Heck-type 5-endo-trig cyclizations promoted by vinylic fluorines: Ring-fluorinated indene and 3H-pyrrole syntheses from 1,1-difluoro-1-alkenes

Article abstract of DOI:10.1016/j.jfluchem.2005.12.023

Arylpalladium or aminopalladium species bearing a 2,2-difluorovinyl group undergo an unusual 5-endo alkene insertion followed by β-fluorine elimination. These processes provide a facile access to ring-fluorinated five-membered carbocyclic and heterocyclic

Full text of DOI:10.1016/j.jfluchem.2005.12.023

Journal of Fluorine Chemistry 127 (2006) 489–504
www.elsevier.com/locate/fluor
Heck-type 5-endo-trig cyclizations promoted by vinylic fluorines:
Ring-fluorinated indene and 3H-pyrrole syntheses
from 1,1-difluoro-1-alkenes
*
Junji Ichikawa , Kotaro Sakoda, Jun Mihara, Naotaka Ito
Department of Chemistry, Graduate School of Science, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received 25 December 2005; accepted 28 December 2005
Available online 21 February 2006
Abstract
Arylpalladium or aminopalladium species bearing a 2,2-difluorovinyl group undergo an unusual 5-endo alkene insertion followed by b-fluorine
elimination. These processes provide a facile access to ring-fluorinated five-membered carbocyclic and heterocyclic compounds starting from an o-
(3,3-difluoroallyl)phenyl trifluoromethanesulfonate and 3,3-difluoroallyl ketone O-pentafluorobenzoyloximes. In both systems, the two vinylic
fluorine atoms are essential for Heck-type 5-endo-trig cyclizations.
# 2006 Elsevier B.V. All rights reserved.
Keywords: 5-endo-trig Cyclization; Heck-type reaction; Pyrrole; Indene; 5-endo Alkene insertion; b-Fluorine elimination; Palladium
1. Introduction
oxidative addition of halides 1 to Pd(0); (ii) the formation of
six-membered palladacycles 2 through nucleophilic substitu-
tion with the enamine on the palladium; (iii) a subsequent
reductive elimination, which leads to the 5-endo-trig type
products [6a,8].
In contemporary organic synthesis, the Heck reaction is one
of the most valuable bond-forming processes promoted by
transition metals [1]. The Heck reaction proceeds via alkene
insertion and b-hydrogen elimination, which are a palladium-
catalyzed coupling of alkenes. The intramolecular version of
the Heck reaction has been widely used to construct a variety of
ring systems. Normally, exo-mode cyclization is the favored
path, as endo-mode cyclization is less likely to form smaller
rings (Scheme 1) [2].
In general, according to Baldwin’s rules [9], the 5-endo-trig
cyclization has long been considered a disfavored process for
the construction of five-membered rings, because of the severe
distortions required in the reaction geometry. In recent
publications, we have reported on nucleophilic 5-endo-trig
cyclizations of 1,1-difluoro-1-alkenes 3 with an N-, O-, or a C-
nucleophile, providing five-membered ring-fluorinated hetero-
and carbocycles, such as indoles, 2-pyrrolines, benzo[b]furans,
2,3-dihydrofurans, indenes, and cyclopentenes (Scheme 3)
[10]. The remarkable reactivity of these alkenes towards
nucleophilic 5-endo-trig cyclizations is probably due to: (i) the
polarization of the carbon–carbon double bond caused by the
two fluorine atoms [11], which exerts an electrostatic attraction
for the intramolecular nucleophile, overcoming the difficulty of
the initial ring formation; (ii) the leaving group ability of
fluoride ions, which suppresses the reverse ring opening.
In the above 5-endo-trig cyclizations, typical metal species,
such as lithium, sodium, and potassium compounds, were
employed as intramolecular nucleophiles (Scheme 3). Thus, we
turned our attention to organotransition metal chemistry to
In particular, 5-endo-trig cyclizations in the Heck reaction
are limited [3,4], and all reports on such 5-endo Heck
cyclizations have been confined to the palladium-catalyzed
reaction of N-vinyl-2-haloarylamines [5] or N-vinyl-2-haloalk-
enylamines (Scheme 2, Path A) [6]. To the best of our
knowledge, one exception is the efficient cyclopentenone
formation via an alka-2,4-dienoylpalladium species [7].
However, the reactions of these vinylamine (enamine-type)
substrates can be interpreted in terms of a mechanism other than
a 5-endo-trig cyclization (Path B), which involves: (i) the
* Corresponding author. Fax: +81 3 5841 4345.
E-mail address: junji@chem.s.u-tokyo.ac.jp (J. Ichikawa).
0022-1139/$ – see front matter # 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2005.12.023

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J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
Scheme 1. exo or endo Alkene insertion in intramolecular Heck reactions.
Scheme 3. Nucleophilic 5-endo-trig cyclizations of 1,1-difluoro-1-alkenes.
broaden the scope of the 5-endo-trig cyclization of 1,1-
difluoro-1-alkenes, as well as to open up a new 5-endo-trig
pathway in Heck-type cyclizations. There is only one example
describing a Heck-type reaction of a 1,1-difluoro-1-alkene
[12]. Heitz reported that arylpalladium iodide complexes
replaced the fluorine atom of 1,1-difluoroethene to afford a-
fluorostyrenes via alkene insertion and subsequent b-fluorine
elimination [13]. Based on these considerations, we expected
that a Heck-type 5-endo-trig cyclization of difluoroalkenes
could be promoted by the electrostatic attraction between the
palladium species and the polarized difluoroalkene double
bonds, even though this pathway is sterically hindered
(Scheme 4). Herein, we report on the results of our studies
on Heck-type 5-endo-trig cyclizations of 1,1-difluoro-1-
alkenes, which provide an approach to ring-fluorinated five-
membered carbocyclic and heterocyclic compounds.
Scheme 4. Heck-type 5-endo-trig cyclizations of 1,1-difluoro-1-alkenes.
minum hydride (DIBAL-H) followed by difluoromethylena-
tion to give difluoroalkene 8 via aldehyde 7. Demethylation of
the methoxy group in 8 and successive trifluoromethanesulfo-
nylation afforded the desired substrate 4 for the cyclization
(Scheme 5).
When 4 was heated with a stoichiometric amount of
Pd(PPh3)4 and PPh3 in N,N-dimethylacetamide (DMA), the
Heck-type 5-endo-trig cyclization proceeded to give indanone
12 (57% yield), instead of the expected 3-fluoroindene 11. As
the formation of 12 seemed to be caused by the hydrolysis of
11, presumably due to the complexation with a Pd(II) generated
during the reaction, the reaction mixture was treated with PhSH
before quenching. Thus, the formation of fluoroindene 11 was
confirmed, and we showed that the 5-endo-trig cyclization was
achieved by arylpalladium(II) species 10, generated via the
oxidative addition of aryl triflate 4 to Pd(0) (Scheme 6). An
attempt to promote this cyclization with a catalytic amount
(10 mol%) of Pd(PPh3)4 and PPh3 (1.0 equiv. vide infra) gave
only a 15% yield of 12.
2. Results and discussion
2.1. Heck-type 5-endo-trig cyclizations with arylpalladium
species
In the reported Heck-type reaction of 1,1-difluoroethene
described above, arylpalladium species were employed as the
intermolecular coupling partners. We first attempted an
intramolecular version of this reaction using an aryl triflate
substrate. Aryl triflate 4 bearing a 3,3-difluoroallyl group at the
ortho position was designed and prepared as follows. Using the
literature method, 2-methylpropanenitrile was treated with
potassium hexamethyldisilazide to generate the corresponding
carbanion, which reacted with 2-fluoroanisole (5) to replace
the fluorine, leading to formation of nitrile 6 [14]. The cyano
group of 6 was transformed by reduction with diisobutylalu-
To confirm the effect of fluorine, we examined the reaction
of a fluorine-free substrate 13, which gave only a trace amount
of the cyclized product 14 (Scheme 7). These results clearly
show that fluorine functions as an activator of the substrates in
the Heck-type 5-endo-trig cyclization.
Scheme 2. Plausible mechanisms for the palladium-catalyzed cyclization of vinylamines.

J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
491
Scheme 5. Preparation of o-(3,3-difluoroallyl)phenyl triflate 4.
2.2. Heck-type 5-endo-trig cyclizations with
aminopalladium species
neaminopalladium species, which afforded nitrogen hetero-
cycles via the insertion of an alkene moiety in a 5-exo fashion
[15]. This prompted us to investigate the 5-endo insertion of an
intramolecular difluoroalkene moiety in 3,3-difluoroallyl
ketone O-pentafluorobenzoyloximes 15, which provides a
synthetic method for ring-fluorinated 3H-pyrrole derivatives
16 (Scheme 8).
Having accomplished a Heck-type 5-endo-trig cyclization
with C-palladium species, as described above, we aimed to
form ring-fluorinated heterocycles via the Heck-type cycliza-
tion with aminopalladium species. Recently, Narasaka
reported that homoallyl ketone O-pentafluorobenzoyloximes
underwent oxidative addition to Pd(0) to generate alkylide-
To synthesize the substrates (3,3-difluoroallyl ketone O-
pentafluorobenzoyloximes 15), we acylated enamines 17,
Scheme 6. Heck-type 5-endo-trig cyclizations of difluoroalkene 4 via C–Pd species.
Scheme 7. Effect of the vinylic substituent on 5-endo Heck-type cyclizations with C–Pd species.

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J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
Scheme 8. Heck-type 5-endo-trig cyclizations of difluoroalkenes 15 via N–Pd species.
derived from aldehydes, with acid chlorides to prepare b-
ketoaldehyde intermediates 18. The selective Wittig-type
difluoromethylenation of 18 gave difluoroallyl ketones 19
[16], which were further transformed into O-pentafluoroben-
zoyloximes 15 via oximation followed by pentafluorobenzoy-
lation (Scheme 9).
Ph3P O and Ph3PF2 [18,19]. When the reaction was conducted
in DMA at higher temperatures (110 8C), the yield of 16a
improved to 71% (Entry 5) [20].
We tried to synthesize other fluoropyrroles 16 under the
above optimized conditions (Table 2). The cyclization of
substrate 15b with a cyclohexane ring successfully afforded the
spiro-type product 16b (Entry 2). Substrate 15c bearing a
conjugated alkene moiety on the oxime carbon readily
underwent cyclization to give the corresponding pyrrole 16c
(Entry 3). The reactions of substrates 15d and 15e bearing a
primary alkyl or an acyl group as R3 resulted in poor yield
(Entries 4 and 5). Furthermore, the construction of a fused
tricyclic system of 4,5-dihydro-3aH-benzo[g]indole 16f, where
the transition state is more strained, was achieved using this
method (Scheme 10). Thus, the catalytic process provides a
facile access to 5-fluoro-3H-pyrroles [21,22].
Then, we investigated the Heck-type cyclization of 15a
(R1 = R2 = Me and R3 = Ph, Z-form [17]) in N,N-dimethylfor-
mamide (DMF) at 80 8C (Scheme 8 and Table 1). The catalytic
reaction gave the desired compound, 5-fluoro-3H-pyrrole 16a,
albeit in only 19% yield (Entry 2). We examined the reagents
required for the reduction of the in situ generated palladium(II)
species to Pd(0). On treatment with Pd(PPh3)4 (10 mol%) and
NEt3 (5.0 equiv.) [12], 16a was obtained in low yield (Entry 3).
After the screening of suitable reductants, we found that a
stoichiometric amount of PPh3 was effective in reducing
C6F5CO2Pd(II)F to Pd(0), which allowed the cyclization to
proceed under palladium catalysis with the generation of
To elucidate the role of the vinylic fluorines, we examined
the reaction of substrates that had atoms other than fluorine at
Scheme 9. Preparation of 3,3-difluoroallyl ketone oximes 15.

J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
493
Table 1
Effect of reductant and conditions on the Heck-type cyclization of 15a (R1 = R2 = Me and R3 = Ph)
Entry
Pd(PPh3)4 (equiv.)
Reductant (equiv.)
Solvent
Conditions
Yield (%)
1
2
3
4
5
0.3
0.1
0.1
0.1
0.1
None
DMF
DMF
DMF
DMF
DMA
80 8C, 1 h
71
19
None
80 8C, 2 h, then 110 8C, 2 h
80 8C, 2 h, then 110 8C, 9 h
100 8C, 4 h
NEt3 (5.0)
PPh3 (1.0)
PPh3 (1.0)
<30
57
110 8C, 8 h
71
the vinylic positions, such as the corresponding monofluo-
roalkene 21a, fluorine-free alkene 21b, dichloroalkene 21c,
and dibromoalkene 21d. These oximes 21a–d were prepared
via the corresponding allyl ketones 23a–d (Scheme 11).
Monofluoroketone 23a was derived from difluoroallyl ketone
19a via hydride reduction of its dimethyl acetal 22 [23].
Dichloroketone 23c [24,25] and dibromoketone 23d [26] were
prepared via dihalomethylenation of ketoaldehyde 18a.
Ketones 23a, 23c, and 23d thus obtained and 23b [27] were
transformed into the desired substrates 21 via oximation
followed by pentafluorobenzoylation [28].
pairs of fluorine and the p-electrons. Such repulsion is much
stronger for fluorine than for other halogens, due to the 2p-
orbital occupancy of both the lone pairs and the p-electrons.
2.3. Conclusion
We have accomplished a 5-endo-trig alkene insertion in the
Heck-type cyclization of an o-(3,3-difluoroallyl)phenyl triflate
and 3,3-difluoroallyl ketone oximes by taking advantage of the
polarized double bond of 1,1-difluoro-1-alkenes. The two
vinylic fluorine atoms were confirmed to be essential for the 5-
endo Heck-type cyclizations. The alkene insertion followed by
b-fluorine elimination provides a facile method for ring-
fluorinated indene and 3H-pyrrole syntheses.
When 21a–d were subjected to the same reaction conditions
as above, no cyclized products were observed (Scheme 12).
Instead, the corresponding ketones were obtained via hydro-
lysis of the oxime moiety of 21a–c, and 21d gave a complex
mixture, presumably due to its vinylic bromides reactive toward
Pd(0). These results clearly show that the two vinylic fluorines
play an important role in this Heck-type 5-endo-trig cycliza-
tion. The major distinction of the 1,1-difluoro-1-alkenes
appears to be the remarkable polarization of the double bond,
which is caused by the repulsive interaction between the lone
3. Experimental
3.1. General experimental procedure
IR spectra were recorded on a Horiba FT-300S spectrometer
1
by ATR (attenuated total reflectance) method. H NMR, 13C
Table 2
Synthesis of 5-fluoro-3H-pyrroles 16 from difluoroalkenes 15a
Entry
1
Substrate 15b
Product 16
Time (h)
8
Yield (%)
71
15a
15b
2
8
78
3
4
1
8
76
29
14
15c
15d
15e
5
12
a
All the reactions were performed with Pd(PPh3)4 (0.1 equiv.) and PPh3 (1.0 equiv.) in DMA at 110 8C.
Each of substrates 15 was a single isomer, while the stereochemistry of 15b–e was not determined.
b

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J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
Scheme 10. Construction of a fused tricyclic system via a Heck-type 5-endo-
trig cyclization.
Scheme 12. Effect of the vinylic substituent on 5-endo Heck-type cyclizations
with N–Pd species.
NMR, and 19F NMR spectra were recorded on a Bruker Avance
500 spectrometer, a Bruker DRX 500, or a JEOL JNM-AL-400
1
spectrometer. H NMR chemical shifts (d) are given in ppm
tional DIBAL-H (4.0 mL, 1.0 M in toluene, 4.0 mmol) was
added dropwise at À78 8C. The mixture was stirred for 0.5 h,
and then hexane, methanol, saturated aqueous NH4Cl, and
10% sulfuric acid were added to quench the reaction. Organic
materials were extracted with CH2Cl2 three times. The
combined extracts were washed with brine and dried over
Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography on
silica gel (AcOEt–hexane 1:4) to give 7 (6.66 g, 95%) as a
colorless liquid.
1H NMR (400 MHz, CDCl3) d 1.38 (6H, s), 3.76 (3H, s),
6.89 (1H, dm, J = 8.0 Hz), 7.00 (1H, ddd, J = 8.0, 8.0, 1.2 Hz),
7.25–7.32 (2H, m), 9.51 (1H, s). 13C NMR (100 MHz, CDCl3) d
22.1, 48.2, 55.1, 110.9, 120.9, 126.7, 128.5, 131.8, 156.4, 203.5.
IR (neat) 2970, 2704, 1724, 1489, 1458, 1437, 1240, 1092,
1026, 752 cmÀ1. HRMS (FAB): calcd for C11H15O2 ([M + H]+)
179.1072, found 179.1045.
downfield from internal Me4Si. 13C NMR chemical shifts (d)
are given in ppm downfield from Me4Si, relative to chloro-
form-d (d = 77.00). 19F NMR chemical shifts (dF) are given in
ppm downfield from internal C6F6. Mass spectra were taken
with a JEOL MS-700M spectrometer. Elemental analyses were
performed with a YANAKO MT-6 CHN Corder apparatus. All
reactions were carried out under argon. Dichloromethane
(CH2Cl2) was distilled from P2O5 and then from CaH2, and
˚
stored over molecular sieves (4 A). THF and Et2O were
purchased as an anhydrous solvent from Kanto Chemical Co.,
˚
Inc. and stored over 4 A molecular sieves. Methanol was
distilled from Mg(OMe)2 and stored over molecular sieves
˚
(3 A). Ethanol was distilled from NaOEt and stored over
˚
molecular sieves (3 A). N,N-dimethylacetamide (DMA) was
distilled under reduced pressure from BaO and stored over
˚
molecular sieves (4 A). DMF was dried over P2O5, then
distilled under reduced pressure from CaH2, and stored over
˚
molecular sieves (4 A). Toluene was dried over CaCl2, then
˚
distilled, and stored over molecular sieves (4 A). Pyridine was
3.2.2. 2-(4,4-Difluoro-2-methylbut-3-en-2-yl)anisole (8)
To a mixture of dibromodifluoromethane (CF2Br2, 5.92 mL,
˚
distilled from CaH2 and stored over molecular sieves (4 A).
˚
64.8 mmol) and microwave-dried molecular sieves (4 A)
Column chromatography and preparative thin-layer chroma-
tography (PTLC) were performed on silica gel (Kanto
Chemical Co. Inc., Silica Gel 60 and Wako Pure Chemical
Industries, Ltd., B5-F), respectively.
powder (6.6 g) in THF (50 mL) was added tris(dimethylami-
no)phosphine (P(NMe2)3, 23.5 mL, 130 mmol) at À78 8C. The
mixture was stirred for 30 min at that temperature, and then
warmed to room temperature. Aldehyde
7
(5.78 g,
32.4 mmol) was added and the mixture was stirred for
10 h. The reaction was quenched with phosphate buffer (pH 7)
and organic materials were extracted with Et2O three times.
The combined extracts were washed with brine and dried
over MgSO4. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography
on silica gel (AcOEt–hexane 1:4) to give 8 (6.18 g, 96%) as a
colorless liquid.
3.2. Heck-type 5-endo-trig cyclizations with arylpalladium
species
3.2.1. 2-(2-Methoxyphenyl)-2-methylpropanal (7)
To
a solution of 2-(2-methoxyphenyl)-2-methylpro-
pionitrile (6.87 g, 39.2 mmol) in CH2Cl2 (80 mL) was added
diisobutylaluminum hydride (DIBAL-H, 39.2 mL, 1.0 M in
toluene, 39.2 mmol) dropwise at À78 8C. After the reaction
mixture was stirred for 1.5 h at room temperature, an addi-
1H NMR (400 MHz, CDCl3) d 1.53 (6H, s), 3.82 (3H, s),
4.54 (1H, dd, JHF = 28.4, 5.8 Hz), 6.85–6.93 (2H, m), 7.19–7.24
Scheme 11. Preparation of allyl ketone oximes 21.

J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
495
(1H, m), 7.27–7.30 (1H, m). 13C NMR (100 MHz, CDCl3) d
28.3 (dd, JCF = 4, 2 Hz), 35.1 (dd, JCF = 5, 3 Hz), 55.1, 88.3
(dd, JCF = 22, 14 Hz), 111.5, 120.2, 125.9, 127.6, 135.9,
154.7 (dd, JCF = 290, 280 Hz), 157.7. 19F NMR (376 MHz,
CDCl3) dF 72.1 (1F, dd, JFF = 54 Hz, JFH = 6 Hz), 74.2 (1F,
dd, JFF = 54 Hz, JFH = 28 Hz). IR (neat) 2968, 1734, 1458,
1437, 1329, 1290, 1242, 1215, 1030, 999, 746 cmÀ1. HRMS
(FAB): calcd for C12H15F2O ([M + H]+) 213.1091, found
213.1135.
3.2.5. 3-Fluoro-1,1-dimethyl-1H-indene (11)
To a solution of triphenylphosphine (PPh3, 124 mg,
0.47 mmol) and tetrakis(triphenylphosphine)palladium (Pd
(PPh3)4, 455 mg, 0.394 mmol) in DMA (20 mL) was added 4
(130 mg, 0.39 mmol). After the reaction mixture was stirred at
110 8C for 9 h, thiophenol (0.16 mL, 1.58 mmol) was added.
Phosphate buffer (pH 7) was added and organic materials were
extracted with Et2O three times. The combined extracts were
washed with water three times and brine, and dried over
MgSO4. After removal of the solvent under reduced pressure,
the residue was purified by preparative thin-layer chromato-
graphy (pentane) to give 11 (64%, determined before
extraction by 19F NMR relative to internal C6H5CF3).
3.2.3. 2-(4,4-Difluoro-2-methylbut-3-en-2-yl)phenol (9)
To a solution of 8 (1.11 g, 5.21 mmol) in CH2Cl2 (25 mL)
was added a solution of tribromoborane (BBr3, 5.2 mL, 1.0 M
in CH2Cl2, 5.2 mmol) dropwise at À30 8C. After the reaction
mixture was stirred for 2 h at À30 8C, phosphate buffer (pH 7)
was added to quench the reaction. Organic materials were
extracted with CH2Cl2 three times. The combined extracts were
washed with brine and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by
column chromatography on silica gel (AcOEt–hexane 1:19) to
give 9 (0.67 g, 65%) as a yellow oil.
1H NMR (400 MHz, CDCl3) d 1.35 (6H, s), 5.62 (1H, s),
7.24–7.34 (4H, m). 13C NMR (100 MHz, CDCl3) d 24.9 (d,
J
CF = 3 Hz), 44.7 (d, JCF = 5 Hz), 117.9 (d, JCF = 13 Hz), 117.9
(d, JCF = 5 Hz), 121.2 (d, JCF = 3 Hz), 126.5, 126.5, 134.6 (d,
CF = 27 Hz), 151.7 (d, JCF = 7 Hz), 157.4 (d, JCF = 280 Hz).
J
19F NMR (376 MHz, CDCl3) dF 23.6 (s). IR (neat) 2956, 2924,
2854, 2360, 2332, 1458, 1375, 1219, 771 cmÀ1. HRMS (FAB):
calcd for C11H12F ([M + H]+) 163.0923, found 163.0924.
1H NMR (400 MHz, CDCl3) d 1.54 (6H, s), 4.59 (1H, dm,
J
HF = 26.7 Hz), 5.10–5.15 (1H, m), 6.72 (1H, d, J = 7.7 Hz),
3.2.6. 3,3-Dimethylindan-1-one (12) [29]
6.89 (1H, dd, J = 7.7, 7.7 Hz), 7.11 (1H, ddd, J = 7.7, 7.7,
1.6 Hz), 7.26 (1H, dd, J = 7.7, 1.6 Hz). 13C NMR (100 MHz,
CDCl3) d 28.3 (dd, JCF = 3, 2 Hz), 34.8 (dd, JCF = 5, 3 Hz), 87.4
(dd, JCF = 21, 13 Hz), 116.7, 120.6, 126.1, 127.8, 133.5, 153.6,
155.1 (dd, JCF = 294, 285 Hz). 19F NMR (376 MHz, CDCl3) dF
75.5 (1F, dd, JFF = 45 Hz, JFH = 5 Hz), 77.2 (1F, dd,
To a solution of PPh3 (50.8 mg, 0.194 mmol) and Pd(PPh3)4
(180 mg, 0.156 mmol) in DMA (10 mL) was added 4 (51.5 mg,
0.156 mmol). After the reaction mixture was stirred at 110 8C
for 9 h, phosphate buffer (pH 7) was added to quench the
reaction. Organic materials were extracted with Et2O three
times. The combined extracts were washed with water three
times and brine, and dried over MgSO4. After removal of the
solvent under reduced pressure, the residue was purified by
preparative thin-layer chromatography on silica gel (AcOEt–
hexane 1:4) to give 12 (14.2 mg, 57%) as a colorless liquid.
1H NMR (400 MHz, CDCl3) d 1.43 (6H, s), 2.60 (2H, s),
7.36–7.71 (4H, m). IR (neat) 2958, 1709, 1604, 1471, 1323,
J
FF = 45 Hz, JFH = 27 Hz).
3.2.4. 2-(4,4-Difluoro-2-methylbut-3-en-2-yl)phenyl
trifluoromethanesulfonate (4)
To a solution of 9 (94 mg, 0.47 mmol) in pyridine (2 mL)
was added trifluoromethanesulfonic anhydride (0.105 mL,
0.62 mmol). After the reaction mixture was stirred for 24 h
at room temperature, an additional trifluoromethanesulfonic
anhydride (0.105 mL, 0.62 mmol) was added, and the reaction
mixture was stirred for 8 h at room temperature. Aqueous 1 M
HCl was added to quench the reaction, and organic materials
were extracted with Et2O three times. The combined extracts
were washed with aqueous 1 M HCl and brine, and then dried
over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by thin-layer chromatography
on silica gel (AcOEt–hexane 1:19) to give 4 (126 mg, 80%) as a
yellow oil.
1290, 1246, 766 cmÀ1
.
3.3. Heck-type 5-endo-trig cyclizations with
aminopalladium species
3.3.1. 1-Benzoylcyclohexane-1-carbaldehyde (18b)
To a solution of benzoyl chloride (11.6 g, 83 mmol) in Et2O
(14 mL) was added 4-(cyclohexylidenemethyl)morpholine
(17b, 12.5 g, 69 mmol) [30] with vigorous stirring over 1 h
at 0 8C, and the solution was heated to reflux for 3 h. Saturated
aqueous sodium bicarbonate (NaHCO3) was added (23 mL) at
0 8C, and the mixture was stirred for 1 h at that temperature.
Organic materials were extracted with Et2O three times. The
combined extracts were washed with brine and dried over
Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography on silica
gel (AcOEt–hexane 1:20) to give 18b (6.9 g, 46%) as a
colorless oil.
1H NMR (400 MHz, CDCl3) d 1.55 (6H, s), 4.61 (1H, dd,
J
HF = 27.2, 4.0 Hz), 7.29–7.35 (3H, m), 7.46–7.51 (1H, m). 13
C
NMR (100 MHz, CDCl3) d 29.1 (dd, JCF = 3, 2 Hz), 34.8 (dd,
J
J
CF = 6, 2 Hz), 88.1 (dd, JCF = 22, 14 Hz), 118.3 (q,
CF = 319 Hz), 121.2 (dd, JCF = 4, 3 Hz), 127.7, 127.8,
128.4, 139.7, 148.6, 155.2 (dd, JCF = 292, 286 Hz). 19F
NMR (376 MHz, CDCl3) dF 75.0 (1F, dd, JFF = 44 Hz,
J
FH = 4 Hz), 77.4 (1F, dd, JFF = 44 Hz, JFH = 27 Hz), 87.5
1H NMR (500 MHz, CDCl3) d 1.41–1.47 (2H, m), 1.49–1.57
(4H, m), 2.04 (2H, ddd, J = 13.1, 7.5, 4.4 Hz), 2.16 (2H, ddd,
J = 13.1, 7.8, 4.6 Hz), 7.41 (2H, t, J = 7.6 Hz), 7.51 (1H, tt,
J = 7.6, 1.2 Hz), 7.69 (2H, d, J = 7.6 Hz), 9.70 (1H, s). 13C
(3F, s). IR (neat) 2979, 1736, 1419, 1325, 1211, 1140, 1066,
895, 879, 766, 598 cmÀ1. Anal. Calcd for C12H11F5O3S: C,
43.64; H, 3.36%. Found: C, 43.49; H, 3.54%.

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J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
NMR (126 MHz, CDCl3) d 22.1, 25.1, 29.6, 64.9, 128.4, 128.5,
132.3, 137.1, 199.6, 201.0. IR (neat) 2935, 1720, 1670, 1446,
1228, 949, 783, 694 cmÀ1. HRMS (FAB): calcd for C14H17O2
([M + H]+) 217.1229, found 217.1213.
2,2-dimethyl-3-oxo-3-phenylpropanal 18a (1.23 g, 6.98 mmol)
[32]. After the mixture was stirred 10 h, the reaction was
quenched with phosphate buffer (pH 7) at 0 8C. After suction
filtration, organic materials were extracted with AcOEt three
times. The combined extracts were washed with brine and dried
over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography
on silica gel (AcOEt–hexane 1:20) to give 19a (1.46 g, quant.)
as a white solid.
3.3.2. (E)-2,2-Dimethyl-3-oxo-5-phenylpent-4-enal (18c)
Compound 18c was prepared by the method described for
18b using (E)-cinnamoyl chloride (5.00 g, 30.0 mmol), Et2O
(6 mL), 4-(2-methylpropenyl)morpholine (17a, 4.23 g,
30.0 mmol), and saturated aqueous NaHCO3 (10 mL). Pur-
ification by column chromatography on silica gel (AcOEt–
hexane 1:20) gave 18c (3.74 g, 62%) as a white solid.
1H NMR (500 MHz, CDCl3) d 1.30 (6H, s), 6.82 (1H, d,
J = 15.6 Hz), 7.17–7.35 (3H, m), 7.38–7.49 (2H, m,), 7.61 (1H,
d, J = 15.6 Hz), 9.59 (1H, s). 13C NMR (126 MHz, CDCl3) d
18.9, 59.3, 120.5, 128.3, 128.8, 131.1, 134.0, 144.6, 197.2,
201.0. IR (neat) 1732, 1722, 1684, 1674, 1599, 1576, 1448,
1329, 1065, 980, 899, 762, 710, 685, 567, 519 cmÀ1. HRMS
(FAB): calcd for C13H15O2 ([M + H]+) 203.1072, found
203.1092.
1H NMR (500 MHz, CDCl3) d 1.46 (6H, s), 4.65 (1H, dd,
J
HF = 27.8, 3.0 Hz), 7.39 (2H, t, J = 7.4 Hz), 7.47 (1H, t,
J = 7.4 Hz), 7.94 (2H, d, J = 7.4 Hz). 13C NMR (126 MHz,
CDCl3) d 26.8, 43.6 (dd, JCF = 3, 3 Hz), 85.7 (dd, JCF = 22,
16 Hz), 128.0, 129.0, 132.0, 135.1, 155.2 (dd, JCF = 293,
288 Hz), 202.0 (dd, JCF = 2, 2 Hz). 19F NMR (471 MHz,
CDCl3) dF 77.2 (1F, dd, JFF = 42 Hz, JFH = 3 Hz), 77.8 (1F, dd,
J
FF = 42 Hz, JFH = 28 Hz). IR (neat) 1734, 1682, 1323, 1215,
997, 795, 715, 700, 690 cmÀ1. HRMS (FAB): calcd for
C12H13F2O ([M + H]+) 211.0935, found 211.0947.
3.3.6. (E)-6,6-Difluoro-4,4-dimethyl-1-phenylhexa-1,5-
dien-3-one (19c)
3.3.3. 2,2-Dimethyl-3-oxododecanal (18d)
Compound 18d was prepared by the method described for
18b using decanoyl chloride (5.47 g, 28.7 mmol), Et2O (7 mL),
and 17a (4.05 g, 28.7 mmol). The reaction mixture was heated
to reflux for 5 h, and saturated aqueous NaHCO3 (10 mL) was
added. Purification by column chromatography on silica gel
(Et2O–hexane 1:10) gave 18d (1.82 g, 28%) as a colorless
liquid.
Compound 19c was prepared by the method described for
19a using CF2Br2 (1.68 g, 7.99 mmol), microwave-dried
˚
molecular sieves (4 A) powder (0.60 g), THF (6.0 mL),
P(NMe2)3 (2.60 g, 16.0 mmol), and 18c (805 mg, 3.98 mmol).
Purification by column chromatography on silica gel (AcOEt–
hexane 1:20) gave 19c (330 mg, 35%) as a white solid.
1H NMR (500 MHz, CDCl3) d 1.36 (6H, s), 4.47 (1H, dd,
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J = 7.0 Hz),
1.21–1.32 (12H, m), 1.33 (6H, s), 1.45 (2H, tt, J = 7.3, 7.3 Hz),
2.44 (2H, t, J = 7.3 Hz), 9.62 (1H, s). 13C NMR (126 MHz,
CDCl3) d 14.0, 19.1, 22.6, 23.3, 29.0, 29.2, 29.3, 29.3, 31.8,
39.0, 60.3, 201.1, 209.3. IR (neat) 2924, 2854, 1734, 1700,
1466, 1366, 1072, 1035, 914, 838, 722 cmÀ1. HRMS (FAB):
calcd for C14H27O2 ([M + H]+) 227.2011, found 227.2006.
JHF = 28.0, 4.2 Hz), 7.07 (1H, d, J = 15.6 Hz), 7.32–7.38 (3H,
m), 7.51–7.57 (2H, m), 7.74 (1H, d, J = 15.6 Hz). 13C NMR
(126 MHz, CDCl3) d 24.6, 43.9 (dd, JCF = 3.7, 3.7 Hz), 83.7
(dd, JCF = 23, 15 Hz), 120.6, 128.1, 128.6, 130.2, 134.4, 143.5,
155.7 (dd, JCF = 294, 288 Hz), 199.4. 19F NMR (471 MHz,
CDCl3) dF 77.6 (1F, br d, JFF = 42 Hz), 78.2 (1F, dd,
JFF = 42 Hz, JFH = 28 Hz). IR (neat) 2974, 1734, 1687, 1608,
1329, 1225, 1134, 1061, 997, 764, 715, 685, 561 cmÀ1. Anal.
Calcd for C14H14F2O: C, 71.17; H, 5.97%, found: C, 71.33; H,
6.20%.
3.3.4. tert-Butyl 3,3-dimethyl-2,4-dioxobutyrate (18e)
Compound 18e was prepared by the method described for
18b using tert-butyl 2-chloro-2-oxoacetate (3.34 g, 20.3 mmol)
[31], Et2O (4 mL), 17a (2.87 g, 20.3 mmol), and saturated
aqueous NaHCO3 (7 mL). Purification by column chromato-
graphy on silica gel (Et2O–hexane 1:10) gave 18e (3.40 g, 59%)
as a colorless oil.
3.3.7. 1,1-Difluoro-3,3-dimethyltridec-1-en-4-one (19d)
Compound 19d was prepared by the method described for
19a using CF2Br2 (3.72 g, 17.7 mmol), microwave-dried
˚
molecular sieves (4 A) powder (1.77 g), THF (13 mL),
1H NMR (500 MHz, CDCl3) d 1.38 (6H, s), 1.54 (9H, s),
9.68 (1H, s). 13C NMR (126 MHz, CDCl3) d 18.8, 27.8, 57.8,
85.5, 160.6, 193.9, 197.8. IR (neat) 2981, 1712, 1460, 1371,
1317, 1259, 1155, 1049, 978, 843, 742 cmÀ1. HRMS (FAB):
calcd for C10H17O4 ([M + H]+) 201.1127, found 201.1132.
P(NMe2)3 (5.77 g, 35.4 mmol), and 18d (2.00 g, 8.85 mmol).
The mixture was stirred for 1.5 h. Purification by column
chromatography on silica gel (Et2O–hexane 1:20) gave 19d
(1.58 g, 68%) as a white solid.
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J = 6.9 Hz),
1.26–1.31 (18H, m), 1.56 (2H, tt, J = 7.1, 7.1 Hz), 2.49 (2H, t,
J = 7.1 Hz), 4.37 (1H, dd, JHF = 27.9, 4.4 Hz). 13C NMR
(126 MHz, CDCl3) d 14.0, 22.6, 24.1, 24.9 (d, JCF = 3 Hz),
29.2, 29.2, 29.4, 29.4, 31.8, 37.0, 45.1(dd, JCF = 4, 4 Hz), 83.9
3.3.5. 4,4-Difluoro-2,2-dimethyl-1-phenylbut-3-en-1-one
(19a)
To a mixture of CF2Br2 (1.68 g, 7.99 mmol) and microwave-
(dd, JCF = 23, 15 Hz), 155.7 (dd, JCF = 294, 287 Hz), 211.7. 19
NMR (471 MHz, CDCl3) dF 76.9 (1F, dd, JFF = 44 Hz,
FH = 4 Hz), 78.2 (1F, dd, JFF = 44 Hz, JFH = 28 Hz). IR (neat)
2925, 2854, 1738, 1716, 1508, 1456, 1331, 1223, 1001,
F
˚
dried molecular sieves (4 A) powder (1.4 g) in THF (10.5 mL)
was added P(NMe2)3 (4.11 g, 25.2 mmol) at À78 8C. The
reaction mixture was stirred for 15 min at that temperature, and
then warmed to room temperature. To the mixture was added
J

J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
497
771 cmÀ1. HRMS (FAB): calcd for C15H27F2O ([M + H]+)
261.2030, found 261.2049.
Na2SO4. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography on silica
gel (NEt3–AcOEt–hexane 1:5:100) to give 22 (2.17g, 80%) as a
colorless oil.
1H NMR (500 MHz, CDCl3) d 1.04 (3H, s), 1.05 (3H, s),
3.29 (6H, s), 4.65 (1H, dd, JHF = 28.7, 7.0 Hz), 7.25 (1H, t,
J = 7.2 Hz), 7.29 (2H, t, J = 7.2 Hz), 7.40 (2H, d, J = 7.2 Hz).
13C NMR (126 MHz, CDCl3) d 24.9, 24.9, 41.8 (dd, JCF = 4,
4 Hz), 51.3, 85.4 (dd, JCF = 24, 12 Hz), 106.3 (dd, JCF = 2,
2 Hz), 127.0, 127.6, 129.3, 138.1, 154.5 (dd, JCF = 293,
281 Hz). 19F NMR (471 MHz, CDCl3) dF 75.1 (1F, dd,
3.3.8. tert-Butyl 5,5-difluoro-3,3-dimethyl-2-oxopent-4-
enoate (19e)
Compound 19e was prepared by the method described for
19a using CF2Br2 (6.82 g, 32.5 mmol), microwave-dried
˚
molecular sieves (4 A) powder (3.88 g), THF (13 mL),
P(NMe2)3 (9.61 g, 58.8 mmol), and 18e (3.91 g, 19.5 mmol).
Purification by column chromatography on silica gel (Et2O–
hexane 1:20) gave 19e (1.13 g, 25%) as a white solid.
1H NMR (500 MHz, CDCl3) d 1.42 (6H, s), 1.55 (9H, s),
4.44 (1H, dd, JHF = 27.5, 3.8 Hz). 13C NMR (126 MHz, CDCl3)
d 24.6 (d, JCF = 3 Hz), 27.7, 43.1 (dd, JCF = 5, 3 Hz), 82.7 (dd,
J
J
FF = 52 Hz, JFH = 29 Hz), 76.1 (1F, dd, JFF = 52 Hz,
FH = 7 Hz). IR (neat) 1738, 1325, 1228, 1178, 1103, 1055,
985, 908, 758, 707 cmÀ1. HRMS (FAB): calcd for C14H19F2O2
([M + H]+) 257.1353, found 257.1341.
J
CF = 25, 15 Hz), 84.3, 156.0 (dd, JCF = 294, 288 Hz), 162.5,
197.5 (dd, JCF = 2, 2 Hz). 19F NMR (471 MHz, CDCl3) dF 78.1
(1F, dd, JFF = 42 Hz, JFH = 4 Hz), 78.2 (1F, dd, JFF = 42 Hz,
3.3.11. (Z)-4-Fluoro-2,2-dimethyl-1-phenylbut-3-en-1-one
(23a)
J
FH = 28 Hz). IR (neat) 2983, 1731, 1716, 1371, 1302, 1228,
1157, 1047, 1001, 841 cmÀ1. Anal. Calcd for C11H16F2O3: C,
56.40; H, 6.88%. Found: C, 56.62; H, 7.12%.
To a solution of 22 (207 mg, 0.81 mmol) in toluene (3 mL)
was added sodium bis(2-methoxyethoxy)aluminum dihydride
(Red-Al1, 0.12 mL, 3.3 M in toluene, 0.40 mmol) at 0 8C.
After heating to reflux for 3 h, the reaction was quenched with
phosphate buffer (pH 7) at 0 8C. The mixture was filtrated
through a Celete pad, and organic materials were extracted with
Et2O three times. The combined extracts were washed with
brine and dried over Na2SO4. After removal of the solvent
under reduced pressure, the residue was dissolved in EtOH and
treated with aqueous 12 M HCl (1.3 mL, 16 mmol). After
stirring at room temperature for 10 min, NaHCO3 (1.29 g,
15 mmol) and phosphate buffer (pH 7) were added at 0 8C.
Organic materials were extracted with Et2O three times. The
combined extracts were washed with brine and dried over
MgSO4. After removal of the solvent under reduced pressure,
the residue was purified by column chromatography on silica
gel (AcOEt–hexane 1:20). Further purification was conducted
by gel permeation chromatography (GPC, CHCl3) to give 23a
(84 mg, 54%) as a colorless liquid.
3.3.9. 2-(2,2-Difluorovinyl)-2-methyl-3,4-
dihydronaphthalen-1(2H)-one (19f)
Compound 19f was prepared by the method described for
19a using CF2Br2 (5.05 g, 24.1 mmol), microwave-dried
˚
molecular sieves (4 A) powder (2.41 g), THF (20 mL),
P(NMe2)3 (7.87 g, 28.2 mmol), and 2-methyl-1-oxo-1,2,3,4-
tetrahydronaphthalene-2-carbaldehyde
(18f,
2.30 g,
12.1 mmol), prepared according to a reported procedure [33]
from 2-hydroxymethylene-3,4-dihydro-2H-naphthalen-1-one
[34]. The mixture was stirred at room temperature for 1.5 h.
Purification by column chromatography on silica gel (AcOEt–
hexane 1:10) gave 19f (2.36 g, 88%) as a pale yellow oil.
1H NMR (500 MHz, CDCl3) d 1.40 (3H, s), 2.14 (1H, ddd,
J = 13.1, 6.3, 6.3 Hz), 2.22 (1H, ddd, J = 13.1, 6.3, 6.3 Hz),
3.00 (1H, dd, J = 6.3, 6.3 Hz), 3.00 (1H, dd, J = 6.3, 6.3 Hz),
4.58 (1H, dd, JHF = 28.4, 4.4 Hz), 7.22 (1H, dd, J = 7.7,
1.1 Hz), 7.29 (1H, ddd, J = 7.7, 7.7, 1.1 Hz), 7.46 (1H, ddd,
J = 7.7, 7.7, 1.1 Hz), 8.04 (1H, dd, J = 7.7, 1.1 Hz). 13C NMR
(126 MHz, CDCl3) d 22.4 (dd, JCF = 2, 2 Hz), 25.4, 34.8 (dd,
1H NMR (500 MHz, CDCl3) d 1.41 (6H, s), 5.76 (1H, dd,
JHF = 20.6 Hz, J = 11.4 Hz), 6.63 (1H, dd, JHF = 83.7 Hz,
J = 11.4 Hz), 7.39 (2H, t, J = 7.5 Hz), 7.47 (1H, t,
J = 7.5 Hz), 7.85 (2H, d, J = 7.5 Hz). 13C NMR (126 MHz,
CDCl3) d 26.5, 45.6 (d, JCF = 8 Hz), 118.3 (d, JCF = 11 Hz),
128.0, 128.9, 131.7, 136.7, 149.7 (d, JCF = 256 Hz), 203.7 (d,
J
CF = 2, 2 Hz), 43.1 (dd, JCF = 4, 4 Hz), 82.2 (dd, JCF = 25,
15 Hz), 126.7, 128.2, 128.7, 130.9, 133.3, 142.9, 156.0 (dd,
CF = 291, 285 Hz), 198.7. 19F NMR (471 MHz, CDCl3) dF
77.4 (1F, dd, JFF = 45 Hz, JFH = 4 Hz), 78.4 (1F, dd,
J
J
J
CF = 2 Hz). 19F NMR (471 MHz, CDCl3) dF 30.9 (dd,
J
FF = 45 Hz, JFH = 28 Hz). IR (neat) 2933, 1736, 1684, 1456,
FH = 84, 21 Hz). IR (neat) 2978, 1736, 1678, 1254, 1169,
1300, 1227, 1192, 889, 739 cmÀ1. HRMS (FAB): calcd for
C13H12F2O ([M + H]+) 223.0935, found 223.0937.
1076, 957, 920, 700 cmÀ1. HRMS (FAB): calcd for C12H14FO
([M + H]+) 193.1029, found 193.1043.
3.3.10. 1,1-Difluoro-4,4-dimethoxy-3,3-dimethyl-1-
phenylbut-1-ene (22)
3.3.12. 4,4-Dichloro-2,2-dimethyl-1-phenylbut-3-en-1-one
(23c) [24]
Ketone 19a (2.22 g, 10.6 mmol), trimethyl orthoformate
(4.48 g, 42.2 mmol), and p-toluenesulfonic acid monohydrate
(1.01 g, 5.3 mmol) were dissolved in MeOH (21 mL) and
heated to reflux for 15 h. NaOMe (0.29 g, 5.3 mmol) was added
through a solid addition funnel at 0 8C. The mixture was diluted
with pentane (30 mL) and filtrated through a Celite pad. The
organic layer was washed with water and brine, and dried over
To a solution of diethyl trichloromethylphosphonate (3.35 g,
13.1 mmol) [25] in THF (40 mL) was added butyllithium
(8.23 mL, 1.6 M in hexane, 13.1 mmol) dropwise at À90 8C.
After stirring for 1 h, 18a (2.31 g, 13.1 mmol) [32] was added,
and then the mixture was stirred at room temperature for 8 h.
The reaction was quenched with phosphate buffer (pH 7), and
organic materials were extracted with Et2O three times. The

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J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
combined extracts were washed with water and brine, and dried
over MgSO4. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography
on silica gel (Et2O–hexane 1:10) to give 23c (956 mg, 30%) as
a colorless oil.
1H NMR (500 MHz, CDCl3) d 1.48 (3H, s), 1.48 (3H, s),
6.38 (1H, s), 7.44 (2H, td, J = 7.7, 1.3 Hz), 7.54 (1H, tt, J = 7.7,
1.3 Hz), 7.9 (2H, dd, J = 7.7, 1.3 Hz). 13C NMR (126 MHz,
CDCl3) d 26.4, 26.4, 48.4, 121.9, 128.2, 129.1, 132.6, 134.5,
135.4, 201.0. IR (neat) 2979, 1682, 1446, 1242, 1165, 906, 849,
715 cmÀ1. HRMS (FAB): calcd for C12H13Cl2O ([M + H]+)
243.0343, found 243.0363.
C12H13F2NO: C, 63.99; H, 5.82; N, 6.22%. Found: C, 63.74; H,
5.87; N, 6.11%. Crystal data. C12H13F2NO, M = 225.23,
˚
monoclinic, a = 7.5652(18), b = 6.3060(15), c = 23.707(6) A,
3
˚
U = 1121.4(5) A , T = 120(2) K, space group P21/c, Z = 4,
m(Mo Ka) = 0.107 mmÀ1, 6907 reflections measured, 2186
unique (Rint = 0.0158) which were used in all calculations. The
final wR(F2) was 0.3643 (all data). The largest residual electron
À3
˚
density hole was À1.338e A
.
3.3.15. [1-(2,2-Difluorovinyl)cyclohexyl]phenylmethanone
oxime (20b)
To a mixture of CF2Br2 (13 g, 63 mmol) and microwave-
˚
dried molecular sieves (4 A) powder (6.4 g) in THF (60 mL)
3.3.13. 4,4-Dibromo-2,2-dimethyl-1-phenylbut-3-en-1-one
(23d) [26]
was added P(NMe2)3 (21 g, 0.13 mol) at À78 8C. The reaction
mixture was stirred at that temperature for 30 min, and 18b
(6.9 g, 32 mmol) was added at room temperature. After stirring
for 10 h, the reaction was quenched with phosphate buffer (pH
7). The mixture was extracted with AcOEt three times. The
combined extracts were washed with brine and dried over
Na2SO4. After removal of the solvent under reduced pressure,
the residue was dissolved in EtOH (50 mL). Pyridine (5.9 g,
74 mmol) and NH2OHÁHCl (3.4 g, 49 mmol) were added, and
the mixture was heated to reflux for 2 h. The reaction was
quenched with phosphate buffer (pH 7) at room temperature.
Organic materials were extracted with AcOEt three times, and
the combined extracts were washed with brine and aqueous 2 M
HCl five times, and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by
recrystalization from hexane to give 20b (5.4 g, 64%) as white
needles.
To a solution of PPh3 (4.23 g, 16.1 mmol) in CH2Cl2
(27 mL) was added CBr4 (2.67 g, 8.05 mmol) through a solid
addition funnel at 0 8C. The reaction mixture was stirred for
20 min at that temperature, and 18a (946 mg, 5.37 mmol) [32]
was added. After stirring at room temperature for 6 h, the
reaction was quenched with water and hexane, and the mixture
was filtrated through a Celite pad. Organic materials were
extracted with AcOEt twice, and the combined extracts were
dried over Na2SO4. After removal of the solvent under reduced
pressure, the residue was purified by column chromatography
on silica gel (AcOEt–hexane 1:20) to give 23d (1.28 g, 72%) as
a pale yellow oil.
1H NMR (500 MHz, CDCl3) d 1.50 (3H, s), 1.50 (3H, s),
7.04 (1H, s), 7.44 (2H, t, J = 7.9 Hz), 7.54 (1H, tt, J = 7.9,
1.2 Hz), 7.98 (2H, dd, J = 7.9, 1.2 Hz). 13C NMR (126 MHz,
CDCl3) d 26.4, 26.4, 50.6, 90.3, 128.2, 129.2, 132.6, 134.5,
143.8, 200.7. IR (neat) 2981, 1676, 1446, 1240, 1163, 976, 874,
787, 710, 685 cmÀ1. HRMS (FAB): calcd for C12H13Br2O
([M + H]+) 330.9333, found 330.9351.
1H NMR (500 MHz, CDCl3) d 1.25 (1H, dtt, J = 11.6, 11.6,
3.1 Hz), 1.37–1.44 (2H, m), 1.53–1.69 (5H, m), 1.82 (2H, br d,
J = 12.2 Hz), 4.07 (1H, dd, JHF = 28.4, 5.2 Hz), 7.13 (2H, dm,
J = 7.0 Hz), 7.38 (1H, tm, J = 7.0 Hz), 7.42 (2H, tm,
J = 7.0 Hz), 8.28 (1H, s). 13C NMR (126 MHz, CDCl3) d
22.3, 25.6, 34.4 (d, JCF = 2 Hz), 42.4 (dd, JCF = 4, 4 Hz), 82.8
(dd, JCF = 24, 13 Hz), 127.9, 128.0, 128.2, 132.9, 155.6 (dd,
3.3.14. 4,4-Difluoro-2,2-dimethyl-1-phenylbut-3-en-1-one
oxime (20a)
To a solution of 19a (1.16 g, 5.5 mmol) in EtOH (10 mL)
was added pyridine (1.2 g, 16 mmol) and hydroxyamine
hydrochloride (NH2OHÁHCl, 0.72 g, 10 mmol). After the
mixture was heated to reflux for 2 h, the reaction was quenched
with phosphate buffer (pH 7) at room temperature. Organic
materials were extracted with AcOEt three times. The
combined extracts were washed with brine and aqueous 2 M
HCl five times, and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by
recrystalization from hexane to give 20a (0.80 g, 64%) as white
needles.
1H NMR (500 MHz, CDCl3) d 1.34 (6H, dd, J = 1.7, 0.6 Hz),
4.29 (1H, dd, JHF = 27.4, 5.4 Hz), 7.13 (2H, ddd, J = 6.7, 1.7,
1.7 Hz), 7.40–7.45 (3H, m), 7.90 (1H, s). 13C NMR (126 MHz,
CDCl3) d 26.9 (d, JCF = 4 Hz), 38.6 (dd, JCF = 5, 4 Hz), 84.9
(dd, JCF = 23, 14 Hz), 127.8, 128.1, 128.3, 132.8, 155.4 (dd,
J
CF = 294, 287 Hz) 163.5. 19F NMR (471 MHz, CDCl3) dF 78.1
(1F, brd, JFF = 42 Hz), 79.0 (1F, dd, JFF = 42 Hz, JFH = 28 Hz).
IR (neat) 3244, 2931, 1736, 1333, 1221, 1182, 1163, 1001, 958,
900, 765, 705 cmÀ1. HRMS (FAB): calcd for C15H18F2NO
([M + H]+) 266.1356, found 266.1351.
3.3.16. (E)-6,6-Difluoro-4,4-dimethyl-1-phenylhexa-1,5-
dien-3-one oxime (20c)
Compound 20c was prepared by the method described for
20a using 19c (330 mg, 1.40 mmol), EtOH (3.0 mL), pyridine
(0.33 g, 4.2 mmol), and NH2OHÁHCl (0.19 g, 2.8 mmol). The
mixture was heated to reflux for 2 h. Purification by column
chromatography on silica gel (hexane–AcOEt 5:1) gave 20c
(119 mg, 34%) as white needles.
1H NMR (500 MHz, CDCl3) d 1.46 (6H, s), 4.43 (1H, dd,
J
HF = 27.3, 4.5 Hz), 6.93 (1H, d, J = 16.9 Hz), 7.30 (1H, t,
J
CF = 294, 286 Hz), 163.8. 19F NMR (471 MHz, CDCl3) dF
76.9 (1F, dd, JFF = 45 Hz, JFH = 5 Hz), 77.5 (1F, dd,
FF = 45 Hz, JFH = 27 Hz). IR (neat) 3255, 2978, 1739, 1452,
1331, 1225, 1130, 1016, 957, 771, 702 cmÀ1. Anal. Calcd for
J = 7.4 Hz), 7.35 (2H, t, J = 7.4 Hz), 7.50 (2H, d, J = 7.4 Hz),
7.53 (1H, d, J = 16.9 Hz), 10.26 (1H, br s). 13C NMR
(126 MHz, CDCl3) d 27.7, 38.3 (dd, JCF = 5, 3 Hz), 86.2
(dd, JCF = 23, 14 Hz), 115.5, 127.1, 128.7, 128.9, 136.6, 139.2,
J

J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
499
155.4 (dd, JCF = 307, 287 Hz), 158.4. 19F NMR (471 MHz,
CDCl3) dF 76.3 (1F, dd, JFF = 45 Hz, JFH = 5 Hz), 77.3 (1F, dd,
J = 15.4, 8.6, 3.8 Hz), 4.63 (1H, dd, JHF = 27.8, 4.9 Hz), 7.15
(1H, dd, J = 7.6, 0.7 Hz), 7.22 (1H, td, J = 7.6, 0.7 Hz), 7.27
(1H, td, J = 7.6, 1.3 Hz), 7.82 (1H, dd, J = 7.6, 1.3 Hz), 9.12
(1H, br s). [minor] d 1.44 (3H, s), 1.96 (1H, ddd, J = 13.7, 8.2,
1.4 Hz), 2.10 (1H, ddd, J = 13.7, 5.3, 5.3 Hz,), 2.91–2.97 (2H,
m), 4.33 (1H, dd, JHF = 26.6, 5.9 Hz), 7.19 (1H, dd, J = 7.6,
0.7 Hz), 7.25 (1H, td, J = 7.6, 0.7 Hz), 7.31 (1H, td, J = 7.6,
1.3 Hz), 8.45 (1H, dd, J = 7.6, 1.3 Hz), 9.12 (1H, br s). 13C
NMR (126 MHz, CDCl3) [major] d 22.5, 26.7, 36.9 (dd,
J
FF = 45 Hz, JFH = 27 Hz). IR (neat) 3276, 2983, 1734, 1448,
1327, 1221, 1124, 955, 752, 690 cmÀ1. Anal. Calcd for
C14H15F2NO: C, 66.92; H, 6.02; N, 5.57%. Found: C, 67.05; H,
6.26; N, 5.47%.
3.3.17. 1,1-Difluoro-3,3-dimethyltridec-1-en-4-one oxime
(20d)
Compound 20d was prepared by the method described for
20a using 19d (1.58 g, 6.06 mmol), EtOH (12 mL), pyridine
(1.44 g, 18.2 mmol), and NH2OHÁHCl (842 mg, 12.1 mmol).
Purification by column chromatography on silica gel (hexane–
AcOEt 5:1) gave 20d (1.35 g, 81%) as a colorless liquid.
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J = 7.0 Hz),
1.24–1.37 (12H, m), 1.32 (6H, s), 1.57 (2H, tt, J = 8.1, 8.1 Hz),
2.25 (2H, t, J = 8.1 Hz), 4.21 (1H, dd, JHF = 25.4, 7.4 Hz), 9.37
(1H, br s). 13C NMR (126 MHz, CDCl3) d 14.1, 22.7, 26.3,
26.3, 27.0, 29.2, 29.3, 29.5, 30.4, 31.9, 38.9 (dd, JCF = 4, 2 Hz),
85.0 (dd, JCF = 22, 15 Hz), 155.6 (dd, JCF = 294, 287 Hz),
164.8. 19F NMR (471 MHz, CDCl3) dF 76.5 (1F, dd,
JCF = 5, 3 Hz), 38.3 (dd, JCF = 3, 3 Hz), 85.2 (dd, JCF = 24,
14 Hz), 125.4 (d, JCF = 6 Hz), 126.7, 128.0, 129.0, 131.6,
139.8, 155.1 (dd, JCF = 292, 284 Hz), 157.0. [minor] d 24.6 (dd,
J
J
CF = 3, 3 Hz), 26.3, 36.2, 38.7 (dd, JCF = 5, 3 Hz), 83.6 (dd,
CF = 23, 14 Hz), 126.0, 126.9 (d, JCF = 7 Hz), 128.7, 129.8,
131.2, 138.7, 155.7 (dd, JCF = 293, 286 Hz), 156.0. 19F NMR
(471 MHz, CDCl3) [major] dF 73.1 (1F, dd, JFF = 50 Hz,
JFH = 5 Hz), 76.2 (1F, dd, JFF = 50 Hz, JFH = 28 Hz). [minor]
dF 76.8 (1F, dd, JFF = 44 Hz, JFH = 6 Hz), 78.0 (1F, dd,
J
FF = 44 Hz, JFH = 27 Hz). IR (neat) 3452, 2935, 1736, 1456,
1323, 1182, 912, 852, 769, 731 cmÀ1. HRMS (FAB): calcd for
C13H14F2NO ([M + H]+) 238.1043, found 238.1062.
J
J
FF = 46 Hz, JFH = 7 Hz), 76.7 (1F, dd, JFF = 46 Hz,
FH = 25 Hz). IR (neat) 3297, 2924, 1736, 1331, 1221, 1128,
3.3.20. (Z)-4-Fluoro-2,2-dimethyl-1-phenylbut-3-en-1-one
oxime (24a)
1001, 945, 721 cmÀ1. HRMS (FAB): calcd for C15H28F2NO
([M + H]+) 276.2139, found 276.2143.
Compound 24a was prepared by the method described for
20a using 23a (156 mg, 0.81 mmol), EtOH (3 mL), pyridine
(0.19 g, 2.4 mmol), and NH2OHÁHCl (0.11 g, 1.6 mmol).
Purification by column chromatography on silica gel (hex-
ane–AcOEt 5:1) gave 24a (112 mg, 75%) as a white solid.
1H NMR (500 MHz, CDCl3) d 1.23 (6H, s), 5.49 (1H, dd,
3.3.18. tert-Butyl 5,5-difluoro-2-hydroxyimino-3,3-
dimethylpent-4-enoate (20e)
Compound 20e was prepared by the method described for
20a using 19e (1.13 g, 4.83 mmol), EtOH (14 mL), pyridine
(1.15 g, 14.5 mmol), and NH2OHÁHCl (671 mg, 9.66 mmol).
The combined extracts were washed with brine and aqueous
0.5 M HCl five times, and dried over Na2SO4. Purification by
column chromatography on silica gel (hexane–AcOEt 5:1)
gave 20e (1.35 g, 71%) as a white solid.
J
HF = 21.2 Hz, J = 11.3 Hz), 6.39 (1H, dd, JHF = 84.3 Hz,
J = 11.3 Hz), 7.11 (2H, d, J = 7.2 Hz), 7.36 (1H, t,
J = 7.2 Hz), 7.40 (2H, t, J = 7.2 Hz), 9.37 (1H, br s). 13C
NMR (126 MHz, CDCl3) d 25.8, 39.5 (d, JCF = 9 Hz), 118.4 (d,
J
J
CF = 11 Hz), 127.8, 127.9, 128.2, 132.7, 149.3 (d,
CF = 254 Hz), 164.0 (d, JCF = 2 Hz). 19F NMR (471 MHz,
1H NMR (500 MHz, CDCl3) d 1.39 (6H, s), 1.55 (9H, s),
4.33 (1H, dd, JHF = 27.1, 4.9 Hz), 8.08 (1H, s). 13C NMR
(126 MHz, CDCl3) d 26.4 (d, JCF = 4 Hz) 28.1, 36.2 (dd,
JCF = 6, 3 Hz), 84.0, 84.1 (dd, JCF = 24, 14 Hz), 155.7 (dd,
CDCl3) dF 28.9 (dd, JFH = 84, 21 Hz). IR (neat) 3267, 2976,
1739, 1670, 1078, 951, 924, 756, 702, 650 cmÀ1. HRMS
(FAB): calcd for C12H15FNO ([M + H]+) 208.1138, found
208.1141.
J
CF = 295, 286 Hz), 157.8, 162.5. 19F NMR (471 MHz, CDCl3)
dF 76.8 (1F, dd, JFF = 44 Hz, JFH = 5 Hz), 78.2 (1F, dd,
FF = 44 Hz, JFH = 27 Hz). IR (neat) 3452, 2983, 1732, 1371,
J
1302, 1227, 1159, 1128, 1078, 1005, 955, 841 cmÀ1. Anal.
Calcd for C11H17F2NO3: C, 53.01; H, 6.87; N, 5.62%. Found:
C, 52.93; H, 6.87; N, 5.35%.
3.3.21. 2,2-Dimethyl-1-phenylbut-3-en-1-one oxime (24b)
Compound 24b was prepared by the method described for
20a using 2,2-dimethyl-1-phenylbut-3-en-1-one (23b, 203 mg,
1.2 mmol) [27], EtOH (2.3 mL), pyridine (0.28 g, 3.5 mmol),
and NH2OHÁHCl (0.16 g, 2.3 mmol). Purification by thin-layer
chromatography on silica gel (hexane–AcOEt 5:1) gave 24b
(193 mg, 88%) as white needles.
1H NMR (500 MHz, CDCl3) d 1.20 (6H, s), 4.97 (1H, d,
J = 17.4 Hz), 5.01 (1H, d, J = 10.6 Hz), 5.91 (1H, dd, J = 17.4,
10.6 Hz), 7.12 (2H, d, J = 6.8 Hz), 7.31 (1H, t, J = 6.8 Hz), 7.36
(2H, t, J = 6.8 Hz), 9.70 (1H, s). 13C NMR (126 MHz, CDCl3) d
25.2, 43.1, 113.0, 127.7, 127.8, 127.9, 133.2, 143.8, 164.1. IR
(neat) 3255, 2970, 1410, 1360, 1012, 968, 951, 918, 769, 717,
696 cmÀ1. HRMS (FAB): calcd for C12H16NO ([M + H]+)
190.1232, found 190.1225.
3.3.19. 2-(2,2-Difluorovinyl)-2-methyl-3,4-dihydro-2H-
naphthalen-1-one oxime (20f)
Compound 20f was prepared by the method described for
20a using 19f (2.36 g, 10.6 mmol), EtOH (32 mL), pyridine
(10.1 g, 127 mmol), and NH2OHÁHCl (5.9 g, 85 mmol). The
reaction mixture was heated to reflux for 10 h. Purification by
column chromatography on silica gel (hexane–AcOEt 5:1)
gave 20f (1.35 g, 49%) as a white solid.
1H NMR (500 MHz, CDCl3) [major] d 1.63 (3H, s), 1.81
(1H, ddd, J = 12.9, 7.5, 3.8 Hz), 1.99 (1H, ddd, J = 12.9, 8.6,
3.8 Hz), 2.71 (1H, ddd, J = 15.4, 7.5, 3.8 Hz), 2.78 (1H, ddd,

500
J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
3.3.22. 4,4-Dichloro-2,2-dimethyl-1-phenylbut-3-en-1-one
oxime (24c)
3.3.25. [1-(2,2-Difluorovinyl)cyclohexyl]phenylmethanone
O-pentafluorobenzoyloxime (15b)
Compound 24c was prepared by the method described for
20a using 23c (971 mg, 4.00 mmol), EtOH (8 mL), pyridine
(0.95 g, 12 mmol), and NH2OHÁHCl (0.56 g, 8.0 mmol).
Purification by column chromatography on silica gel (hex-
ane–AcOEt 5:1) gave 24c (433 mg, 42%) as a colorless liquid.
1H NMR (500 MHz, CDCl3) d 1.39 (6H, s), 5.90 (1H, s),
7.18 (2H, tm, J = 7.2 Hz), 7.39 (1H, tt, J = 7.2, 1.4 Hz), 7.43
(2H, tm, J = 7.2 Hz), 8.38 (1H, br s). 13C NMR (126 MHz,
CDCl3) d 26.3, 42.9, 122.1, 127.7, 128.2, 128.4, 132.9, 134.7,
162.0. IR (neat) 3261, 2978, 1608, 1385, 1271, 1014, 958, 906,
849, 742, 698, 660, 598 cmÀ1. HRMS (FAB): calcd for
C12H14Cl2NO ([M + H]+) 258.0452, found 258.0450.
Compound 15b was prepared by the method described for
15a using 20b (4.2 g, 16 mmol), CH2Cl2 (40 mL), NEt3 (3.2 g,
32 mmol), and C6F5COCl (5.5 g, 24 mmol). Purification by
column chromatography on silica gel (hexane–AcOEt 10:1)
gave 15b (5.6 g, 78%) as a white solid.
1H NMR (500 MHz, CDCl3) d 1.34 (1H, dtt, J = 12.8, 10.5,
4.1 Hz), 1.46 (2H, ddddd, J = 13.5, 10.5, 10.5, 3.8, 3.4 Hz),
1.60 (1H, dtt, J = 12.8, 4.3, 3.8 Hz), 1.70 (2H, ddddd, J = 13.5,
4.5, 4.3, 4.1, 3.7 Hz), 1.81–1.90 (2H, m), 1.90–1.98 (2H, m),
4.14 (1H, dd, JHF = 28.1, 4.8 Hz), 7.08–7.11 (2H, m), 7.37–7.40
(3H, m). 13C NMR (126 MHz, CDCl3) d 22.2, 25.4, 34.2 (dd,
J
CF = 3, 1 Hz), 43.8 (dd, JCF = 4, 4 Hz), 82.0 (dd, JCF = 24,
8 Hz), 107.0 (td, JCF = 17, 2 Hz), 126.7, 128.0, 128.8, 131.8,
137.5 (ddddd, JCF = 256, 16, 16, 5, 2 Hz), 143.2 (dtt, JCF = 261,
13, 5 Hz), 145.1 (dddd, JCF = 252, 16, 7, 4 Hz), 155.9 (dd.
3.3.23. 4,4-Dibromo-2,2-dimethyl-1-phenylbut-3-en-1-one
oxime (24d)
Compound 24d was prepared by the method described for
20a using 23d (1.61 g, 4.87 mmol), EtOH (9.8 mL), pyridine
(1.16 g, 14.6 mmol), and NH2OHÁHCl (678 mg, 9.76 mmol).
Purification by column chromatography on silica gel (hexane–
AcOEt 5:1) gave 24d (1.01 g, 66%) as a pale yellow solid.
1H NMR (500 MHz, CDCl3) d 1.33 (6H, s), 6.49 (1H, s),
7.05 (1H, br s), 7.15 (2H, d, J = 8.1 Hz), 7.32 (1H, t,
J = 8.1 Hz), 7.36 (2H, t, J = 8.1 Hz). 13C NMR (126 MHz,
CDCl3) d 26.6, 45.0, 90.0, 127.8, 128.2, 128.5, 132.9, 142.8,
161.4. IR (neat) 3240, 2974, 1460, 1443, 1016, 951, 883, 766,
694 cmÀ1. HRMS (FAB): calcd for C12H14Br2NO ([M + H]+)
345.9442, found 345.9428.
J
CF = 297, 288 Hz), 156.6, 173.6. 19F NMR (471 MHz, CDCl3)
dF 1.5 (2F, dddd, JFF = 22, 20, 10, 5 Hz), 13.4 (1F, tt, JFF = 22,
4 Hz), 24.4 (2F, dddd, JFF = 20, 5, 5, 4 Hz), 79.6 (1F, br d,
J
FF = 38 Hz), 80.6 (1F, dd, JFF = 38 Hz, JFH = 28 Hz). IR (neat)
1734, 1523, 1496, 1325, 1180, 1167, 995, 922, 891, 831, 731,
702, 696 cmÀ1. HRMS (FAB): calcd for C22H17F7NO2
([M + H]+) 460.1148, found 460.1156.
3.3.26. (E)-6,6-Difluoro-4,4-dimethyl-1-phenylhexa-1,5-
dien-3-one O-pentafluorobenzoyloxime (15c)
Compound 15c was prepared by the method described for
15a using 20c (119 mg, 0.47 mmol), CH2Cl2 (2 mL), NEt3
(95 mg, 0.94 mmol), and C6F5COCl (0.16 g, 0.71 mmol).
Purification by thin-layer chromatography on silica gel
(hexane–AcOEt 5:1) gave 15c (189 mg, 87%) as a white solid.
1H NMR (500 MHz, CDCl3) d 1.54 (6H, s), 4.50 (1H, dd,
3.3.24. 4,4-Difluoro-2,2-dimethyl-1-phenylbut-3-en-1-one
O-pentafluorobenzoyloxime (15a)
To a solution of oxime 20a (0.80 g, 3.5 mmol) in CH2Cl2
(10 mL) were added NEt3 (0.72 g, 7.1 mmol) and pentafluor-
obenzoyl chloride (C6F5COCl, 1.2 g, 5.3 mmol) at 0 8C. After
the mixture was stirred for 15 min, the reaction was quenched
with phosphate buffer (pH 7). Organic materials were extracted
with CH2Cl2 three times, and the combined extracts were
washed with brine and dried over Na2SO4. After removal of the
solvent under reduced pressure, the residue was purified by
column chromatography on silica gel (hexane–AcOEt 10:1) to
give 15a (1.4 g, 92%) as a colorless oil.
J
HF = 27.1, 4.5 Hz), 6.83 (1H, d, J = 16.7 Hz), 7.31 (1H, d,
J = 16.7 Hz), 7.35–7.41(3H, m), 7.48 (2H, dd, J = 7.6, 1.5 Hz).
13C NMR (126 MHz, CDCl3) d 27.5, 39.3 (dd, JCF = 5, 3 Hz),
85.6 (dd, JCF = 24, 14 Hz), 107.3 (td, JCF = 17, 3 Hz), 114.9,
127.3, 128.9, 129.8, 135.3, 137.7 (ddddd, JCF = 256, 18, 13, 6,
3 Hz), 141.2, 143.3 (dtt, JCF = 259, 13, 5 Hz), 145.3 (dddd,
J
CF = 255, 17, 6, 3 Hz), 155.7 (dd, JCF = 295, 287 Hz), 156.5,
174.2. 19F NMR (471 MHz, CDCl3) dF 1.5 (2F, dddd, JFF = 26,
21, 11, 5 Hz), 13.6 (1F, tt, JFF = 21, 5 Hz), 24.3 (2F, dddd,
JFF = 26, 5, 5, 5 Hz), 77.5 (1F, dd, JFF = 42 Hz, JFH = 27 Hz),
1H NMR (500 MHz, CDCl3) d 1.48 (6H, d, J = 1.4 Hz), 4.38
(1H, dd, JHF = 27.1, 5.0 Hz), 7.07–7.10 (2H, m), 7.39–7.41
(3H, m). 13C NMR (126 MHz, CDCl3) d 26.6 (dd, JCF = 4,
1 Hz), 39.8 (dd, JCF = 6, 4 Hz), 84.1 (dd, JCF = 25, 13 Hz),
106.9 (td, JCF = 11, 4 Hz), 126.6, 128.1, 128.9, 131.8, 137.5
(ddddd, JCF = 256, 14, 14, 6, 2 Hz), 143.2 (dtt, JCF = 243, 17,
5 Hz), 145.3 (dddd, JCF = 238, 15, 7, 4 Hz), 155.7 (dd,
78.4 (1F, dd, JFF = 42 Hz, JFH = 5 Hz). IR (neat) 1753, 1523,
1500, 1327, 1194, 1095, 1005, 931, 702 cm–1. HRMS (FAB):
calcd for C21H15F7NO2 ([M + H]+) 446.0991, found 446.1003.
3.3.27. 1,1-Difluoro-3,3-dimethyltridec-1-en-4-one O-
pentafluorobenzoyloxime (15d)
J
CF = 295, 287 Hz), 156.5, 174.2 (dd, JCF = 4, 4 Hz). 19F NMR
Compound 15d was prepared by the method described for
15a using 20d (1.33 g, 4.84 mmol), CH2Cl2 (10 mL), NEt3
(980 mg, 9.69 mmol), and C6F5COCl (1.68 g, 7.29 mmol).
Purification by column chromatography on silica gel (hexane–
AcOEt 10:1) gave 15d (1.75 g, 77%) as a colorless liquid.
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J = 7.0 Hz),
1.21–1.31 (10H, m), 1.35 (2H, tt, J = 7.3, 6.9 Hz), 1.43 (6H, s),
1.56 (2H, tt, J = 7.9, 7.3 Hz), 2.35 (2H, t, J = 7.9 Hz), 4.32 (1H,
(471 MHz, CDCl3) dF 1.5 (2F, dddd, JFF = 26, 20, 12, 5 Hz),
13.6 (1F, tt, JFF = 20, 5 Hz), 24.3 (2F, dddd, JFF = 26, 5, 5,
5 Hz), 78.4 (1F, dd, JFF = 42 Hz, JFH = 5 Hz), 77.5 (1F, dd,
J
FF = 42 Hz, JFH = 27 Hz). IR (neat) 1753, 1523, 1500, 1327,
.
1194, 1095, 1005, 931, 702 cmÀ1
Anal. Calcd for
C19H12F7NO2: C, 54.43; H, 2.88; N, 3.34%. Found: C,
54.45; H, 3.04; N, 3.33%.

J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
501
dd, JHF = 26.8, 5.1 Hz). 13C NMR (126 MHz, CDCl3) d 14.0,
22.6, 26.1 (d, JCF = 3 Hz), 27.0, 28.8, 28.9, 29.2, 29.3, 30.1,
31.8, 40.0 (dd, JCF = 5, 3 Hz), 84.3 (dd, JCF = 24, 14 Hz), 107.4
(td, JCF = 17, 4 Hz), 137.7 (ddddd, JCF = 256, 17, 15, 6, 1 Hz),
143.3 (dtt, JCF = 261, 13, 5 Hz), 145.3 (dddd, JCF = 255, 15, 8,
4 Hz), 155.8 (dd, JCF = 295, 287 Hz), 156.7, 174.6. 19F NMR
(471 MHz, CDCl3) dF 1.8 (2F, dddd, JFF = 26, 21, 11, 5 Hz),
13.7 (1F, tt, JFF = 21, 5 Hz,), 24.4 (2F, dddd, JFF = 26, 5, 5,
5 Hz), 77.8 (1F, dd, JFF = 43 Hz, JFH = 5 Hz), 78.2 (1F, dd,
JCF = 260, 18, 7, 3, 2 Hz), 155.2 (dd, JCF = 292, 286 Hz),
156.1, 165.5. [minor] d 24.1 (dd, JCF = 2, 2 Hz), 26.0, 36.3, 39.8
(dd, JCF = 5, 3 Hz), 82.5 (dd, JCF = 24, 15 Hz), 107.2 (td,
J
CF = 17, 3 Hz), 125.9, 128.7, 128.9, 131.0, 131.1, 137.7
(ddddd, JCF = 257, 18, 10, 4, 2 Hz), 139.4, 143.4 (dtt,
CF = 260, 13, 4 Hz), 145.1 (ddddd, JCF = 260, 18, 7, 3,
J
2 Hz), 155.7 (dd, JCF = 294, 288 Hz), 157.0, 165.9. 19F NMR
(471 MHz, CDCl3) [major] dF 2.1 (2F, dddd, JFF = 26, 21, 12,
6 Hz), 14.2 (1F, tt, JFF = 21, 5 Hz), 24.3 (2F, dddd, JFF = 26, 6,
6, 5 Hz), 74.1 (1F, br d, JFF = 46 Hz), 77.7 (1F, dd, JFF = 46 Hz,
J
FF = 43 Hz, JFH = 27 Hz). IR (neat) 2927, 1763, 1736, 1496,
1325, 1188, 997, 866 cmÀ1. HRMS (FAB): calcd for
C22H27F7NO2 ([M + H]+) 470.1930, found 470.1928.
JFH = 27 Hz). [minor] dF 1.8 (2F, dddd, JFF = 26, 20, 11, 5 Hz),
13.7 (1F, tt, JFF = 20, 4 Hz), 24.5 (2F, dddd, JFF = 26, 5, 5,
4 Hz), 77.4 (1F, dd, JFF = 43 Hz, JFH = 4 Hz), 78.0 (1F, dd,
JFF = 43 Hz, JFH = 28 Hz). IR (neat) 1750, 1525, 1496, 1325,
1194, 1005, 922, 872, 775, 739 cmÀ1. HRMS (FAB): calcd for
C20H13F7NO2 ([M + H]+) 432.0835, found 432.0853.
3.3.28. tert-Butyl 5,5-difluoro-2-
pentafluorobenzoyloxyimino-3,3-dimethylpent-4-enoate
(15e)
Compound 15e was prepared by the method described for
15a using 20e (35.3 mg, 0.142 mmol), CH2Cl2 (2 mL), NEt3
(28 mg, 0.28 mmol), and C6F5COCl (49 mg, 0.21 mmol).
Purification by thin-layer chromatography on silica gel
(hexane–AcOEt 5:1) gave 15e (41 mg, 64%) as a white solid.
1H NMR (500 MHz, CDCl3) d 1.51 (9H, s), 1.52 (6H, br s),
4.40 (1H, dd, JHF = 26.8, 4.4 Hz). 13C NMR (126 MHz, CDCl3)
d 26.3 (d, JCF = 4 Hz), 27.8, 37.5 (dd, JCF = 6, 3 Hz), 83.3 (dd,
3.3.30. (Z)-4-Fluoro-2,2-dimethyl-1-phenylbut-3-en-1-one
O-pentafluorobenzoyloxime (21a)
Compound 21a was prepared by the method described for
15a using 24a (112 mg, 0.54 mmol), CH2Cl2 (1.5 mL), NEt3
(109 mg, 1.08 mmol), and C6F5COCl (166 mg, 0.72 mmol).
Purification by thin-layer chromatography on silica gel
(hexane–AcOEt 5:1) gave 21a (132 mg, 61%) as a colorless oil.
1H NMR (500 MHz, CDCl3) d 1.41 (6H, s), 5.59 (1H, dd,
J
CF = 26, 14 Hz), 85.4, 107.4 (td, JCF = 16, 4 Hz), 137.7
(ddddd, JCF = 257, 16, 16, 5, 1 Hz), 143.6 (dtt, JCF = 261, 14,
5 Hz), 145.4 (dddd, JCF = 260, 17, 6, 4 Hz), 155.6, 156.0 (dd,
JHF = 20.7 Hz, J = 11.3 Hz), 6.52 (1H, dd, JHF = 83.6 Hz,
J = 11.3 Hz), 7.10 (2H, dd, J = 7.6, 2.0 Hz), 7.37–7.42 (3H,
m). 13C NMR (126 MHz, CDCl3) d 25.5, 40.7 (d, JCF = 10 Hz),
106.8 (td, JCF = 16, 4 Hz), 117.4 (d, JCF = 12 Hz), 126.7, 127.9,
128.8, 131.7, 137.5 (ddddd, JCF = 255, 16, 14, 5, 2 Hz), 143.1
(dtt, JCF = 246, 13, 5 Hz), 145.1 (dddd, JCF = 259, 18, 7, 4 Hz),
150.1 (d, JCF = 256 Hz), 156.4, 174.7 (d, JCF = 3 Hz). 19F NMR
(471 MHz, CDCl3) dF 1.5 (2F, dddd, JFF = 26, 21, 12, 6 Hz),
13.6 (1F, tt, JFF = 21, 4 Hz), 24.4 (2F, dddd, JFF = 26, 6, 5,
4 Hz), 31.0 (1F, dd, JFH = 84, 21 Hz). IR (neat) 1759, 1496,
1325, 1190, 1080, 1001, 926, 876, 700 cmÀ1. HRMS (FAB):
calcd for C19H14F6NO2 ([M + H]+) 402.0929, found 402.0909.
J
CF = 298, 288 Hz), 160.3, 166.1. 19F NMR (471 MHz, CDCl3)
dF 2.0 (2F, dddd, JFF = 28, 20, 12, 6 Hz), 14.9 (1F, tt, JFF = 20,
5 Hz), 24.4 (2F, dddd, JFF = 28, 6, 6, 5 Hz), 78.7 (1F, dd,
J
J
FF = 40 Hz, JFH = 4 Hz), 78.2 (1F, dd, JFF = 40 Hz,
FH = 27 Hz). IR (neat) 1732, 1496, 1327, 1182, 1157, 1066,
1003, 874 cmÀ1. Anal. Calcd for C18H16F7NO4: C, 48.77; H,
3.64; N, 3.16%. Found: C, 48.85; H, 3.76; N, 2.99%.
3.3.29. 2-(2,2-Difluorovinyl)-2-methyl-3,4-dihydro-2H-
naphthalen-1-one O-pentafluorobenzoyloxime (15f)
Compound 15f was prepared by the method described for
15a using 20f (1.24 g, 5.2 mmol), CH2Cl2 (10 mL), NEt3
(1.06 g, 10.5 mmol), and C6F5COCl (1.81 g, 7.9 mmol). The
reaction mixture was stirred at 0 8C for 1 h, and purification by
column chromatography on silica gel (hexane–AcOEt 10:1)
gave 15f (1.65 g, 72%) as a white solid.
3.3.31. 2,2-Dimethyl-1-phenylbut-3-en-1-one O-
pentafluorobenzoyloxime (21b)
Compound 21b was prepared by the method described for
15a using 24b (167 mg, 0.88 mmol), CH2Cl2 (2 mL), NEt3
(0.18 g, 1.8 mmol), C6F5COCl (0.30 g, 1.3 mmol). Purification
by thin-layer chromatography on silica gel (hexane–AcOEt
5:1) gave 21b (0.30 g, 89%) as a white solid.
1H NMR (500 MHz, CDCl3) [major] d 1.59 (3H, s), 1.85
(1H, ddd, J = 13.3, 6.8, 3.7 Hz), 2.00 (1H, ddd, J = 13.3, 9.2,
3.8 Hz), 2.77 (1H, ddd, J = 16.0, 6.8, 3.8 Hz), 2.83 (1H, ddd,
J = 16.0, 9.2, 3.7 Hz), 4.52 (1H, dd, JHF = 27.0, 4.2 Hz), 7.20
(1H, d, J = 7.4 Hz), 7.37 (1H, td, J = 7.4, 1.5 Hz), 7.38 (1H, td,
J = 7.4, 1.5 Hz), 8.14 (1H, d, J = 7.4 Hz). [minor] d 1.53 (3H,
s), 2.08 (1H, ddd, J = 15.1, 7.5, 0.9 Hz), 2.20 (1H, ddd,
J = 15.1, 4.9, 4.9 Hz), 2.95–3.07 (2H, m), 4.44 (1H, dd,
1H NMR (500 MHz, CDCl3) d 1.38 (6H, s), 5.13 (1H, d,
J = 17.4 Hz), 5.18 (1H, dd, J = 10.6, 0.7 Hz), 6.00 (1H, dd,
J = 17.4, 10.6 Hz), 7.08–7.11 (2H, m), 7.34–7.37 (3H, m). 13
NMR (126 MHz, CDCl3) d 25.0, 44.4, 107.0 (td, JCF = 17,
4 Hz), 114.4, 126.7, 127.7, 128.6, 132.2, 137.5 (ddddd,
C
J
CF = 256, 17, 13, 6, 2 Hz), 142.5, 143.1 (dtt, JCF = 260, 17,
J
HF = 27.5, 4.4 Hz), 7.20–7.29 (3H, m), 7.95 (1H, d,
5 Hz), 145.1 (dddd, JCF = 259, 16, 8, 4 Hz), 156.5, 175.2. 19F
NMR (471 MHz, CDCl3) dF 1.4 (2F, dddd, JFF = 19, 19, 13,
6 Hz), 13.3 (1F, tt, JFF = 19, 5 Hz), 24.4 (2F, dddd, JFF = 19, 6,
5, 4 Hz). IR (neat) 1761, 1651, 1522, 1496, 1325, 1190, 995,
922, 864, 706 cmÀ1. HRMS (FAB): calcd for C19H15F5NO2
([M + H]+) 384.1023, found 384.1021.
J = 8.0 Hz). 13C NMR (126 MHz, CDCl3) [major] d 23.0,
26.1, 37.9 (dd, JCF = 5, 2 Hz), 38.3 (dd, JCF = 2, 2 Hz), 85.1
(dd, JCF = 25, 14 Hz), 107.2 (td, JCF = 17, 3 Hz), 125.6, 126.9,
127.0, 128.2, 131.1, 137.7 (ddddd, JCF = 257, 18, 10, 4, 2 Hz),
141.0, 143.4 (dtt, JCF = 260, 13, 4 Hz), 145.1 (ddddd,

502
J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
3.3.32. 4,4-Dichloro-2,2-dimethyl-1-phenylbut-3-en-1-one
O-pentafluorobenzoyloxime (21c)
3097, 3060, 2972, 1633, 1460, 1279, 1254, 1132, 1012, 945,
783, 702 cmÀ1. HRMS (FAB): calcd for C12H13FN ([M + H]+)
190.1032, found 190.1038.
Compound 21c was prepared by the method described
for 15a using 24c (231 mg, 0.891 mmol), CH2Cl2 (2 mL), NEt3
(180 mg, 1.78 mmol), and C6F5COCl (307 mg, 1.33 mmol).
The reaction mixture was stirred at 0 8C for 0.5 h, and
purification by thin-layer column chromatography on silica gel
(hexane–AcOEt 10:1) gave 21c (262 mg, 65%) as a colorless
liquid.
3.3.35. 3-Fluoro-1-phenyl-2-azaspiro[4.5]deca-1,3-diene
(16b)
Compound 16b was synthesized by the method described for
16a using 15b (87 mg, 0.19 mmol), Pd(PPh3)4 (23 mg,
0.019 mmol), PPh3 (50 mg, 0.19 mmol), and DMA (10 mL).
Purification by thin-layer chromatography on silica gel
(benzene–hexane 1:1) gave 16b (34 mg, 78%) as a yellow oil.
1H NMR (500 MHz, CDCl3) d 1.38–1.58 (5H, m), 1.87–1.94
(3H, m), 2.13 (1H, td, J = 11.2 Hz, JHF = 3.3 Hz), 2.13 (1H, td,
J = 11.2 Hz, JHF = 3.3 Hz), 5.86 (1H, d, JHF = 6.3 Hz), 7.42–
7.46 (3H, m), 8.03–8.07 (2H, m). 13C NMR (126 MHz, CDCl3)
d 24.8, 25.6, 32.6 (d, JCF = 2 Hz), 61.4, 102.3 (d, JCF = 15 Hz),
128.3, 128.5, 129.1, 130.7, 163.3 (d, JCF = 261 Hz), 183.5 (d,
1H NMR (500 MHz, CDCl3) d 1.53 (6H, s), 5.94 (1H, s),
7.12–7,15 (2H, m), 7.37–7.42 (3H, m). 13C NMR (126 MHz,
CDCl3) d 26.3, 43.9, 106.9 (td, JCF = 15, 4 Hz), 123.3, 126.6,
128.2, 129.0, 131.9, 133.3, 137.5 (ddddd, JCF = 255, 17, 13, 5,
2 Hz), 143.1 (dtt, JCF = 264, 17, 5 Hz), 145.1 (ddddd,
J
CF = 254, 16, 8, 3, 2 Hz), 156.6, 172.4. 19F NMR
(471 MHz, CDCl3) dF 1.5 (2F, dddd, JFF = 26, 21, 11, 5 Hz),
13.5 (1F, tt, JFF = 21, 4 Hz), 24.4 (2F, dddd, JFF = 26, 5, 5,
4 Hz). IR (neat) 1756, 1496, 1325, 1188, 995, 930, 870,
J
J
CF = 11.5 Hz). 19F NMR (471 MHz, CDCl3) dF 48.6 (ddd,
698 cmÀ1
.
HRMS (FAB): calcd for C19H13Cl2F5NO2
FH = 6, 3, 3 Hz). IR (neat) 2933, 1626, 1450, 1442, 1317, 1286,
([M + H]+) 452.0244, found 452.0215.
1275, 1198, 997, 773, 758, 721, 688 cmÀ1. HRMS (FAB): calcd
for C15H17FN ([M + H]+) 230.1345, found 230.1336.
3.3.33. 4,4-Dibromo-2,2-dimethyl-1-phenylbut-3-en-1-one
O-pentafluorobenzoyloxime (21d)
3.3.36. (E)-5-Fluoro-3,3-dimethyl-2-styryl-3H-pyrrole
(16c)
Compound 21d was prepared by the method described for
15a using 24d (1.11 g, 3.2 mmol), CH2Cl2 (6.4 mL), NEt3
(0.65 g, 6.4 mmol), C6F5COCl (1.10 g, 4.8 mmol). Purification
by column chromatography on silica gel (hexane–AcOEt 10:1)
gave 21d (1.42 g, 82%) as a white solid.
Compound 16c was synthesized by the method described for
16a using 15c (52 mg, 0.11 mmol), Pd(PPh3)4 (13 mg,
0.011 mmol), PPh3 (30 mg, 0.11 mmol), and DMA (6 mL).
The reaction mixture was heated at 110 8C for 1 h, and
purification by thin-layer chromatography on silica gel
(benzene–hexane 1:1) gave 33b (19 mg, 76%) as a yellow oil.
1H NMR (500 MHz, CDCl3) d 1.36 (3H, s), 1.37 (3H, s),
5.26 (1H, d, JHF = 6.8 Hz), 6.91 (1H, d, J = 16.4 Hz), 7.35 (1H,
tt, J = 7.2, 1.6 Hz), 7.39 (2H, tm, J = 7.2 Hz), 7.53 (1H, d,
J = 16.4 Hz), 7.56 (2H, dd, J = 7.2, 1.6 Hz). 13C NMR
(126 MHz, CDCl3) d 22.3, 22.3, 54.3, 104.8 (d, JCF = 15 Hz),
118.7 (d, JCF = 2 Hz), 127.5, 128.9, 129.5, 135.7, 138.3, 162.6
(d, JCF = 261 Hz), 184.0 (d, JCF = 12 Hz). 19F NMR (471 MHz,
CDCl3) dF 48.7 (d, JFH = 7 Hz). IR (neat) 2968, 1628, 1618,
1292, 1132, 972, 754, 702 cmÀ1. HRMS (FAB): calcd for
C14H15FN ([M + H]+) 216.1189, found 216.1165.
1H NMR (500 MHz, CDCl3) d 1.54 (6H, s), 6.58 (1H, s),
7.14–7.18 (2H, m), 7.24 (1H, tm, J = 6.7 Hz), 7.41 (2H, dd,
J = 5.2, 1.9 Hz). 13C NMR (126 MHz, CDCl3) d 26.1, 45.8,
91.1, 106.9 (td, JCF = 16, 3 Hz), 126.6, 128.0, 128.9, 131.8,
137.4 (ddddd, JCF = 255, 13, 11, 4, 1 Hz), 141.4, 143.0 (dtt,
J
CF = 260, 13, 5 Hz), 145.0 (dddd, JCF = 256, 15, 8, 4 Hz),
156.6, 171.8. 19F NMR (471 MHz, CDCl3) dF 1.5 (2F, dddd,
JFF = 26, 20, 12, 6 Hz), 13.5 (1F, tt, JFF = 20, 4 Hz), 24.4 (2F,
dddd, JFF = 26, 6, 5, 4 Hz). IR (neat) 1761, 1522, 1496, 1325,
1186, 995, 928, 858, 772, 708, 698 cmÀ1. HRMS (FAB): calcd
for C19H13Br2F5NO2 ([M + H]+) 539.9233, found 539.9225.
3.3.34. 5-Fluoro-3,3-dimethyl-2-phenyl-3H-pyrrole (16a)
O-Pentafluorobenzoyloxime 15a (72 mg, 0.17 mmol),
Pd(PPh3)4 (20 mg, 0.017 mmol), and PPh3 (49 mg, 0.17 mmol)
were dissolved in DMA (7 mL) and heated at 110 8C for 8 h.
The reaction was quenched with phosphate buffer (pH 7) at
room temperature, and organic materials were extracted with
AcOEt three times. The combined extracts were washed with
brine and dried over Na2SO4. After removal of the solvent
under reduced pressure, the residue was purified by thin-layer
chromatography on silica gel (benzene–hexane 1:1) to give 16a
(27 mg, 71%) as a yellow oil.
3.3.37. 5-Fluoro-3,3-dimethyl-2-nonyl-3H-pyrrole (16d)
Compound 16d was synthesized by the method described for
16a using 15d (149 mg, 0.32 mmol), Pd(PPh3)4 (37 mg,
0.032 mmol), PPh3 (83 mg, 0.32 mmol), and DMA (16 mL).
The reaction was quenched with saturated aqueous sodium
bicarbonate at À10 8C, and organic materials were extracted
with AcOEt three times at room temperature. The combined
extracts were washed with brine and dried over Na2SO4. After
removal of the solvent under reduced pressure, the residue was
purified by thin-layer chromatography on silica gel (deactivated
by treatment with AcOEt–Et3N 100:1, then dried) (NEt3–
benzene–hexane 1:50:50 and then NEt3–AcOEt–hexane
1:10:90) gave 16d (21 mg, 29%) as a yellow oil (16d was
unstable under acidic conditions).
1H NMR (500 MHz, CDCl3) d 1.49 (6H, d, J = 1.2 Hz), 5.32
(1H, d, JHF = 6.4 Hz), 7.44–7.48 (2H, m), 7.99–8.01 (3H, m).
13C NMR (126 MHz, CDCl3) d 23.1 (d, JCF = 3 Hz), 55.0,
106.4 (d, JCF = 15 Hz), 128.1, 128.6, 130.8, 132.0 (d,
J
CF = 1 Hz), 161.8 (d, JCF = 261 Hz), 183.5 (d, JCF = 11 Hz).
1H NMR (500 MHz, CDCl3) d 0.88 (3H, t, J = 6.8 Hz),
1.18–1.39 (12H, m), 1.27 (6H, s), 1.60 (2H, tt, J = 7.2, 7.2 Hz),
19F NMR (471 MHz, CDCl3) dF 47.8 (d, JFH = 6 Hz). IR (neat)

J. Ichikawa et al. / Journal of Fluorine Chemistry 127 (2006) 489–504
503
2.32 (2H, t, J = 7.2 Hz), 5.18 (1H, d, JHF = 5.9 Hz). 13C NMR
(126 MHz, CDCl3) d 14.1, 22.4 (d, JCF = 2 Hz), 22.6 (d,
References
[1] For reviews on the Heck reaction.
J
J
CF = 4 Hz), 28.6, 29.1, 29.1, 29.3, 29.4, 31.7, 34.4, 54.1 (d,
CF = 2 Hz), 104.0 (d, JCF = 15 Hz), 162.4 (d, JCF = 261 Hz),
(a) E. Negishi (Ed.), Handbook of Organopalladium Chemistry for
Organic Synthesis, vol. I and II, Wiley, New York, 2002;
(b) J.J. Li, G.W. Gribble, Palladium in Heterocyclic Chemistry: A Guide
for the Synthetic Chemist, Elsevier, Oxford, 2000.
[2] For reviews on intramolecular Heck reactions, see.
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Organic Reactions, vol. 60, Wiley, New York, 2002 (Chapter 2);
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(Chapter 3).
184.3 (d, JCF = 12 Hz). 19F NMR (471 MHz, CDCl3) dF 48.3 (d,
J
FH = 6 Hz). IR (neat) 2922, 2852, 1738, 1691, 1522, 1377,
1176, 1120, 1080, 721, 542 cmÀ1. HRMS (FAB): calcd for
C15H27FN ([M+H]+) 240.2128, found 240.2139.
3.3.38. tert-Butyl 5-fluoro-3,3-dimethyl-3H-pyrrole-2-
carboxylate (16e)
[3] 5-endo-trig Cyclizations of alkenyl- and arylpalladiums are less efficient.
(a) P. Wiedenau, B. Monse, S. Blechert, Tetrahedron 51 (1995) 1167–
1176;
Compound 16e was synthesized by the method described for
16a using 15e (105 mg, 0.24 mmol), Pd(PPh3)4 (27 mg,
0.024 mmol), PPh3 (62 mg, 0.24 mmol), and DMA (12 mL).
Purification by thin-layer chromatography on silica gel
(benzene–hexane 1:1) gave 16e (7.1 mg, 14%) as a colorless oil.
1H NMR (500 MHz, CDCl3) d 1.42 (6H, s), 1.59 (9H, s),
5.49 (1H, d, JHF = 6.9 Hz). 13C NMR (126 MHz, CDCl3) d 20.7
(d, JCF = 3 Hz), 28.1, 56.1, 83.2, 111.2 (d, JCF = 14 Hz), 159.1,
161.0 (d, JCF = 267 Hz), 177.4 (d, JCF = 9 Hz). 19F NMR
(471 MHz, CDCl3) dF 49.6 (d, JFH = 7 Hz). IR (neat) 3726,
1733, 1460, 1435, 1219, 1097, 955, 771, 692, 669, 523 cm–1.
HRMS (FAB): calcd for C11H17FNO2 ([M + H]+) 214.1243,
found 214.1265.
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(c) B. O’Connor, Y. Zhang, E. Negishi, Tetrahedron Lett. 29 (1988) 3903–
3906.
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Cu) species, see:
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(a) N. Cadran, K. Cariou, G. Herve, C. Aubert, L. Fensterbank, M.
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(b) T. Watanabe, S. Arai, A. Nishida, Synlett (2004) 907–909;
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(d) K. Yamazaki, Y. Kondo, Chem. Commun. (2002) 210–211;
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´ ´ ´
(e) A. Garcıa, D. Rodrıguez, L. Castedo, C. Saa, D. Domınguez, Tetra-
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(f) C.-Y. Chen, D.R. Lieberman, R.D. Larsen, T.R. Verhoeven, P.J. Reider,
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3.3.39. 2-Fluoro-3a-methyl-4,5-dihydro-3aH-
benzo[g]indole (16f)
(g) L.-C. Chen, S.-C. Yang, H.-M. Wang, Synthesis (1995) 385–386;
´
(h) K. Koerber-Ple, G. Massiot, Synlett (1994) 759–760;
Compound 16f was synthesized by the method described for
16a using 15f (24 mg, 0.055 mmol), Pd(PPh3)4 (19 mg,
0.017 mmol), PPh3 (15 mg, 0.055 mmol), and DMA (3 mL).
Purification by thin-layer chromatography on silica gel
(benzene-hexane 1:1) gave 16f (5.2 mg, 47%) as a colorless oil.
1H NMR (500 MHz, CDCl3) d 1.24 (3H, s), 1.78 (1H, ddd,
J = 13.1, 12.9, 5.9 Hz), 2.24 (1H, ddd, J = 13.1, 5.7, 1.0 Hz),
2.93 (1H, ddd, J = 17.6, 5.9, 1.0 Hz), 3.14 (1H, ddd, J = 17.6,
12.9, 5.7 Hz), 5.34 (1H, d, JHF = 6.8 Hz), 7.25 (1H, d,
J = 7.5 Hz), 7.30 (1H, t, J = 7.5 Hz), 7.40 (1H, td, J = 7.5,
1.0 Hz), 7.94 (1H, dd, J = 7.5, 1.0 Hz). 13C NMR (126 MHz,
CDCl3) d 17.9 (d, JCF = 3 Hz), 25.9, 32.4 (d, JCF = 3 Hz), 53.1
(d, JCF = 2 Hz), 102.8 (d, JCF = 15 Hz), 125.5, 126.8, 128.9,
129.0 (d, JCF = 1 Hz), 131.3, 139.7, 164.2 (d, JCF = 264 Hz),
185.6 (d, JCF = 13 Hz). 19F NMR (471 MHz, CDCl3) dF 50.5 (d,
(i) J.P. Michael, S.-F. Chang, C. Wilson, Tetrahedron Lett. 34 (1993)
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4523 [N-vinyl-2-halovinylamines];
(c) B.R. Henke, C.J. Aquino, L.S. Birkemo, D.K. Croom, R.W. Dough-
erty Jr., G.N. Ervin, M.K. Grizzle, G.C. Hirst, M.K. James, M.F. Johnson,
K.L. Queen, R.G. Sherrill, E.E. Sugg, E.M. Suh, J.W. Szewczyk, R.J.
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[2-Haloaryl vinyl ether].
[7] (a) S.V. Gagnier, R.C. Larock, J. Am. Chem. Soc. 125 (2003) 4804–
4807;
´
(b) E. Negishi, C. Coperet, S. Ma, T. Mita, T. Sugihara, J.M. Tour, J. Am.
J
FH = 7 Hz). IR (neat) 2929, 1684, 1616, 1464, 1281, 1248,
775, 739 cmÀ1. HRMS (FAB): calcd for C13H13FN ([M + H]+)
202.1032, found 202.1048.
Chem. Soc. 118 (1996) 5904–5918.
[8] For palladacycle intermediates in five-membered-ring construction, see
also:
Acknowledgements
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