H), 1.18 (t, J 7.1, 3
H); 13C NMR (100 MHz, CDCl3) δ (ppm) 154.6 (app t, JC−F 292.3),
152.1, 148.6, 146.3 (dd, JC−F 6.7, 3.8), 132.4 (dd, JC−F 7.1, 3.5), 126.1
(br d, JC−F 6.9), 122.8, 109.8 (dd, JC−F 39.7, 20.1), 42.2, 41.6, 13.7,
12.7; 19F NMR (376 MHz, CDCl3) δ (ppm) −91.5 (d, J 45.4, 1 F),
−102.5 (d, J 45.4, 1 F); HRMS (NSI) m/z calcd for C12H15F2N2O2
[M + H]+ 257.1096, found 257.1099; LRMS m/z (CI) 257 [M + H]+;
GC (98%) tR 11.28 min.
10bs (35 mg, 57%) as a pale brown oil: Rf (40% diethyl ether in
hexane) 0.52; IR νmax(film)/cm−1 2977, 2938, 2878, 1726, 1422, 1295,
1215, 1154, 1107, 760, 734; H NMR (400 MHz, CDCl3) δ (ppm)
1
7.95−7.87 (m, 2 H), 7.67 (s, 1 H), 7.47−7.38 (m, 2 H), 3.41 (q, J 7.0,
2 H), 3.33 (q, J 7.0, 2 H), 1.22 (t, J 7.0, 3 H), 1.16 (t, J 7.0, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 154.6 (dd, JC−F 292.2, 284.5),
152.5, 139.3, 136.7 (d, JC−F 2.7), 127.5 (t, JC−F 3.7), 124.8 (d, JC−F
4.9), 124.2, 124.1, 122.3, 122.2, 107.1 (dd, JC−F 44.1, 21.2), 42.0, 41.4,
13.6, 12.8; 19F NMR (376 MHz, CDCl3) δ (ppm) −94.9 (d, J 49.4, 1
F), −104.3 (d, J 49.4, 1 F); HRMS (NSI) m/z calcd for
C15H16F2NO2S [M + H]+ 312.0864, found 312.0862; LRMS m/z
(CI) 312 [M + H]+; GC (98%) tR 13.37 min.
1,1-Difluoro-2-(N,N-diethylcarbamoyloxy)-1,3-butadiene (10bt).
Prepared from 8b (569 mg, 1.87 mmol) and 9u (300 mg, 2.24
mmol) using general procedure 3 to afford 10bu (113 mg, 30%) as a
colorless oil after Kugelrohr distillation (90 °C/100 mbar): Rf (40%
1
diethyl ether in hexane) 0.46; H NMR (400 MHz, CDCl3) δ (ppm)
6.36 (dddd, J 17.2, 11.2, JH−F 3.4, 1.6, 1 H), 5.23 (d, J 17.2, 1 H),
5.19−5.15 (m, including app d, J 11.2, 1 H), 3.44−3.32 (m, 4 H),
1.15−1.26 (m, 6 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 154.3
(dd, JC−F 295.0, 291.0), 152.4, 124.2 (d, JC−F 4.6), 113.2 (dd, JC−F 11.9,
4.3), 112.4 (dd, JC−F 40.6, 18.2), 42.6, 41.9, 14.1, 13.2; 19F NMR (376
MHz, CDCl3) δ (ppm) −95.6 (d, J 40.6, 1 F), −105.6 (d, J 40.6, 1 F).
These data were consistent with those reported previously.10
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(4-isoquinolyl)-
ethene (10bp). Prepared from 8b (50 mg, 0.17 mmol) and 9p (46 mg,
0.2 mmol) using general procedure 2 to afford 10bp (22 mg, 44%) as a
colorless oil: Rf (100% diethyl ether) 0.65; IR νmax(film)/cm−1 2979,
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-deuterioethene (22).
n-Butyllithium (720 μL of a 2 M solution in hexanes) was added
dropwise over 2 min to a solution of 1-(N,N-diethylcarbamoyloxy)-
2,2-difluoro-1-(tributylstannyl)ethene (610 mg, 1.30 mmol) in THF
(6 mL) with stirring at −78 °C. The reaction solution turned pale
yellow after butyllithium addition and was stirred for 45 min at −78
°C. Deuterated methanol (d4, 53 μL, 1.30 mmol) was added in one
portion, and the reaction solution was stirred for a further 1 h at −78
°C and 1 h at room temperature (18 °C). Careful Kugelrohr
distillation of the reaction mixture separated the volatile components.
Hexane and THF were removed first (18 °C/50 mbar). Deuterated
species 22 was then isolated (75 °C/25 mbar) as a colorless oil (97
mg, 41%): IR νmax(film)/cm−1 2982, 2941, 2883, 1726, 1424, 1293,
1
2938, 1724, 1422, 1282, 1187, 1142, 1113, 958, 786, 755; H NMR
(400 MHz, CDCl3) δ (ppm) 9.29 (s, 1 H), 8.70 (s, 1 H), 8.15 (br d, J
8.5, 1 H), 8.04 (d, J 8.2, 1 H), 7.83−7.78 (m, 1 H), 7.70−7.64 (m, 1
H), 3.38 (q, J 6.9, 2 H), 3.29 (q, J 7.0, 2 H), 1.18 (t, J 7.0, 3 H), 1.12 (t,
J 7.0, 3 H); 13C NMR (100 MHz, CDCl3) δ (ppm) 154.6 (dd, JC−F
293.7, 285.1), 153.6, 152.3, 144.3 (t, JC−F 3.0), 133.4, 130.7, 127.8,
127.6, 127.1, 123.6, 120.7 (d, JC−F 4.7), 107.8 (dd, JC−F 45.5, 20.2),
42.0, 41.5, 13.6, 12.7; 19F NMR (376 MHz, CDCl3) δ (ppm) −93.9
(d, J 49.1, 1 F), −104.2 (d, J 49.1, 1 F); HRMS (NSI) m/z calcd for
C16H17F2N2O2 [M + H]+ 307.1253, found 307.1255; LRMS m/z (CI)
307 [M + H]+; GC (98%) tR 13.65 min.
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(6′-bromo-3-pyridyl)
ethene (10bq). Prepared from 8b (50 mg, 0.17 mmol) and 9q (47 mg,
0.17 mmol) using general procedure 3 (90 °C for 3 h) to afford 10bq
(29 mg, 52%) as a pale yellow oil. Rf (40% diethyl ether in hexane)
0.26; IR νmax(film)/cm−1 2979, 2941, 1731, 1461, 1424, 1280, 1148,
1090, 980; 1H NMR (400 MHz, CDCl3) δ (ppm) 8.43 (d, J 2.5, 1 H),
7.60 (ddd, J 8.4, J 2.5, 0.7, 1 H), 7.52 (d, J 8.4, 1 H), 3.45 (q, J 7.2, 2
H), 3.37 (q, J 7.2, 2 H), 1.27 (t, J 7.1, 3 H), 1.20 (t, J 7.1, 3 H); 13C
NMR (100 MHz, CDCl3) δ (ppm) 154.6 (dd, JC−F 293.1, 291.8),
152.0 (t, JC−F 2.9), 146.5 (dd, JC−F 6.5, 4.0), 140.9, 134.8 (dd, JC−F 7.3,
3.3), 127.4, 125.6 (d, JC−F 6.8), 109.3 (dd, JC−F 39.4, 21.5), 42.3, 41.6,
13.7, 12.7; 19F NMR (376 MHz, CDCl3) δ (ppm) −90.4 (d, J 43.5, 1
F), −101.3 (d, J 43.5, 1 F); HRMS (NSI) m/z calcd for
C12H14BrF2N2O2 [M + H]+ 335.0201, found 335.0206; LRMS m/z
(CI) 335 [M + H]+; GC (98%) tR 12.77 min.
1
1275, 1178, 1100, 842, 740, 635; H NMR (400 MHz, CDCl3) δ
(ppm) 3.38−3.29 (m, 4 H), 1.17 (t, J 7.1, 6 H); 13C NMR (100 MHz,
CDCl3) δ (ppm) 154.6 (dd, JC−F 287.9, 274.7), 151.8, 101.2−99.9 (m,
including JC−F and JC‑D) 42.0, 41.3, 13.4, 12.7; 19F NMR (376 MHz,
CDCl3) δ (ppm) −97.5 (dt, J 72.8, JF‑D 2.3, 1 F), −117.8 (d, J 72.8, 1
F); HRMS (APCI) m/z calcd for C7H11DF2NO2 [M + NH4]+
198.1159, found 198.1159; LRMS m/z (CI) 181 [M + H]+ ; GC
(98%) tR 9.42 min.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedure and characterization for potassium
1
trifluoroborates and H, 19F, and 13C NMR spectra and GC−
MS chromatograms for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
1-(N,N-Diethylcarbamoyloxy)-2,2-difluoro-1-(6′-methoxy-2-
pyridyl)ethene (10br). Prepared from 8b (50 mg, 0.17 mmol) and 9r
(43 mg, 0.20 mmol) using general procedure 1 to afford 10br (33 mg,
70%) as a yellow oil: Rf (20% diethyl ether in cyclohexane) 0.1; IR
νmax(film)/cm−1 2979, 2341, 1728, 1578, 1466, 1262, 1153, 1047, 800;
1H NMR (400 MHz, CDCl3) δ (ppm) 7.56 (app t, J 8.1, 1 H), 6.98 (d,
AUTHOR INFORMATION
■
Corresponding Author
J 7.6, 1 H), 6.63 (d, J 8.3, 1 H), 3.89 (s, 3 H), 3.48 (q, J 7.1 2 H), 3.43
(q, J 7.1 2 H), 1.29 (t, J 7.1, 3 H) 1.19 (t, J 7.1, 3 H); 13C NMR (100
MHz, CDCl3) δ (ppm) 163.4, 156.5 (dd, JC−F 296, 292), 153.1 (t, JC−F
2.4), 146.8 (dd, JC−F 8.8, 3.3), 138.8, 113.4 (dd, JC−F 8.9, 4.4), 112.6
(dd, JC−F 34.3, 18.8), 109.9 (t, JC−F 2.2), 53.1, 42.6, 42.1, 14.2, 13.3;
19F NMR (376 MHz, CDCl3) δ (ppm) −90.6 (d, J 34.4, 1 F), −97.9
*E-mail: jonathan.percy@strath.ac.uk.
ACKNOWLEDGMENTS
■
We thank the EPSRC Pharma Synthesis Studentship Scheme
and GSK (studentship for P.G.W.), the Carnegie Trust
(undergraduate vacation scholarship for A.W.M.), the EPSRC
National Mass Spectrometry Service Centre, Swansea, for
accurate mass measurements, and Dr. Judith Huggan and Dr.
David Breen (Strathclyde Institute for Pharmaceutical and
Biomedical Sciences) for a gift of boronic acids.
(d, J 34.4, 1 F); HRMS (ESI) m/z calcd for C13H17F2N2O3 [M + H]+
287.1202, found 287.1196; LRMS m/z (ESI) 287 [M + H]+; LC
(98%) tR 1.21 min.
1 - ( N , N - D i e t h y l c a r b a m o y l o x y ) - 2 , 2 - d i fl u o r o - 1 - ( 3 -
benzothiophenyl)ethene (10bs). Prepared from 8b (50 mg, 0.17
mmol) and 9s (47 mg, 0.2 mmol) using general procedure 1 to afford
I
dx.doi.org/10.1021/jo3011705 | J. Org. Chem. XXXX, XXX, XXX−XXX

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