Ni-catalyzed α-arylation of secondary α-bromo-α-fluoro- β-lactam: Cross-coupling of a secondary fluorine-containing electrophile

Article abstract of DOI:10.1016/j.tet.2012.12.002

A highly diastereoselective cross-coupling reaction of an α-bromo-α-fluoro-β-lactam with a wide range of aryl Grignard reagents was catalyzed by Ni/bis(oxazoline) in yields of up to 98%. The product was obtained diastereoselectively as an anti-isomer. This is the first successful α-arylation of an α-fluoro-β-lactam to produce diverse α-aryl-α-fluoro-β-lactams.

Full text of DOI:10.1016/j.tet.2012.12.002

Tetrahedron 69 (2013) 1559e1565
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Ni-catalyzed a-arylation of secondary a-bromo-a-fluoro-b-lactam:
cross-coupling of a secondary fluorine-containing electrophile
Atsushi Tarui a, Shoji Kondo a, Kazuyuki Sato a, Masaaki Omote a, Hideki Minami b, Yoshihisa Miwa b,
,
Akira Ando a
*
a Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotoge-cho, Hirakata, Osaka 573-0101, Japan
b Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-1-1 Hirokoshingai, Kure, Hiroshima 737-0112, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 October 2012
Received in revised form 1 December 2012
Accepted 3 December 2012
Available online 7 December 2012
A highly diastereoselective cross-coupling reaction of an a-bromo-a-fluoro-b-lactam with a wide range
of aryl Grignard reagents was catalyzed by Ni/bis(oxazoline) in yields of up to 98%. The product was
obtained diastereoselectively as an anti-isomer. This is the first successful -arylation of an -fluoro-
-lactam to produce diverse -aryl- -fluoro- -lactams.
Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
a
a
b
a
a
b
Keywords:
Fluorine
Fluoro-b-lactam
Cross-coupling
Kumada reaction
Diastereoselective
1. Introduction
studied. Furthermore, the
mains unexplored, despite the potential importance of
-fluoro- -lactams in the antibiotic activity.
A cross-coupling reaction is very useful method for an arylation
a
-arylation of
a
-fluoro-
b
-lactams re-
a
-arylated-
b
-Lactam antibiotics, such as penicillin, are important class of
drugs, which are active against gram-positive bacteria. The in-
teraction between the -lactam ring and the penicillin-binding
protein inhibits bacterial cell wall biosynthesis.1 The
-lactam
a
b
b
of halogenated substrates. Among reported many cross-coupling
reactions, Kumada coupling reaction, which use Grignard re-
agents as a nucleophilic species, has been utilized to form car-
bonecarbon bond.6 Recently, Fu and co-workers have reported the
Ni-catalyzed Kumada, Suzuki, and Negishi cross-coupling reactions
b
ring is important because the electrophilicity and distortion angle
of the amide bond alter the antibiotic activity. Additionally, other
bioactivities of b-lactam compounds have also been attracted to-
ward an interaction with several enzymes.2 Albeit fluorine-
containing compounds have been broadly utilized in the field of
of a series of a
-haloketone and amide scaffolds.6h,7,8 Ge and Hart-
wig reported the Ni-catalyzed cross-coupling reaction of an aryl
halide with a metal enolate derived from an aromatic ketone.9
These reactions achieved high enantiocontrol of the product. In
addition, Lei and co-workers and Hartwig and co-workers both
medicinal chemistry,3 monofluorinated
b
-lactam is less in-
vestigated in this area. From the structural point of view, a fluorine
atom incorporated into the -lactam ring participates in the acti-
vation of the amide bond through an electronic inductive effect.
Welch and co-workers reported the synthesis of an -alkylated-
fluoro-
-lactam that was expected to show increased bioactivity.4
Shibata and co-workers also have reported the enantioselective
synthesis of -alkylated- -fluoro- -lactam by using fluorination of
malonate followed by multistep approach.5 To the best of our
knowledge, no other example of the direct -alkylation of an
fluoro- -lactam has been reported except for from Welch and co-
wokers,4 although
-difluoro- -lactams have been extensively
b
independently reported the
a-arylation of an ester using Ni- and
a
a-
Pd-catalyzed cross-coupling reactions.10 Despite the development
b
of many coupling reactions for
arylation of -halo- -lactams is still a challenging task.
Recently, we reported the diastereoselective synthesis of syn-
a
-carbonyl substrates, the direct
a
-
-
a
b
a
a
b
a
bromo-a-fluoro-b-lactams (1) by the Reformatsky reaction of ethyl
a
a
-
dibromofluoroacetate with imines (Scheme 1).11 The reaction pro-
ceeded under mild conditions, and there were no limitations on the
substrate. The bromine atom is particularly one of the most useful
as substituents for the above described cross-coupling reactions.
b
a,
a
b
Therefore, investigating the direct
tams is a natural extension of this work. Herein, we report the
a-arylation of a-fluoro-b-lac-
* Corresponding author. Tel./fax: þ81 72 866 3142; e-mail address: aando@
pharm.setsunan.ac.jp (A. Ando).
0040-4020/$ e see front matter Crown Copyright Ó 2012 Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.12.002

1560
A. Tarui et al. / Tetrahedron 69 (2013) 1559e1565
cross-coupling reaction of an
a
-bromo-
a
-fluoro-
b
-lactam with
presence of NiCl2$DME. However, the reaction produced the same
product, anti-2a, as a single diastereomer (Scheme 2). A similar
result was observed using achiral bis(oxazoline) ligand 3b. It was
assumed that the steric hindrance between the aryl group on the
Grignard reagent and the C4 phenyl group on the convex face of the
substrate produced the diastereoselectivity. This was consistent
with obtaining the same anti-2a diastereomer, regardless of the
configuration of 1a and the ligand.
several aryl Grignard reagents. We used the reaction conditions
reported by Fu and co-workers as the starting point for our cross-
coupling reaction with 1.6h
Scheme 1. Synthesis of a-bromo-a-fluoro-b-lactams (1).
2. Results and discussion
The reaction of syn-1a (racemic) with PhMgBr gave the coupling
product (2a) diastereoselectively in a moderate yield with the
combination of NiCl2$DME and bis(oxazoline) ligand 3a (Table 1,
entry 1).12 In order to improve the yield of 2a, the reaction condi-
tions were optimized. The results are summarized in Table 1. When
the reaction was carried out at 0 ꢀC, the yield of 2a increased to 98%
(entry 3). This reaction also proceeded in THF in the good yield as
well as in DME (entry 4). However, hexane was not effective in this
coupling reaction. When the amount of PhMgBr was reduced to
1.5 equiv, the product was obtained in 98% yield (entry 6). Addi-
tionally, when the catalyst and ligand loadings were reduced to 5
and 6 mol %, respectively, the yield increased (entry 8). During the
optimization of the reaction conditions, anti-2a was obtained as
a single diastereomer in all cases.
Scheme 2. Diastereoselective formation of anti-2a from the syn/anti-mixture of 1a.
The reaction conditions detailed in entry 8 of Table 1 were used
for evaluating the scope of the Ni-catalyzed coupling reaction of
a-
bromo- -fluoro- -lactams 1aec with a series of aryl Grignard re-
a
b
agents (Table 2). The 2-naphthyl group was coupled with 1a
smoothly in a good yield (entry 5). In contrast, the reaction with 1-
naphthylMgBr was sluggish due to steric hindrance (entry 4). p-
Table 2
Table 1
Scope of the cross-coupling reaction of
Grignard reagents
a-bromo-a-fluoro-b-lactams with various
Optimization of reaction conditions
Entrya
R1
R2
Yieldb (%)
1
2
3
Bn
Ph
PMB
Ph
Ph
Ph
98
79
76
Entry Ni cat.
Ligand
PhMgBr Solvent Temp (ꢀC) Yielda,b (%)
(equiv)
(mol %) (mol %)
4
Bn
Bn
Bn
30c
2a
1a
1
2
3
4
5
6
7
8
10
10
10
10
10
10
10
5
3
1
10
10
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
12
12
12
12
12
12
12
6
2
2
2
2
DME
DME
DME
THF
Hexane
THF
THF
THF
THF
THF
ꢁ60
ꢁ20
0
0
0
0
0
0
0
56
93
98
84
d
37
d
d
d
49
d
34
d
36
73
d
d
5
6
84
82
2
1.5
1.1
1.5
1.5
98
63
(98)
64
d
7
8
9
85
84
98
9
4
10
11
12
1.2 1.5
0
0
0
3ac 12
3b 12
2
2
DME
DME
94
88
10
11
12
13
93
85
Bn
74c
88
Determined by 19F NMR spectroscopy. Benzotrifluoride was used as an internal
a
standard.
b
c
Isolated yield in parenthesis.
(S)-3a was used instead of (R)-3a.
14
15
Bn
Bn
90
61
Interestingly, when (S)-3a or achiral BOX ligand 3b was used, the
same diastereomer was obtained (entries 11, 12). The origin of this
diastereoselectivity was investigated by using (R)-ligand 3a in the
reaction of the syn/anti-1a diastereo-mixture with PhMgBr in the

A. Tarui et al. / Tetrahedron 69 (2013) 1559e1565
1561
Table 2 (continued )
product 4c in 54% yield (Scheme 3). X-ray analysis of 4c allowed the
configuration of C4 proton and C3 fluorine to be assigned as anti
(Fig. 2).14,15 The stereochemistry of the other coupling products was
tentatively assumed by analogy.
Entrya
R1
R2
Yieldb (%)
26d
16
Bn
a
Condition:
a-bromo-a-fluoro-b-lactam (0.5 mmol), ArMgBr (0.75 mmol),
NiCl2$DME (0.025 mmol) and ligand (0.03 mmol) in THF (5 mL) at 0 ꢀC for 0.5 h.
b
Isolated yields.
Two equivalents of the Grignard reagent was used.
This reaction was performed in 3 mmol scale based on 1.
c
d
Scheme 3. Oxidative removal of the p-methoxybenzyl group.
Substituted ArMgBr reagents provided the corresponding coupling
products in excellent yields, regardless of the electron-donating
groups (Me, MeO) and the electron-withdrawing groups (Cl, CF3),
on the aromatic ring (entries 6e9). In addition, m-substituted
ArMgBr reagents gave good yields in our cross-coupling (entries
10e13). However, o-substituted ArMgBr reagents and 1-
naphthylMgBr (Table 2, entry 4) were not effective in this cou-
pling system. These results could be explained by the steric hin-
drance of the Grignard reagent. Heterocyclic ArMgBr reagents
successfully produced the corresponding products (entries 14e16).
In contrast, the alkylation of 1a with MeMgBr did not work well in
this cross-coupling system.
4. Conclusion
In conclusion, we have reported the first cross-coupling of
a-
bromo- -fluoro- -lactams, which is a fluorinated second-aryl car-
a
b
bonyl substrate, by the Ni/bis(oxazoline)-catalyzed Kumada cou-
pling reaction. Yields of up to 98%, and high diastereoselectivities
were achieved with a wide variety of arylMgBr substrates. Some of
the hetero-aromatic derivatives were also obtained in good yields.
Further efforts to introduce alkyl, alkenyl, and alkynyl nucleophiles
for this coupling reaction are in progress.
5. Experimental
3. The plausible reaction mechanism and determination of
the relative configuration of coupling product
5.1. General information and materials
1H NMR and 13C NMR spectra were recorded on JNM-GX400 and
JEOL-ECA-600SN spectrometers. 19F NMR spectra were recorded on
Hitachi FT-NMR R-90H and JEOL-ECA-600SN spectrometer. Chem-
ical shifts of 1H NMR and 13C NMR are reported in parts per million
from tetramethylsilane (TMS) as an internal standard. Chemical
shifts of 19F NMR are reported in parts per million from benzotri-
fluoride as an internal standard. All data are reported as follows:
chemical shifts, relative integration value, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, dd¼doublet doublet, br¼broad, br
s¼broad-singlet, m¼multiplet), coupling constants (Hertz). Mass
spectra were obtained on JEOL JMS-700T spectrometer. IR spectra
wererecordedonJASCOFT/IR-410. Meltingpointswere measuredon
Yanagimoto micro melting point apparatus MP-S3 and were
uncorrected.
The plausible mechanism of this coupling reaction was shown in
Fig. 1. In a general Kumada coupling,13 the Grignard reagent re-
duced the Ni (II) catalyst to the Ni (0) species along with the biaryl.
Then, oxidative addition of a-bromo-a-fluoro-b-lactam (1) to the Ni
(0) gave the Ni (II) complex i followed by transmetallation of
ArMgBr reagent leading to the complex ii. This complex ii elimi-
nated the coupling product 2 reductively and regenerated the Ni (0)
catalyst. The catalytic cycle was completed in this way.
Diethyl ether (Et2O) was distilled over benzophenone ketyl so-
dium just before use. Dimethoxyethane (DME) and hexane were
distilled over CaH2 just before use. All commercially available ma-
terials were used as received without further purification. All ex-
periments were carried out under argon atmosphere in flame-dried
glassware using standard inert techniques for introducing reagents
and solvents unless otherwise noted.
5.2. Synthesis of
a-bromo-a-fluoro-b-lactam (1a) by the
Reformatsky-type reaction11
Ethyl dibromofluoroacetate (45 mmol) was added to a solution
of benzylidenbenzylamine (30 mmol) in Et2O (120 mL) at 0 ꢀC. Then
1.0 M Et2Zn in hexane (45 mL, 45 mmol) was slowly added to the
mixture at 0 ꢀC, and the resulting mixture was stirred at same
temperature for 1 h. The mixture was quenched with saturated
aqueous NaHCO3, and was filtered through Celite pad. The filtrate
was extracted with AcOEt, and then the extract was washed with
brine and dried over MgSO4. The solvent was removed in vacuo and
the residue was purified by column chromatography (AcOEt/
hexane¼1:9) and then recrystallization from AcOEt/hexane to give
1a (7 g, 70%) as a colorless solid; mp 81.5e82.0 ꢀC; 1H NMR (CDCl3,
Fig. 1. The plausible reaction mechanism.
To determine the relative configuration of coupling product 2,
treatment of 3-fluoro-1-(4-methoxybenzyl)-3,4-diphenyl-azetidin-
2-one (2c) with cerium ammonium nitrate (CAN) led to the oxidative
cleavage of the p-methoxybenzyl group affording the deprotected

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A. Tarui et al. / Tetrahedron 69 (2013) 1559e1565
Fig. 2. X-ray analysis of 3-fluoro-3,4-diphenylazetidin-2-one (4c).
400 MHz)
d
: 3.93 (1H, d, J¼14.9 Hz), 4.77 (1H, d, J¼10.3 Hz), 4.97
(dr syn/anti¼1/1) was prepared by mixing the syn/anti-mixture of
1a (dr syn/anti¼1/10) and the above described syn-1a; 1H NMR
(1H, d, J¼14.9 Hz), 7.13 (2H, m), 7.20 (2H, m), 7.32 (3H, m), 7.44 (3H,
m); 13C NMR (CDCl3, 100 MHz)
d: 44.9, 69.4 (d, J¼25 Hz), 106.2 (d,
(400 MHz, CDCl3)
d
: 3.93 (0.5H, d, J¼14.8 Hz), 3.94 (0.5H, d,
J¼299 Hz), 127.8, 128.3, 128.5, 128.7, 129.0, 129.7, 132.2, 133.3, 161.0
J¼14.8 Hz), 4.78 (0.5H, d, J¼10.4 Hz), 4.85 (0.5H, d, J¼2.7 Hz), 4.94
(0.5H, d, J¼14.9 Hz), 4.98 (0.5H, d, J¼14.8 Hz), 7.11e7.15 (2H, m),
7.20e7.22 (1H, m), 7.26e7.28 (1H, m), 7.32e7.34 (3H, m), 7.43e7.46
(d, J¼26 Hz); 19F NMR (CDCl3, 600 MHz)
: ꢁ54.9 (1F, d, J¼10.3 Hz);
d
MS m/z¼333 (Mþ); HRMS (pos-FAB, Gly.) calcd for C16H13BrFNO:
334.024 ([MþH]þ), found: 334.024 ([MþH]þ, 100%), 336.023 (96);
IR (KBr) cmꢁ1: 1787, 1204.
(3H, m); 13C NMR (100 MHz, CDCl3)
d
: 44.4 (d, J¼2 Hz), 44.9 (d,
J¼2 Hz), 69.4 (d, J¼25 Hz), 72.4 (d, J¼23 Hz), 99.4 (d, J¼308 Hz),
106.2 (d, J¼299 Hz), 127.8, 128.0, 128.1, 128.3, 128.3, 128.3, 128.5,
128.7, 129.0, 129.0, 129.7, 129.9, 130.3, 132.2, 133.3, 160.9 (d,
5.3. Synthesis of syn/anti-mixture of a-bromo-a-fluoro-b-
lactam (1a)11
J¼25 Hz), 161.0 (d, J¼26 Hz); 19F NMR (600 MHz, CDCl3)
: ꢁ65.5
d
(0.5F, s), ꢁ54.9 (0.5F, d, J¼10.3 Hz); MS (pos-FAB, NBA) m/z¼334
([MþH]þ); HRMS calcd for C16H13BrFNO: 334.024 ([MþH]þ), found:
334.023 ([MþH]þ, 100%), 336.023 (98).
Benzylamine (66 mmol) was added to the solution of trime-
thylaluminum (69 mmol, 1 M trimethylaluminum in hexane solu-
tion was used) in CH2Cl2 (60 mL) at ꢁ10 ꢀC. The mixture was
allowed to warm to ambient temperature, and then ethyl dibro-
mofluoroacetate (30 mmol) was added to resulting mixture. The
reaction was quenched with aqueous 10% HCl, and the mixture was
extracted with AcOEt, and then the extract was washed with brine
and dried over MgSO4. The solvent was removed in vacuo and the
residue was purified by column chromatography (AcOEt/
hexane¼1:4) and then recrystallization from AcOEt/hexane to give
Benzyl dibromofluoroacetamide (7.8 g, 80%) as a colorless solid.
Benzyl dibromofluoroacetamide (24 mmol) was added to a so-
lution of benzaldehyde (8 mmol) and RhCl(PPh3)3 (0.08 mmol) in
CH2Cl2 (64 mL) at ꢁ10 ꢀC. Then 1.0 M Et2Zn in hexane (24 mL,
24 mmol) was slowly added to the mixture at ꢁ10 ꢀC, and the
resulting mixture was stirred at ambient temperature for 1 h. The
reaction was quenched with aqueous 10% HCl, and the mixture was
extracted with AcOEt, and then the extract was washed with brine
and dried over MgSO4. The solvent was removed in vacuo and the
residue was purified by column chromatography (AcOEt/
hexane¼1:4) to give N-benzyl-2-bromo-2-fluoro-3-hydroxyl-3-
phenylpropanamide (2.4 g, 86%, dr 4:3).
5.4. Synthesis of achiral bis(oxazoline) ligand (3b)16
Ethanolamine (0.64 mL,10.5 mmol) was added to the suspension
of K2CO3 (2.76 g, 20 mmol) in CH2Cl2 (20 mL) at 0 ꢀC. Dimethylma-
lonyl dichloride (0.66 mL, 5 mmol) in CH2Cl2 (5 mL) was added
dropwise to the cold mixture. The mixture was allowed to warm to
ambient temperature and stirred for 15 h. MeOH (20 mL) was added
and the mixture was stirred for 1 h. The whole reaction mixture was
filtered through Celite pad and rinsed twice with MeOH (2ꢂ10 mL).
The filtrate was concentrated in vacuo. The crude product was used
directly into the next step without further purification.
The bisamide was dissolved in toluene and heated to 70 ꢀC.
Thionyl chloride (1.5 mL, 20 mmol) was added to the mixture and
the resulting mixture was stirred at same temperature for 5 h. The
reaction mixture was cooled to ambient temperature. The reaction
was quenched by saturated aqueous NaHCO3, and the mixture was
extracted with CHCl3 (5ꢂ20 mL), and then the extract was dried
over MgSO4. The solvent was removed in vacuo and to provide the
crude product (934 mg) as a solid.
2.2 M DEAD in toluene (0.57 mL, 1.25 mmol) was added to the
solution of diastereomixtures of N-benzyl-2-bromo-2-fluoro-3-
hydroxyl-3-phenylpropanamide (1 mmol) and PPh3 (1.5 mmol) in
THF (5 mL) at 0 ꢀC, and then the resulting mixture was stirred at
reflux for 3 h. The reaction was quenched with aqueous 10% HCl,
and the mixture was extracted with AcOEt, and then the extract
was washed with brine and dried over MgSO4. The solvent was
removed in vacuo and the residue was purified by column chro-
matography (AcOEt/hexane¼1:4) to give syn/anti-mixture of 1a
(234 mg, 70%, dr syn/anti¼1/10). The desired diastereomixtures 1a
The crude chlorinated amide was dissolved in 17 mL of 5%
methanolic NaOH solution (0.98 g NaOH was completely dissolved
in 1 mL H2O; then diluted with 19 mL MeOH. This solution 17 mL
was used) and heated to reflux for 2 h. The reaction was cooled to
ambient temperature and added H2O (10 mL). The resulting mix-
ture was extracted with CHCl3 (5ꢂ10 mL), and then the extract was
dried over MgSO4. The solvent was removed in vacuo and to pro-
vide the crude product as a pale yellow oil. The oil was refrigerated
to afford analytical pure bis(oxazoline) 3b (619 mg, 68%, three
steps) as a slight yellow wax solid. Bis(oxazoline) 3b was used to the

A. Tarui et al. / Tetrahedron 69 (2013) 1559e1565
1563
titled cross-coupling reaction without further purification; 1H NMR
90 MHz)
d
: ꢁ102.8 (1F, s); MS m/z¼361 (Mþ); HRMS (EI) calcd for
(CDCl3, 400 MHz)
d
: 1.53 (6H, s), 3.88 (4H, t, J¼9.5 Hz), 4.30 (4H, t,
C23H20FNO2: 361.148 (Mþ), found: 361.148 (Mþ); IR (neat) cmꢁ1
1768, 702.
:
J¼9.5 Hz); MS m/z¼182 (Mþ); HRMS (EI) calcd for C9H14N2O2:
182.106 (Mþ), found: 182.106 (Mþ).
5.6.4. anti-1-Benzyl-3-fluoro-3-(naphthalen-1-yl)-4-phenylazetidin-
2-one (2d). The titled product (2d) was purified by column chro-
matography (AcOEt/hexane¼1:4) and was obtained as a colorless
solid (57 mg, 30%). Two equivalents of the Grignard reagent was
5.5. Preparation of Grignard reagents
Magnesium turning (5.5 mmol) and a piece of iodine were placed
in a flask. To the flask was added anhydrous THF (4.5 mL) and aryl
bromides (0.5 mmol). The mixture was heated until discolored io-
dine, and then additional aryl bromide (4.5 mmol) was added slowly
to the mixture. After all aryl bromide was added, the reaction mix-
ture was heated to reflux except for in the case of PhMgBr. The
mixturewasstirredfor 2e3 h. In thecase of PhMgBr, the mixturewas
stirred at ambient temperature. All aryl Grignard reagents were
prepared by this manner. The concentration of Grignard reagents
were titrated by the method of Paquette with modifications.17
used; mp 50.0e51.0 ꢀC; 1H NMR (CDCl3, 400 MHz)
d: 3.89 (1H, dd,
J¼15.1, 2.2 Hz), 4.69 (1H, d, J¼3.7 Hz), 5.01 (1H, d, J¼15.1 Hz),
7.03e7.08 (2H, m), 7.18e7.20 (3H, m), 7.33e7.37 (1H, m), 7.43e7.52
(7H, m), 7.61e7.63 (1H, m), 7.86e7.92 (2H, m), 8.01e8.04 (1H, m);
13C NMR (CDCl3, 100 MHz)
d
: 43.7 (m), 68.3 (d, J¼25 Hz), 103.0 (d,
J¼226 Hz),124.8, 125.0 (d, J¼4 Hz), 125.9 (d, J¼6 Hz), 126.0, 126.5 (d,
J¼1 Hz), 127.7, 128.1, 128.6, 128.7, 129.3, 129.3 (d, J¼1 Hz), 130.1,
130.3, 130.7 (d, J¼3 Hz), 130.8, 132.4, 133.9, 164.5 (d, J¼25 Hz); 19F
NMR (CDCl3, 90 MHz)
d
: ꢁ92.5 (1F, s); MS m/z¼381 (Mþ); HRMS
(EI) calcd for C26H20FNO: 381.153 (Mþ), found: 381.153 (Mþ); IR
(KBr) cmꢁ1: 1766, 700.
5.6. General procedures for the Kumada cross-coupling
reaction
5.6.5. anti-1-Benzyl-3-fluoro-3-(naphthalen-2-yl)-4-phenylazetidin-
2-one (2e). The titled product (2e) was purified by column chro-
matography (AcOEt/hexane¼1:4) and was obtained as a colorless
solid (160 mg, 84%); mp 111.0e111.5 ꢀC; 1H NMR (CDCl3, 400 MHz)
(R,R)-2,20-Isopropylidene-bis(4-phenyl-2-oxazoline)
((R)-3a;
10.0 mg, 0.03 mmol) and NiCl2$DME (5.5 mg, 0.025 mmol) were
added to a flask equipped with a stir bar. To the flask was added
anhydrous THF (5 mL) and 1 (0.5 mmol) and cooled to 0 ꢀC. Finally,
a solution of Grignard reagent in THF (0.75 mmol) was added
slowly and the mixture was stirred at same temperature for 0.5 h.
The reaction was quenched by aqueous 10% HCl and the mixture
was extracted with AcOEt, and then the extract was washed with
brine and dried over MgSO4. The solvent was removed in vacuo and
the residue was purified by column chromatography to give 2.
d
: 4.00 (1H, dd, J¼14.7, 2.4 Hz), 4.73 (1H, d, J¼2.9 Hz), 5.07 (1H, d,
J¼14.7 Hz), 7.19e7.22 (2H, m), 7.29e7.53 (11H, m), 7.81e7.87 (3H,
m), 7.93 (1H, m); 13C NMR (CDCl3, 100 MHz)
: 44.4 (m), 68.6 (d,
d
J¼25 Hz), 102.3 (d, J¼225 Hz), 122.2 (d, J¼5 Hz), 124.9 (d, J¼8 Hz),
126.5, 126.8, 127.6, 128.0, 128.1 (d, J¼8 Hz), 128.3, 128.5, 128.7, 128.8,
129.1, 131.4 (d, J¼23 Hz), 132.1, 132.8, 133.4 (d, J¼2 Hz), 134.4, 164.8
(d, J¼25 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ101.9 (1F, s); MS m/
d
z¼381 (Mþ); HRMS (EI) calcd for C26H20FNO: 381.153 (Mþ), found:
5.6.1. anti-1-Benzyl-3-fluoro-3,4-diphenylazetidin-2-one (2a). The
titled product (2a) was purified by column chromatography (AcOEt/
hexane¼1:4) and was obtained as a colorless solid (163 mg, 98%); mp
381.153 (Mþ); IR (KBr) cmꢁ1: 1747.
5.6.6. anti-1-Benzyl-3-fluoro-3-(4-methylphenyl)-4-phenyazetidin-
2-one (2f). The titled product (2f) was purified by column chro-
matography (AcOEt/hexane¼1:4) and was obtained as a colorless
solid (152 mg, 88%); mp 124.0e125.0 ꢀC; 1H NMR (CDCl3, 400 MHz)
71.0e72.0 ꢀC; 1H NMR (CDCl3, 600 MHz)
d
: 3.97 (1H, dd, J¼14.8,
2.3 Hz), 4.65 (1H, d, J¼3.5 Hz), 5.02 (1H, d, J¼14.8 Hz), 7.16e7.17 (2H,
m), 7.29e7.32 (5H, m), 7.34 (5H, m), 7.41e7.43 (3H, m); 13C NMR
(CDCl3,150 MHz)
d
: 44.3, 68.6 (d, J¼25 Hz),102.2 (d, J¼225 Hz),125.3
d
: 2.35 (3H, s), 3.96 (1H, dd, J¼14.8, 2.4 Hz), 4.64 (1H, d, J¼3.5 Hz),
5.01 (1H, d, J¼14.8 Hz), 7.14e7.20 (4H, m), 7.27e7.32 (7H, m),
7.41e7.43(3H, m);13C NMR(CDCl3,100 MHz)
(d, J¼7 Hz), 128.2,128.3,128.7, 128.8,128.9, 129.0, 129.2, 129.4,132.2,
134.3 (d, J¼24 Hz),133.5,165.0 (d, J¼25 Hz); 19F NMR (CDCl3, 90 MHz)
d: 21.2, 44.3 (d, J¼2 Hz),
d
: ꢁ102.4 (1F, s); MS m/z¼331 (Mþ); HRMS (EI) calcd for C22H18FNO:
68.5 (d, J¼25 Hz), 102.1 (d, J¼224 Hz), 125.2 (d, J¼7 Hz), 127.9, 128.1,
128.5,128.6,128.8,129.0,129.4,131.1 (d, J¼24 Hz),132.2,134.4,139.3
331.137 (Mþ), found: 331.137 (Mþ); IR (KBr) cmꢁ1: 1765, 699.
(d, J¼2 Hz), 164.9 (d, J¼25 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ100.7
d
5.6.2. anti-3-Fluoro-1,3,4-triphenylazetidin-2-one (2b). The titled
product (2b) was purified by column chromatography (AcOEt/
hexane¼1:9) and was obtained as a colorless solid (126 mg, 79%);
(1F, s); MS m/z¼345 (Mþ); HRMS (EI) calcd for C23H20FNO: 345.153
(Mþ), found: 345.153 (Mþ); IR (KBr) cmꢁ1: 1773.
mp 155.5e156.0 ꢀC; 1H NMR (CDCl3, 400 MHz)
d: 5.33 (1H, d,
5.6.7. anti-1-Benzyl-3-fluoro-3-(4-methoxyphenyl)-4-phenylazeti-
din-2-one (2g). The titled product (2g) was purified by column
chromatography (AcOEt/hexane¼1:4) and was obtained as a color-
less solid (154 mg, 85%); mp 106.0e107.0 ꢀC; 1H NMR (CDCl3,
400 MHz)
J¼3.4 Hz), 5.00 (1H, d, J¼14.8 Hz), 6.90e6.92 (2H, m), 7.13e7.15 (2H,
m), 7.28e7.44 (10H, m);13C NMR (CDCl3,100 MHz)
J¼3.2 Hz), 7.11e7.15 (1H, m), 7.28e7.32 (2H, m), 7.40e7.47 (10H, m),
7.56e7.58 (2H, m); 13C NMR (CDCl3, 100 MHz)
d
: 69.2 (d, J¼26 Hz),
100.9 (d, J¼223 Hz), 117.8, 124.9, 125.4 (d, J¼7 Hz), 127.6, 128.8,
128.9, 129.0, 129.1, 129.5 (d, J¼2 Hz), 131.9, 134.0 (d, J¼24 Hz), 136.4
d: 3.81 (3H, s), 3.96 (1H, dd, J¼14.8, 2.4 Hz), 4.66 (1H, d,
(d, J¼2 Hz), 161.9 (d, J¼25 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ99.8
d
(1F, s); MS m/z¼317 (Mþ); HRMS (EI) calcd for C21H16FNO: 317.122
d: 44.2(d, J¼1 Hz),
(Mþ), found: 317.122 (Mþ); IR (KBr) cmꢁ1: 1748.
55.3, 68.4 (d, J¼26 Hz), 101.9 (d, J¼224 Hz), 114.2, 126.2 (d, J¼24 Hz),
127.1 (d, J¼6 Hz), 127.9, 128.1, 128.4, 128.6, 128.7, 129.0, 132.3, 134.4,
5.6.3. anti-3-Fluoro-1-(4-methoxybenzyl)-3,4-diphenylazetidin-2-
one (2c). The titled product (2c) was purified by column chroma-
tography (AcOEt/hexane¼1:4) and was obtained as a colorless oil
160.3 (d, J¼2 Hz), 165.0 (d, J¼25 Hz); 19F NMR (CDCl3, 90 MHz)
d:
ꢁ97.2 (1F, s); MS m/z¼361 (Mþ); HRMS (EI) calcd for C23H20FNO2:
361.148 (Mþ), found: 361.148 (Mþ); IR (KBr) cmꢁ1: 1750, 701.
(206 mg, 76%); 1H NMR (CDCl3, 400 MHz)
d: 3.97 (3H, s), 3.93 (1H, dd,
J¼14.9, 2.4 Hz), 4.63 (1H, d, J¼3.5 Hz), 4.97 (1H, d, J¼14.8 Hz), 6.82
5.6.8. anti-1-Benzyl-3-(4-chlorophenyl)-3-fluoro-4-phenylazetidin-
2-one (2h). The titled product (2h) was purified by column chro-
matography (eluted with AcOEt/hexane¼1:9/1:4) and was ob-
(2H, d, J¼8.7 Hz), 7.08 (2H, d, J¼8.7 Hz), 7.31e7.33 (2H, m), 7.38 (5H,
m), 7.42e7.45 (3H, m); 13C NMR (CDCl3,100 MHz)
d: 43.6 (d, J¼2 Hz),
55.2, 68.3 (d, J¼25 Hz), 102.0 (d, J¼225 Hz), 114.1, 125.1 (d, J¼7 Hz),
126.3, 128.1 (d, J¼2 Hz), 128.6, 128.7, 129.0, 129.2 (d, J¼2 Hz), 129.8,
132.1, 134.1 (d, J¼24 Hz), 159.2, 164.6 (d, J¼25 Hz); 19F NMR (CDCl3,
tained as a colorless oil (154 mg, 84%); 1H NMR (CDCl3, 400 MHz)
d:
3.96 (1H, dd, J¼14.8, 2.4 Hz), 4.60 (1H, d, J¼3.5 Hz), 5.02 (1H, d,
J¼14.8 Hz), 7.15e7.17 (2H, m), 7.30e7.38 (9H, m), 7.43e7.45 (3H, m);

1564
A. Tarui et al. / Tetrahedron 69 (2013) 1559e1565
13C NMR (CDCl3, 100 MHz)
d
: 44.3 (d, J¼2 Hz), 68.4 (d, J¼25 Hz),
and was obtained as a colorless oil (175 mg, 88%); 1H NMR (CDCl3,
400 MHz)
101.6 (d, J¼225 Hz), 126.6 (d, J¼7 Hz), 128.1 (d, J¼1 Hz), 128.5, 128.7,
d
: 3.99 (1H, dd, J¼14.7, 2.4 Hz), 4.61 (1H, d, J¼3.6 Hz), 5.05
128.8, 129.0, 129.2, 131.7, 132.5, 132.7, 134.2, 135.3 (d, J¼2 Hz), 164.3
(1H, d, J¼14.7 Hz), 7.19e7.21 (2H, m), 7.30e7.34 (5H, m), 7.44e7.46
(d, J¼24 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ97.2 (1F, s); MS m/z¼365
d
(3H, m), 7.52e7.58 (3H, m), 7.63e7.65 (1H, m); 13C NMR (CDCl3,
(Mþ); HRMS (EI) calcd for C22H17ClFNO: 365.098 (Mþ), found:
100 MHz)
d
: 44.5 (d, J¼2 Hz), 68.6 (d, J¼25 Hz), 101.7 (d, J¼227 Hz),
365.098 (Mþ, 100%), 367.095 (35); IR (neat) cmꢁ1: 1768.
121.7 (m), 123.5 (q, J¼272 Hz), 126.0 (qd, J¼4, 1 Hz), 128.1 (d,
J¼1 Hz), 128.3, 128.5, 128.8, 129.0, 129.3 (d, J¼6 Hz), 130.3 (q,
J¼33 Hz), 131.5 (d, J¼1 Hz), 134.2, 135.3 (d, J¼24 Hz), 164.1 (d,
J¼24 Hz); 19F NMR (CDCl3, 90 MHz, hexafluorobenzene was used as
5.6.9. anti-1-Benzyl-3-fluoro-4-phenyl-3-{4-(trifluoromethyl)phe-
nyl}azetidin-2-one (2i). The titled product (2i) was purified by col-
umn chromatography (AcOEt/hexane¼1:9) and was obtained as
an internal standard)
d
: 99.4 (3F, s), ꢁ6.4 (1F, s); MS m/z¼365 (Mþ);
a colorless oil (195 mg, 98%); 1H NMR (CDCl3, 400 MHz)
d: 3.98 (1H,
HRMS (EI) calcd for C23H17F4NO: 399.125 (Mþ), found: 399.125
dd, J¼14.6, 2.4 Hz), 4.62 (1H, d, J¼3.5 Hz), 5.05 (1H, d, J¼14.6 Hz),
(Mþ); IR (neat) cmꢁ1: 1770, 1336, 1171, 1130, 700.
7.18e7.20 (2H, m), 7.30e7.34 (5H, m), 7.45e7.47 (5H, m), 7.63e7.66
(2H, m); 13C NMR (CDCl3, 100 MHz)
d: 44.5 (m), 68.6 (m), 101.7 (d,
5.6.14. anti-1-Benzyl-3-fluoro-3-{3,4-(methylenedioxy)phenyl}-4-
phenylazetidin-2-one (2n). The titled product (2n) was purified by
column chromatography (AcOEt/hexane¼1:4) and was obtained as
a colorless solid (169 mg, 90%); mp 92.0e92.5 ꢀC; 1H NMR (CDCl3,
J¼226 Hz), 123.6 (q, J¼273 Hz), 125.4 (d, J¼8 Hz), 125.8 (q, J¼4 Hz),
128.1 (m), 128.2, 128.6, 128.8, 128.9, 129.3, 131.4 (m), 131.5, 134.2,
138.0 (d, J¼24 Hz), 163.9 (d, J¼24 Hz); 19F NMR (CDCl3, 90 MHz,
hexafluorobenzene was used as an internal standard)
d: 99.2 (3F, S),
400 MHz)
d
: 3.96 (1H, dd, J¼14.8, 2.4 Hz), 4.63 (1H, d, J¼3.5 Hz),
ꢁ6.4 (1F, s); MS m/z¼399 (Mþ); HRMS (EI) calcd for C23H17F4NO:
399.125 (Mþ), found: 399.125 (Mþ); IR (neat) cmꢁ1: 1769,1326,1168,
1128, 700.
5.00 (1H, d, J¼14.8 Hz), 5.97 (2H, s), 6.80 (1H, d, J¼8.0 Hz), 6.86 (1H,
d, J¼1.6 Hz), 6.94e6.96 (1H, m), 7.13e7.15 (2H, m), 7.29e7.32 (5H,
m), 7.42e7.44 (3H, m); 13C NMR (CDCl3, 100 MHz)
d: 44.2 (d,
J¼2 Hz), 68.4 (d, J¼26 Hz), 101.7 (d, J¼226 Hz), 101.3, 106.2 (d,
J¼7 Hz), 108.4, 119.5 (d, J¼7 Hz), 127.6 (d, J¼24 Hz), 128.0, 128.1,
128.4, 128.6, 128.8, 129.0, 132.0, 134.2, 147.9, 148.4 (d, J¼3 Hz), 164.7
5.6.10. anti-1-benzyl -3-fluoro-3-(3-methylphenyl)-4-phenyazetidin-
2-one (2j). The titled product (2j) was purified by column chroma-
tography (AcOEt/hexane¼1:4) and was obtained as a colorless oil
(d, J¼25 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ96.9 (1F, s); MS m/z¼375
d
(160 mg, 93%); 1H NMR (CDCl3, 400 MHz)
d
: 2.32 (3H, s), 3.96 (1H, dd,
(Mþ); HRMS (EI) calcd for C23H20FNO2: 375.127 (Mþ), found:
J¼14.7, 2.2 Hz), 4.65 (1H, d, J¼3.5 Hz), 5.03 (1H, d, J¼14.7 Hz),
375.127 (Mþ); IR (KBr) cmꢁ1: 1747, 699.
7.16e7.20 (5H, m), 7.27e7.33 (6H, m), 7.42e7.44 (3H, m); 13C NMR
(CDCl3, 100 MHz)
d
: 21.4, 44.3 (d, J¼2 Hz), 68.5 (d, J¼25 Hz), 102.1 (d,
5.6.15. anti-3-(Benzofuran-5-yl)-1-benzyl-3-fluoro-4-phenylazeti-
din-2-one (2o). The titled product (2o) was purified by column
chromatography (AcOEt/hexane¼1:9) and was obtained as a color-
less solid (112 mg, 61%); mp 108e110 ꢀC; 1H NMR (CDCl3, 400 MHz)
J¼225 Hz),122.1 (d, J¼8 Hz),125.6 (d, J¼7 Hz),128.0,128.1 (d, J¼2 Hz),
128.5, 128.6 (d, J¼2 Hz),128.8,129.0,129.9 (d, J¼2 Hz),132.1,134.0 (d,
J¼23 Hz),134.4,138.5,164.9 (d, J¼24 Hz); 19F NMR (CDCl3, 90 MHz)
d:
ꢁ103.0 (1F, s); MS m/z¼345 (Mþ); HRMS (EI) calcd for C23H20FNO:
d
: 3.99 (1H, dd, J¼14.8, 2.2 Hz), 4.72 (1H, d, J¼3.5 Hz), 5.03 (1H, d,
345.153 (Mþ), found: 345.153 (Mþ); IR (neat) cmꢁ1: 1768, 701.
J¼14.8 Hz), 6.76e6.77 (1H, m), 7.15e7.18 (2H, m), 7.27e7.36 (6H, m),
7.43e7.47 (3H, m), 7.50e7.53 (1H, m), 7.65e7.66 (1H, m), 7.73 (1H,
5.6.11. anti-1-Benzyl-3-fluoro-3-(3-methoxyphenyl)-4-phenylazeti-
din-2-one (2k). The titled product (2k) was purified by column
chromatography (AcOEt/hexane¼1:4) and was obtained as a color-
m); 13C NMR (CDCl3, 100 MHz)
d: 44.2 (d, J¼2 Hz), 68.7 (d, J¼26 Hz),
102.2 (d, J¼225 Hz), 106.6, 111.8, 118.9 (d, J¼7 Hz), 121.8 (d, J¼6 Hz),
127.6, 127.9, 128.1 (d, J¼1 Hz), 128.4, 128.6, 128.8, 128.9, 129.0, 132.1,
134.3, 145.8, 155.0 (d, J¼2 Hz), 165.0 (d, J¼24 Hz); 19F NMR (CDCl3,
less oil (153 mg, 85%); 1H NMR (CDCl3, 400 MHz)
d: 3.45 (3H, s),
3.96 (1H, dd, J¼14.7, 2.3 Hz), 4.65 (1H, d, J¼3.4 Hz), 5.03 (1H, d,
90 MHz)
d
: ꢁ96.5 (1F, s); MS m/z¼371 (Mþ); HRMS (EI) calcd for
J¼14.7 Hz), 6.90e6.96 (3H, m), 7.18e7.20 (2H, m), 7.29e7.33 (6H,
C24H18FNO2: 371.132 (Mþ), found: 375.132 (Mþ); IR (KBr) cmꢁ1
1770, 699.
:
m), 7.43e7.44 (3H, m); 13C NMR (CDCl3, 100 MHz)
d: 44.3 (d,
J¼2 Hz), 55.2, 68.6 (d, J¼25 Hz), 102.0 (d, J¼225 Hz), 110.1 (d,
J¼8 Hz), 115.2 (d, J¼2 Hz), 117.1 (d, J¼8 Hz), 128.0, 128.1, 128.5, 128.6,
128.8, 129.0, 129.8, 132.0, 134.4, 135.5 (d, J¼23 Hz), 159.7, 164.6 (d,
5.6.16. anti-1-Benzyl-3-fluoro-3-(1-methyl-1H-indol-5-yl)-4-pheny-
lazetidin-2-one (2p). The titled product (2p) was prepared using
NiCl2$DME (33 mg, 0.15 mmol), ligand 3a (60 mg, 0.18 mmol), THF
(30 mL),1a (1.0 g, 3 mmol), and the corresponding Grignard reagent
(4.5 mmol). The crude product was purified by column chroma-
tography (eluted with AcOEt/hexane¼1:9/1:3) and was obtained
as a colorless solid (299 mg, 26%); mp 127.0e128.5 ꢀC; 1H NMR
J¼24 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ103.7 (1F, s); MS m/z¼361
d
(Mþ); HRMS (EI) calcd for C23H20FNO2: 361.148 (Mþ), found:
361.148 (Mþ); IR (neat) cmꢁ1: 1770, 700.
5.6.12. anti-1-Benzyl-3-(3-chlorophenyl)-3-fluoro-4-phenylazetidin-
2-one (2l). The titled product (2l) was purified by column chro-
matography (AcOEt/hexane¼1:9) and was obtained as a colorless
oil (136 mg, 74%) Two equivalents of the Grignard reagent was used;
(CDCl3, 400 MHz)
d
: 3.79 (3H, s), 3.99 (1H, dd, J¼14.8, 2.3 Hz), 4.77
(1H, d, J¼3.3 Hz), 5.04 (1H, d, J¼14.8 Hz), 6.49 (1H, d, J¼3.1 Hz), 7.09
(1H, d, J¼3.1 Hz), 7.13e7.16 (2H, m), 7.25e7.45 (10H, m), 7.79 (1H,
1H NMR (CDCl3, 400 MHz)
d
: 3.97 (1H, dd, J¼14.7, 2.3 Hz), 4.61 (1H,
d, J¼3.5 Hz), 5.03 (1H, d, J¼14.7 Hz), 7.18e7.26 (3H, m), 7.30e7.43
(8H, m), 7.44e7.46 (3H, m); 13C NMR (CDCl3, 100 MHz)
: 44.4 (d,
m); 13C NMR (CDCl3, 100 MHz)
d: 32.9, 44.1 (d, J¼2 Hz), 68.6 (d,
J¼26 Hz),101.5,102.7 (d, J¼224 Hz),109.6,118.9 (d, J¼7 Hz),119.2 (d,
J¼5 Hz), 124.9 (d, J¼23 Hz), 127.8, 128.0, 128.1 (d, J¼2 Hz), 128.4,
128.6, 128.7, 128.8, 129.7, 132.6, 134.4, 136.8 (d, J¼2 Hz), 165.5 (d,
d
J¼2 Hz), 68.5 (d, J¼25 Hz), 101.4 (d, J¼226 Hz), 123.1 (d, J¼8 Hz),
125.2 (d, J¼7 Hz), 128.1 (d, J¼1 Hz), 128.2, 128.5, 128.5, 128.7, 128.9,
129.2, 129.4 (d, J¼2 Hz), 130.1, 131.6, 134.2, 134.8, 136.0 (d, J¼24 Hz),
J¼25 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ93.2 (1F, s); MS m/z¼384
d
(Mþ); HRMS (EI) calcd for C25H21FN2O: 384.164 (Mþ), found:
164.1 (d, J¼24 Hz); 19F NMR (CDCl3, 90 MHz)
: ꢁ104.4 (1F, s); MS m/
d
384.164 (Mþ); IR (KBr) cmꢁ1: 1755, 695.
z¼365 (Mþ); HRMS (EI) calcd for C22H17ClFNO: 365.098 (Mþ),
found: 365.098 (Mþ, 100%), 367.096 (34); IR (neat) cmꢁ1: 1769, 700.
5.7. Deprotection of the coupling product (2c)
5.6.13. anti-1-Benzyl-3-fluoro-4-phenyl-3-{3-(trifluoromethyl)phe-
nyl}azetidin-2-one (2m). The titled product (2m) was purified by
column chromatography (eluted with AcOEt/hexane¼1:9/1:4)
5.7.1. anti-3-Fluoro-3,4-diphenylazetidin-2-one (4c). This reaction
was carried out under air without inert techniques. anti-3-Fluoro-
1-(4-methoxybenzyl)-3,4-diphenylazetidin-2-one (2c, 190 mg,

A. Tarui et al. / Tetrahedron 69 (2013) 1559e1565
1565
3. (a) Kirk, K. L. Org. Process Res. Dev. 2008, 12, 305e321; (b) Purser, S.; Moore, P.
R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320e330; (c) O’Hagan,
D. J. Fluorine Chem. 2010, 131, 1071e1081.
4. (a) Welch, J. T.; Araki, K.; Kawecki, R.; Wichtowski, J. A. J. Org. Chem. 1993, 58,
2454e2462; (b) Kawecki, R.; Welch, J. T. Tetrahedron Lett. 1993, 34, 3087e3090.
5. Reddy, D. S.; Shibata, N.; Nagai, J.; Nakamura, S.; Toru, T.; Kanemasa, S. Angew.
Chem., Int. Ed. 2008, 47, 164e168.
0.52 mmol) were added to a flask equipped with a stir bar. To the
flask was added CH3CN/H2O (10 mL 9:1) and cooled to 0 ꢀC. Finally,
cerium ammonium nitrate (855 mg, 1.56 mmol) was added one
portion and the mixture was stirred at ambient temperature for
16 h. The reaction was quenched by aqueous saturated NaHCO3 and
the mixture was extracted with AcOEt, and then the extract was
washed with aqueous 10% Na2SO3, brine and dried over MgSO4. The
solvent was removed in vacuo and the residue was purified by silica
gel column chromatography (AcOEt/hexane¼3:7) to give 4c
(68 mg, 54%) as a colorless solid; mp 154.0e155.5 ꢀC; 1H NMR
6. For Kumada coupling: (a) Corriu, R. J. P.; Masse, J. P. J. Chem. Soc., Chem. Com-
mun. 1972, 144; (b) Tamao, K.; Sumitani, K.; Kumada, M. J. Am. Chem. Soc. 1972,
94, 4374e4376; (c) Liu, P.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123,
10772e10773; (d) Banno, T.; Hayakawa, Y.; Umeno, M. J. Organomet. Chem.
€
ꢀ
2002, 653, 288e291; (e) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856e13863; (f) Ackermann, L.; Althammer, A. Org. Lett.
2006, 8, 3457e3460; (g) Martin, R.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129,
3844e3845; (h) Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264e1266.
7. For Suzuki coupling: Ludin, P. M.; Fu, G. C. J. Am. Chem. Soc. 2010, 132,
11027e11029.
(CDCl3, 400 MHz)
d
: 4.97 (1H, d, J¼3.9 Hz), 6.60 (1H, br s), 7.41e7.48
(8H, m), 7.55e7.57 (2H, m); 13C NMR (CDCl3, 100 MHz)
d
: 65.7 (m),
103.2 (d, J¼227 Hz), 125.3 (d, J¼7 Hz), 127.2, 128.5, 128.8, 128.9,
129.4 (d, J¼2 Hz), 133.9 (d, J¼23 Hz), 134.1, 165.2 (d, J¼25 Hz); 19F
8. For Negishi coupling: Fischer, C.; Fu, G. C. J. Am. Chem. Soc. 2005, 127,
4594e4595.
9. Ge, S.; Hartwig, J. F. J. Am. Chem. Soc. 2011, 133, 16330e16333.
10. (a) Liu, C.; He, C.; Shi, W.; Chen, M.; Lei, A. Org. Lett. 2007, 9, 5601e5604; (b)
Hama, T.; Liu, X.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2003, 125,
11176e11177.
NMR (CDCl3, 90 MHz)
d
: ꢁ100.9 (1F, m); MS m/z¼241 (Mþ); HRMS
(EI) calcd for C15H12FNO: 241.090 (Mþ), found: 241.090 (Mþ); IR
(KBr) cmꢁ1: 3203, 1759, 1730, 697.
11. Tarui, A.; Kawashima, N.; Sato, K.; Omote, M.; Miwa, Y.; Minami, H.; Ando, A.
Tetrahedron Lett. 2010, 51, 2000e2003.
Supplementary data
12. The Ni catalyst and Ph-BOX ligand 3a are commercially available.
13. Tasler, S.; Lipshutz, B. H. J. Org. Chem. 2003, 68, 1190e1199.
14. CCDC 898418 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge from the Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2012.12.002.
15. Generally, the anti vicinal coupling constant value for small cyclic compounds
(3 or 4 membered rings) is smaller than syn value. This also applies to vicinal
HeF coupling constants. The vicinal HeF coupling constant of 2a was 3.5 Hz.
The vicinal HeF coupling constant on small cyclic rings is described in the
following book: Dorbier, W. R., Jr. Guide to Fluorine NMR for Organic Chemist;
John Wiley & Sons: New Jersey, 2009, pp 46e47.
16. Miao, L.; Haque, I.; Manzoni, M. R.; Tham, W. S.; Chemler, S. R. Org. Lett. 2010,
12, 4739e4741.
17. Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503e2506.
References and notes
1. (a) Nangia, A.; Biradha, K.; Desiraju, G. R. J. Chem. Soc., Perkin Trans. 2 1996,
943e953; (b) Martel, C. C.; Amoroso, A.; Woon, E. C. Y.; Zervosen, A.; Inglis, S.;
Martins, A.; Verlaine, O.; Rydzik, A. M.; Job, V.; Luxen, A.; Joris, B.; Schofield, C.
J.; Dessen, A. ACS Chem. Biol. 2011, 6, 943e951.
2. Galletti, P.; Giacomini, D. Curr. Med. Chem. 2011, 18, 4265e4283.