Asymmetric Synthesis of α-Chloro-α-halo Ketones by Decarboxylative Chlorination of α-Halo-β-ketocarboxylic Acids

Article abstract of DOI:10.1055/s-0039-1690009

Chiral α-chloro-α-fluoro ketones were synthesized by enantio-selective decarboxylative chlorination of α-chloro-β-ketocarboxylic acids in the presence of a chiral amine catalyst. The reaction yielded the corresponding α-chloro-α-fluoro ketones with modera

Full text of DOI:10.1055/s-0039-1690009

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–H
special topic
A
en
K. Kitahara et al.
Special Topic
Synthesis
Asymmetric Synthesis of -Chloro--halo Ketones by Decarboxyl-
ative Chlorination of -Halo--ketocarboxylic Acids
Kazumasa Kitahara
tBu
C1
Haruna Mizutani
tBu
Seiji Iwasa
O
O
C1 (cat.)
NCS
Kazutaka Shibatomi*
0
0
0
0-
0
0
0
1-6
3
6
8-4
8
2
3
CO2H
Cl
R1
R1
*
CO2Et
NH2
– CO2
R2
F
R2
F
Department of Applied Chemistry and Life Science, Toyohashi
University of Technology, 1-1 Hibarigaoka, Tempaku-cho,
Toyohashi 441-8580, Japan
up to 90% ee
9 examples
77–98% yield
tBu
shiba@chem.tut.ac.jp
tBu
Published as part of the Special Topic Halogenation methods
(with a view towards radioimaging applications)
Received: 06.06.2019
Accepted after revision: 05.07.2019
Published online: 23.07.2019
ketones with a chiral primary amine catalyst bearing an
axially chiral binaphthyl backbone (Scheme 1d).6 Subse-
quently, we applied this method to the synthesis of racemic
-chloro--fluoro ketones.7 Based on the aforementioned
works, in this study, we achieved the catalytic enantioselec-
tive synthesis of -chloro--fluoro ketones by decarboxyl-
ative chlorination of -fluoro--ketocarboxylic acids with a
chiral amine catalyst (Scheme 1e).
DOI: 10.1055/s-0039-1690009; Art ID: ss-2019-c0320-st
Abstract Chiral -chloro--fluoro ketones were synthesized by enantio-
selective decarboxylative chlorination of -chloro--ketocarboxylic ac-
ids in the presence of a chiral amine catalyst. The reaction yielded the
corresponding -chloro--fluoro ketones with moderate-to-high enan-
tioselectivity (up to 90% ee). The method was also applied to the syn-
thesis of -bromo--chloro ketones with 90% ee.
a) β-Keto esters3b,5a–d
Key words decarboxylative chlorination, chiral amine catalyst, enantio-
selective synthesis, -ketocarboxylic acids, fluorinated compounds
O
O
chiral Lewis acid (cat.)
[Cl+] and [F+]
CO2R2
CO2R2
R1
R1
*
F
Cl
b) Aldehydes3a,c,5e
Chiral fluorinated compounds have been attracting in-
creasing attention in the field of medicinal chemistry as the
introduction of fluorine atom(s) into biologically active
compounds often modifies their biological activity and/or
pharmacokinetic behavior.1 Therefore, numerous synthetic
methods for chiral fluorinated compounds have been devel-
oped in the past two decades.2 Our research group also de-
veloped some synthetic methods for chiral fluorinated
compounds.3,4 One such distinctive method is the asym-
metric synthesis of -chloro--fluorocarbonyl com-
pounds3,5 and the subsequent SN2 reaction of the chlorine
atom to yield the corresponding -fluoro--heteroatom-
substituted carbonyl compounds without loss of enantio-
purity. We have developed catalytic methods for the asym-
metric synthesis of -chloro--fluoro--keto esters3b and
-chloro--fluoroaldehydes3a,c with high enantioselectivity
(Scheme 1a,b). A catalytic version of enantioselective syn-
thesis of -chloro--fluoro ketones has not been achieved
yet, although the synthesis was achieved by chlorination of
-fluorosilyl enolate with a stoichiometric amount of a chi-
ral chlorinating reagent (Scheme 1c).3a Recently, our re-
search group has achieved the enantioselective decarboxyl-
ative chlorination of -ketocarboxylic acids to yield -chloro
chiral amine (cat.)
[F+]
R
R
*
O
O
F
Cl
Cl
c) Ketones3a
OSi
O
chiral chlorinating reagent
F
F
R1
R1
Cl
*
R2
R2
d) Our recent work (asymmetric decarboxylative chlorination)6a
O
O
chiral amine (cat.)
[Cl+]
CO2H
Cl
*
R1
R1
R2 R3
R2 R3
e) This work
O
O
chiral amine (cat.)
[Cl+]
CO2H
Cl
*
R1
R1
R2
F
R2
F
Scheme 1 Synthetic methods for -chloro--fluorocarbonyl com-
pounds
First, -fluoro--ketocarboxylic acids 2 were synthe-
sized from the corresponding tert-butyl -fluoro--keto es-
ters 1 (Table 1). Treatment of -keto esters 1 with 20 equiv-
alents of trifluoroacetic acid in dichloromethane yielded
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H
Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B
K. Kitahara et al.
Special Topic
Synthesis
the corresponding -ketocarboxylic acids 2 in good-to-high
yields. Some carboxylic acids 2 were obtained as a mixture
with 1–4% of decarboxylated product after purification by
silica gel column chromatography because they sponta-
neously decomposed by releasing carbon dioxide at ambi-
ent temperature.
sults,6 we chose chiral primary amine C1 as the catalyst and
N-chlorosuccinimide (NCS) as the chlorination reagent. The
reaction of 2a in toluene successfully yielded the corre-
sponding -chloro--fluoro ketone 3a with an enantiose-
lectivity of 78% ee at room temperature (Table 2, entry 1).
The reaction at lower temperature significantly increased
the enantioselectivity to 90% ee (entries 2, 3). We then
screened the substrate scope of the reaction at 0 °C. Conse-
Table 1 Synthesis of -Fluoro--ketocarboxylic Acidsa
O
O
Table 2 Substrate Scopea
CO2tBu
trifluoroacetic acid (20 equiv)
CH2Cl2, 25 °C, time
CO2H
R1
R1
R2
F
R2
F
Ar
1
2
O
O
CO2Et
NH2
C1 (10 mol%)
NCS (1.5 equiv)
CO2H
Cl
Yield (%)b
72
R1
R1
*
Entry
1
Product
Time (min)
80
R2
F
R2
F
toluene, temp, time
O
Ar
2
3
CO2H
F
C1: Ar = 3,5-(tBu)2C6H3
2a
2b
2c
Entry Product
Temp (°C) Time (h) Yield (%)b ee (%)c
O
O
CO2H
1
2
3
Cl
r.t.
0
13
63
240
95
98
95
78
86
90
Cl
2
3
90
50
86
62
F
3a
3b
3c
F
–10
O
O
O
O
Cl
Cl
CO2H
4
0
62
95
86
83
44
F
F
O
O
CO2H
F
4
5
6
2d
2e
2f
90
60
60
80
92
62
5
–20
120
Cl
Br
O
F
O
CO2H
F
Ph
Cl
6
3d
3e
3f
0
0
0
17
89
82
79
36
13
33
Me
F
Br
O
O
CO2H
F
Cl
Ph
7
132
12
Ph
F
Ph
Me
O
CO2H
F
O
Cl
7
8
9
2g
2h
2i
60
90
90
85
71
85
Ph
8
Ph
F
Ph
Ph
O
O
CO2H
F
Cl
Me
9
3g
3h
3i
0
0
0
27
15
17
81
77
79
29
45
2
Ph
F
Ph
Ph
O
CO2H
F
O
O
Cl
Me
10
11
Me
Me
F
Ph
Ph
a Reactions were performed with 20 equiv of trifluoroacetic acid at 25 °C in
CH2Cl2.
Cl
b Isolated yield.
F
Ph
Subsequently, the resulting -fluoro--ketocarboxylic
acids 2 were subjected to enantioselective decarboxylative
chlorination with an electrophilic chlorinating reagent and
a chiral amine catalyst. Based on our previous research re-
a Reactions were performed using 1.5 equiv of NCS and 10 mol% of chiral
amine catalyst C1 in toluene at 0 °C, unless otherwise noted.
b Isolated yield.
c Determined via chiral HPLC analysis.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

C
K. Kitahara et al.
Special Topic
Synthesis
quently, high enantioselectivity was observed in the reac-
tion with tetralone- and 4-chromanone-derived -fluoro-
-ketocarboxylic acids 2a and 2b (entries 1–4), whereas
poor-to-moderate enantioselectivity was observed in the
reaction with indanone-derived substrates 2c,d and acyclic
substrates 2e–i (entries 5–11). It was reported that the re-
sulting chiral -chloro--fluoro ketones 3 could be convert-
ed into -fluoro--heteroatom-substituted ketones by the
SN2 reaction of the chlorine atom.3a
This method was also applied to the enantioselective
synthesis of -bromo--chloro ketone 6. -Bromo--keto
ester 4 was treated with 20 equivalents of trifluoroacetic
acid to yield -bromo--ketocarboxylic acid 5 in 74% yield.
Enantioselective chlorination of 5 with C1 and NCS afforded
the desired product 6 in 98% yield with enantioselectivity
of 90% ee (Scheme 2).
fluoro ketones and -fluoro--sulfenyl ketones without loss
of enantiopurity by the SN2 reaction at the chlorine atom.
Thus, the method enables the flexible synthesis of chiral -
fluoro--heteroatom-substituted ketones, which would be
useful in the preparation of biologically relevant molecules.
All reactions were performed in dried glassware under an argon at-
mosphere and stirring using magnetic stir-plates. TLC analysis was
performed using pre-coated silica gel plates with a fluorescent indica-
tor (F254) (Merck Millipore, Darmstadt, Germany). Visualization was
accomplished using UV light (254 nm), phosphomolybdic acid, or
p-anisaldehyde. Flash column chromatography was performed using
silica gel 60 (mesh size 40–100) supplied by Kanto Chemical Co., Inc.
(Tokyo, Japan). 1H, 13C, and 19F NMR spectra were recorded on a
JNM-ECX 500 (500 MHz 1H, 126 MHz 13C, 470 MHz 19F) instrument
(JEOL Ltd., Tokyo, Japan). Chemical shift values () are reported in
ppm (TMS:  = 0.00 or residual MeOH:  = 3.30 for 1H; hexafluoroben-
zene:  = −162.2 for 19F; residual CHCl3:  = 77.0 or MeOH:  = 49.0 for
13C). All 13C NMR spectra were recorded with 1H-decoupling. IR spec-
tra were recorded on an FT/IR-4600 instrument (JASCO Co., Ltd., To-
kyo, Japan). Direct analysis in real time (DART) mass (positive mode)
analysis was performed on a JMS-T100TD time-of-flight mass spec-
trometer (JEOL Ltd.). Melting points were recorded on a YANACO MP-
500P micro melting point apparatus (Japan). Optical rotations were
measured on a P-1030 digital polarimeter (JASCO Co., Ltd.). Analytical
high-performance liquid chromatography (HPLC) was performed on a
PU1586 instrument with an MD-2018 plus diode array detector
(JASCO Co., Ltd.). The enantiomeric purity of the compounds was de-
termined through HPLC analysis using chiral stationary phase col-
umns.
O
O
trifluoroacetic acid
(20 equiv)
CO2tBu
CO2H
Br
Br
CH2Cl2, 25 °C, 60 min
4
5: 74% yield
O
C1 (10 mol%)
NCS (1.5 equiv)
Cl
Br
*
6: 98% yield
90% ee
toluene, –20 °C, 46 h
Scheme 2 Asymmetric synthesis of -bromo--chloro ketone 6
The proposed reaction mechanism of enantioselective
decarboxylative chlorination is shown in Scheme 3. Chiral
amine catalyst C1 promotes decarboxylation from a carbox-
yl group to form chiral ammonium enolate intermediate,
which is trapped by electrophilic chlorinating reagent faster
than protonation to yield the corresponding -chloro--
fluoro ketone 3.
Commercial-grade reagents and solvents were used without further
purification unless otherwise noted. Anhyd DMF and Et3N were pur-
chased from Sigma-Aldrich (St. Louis, MO, USA). Anhyd toluene,
CH2Cl2, and THF were purchased from Kanto Chemical Co., Inc. and
used after purification using a Glass Contour solvent dispensing sys-
tem (Pure Process Technology, Nashua, NH). For the synthesis of -al-
kyl--keto esters, see the Supporting Information. Chiral primary
amine C1 was prepared by following the reported method.6b
O
O
H3N
H
*
R1
O
EtO2C
F
O
-Alkyl--fluoro--keto Esters 1
–
CO2
R2
F
R1
H2N
EtO2C
-Alkyl--fluoro--keto esters 1 were prepared by following the Gen-
eral Procedure A (→ 1a–e, 1g, 1i) or General Procedure B (→ 1f, 1h).
1H NMR spectra of -alkyl--fluoro--keto esters 1a,8 1c,8 1d,9 1e,10
1g,11 and 1i4f were in good agreement with those reported in the lit-
erature.
2
*
R2
[Cl+]
*
C1
=
O
EtO2C NH2
Cl
R1
*
General Procedure A
R2
F
3
The respective -alkyl--keto ester (1.32 mmol) was added to a
stirred suspension of NaH (60% in oil, washed with hexane and dried
in vacuo, 35 mg, 1.45 mmol, 1.1 equiv) in THF (6.7 mL) at 0 °C, and the
mixture was stirred at 0 °C for 30 min and then at r.t. for 30 min. Sub-
sequently, N-fluorobenzenesulfonimide (NFSI) (1.1 equiv, 1.45 mmol)
was added, and the reaction mixture was stirred at 0 °C for 45 min.
The mixture was quenched by adding sat. aq NH4Cl at 0 °C, and then
extracted with CH2Cl2. The combined extracts were dried (anhyd
Na2SO4), concentrated, and the residue purified by flash column
chromatography on silica gel (hexane/EtOAc 7:1) to yield the desired
-alkyl--fluoro--keto ester.
Scheme 3 Proposed reaction mechanism
In conclusion, we have achieved the catalytic enantiose-
lective synthesis of -chloro--fluoro ketones 3 for the first
time by the chiral amine-catalyzed decarboxylative chlori-
nation of -fluoro--ketocarboxylic acids. -Bromo--
chloro ketone 6 was also synthesized using this method
with high enantioselectivity. It is known that the resulting
-chloro--fluoro ketones can be converted into -azido--
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

D
K. Kitahara et al.
Special Topic
Synthesis
General Procedure B
HRMS (DART): m/z [M + NH4]+ calcd for C14H21FO3N: 270.1506; found:
270.1507.
The respective -alkyl--keto ester (2 mmol) was added to a suspen-
sion of NaH (60% in oil, washed with hexane and dried in vacuo, 53
mg, 2.2 mmol, 2.2 equiv) in THF (10 mL for 1f, 6 mL for 1h) at 0 °C.
The mixture was stirred at r.t. for 20 min. Subsequently, the mixture
was diluted with DMF (10 mL), SelectfluorTM (1.1 equiv, 2.2 mmol)
was added at 0 °C, and stirred for 14 h. After the addition of H2O, the
aqueous layer was extracted with Et2O. The combined extracts were
dried (anhyd NaSO4), concentrated, and the residue purified by flash
column chromatography on silica gel (hexane/EtOAc 10:1) to yield the
desired -alkyl--fluoro--keto ester.
-Fluoro--ketocarboxylic Acids 2
-Fluoro--ketocarboxylic acids 2 were synthesized by acidolysis of
the corresponding -fluoro--keto esters 1. 1H NMR spectra of -fluo-
ro--ketocarboxylic acids 2a,7 2g,7 and 2i7 were in good agreement
with those reported in the literature. Melting point of the resulting
carboxylic acids was not measured because of their thermal instabili-
ty.
6-Chloro-3-fluoro-4-oxochromane-3-carboxylic Acid (2b); Typical
Procedure
tert-Butyl 6-Chloro-3-fluoro-4-oxochromane-3-carboxylate (1b)
Prepared by following the General Procedure A; yield: 329 mg (83%);
white solid; Rf = 0.45 (hexane/EtOAc 4:1); mp 86.0 °C.
Trifluoroacetic acid (2.4 g, 21.1 mmol, 20 equiv) was added to a
stirred solution of -alkyl--fluoro--keto ester 1b (315 mg, 1.05
mmol) in CH2Cl2 (5.3 mL) at 0 °C, and the reaction mixture was stirred
at r.t. for 90 min. The mixture was concentrated, and then purified by
flash column chromatography on silica gel (hexane/Et2O 4:1 to 1:2) to
yield 2b; yield: 222 mg (86%); white solid; Rf = 0.09 (CH2Cl2/MeOH
9:1).
IR (NaCl): 2982, 2935, 1762, 1704, 1606, 1475, 1422, 1288, 1156,
1117, 1099, 832, 640 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.90 (d, J = 2.7 Hz, 1 H, HAr), 7.51 (dd,
J = 8.8, 2.7 Hz, 1 H, HAr), 7.01 (d, J = 8.8 Hz, 1 H, HAr), 4.76 (dd, J = 21.8,
12.6 Hz, 1 H, CHH′), 4.61 (dd, J = 12.6, 9.5 Hz, 1 H, CHH′), 1.47 (s, 9 H,
C3H9).
13C NMR (CDCl3, 126 MHz):  = 182.5 (d, J = 20.4 Hz, CO), 163.6 (d,
J = 24.0 Hz, COO), 159.3 (CAr), 136.9 (CAr), 128.0 (CAr), 127.0 (CAr), 120.2
(CAr), 119.7 (CAr), 88.5 (d, J = 197.9 Hz, CF), 85.3 (CH2), 70.4 (d, J = 26.4
Hz, CC3H9), 27.8 (C3H9).
IR (NaCl): 3626, 3414, 1714, 1667, 1473, 1267, 1212, 1109, 900, 818,
637 cm–1
.
1H NMR (CD3OD, 500 MHz):  = 7.79 (d, J = 2.7 Hz, 1 H, HAr), 7.55 (dd,
J = 8.8, 2.3 Hz, 1 H, HAr), 7.06 (d, J = 8.8 Hz, 1 H, HAr), 4.86–4.73 (m, 2 H,
CH2).
13C NMR (CD3OD, 126 MHz):  = 183.7 (d, J = 20.4 Hz, CO), 167.5 (d,
J = 25.2 Hz, COO), 161.0 (CAr), 138.0 (CAr), 128.8 (CAr), 127.5 (CAr), 121.2
(CAr), 121.1 (CAr), 90.3 (d, J = 195.5 Hz, CF), 71.6 (d, J = 26.4 Hz, CH2).
19F NMR (CDCl3, 470 MHz):  = –173.7 (d, J = 22.0 Hz).
HRMS (DART): m/z [M + NH4]+ calcd for C14H18ClFO4N: 318.0908;
found: 318.0906.
19F NMR (CD3OD, 470 MHz):  = –182.5 (s).
tert-Butyl 2-Fluoro-3-oxo-2,3-diphenylpropanoate (1f)
HRMS (DART): m/z [M + NH4]+ calcd for C10H10ClFO4N: 262.0282;
found: 262.0285.
Prepared by following the General Procedure B; yield: 346 mg (55%);
colorless oil; Rf = 0.36 (hexane/EtOAc 10:1).
2-Fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylic Acid (2c)
IR (NaCl): 3064, 2980, 2935, 1749, 1696, 1597, 1449, 1371, 1261,
1153, 1071, 751, 698, 614, 410 cm–1
.
Following the Typical Procedure, 1c (312 mg, 1.25 mmol) was used
and the product was purified by flash column chromatography on sil-
ica gel (hexane/Et2O 4:1 to 1:5); yield: 151 mg (62%); pale purple sol-
id; Rf = 0.14 (CH2Cl2/MeOH 5:1).
1H NMR (CDCl3, 500 MHz):  = 7.98 (d, J = 8.0 Hz, 2 H, HAr), 7.59–7.57
(m, 2 H, HAr), 7.49–7.46 (t, J = 7.4 Hz, 1 H, HAr), 7.40–7.33 (m, 5 H, HAr),
1.42 (s, 9 H, C3H9).
IR (NaCl): 3462, 2961, 2917, 2848, 1721, 1605, 1268, 1200, 923, 660
13C NMR (CDCl3, 126 MHz):  = 191.0 (d, J = 26.4 Hz, CO), 165.0 (d,
J = 26.4 Hz, COO), 133.7 (CAr), 133.5 (CAr), 129.6 (d, J = 22.8 Hz, CAr),
128.9 (CAr), 128.2 (CAr), 128.0 (CAr), 125.5 (d, J = 8.4 Hz, CAr), 98.4 (d,
J = 199.1 Hz, CF), 84.2 (CC3H9), 27.4 (C3H9).
19F NMR (CDCl3, 470 MHz):  = –156.3 (s).
HRMS (DART): m/z [M + NH4]+ calcd for C19H23FO3N: 332.01662;
cm–1
.
1H NMR (CD3OD, 500 MHz):  = 7.78–7.72 (m, 2 H, HAr), 7.58 (d, J = 7.6
Hz, 1 H, HAr), 7.48 (t, J = 7.6 Hz, 1 H, HAr), 3.80 (dd, J = 17.6, 10.7 Hz, 1
H, CHH′), 3.41 (dd, J = 23.3, 17.6 Hz, 1 H, CHH′).
13C NMR (CD3OD, 126 MHz):  = 197.7 (d, J = 18.0 Hz, CO), 170.3 (d,
J = 28.8 Hz, COO), 152.9 (d, J = 4.8 Hz, CAr), 138.0 (CAr), 134.6 (CAr),
129.7 (CAr), 128.0 (CAr), 126.0 (CAr), 95.8 (d, J = 197.9 Hz, CF), 39.2 (d,
J = 25.2 Hz, CH2).
found: 332.1663.
tert-Butyl 2-Fluoro-3-oxo-2-phenylbutanoate (1h)
19F NMR (CD3OD, 470 MHz):  = –172.4 (d, J = 14.7 Hz).
HRMS (DART): m/z [M + NH4]+ calcd for C10H11FO3N: 212.0723; found:
Prepared by following the General Procedure B; yield: 415 mg (82%);
colorless oil; Rf = 0.41 (hexane/EtOAc 10:1).
212.0721.
IR (NaCl): 2981, 2935, 1728, 1450, 1371, 1356, 1277, 1155, 1069, 838,
756, 697, 566 cm–1
.
5-Bromo-2-fluoro-1-oxo-2,3-dihydro-1H-indene-2-carboxylic
Acid (2d)
1H NMR (CDCl3, 500 MHz):  = 7.55–7.53 (m, 2 H, HAr), 7.43–7.39 (m,
3 H, HAr), 2.29 (d, J = 5.0 Hz, 3 H, CH3), 1.50 (s, 9 H, C3H9).
13C NMR (CDCl3, 126 MHz):  = 200.1 (d, J = 29.0 Hz, CO), 164.2 (d,
J = 25.2 Hz, COO), 132.7 (d, J = 21.6 Hz, CAr), 128.9 (CAr), 128.1 (CAr),
125.3 (d, J = 9.6 Hz, CAr), 98.6 (d, J = 199.1 Hz, CF), 84.1 (CC3H9), 27.5
(C3H9), 25.2 (CH3).
Following the Typical Procedure, 1d (228 mg, 0.693 mmol) was used
and the product was purified by flash column chromatography on sil-
ica gel (hexane/Et2O 4:1 to 1:5); yield: 152 mg (80%); white solid;
Rf = 0.35 (CH2Cl2/MeOH 5:1).
IR (NaCl): 3486, 2361, 2340, 1725, 1593, 1267, 1210, 1057, 923, 668,
19F NMR (CDCl3, 470 MHz):  = –161.9 (s).
491 cm–1
.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

E
K. Kitahara et al.
Special Topic
Synthesis
1H NMR (CD3OD, 500 MHz):  = 7.82 (s, 1 H, HAr), 7.68–7.65 (m, 2 H,
HAr), 3.80 (dd, J = 18.0, 9.9 Hz, 1 H, CHH′), 3.42 (dd, J = 23.3, 18.0 Hz, 1
H, CHH′).
19F NMR (CDCl3, 470 MHz):  = –163.9 (s).
HRMS (DART): m/z [M + NH4]+ calcd for C10H13FO3N: 214.0880; found:
214.0880.
13C NMR (CD3OD, 126 MHz):  = 196.5 (d, J = 19.2 Hz, CO), 169.8 (d,
J = 28.8 Hz, COO), 154.4 (d, J = 4.8 Hz, CAr), 133.6 (CAr), 133.3 (CAr),
133.1 (CAr), 131.3 (CAr), 127.3 (CAr), 95.7 (d, J = 199.1 Hz, CF), 38.9 (d,
J = 24.0 Hz, CH2).
-Chloro--fluoro Ketones 3
Enantioselective decarboxylative chlorination of 2 was performed by
following the Typical Procedure described below. A few starting com-
pounds 2 contained 1–4% of decarboxylated product before use.
19F NMR (CD3OD, 470 MHz):  = –173.8 (d, J = 22.0 Hz).
HRMS (DART): m/z [M + NH4]+ calcd for C10H10BrFO3N: 289.9828;
found: 289.9828.
3,6-Dichloro-3-fluorochroman-4-one (3b); Typical Procedure
-Fluoro--ketocarboxylic acid 2b (74 mg, 0.303 mmol) was added to
a stirred solution of C1 (10 mol%, 0.0303 mmol) and NCS (1.5 equiv,
0.455 mmol) in toluene (1.5 mL). The reaction mixture was stirred at
0 °C for 62 h. Then, the mixture was directly subjected to flash col-
umn chromatography on silica gel (hexane/CH2Cl2 2:1 then hex-
ane/EtOAc 20:1) to give 3b; yield: 67.7 mg (95%, 83% ee); white solid;
Rf = 0.27 (hexane/CH2Cl2 2:1); mp 71.9 °C; []D27.7 +71.38 (c 1.28, CH-
Cl3).
2-Fluoro-2-methyl-3-oxo-3-phenylpropanoic Acid (2e)
Following the Typical Procedure, 1e (300 mg, 1.19 mmol) was used
and the product was purified by flash column chromatography on sil-
ica gel (hexane/Et2O 4:1 to 1:2); yield: 214 mg (92%), including 1% of
decarboxylated product; colorless oil; Rf = 0.20 (CH2Cl2/MeOH 5:1).
IR (NaCl): 3513, 3072, 1697, 1597, 1449, 1271, 1132, 981, 698, 657,
535, 431, 423 cm–1
.
HPLC: DAICEL CHIRALCEL OJ–H (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(500:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 24.9 min (minor),
tR = 42.8 min (major).
1H NMR (CDCl3, 500 MHz):  = 11.2 (s, 1 H, CO2H), 8.06–8.04 (m, 2 H,
HAr), 7.60–7.56 (m, 1 H, HAr), 7.46–7.42 (m, 2 H, HAr), 1.90 (d, J = 22.5
Hz, 3 H, CH3).
13C NMR (CDCl3, 126 MHz):  = 191.6 (d, J = 24.0 Hz, CO), 173.4 (d,
J = 25.2 Hz, COO), 134.2 (CAr), 132.9 (d, J = 3.6 Hz, CAr), 129.8 (d, J = 4.8
Hz, CAr), 128.7 (CAr), 96.9 (d, J = 197.9Hz, CF), 21.1 (d, J = 22.8 Hz, CH3).
IR (NaCl): 3082, 2921, 2860, 1713, 1604, 1476, 1424, 1280, 1213,
1114, 1051, 654, 443, 426 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.94 (d, J = 2.3 Hz, 1 H, HAr), 7.55 (ddd,
J = 9.0, 2.7, 1.0 Hz, 1 H, HAr), 7.05 (d, J = 8.8 Hz, 1 H, HAr), 4.70–4.63 (m,
2 H, CH2).
13C NMR (CDCl3, 126 MHz):  = 179.5 (d, J = 21.6 Hz, CO), 158.6 (CAr),
137.4 (CAr), 128.8 (CAr), 127.7 (CAr), 119.9 (CAr), 118.5 (CAr), 99.9 (d,
J = 256.7 Hz, CF), 72.8 (d, J = 31.2 Hz, CH2).
19F NMR (CDCl3, 470 MHz):  = –153.0 (q, J = 22.0 Hz).
HRMS (DART): m/z [M + NH4]+ calcd for C10H13FO3N: 214.0880; found:
214.0881.
2-Fluoro-3-oxo-2,3-diphenylpropanoic Acid (2f)
19F NMR (CDCl3, 470 MHz):  = –136.0 (s).
HRMS (DART): m/z [M + NH4]+ calcd for C9H9Cl2FO2N: 251.9994;
Following the Typical Procedure, 1f (345 mg, 1.10 mmol) was used
and the product was purified by flash column chromatography on sil-
ica gel (hexane/Et2O 4:1 to 1:4); yield: 175 mg (62%); white solid;
Rf = 0.1 (CH2Cl2/MeOH 9:1).
found: 251.9997.
2-Chloro-2-fluoro-3,4-dihydronaphthalen-1(2H)-one (3a)
IR (NaCl): 3020, 2830, 1731, 1684, 1446, 1278, 1228, 1069, 887, 696,
676, 563 cm–1
.
Following the Typical Procedure, 2a (30 mg, 0.146 mmol) was used
and the reaction was carried out at –20 °C for 10 d, and the product
was purified by flash column chromatography on silica gel (hex-
1H NMR (CD3OD, 500 MHz):  = 7.93 (d, J = 7.6 Hz, 2 H, HAr), 7.56–7.52
(m, 3 H, HAr), 7.41–7.39 (m, 5 H, HAr).
13C NMR (CD3OD, 126 MHz):  = 192.8 (d, J = 26.4 Hz, CO), 169.4 (d,
J = 26.4 Hz, COO), 135.5 (d, J = 21.6 Hz, CAr), 135.0 (CAr), 134.9 (d,
J = 3.6 Hz, CAr), 130.9 (d, J = 4.8 Hz, CAr), 130.2 (CAr), 129.6 (CAr), 129.4
(CAr), 126.8 (d, J = 8.4 Hz, CAr), 100.1 (d, J = 197.9 Hz, CF).
ane/Et2O 10:1 to 5:1); yield: 27.6 mg (95%, 90% ee); white solid;
27.8
Rf = 0.36 (hexane/CH2Cl2 2:1); mp 75.4 °C; []D
+74.96 (c 1.49,
CHCl3).
HPLC: DAICEL CHIRALCEL OB–H (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(9:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 9.5 min (major),
tR = 11.3 min (minor).
19F NMR (CD3OD, 470 MHz):  = –162.7 (d, J = 22.0 Hz).
HRMS (DART): m/z [M + NH4]+ calcd for C15H15FO3N: 276.1036; found:
IR (NaCl): 2922, 2852, 1709, 1603, 1455, 1306, 1227, 1136, 1038, 932,
829, 731, 654 cm–1
.
276.1035.
1H NMR (CDCl3, 500 MHz):  = 8.13 (dd, J = 8.0, 1.2 Hz, 1 H, HAr), 7.58
(dt, J = 7.6, 1.2 Hz, 1 H, HAr), 7.40 (t, J = 7.6 Hz, 1 H, HAr), 7.30 (d, J = 7.6
Hz, 1 H, HAr), 3.35 (ddd, J = 17.0, 12.0, 4.2 Hz, 1 H, PhCHH′), 3.12
(quintd, J = 17.2, 2.3 Hz, 1 H, PhCHH′), 2.84–2.78 (m, 1 H, CHH′), 2.74–
2.67 (m, 1 H, CHH′).
13C NMR (CDCl3, 126 MHz):  = 185.3 (d, J = 21.6 Hz, CO), 142.0 (CAr),
134.8 (CAr), 129.1 (CAr), 128.8 (CAr), 128.8 (CAr), 127.5 (CAr), 105.2 (d,
J = 256.7 Hz, CF), 37.2 (d, J = 20.4 Hz, PhCH2), 26.9 (d, J = 7.2 Hz, CH2).
2-Fluoro-3-oxo-2-phenylbutanoic Acid (2h)
Following the Typical Procedure, 1h (302 mg, 1.20 mmol) was used
and the product was purified by flash column chromatography on sil-
ica gel (hexane/Et2O 4:1 to 1:2); yield: 167 mg (71%), including 4% of
protonated product; colorless oil; Rf = 0.36 (CH2Cl2/MeOH 5:1).
IR (NaCl): 3504, 3064, 1735, 1686, 1596, 1449, 1259, 1212, 1186,
1070, 696, 663 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 10.67 (s, 1 H, COOH), 7.57–7.55 (m, 2
H, HAr), 7.42–7.40 (m, 3 H, HAr), 2.32 (d, J = 5.0 Hz, 3 H, CH3).
13C NMR (CDCl3, 126 MHz):  = 200.3 (d, J = 28.8 Hz, CO), 169.9 (d,
J = 26.4 Hz, COO), 131.7 (d, J = 21.6 Hz, CAr), 129.7 (CAr), 128.6 (CAr),
125.1 (d, J = 9.6 Hz, CAr), 98.2 (d, J = 200.3 Hz, CF), 25.3 (CH3).
19F NMR (CDCl3, 470 MHz):  = –116.8 (s).
HRMS (DART): m/z [M + NH4]+ calcd for C10H12ClFON: 216.0591;
found: 216.0590.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

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K. Kitahara et al.
Special Topic
Synthesis
2-Chloro-2-fluoro-2,3-dihydro-1H-inden-1-one (3c)
19F NMR (CDCl3, 470 MHz):  = –106.7 (q, J = 22.0 Hz).
HRMS (DART): m/z [M + H]+ calcd for C9H9ClFO: 187.0326; found:
187.0324.
Following the Typical Procedure, 2c (50 mg, 0.266 mmol) was used
and the reaction was performed at –20 °C for 5 d. The product was
purified by flash column chromatography on silica gel (hexane/CH2Cl2
5:1 to 1:1); yield: 42.3 mg (86%, 44% ee); white solid; Rf = 0.24 (hex-
ane/CH2Cl2 2:1); mp 53.5 °C; []D27.7 +11.30 (c 1.06, CHCl3).
2-Chloro-2-fluoro-1,2-diphenylethan-1-one (3f)
Following the Typical Procedure, 2f (93 mg, 0.306 mmol) was used
and the product was purified by flash column chromatography on sil-
ica gel (hexane/CH2Cl2 2:1, then hexane/Et2O 30:1); yield: 59.8 mg
HPLC: DAICEL CHIRALCEL OB–H (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(9:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 19.6 min (minor),
tR = 9.9 min (major).
27.7
(79%, 33% ee); colorless oil; Rf = 0.42 (hexane/CH2Cl2 2:1); []D
+7.99 (c 1.43, CHCl3).
IR (NaCl): 3065, 2963, 2868, 1740, 1611, 1469, 1306, 1217, 1103,
1000, 919, 734, 658, 416 cm–1
.
HPLC: DAICEL CHIRALPAK IA–3 (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(150:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 6.4 min (minor),
tR = 5.9 min (major).
1H NMR (CDCl3, 500 MHz):  = 7.88 (d, J = 7.6 Hz, 1 H, HAr), 7.75 (dt,
J = 7.6, 1.2 Hz, 1 H, HAr), 7.52–7.47 (m, 2 H, HAr), 3.90–3.80 (m, 2 H,
CH2).
13C NMR (CDCl3, 126 MHz):  = 191.6 (d, J = 22.8 Hz, CO), 146.9 (d,
J = 7.8 Hz, CAr), 137.3 (CAr), 131.0 (CAr), 129.0 (CAr), 126.5 (CAr), 126.1
(CAr), 105.9 (d, J = 261.5 Hz, CF), 43.8 (d, J = 24.0 Hz, CH2).
IR (NaCl): 3063, 1703, 1596, 1448, 1238, 1216, 1090, 1017, 877, 817,
744, 694, 631 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.99–7.97 (m, 2 H, HAr), 7.66–7.62 (m,
2 H, HAr), 7.56–7.53 (m, 1 H, HAr), 7.45–7.38 (m, 2 H, HAr).
13C NMR (CDCl3, 126 MHz):  = 188.7 (d, J = 28.8 Hz, CO), 136.4 (d,
J = 22.8 Hz, CAr), 133.8 (CAr), 132.0 (d, J = 2.4 Hz, CAr), 130.6 (d, J = 4.8
Hz, CAr), 130.3 (CAr), 128.7 (CAr), 128.4 (CAr), 125.8 (d, J = 7.2 Hz, CAr),
109.8 (d, J = 255.5 Hz, CF).
19F NMR (CDCl3, 470 MHz):  = –121.0 (s).
HRMS (DART): m/z [M + NH4]+ calcd for C9H10ClFON: 202.0435;
found: 202.0434.
5-Bromo-2-chloro-2-fluoro-2,3-dihydro-1H-inden-1-one (3d)
19F NMR (CDCl3, 470 MHz):  = –107.1 (s).
HRMS (DART): m/z [M + NH4]+ calcd for C14H14ClFON: 266.0748;
found: 266.0749.
Following the Typical Procedure, 2d (82 mg, 0.300 mmol) was used
and the product was purified by flash column chromatography on sil-
ica gel (hexane/CH2Cl2 2:1, then hexane/EtOAc 30:1); yield: 70.2 mg
(89%, 36% ee); white solid; Rf = 0.27 (hexane/EtOAc 30:1); mp
116.5 °C; []D27.6 –13.08 (c 1.06, CHCl3).
2-Chloro-2-fluoro-1,3-diphenylpropan-1-one (3g)
Following the Typical Procedure, 2g (96 mg, 0.354 mmol) and toluene
(3.6 mL) were used, and the product was purified by flash column
chromatography on silica gel (hexane/EtOAc 100:0 to 95:5); yield:
75.8 mg (81%, 29% ee); white solid; Rf = 0.45 (hexane/CH2Cl2 2:1); mp
49.7 °C; []D27.5 +15.01 (c 0.99, CHCl3).
HPLC: DAICEL CHIRALCEL OB–H (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(9:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 16.4 min (minor),
tR = 23.8 min (major).
IR (NaCl): 3078, 3061, 2929, 1735, 1594, 1571, 1423, 1293, 1212,
1186, 1111, 1056, 999, 919, 845, 748, 667, 596 cm–1
.
HPLC: DAICEL CHIRALCEL OD–H (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(500:1), flow rate = 0.5 mL/min,  = 254 nm; tR = 17.2 min (minor),
tR = 19.5 min (major).
1H NMR (CDCl3, 500 MHz):  = 7.75 (d, J = 8.0 Hz, 1 H, HAr), 7.66–7.64
(m, 2 H, HAr), 3.87–3.79 (m, 2 H, CH2).
13C NMR (CDCl3, 126 MHz):  = 190.5 (d, J = 22.8 Hz, CO), 148.3 (d,
J = 4.8 Hz, CAr), 132.9 (CAr), 132.7 (CAr), 129.8 (CAr), 129.8 (CAr), 127.2
(CAr), 105.4 (d, J = 262.7 Hz, CF), 43.4 (d, J = 24.0 Hz, CH2).
19F NMR (CDCl3, 470 MHz):  = –120.6 (d, J = 14.7 Hz).
HRMS (DART): m/z [M + NH4]+ calcd for C9H9BrClFON: 279.9540;
IR (NaCl): 3064, 3033, 2923, 2851, 1697, 1597, 1448, 1264, 1133, 892,
698, 593 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 8.06–8.03 (m, 2 H, HAr), 7.57–7.53 (m,
1 H, HAr), 7.43–7.40 (m, 2 H, HAr), 7.33–7.26 (m, 5 H, HAr), 3.83 (dd,
J = 22.6, 14.5 Hz, 1 H, CHH′), 3.67 (dd, J = 22.2, 14.5 Hz, 1 H, CHH′).
13C NMR (CDCl3, 126 MHz):  = 190.0 (d, J = 30.0 Hz, CO), 133.8 (CAr),
132.6 (CAr), 132.1 (d, J = 3.6 Hz, CAr), 131.2 (CAr), 130.3 (d, J = 4.8 Hz,
CAr), 128.4 (CAr), 128.2 (CAr), 127.6 (CAr), 108.9 (d, J = 262.7 Hz, CF),
45.1 (d, J = 20.4 Hz, CH2).
found: 279.9543.
2-Chloro-2-fluoro-1-phenylpropan-1-one (3e)
Following the Typical Procedure, 2e (66 mg, 0.335 mmol) and toluene
(3.4 mL) was used, and the product was purified by flash column
chromatography on silica gel (pentane/CH2Cl2 100:0 to 25:1); yield:
51.2 mg (82%, 13% ee); colorless oil; Rf = 0.43 (hexane/CH2Cl2 2:1);
[]D not determined because of low enantioselectivity.
19F NMR (CDCl3, 470 MHz):  = –115.4 (t, J = 22.0 Hz).
HRMS (DART): m/z [M + H]+ calcd for C15H13ClFO: 263.0639; found:
263.0641.
HPLC: DAICEL CHIRALCEL OJ–H (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(1000:1), flow rate = 0.5 mL/min,  = 254 nm; tR = 15.2 min (minor),
tR = 14.5 min (major).
1-Chloro-1-fluoro-1-phenylpropan-2-one (3h)
Following the Typical Procedure, 2h (66 mg, 0.335 mmol) and toluene
(3.4 mL) were used, and the product was purified by flash column
chromatography on silica gel (pentane/CH2Cl2 9:1 to 7:3); yield: 48.1
IR (NaCl): 3064, 3001, 2943, 1699, 1599, 1449, 1380, 1282, 1151,
27.5
1081, 984, 893, 807, 705, 653, 541 cm–1
.
mg (77%, 45% ee); colorless oil; Rf = 0.45 (hexane/CH2Cl2 2:1); []D
+285.02 (c 1.02, CHCl3).
1H NMR (CDCl3, 500 MHz):  = 8.18 (m, 2 H, HAr), 7.60 (t, J = 7.5 Hz, 1
H, HAr), 7.47 (t, J = 7.8 Hz, 2 H, HAr), 2.17 (d, J = 20.3 Hz, 3 H, CH3).
13C NMR (CDCl3, 126 MHz):  = 189.2 (d, J = 23.0 Hz, CO), 134.0 (CAr),
131.3 (d, J = 3.6 Hz, CAr), 130.6 (d, J = 6.0 Hz, CAr), 128.4 (CAr), 108.4 (d,
J = 256.7 Hz, CF), 27.3 (d, J = 22.8 Hz, CH3).
HPLC: DAICEL CHIRALPAK IA–3 (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(500:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 5.9 min (minor),
tR = 6.3 min (major).
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

G
K. Kitahara et al.
Special Topic
Synthesis
IR (NaCl): 3063, 1702, 1596, 1448, 1238, 1216, 817, 744, 694, 631 cm–
.
1H NMR (CDCl3, 500 MHz):  = 7.61–7.57 (m, 2 H, HAr), 7.46–7.43 (m,
3 H, HAr), 2.35 (d, J = 3.4 Hz, 3 H, CH3).
13C NMR (CDCl3, 126 MHz):  = 187.8 (CO), 166.0 (COO), 142.2 (CAr),
134.1 (CAr), 129.7 (CAr), 128.8 (CAr), 128.7 (CAr), 127.1 (CAr), 84.1 (CBr),
66.5 (CC3H9), 35.8 (PhCH2), 27.6 (C3H9), 26.9 (CH2).
1
HRMS (DART): m/z [M + NH4]+ calcd for C15H21BrO3N: 342.0705;
found: 342.0704.
13C NMR (CDCl3, 126 MHz):  = 196.8 (d, J = 31.2 Hz, CO), 134.8 (d,
J = 22.8 Hz, CAr), 130.4 (CAr), 128.6 (CAr), 125.9 (d, J = 7.2 Hz, CAr), 108.7
(d, J = 255.5 Hz, CF), 23.7 (CH3).
2-Bromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylic Acid
(5)
19F NMR (CDCl3, 470 MHz):  = –115.8 (s).
Trifluoroacetic acid (2.4 g, 18.4 mmol, 20 equiv) was added to a
stirred solution of 4 (300 mg, 0.919 mmol) in CH2Cl2 (4.6 mL) at 0 °C,
and the reaction mixture was stirred at r.t. for 60 min. The mixture
was concentrated, and then purified by flash column chromatography
on silica gel (hexane/Et2O 4:1 to 1:2) to give 5; yield: 183 mg (74%),
including 2% of protonated product; white solid; Rf = 0.34 (CH2Cl2/
MeOH 5:1).
HRMS (DART): m/z [M + H]+ calcd for C9H9ClFO: 187.0326; found:
187.0327.
3-Chloro-3-fluoro-4-phenylbutan-2-one (3i)
Following the Typical Procedure, 2i (64 mg, 0.306 mmol) and toluene
(3 mL) were used, and the product was purified by flash column chro-
matography on silica gel (hexane/Et2O 10:1 to 5:1 then hexane/EtOAc
100:0 to 92:8); yield: 48.3 mg (79%, 2% ee); colorless oil; Rf = 0.15
(hexane only); []D not determined because of low enantioselectivity.
IR (NaCl): 3509, 2938, 1729, 1682, 1597, 1455, 1428, 1297, 1225, 910,
787, 734 cm–1
.
1H NMR (CD3OD, 500 MHz):  = 8.00 (d, J = 8.0 Hz, 1 H, HAr), 7.55 (t,
J = 6.9 Hz, 1 H, HAr), 7.35 (t, J = 7.6 Hz, 1 H, HAr), 7.32 (d, J = 6.9 Hz, 1 H,
HAr), 3.19–3.13 (m, 1 H, PhCHH′), 3.06–3.03 (m, 1 H, PhCHH′), 2.93–
2.88 (m, 1 H, CHH′), 2.57–2.53 (m, 1 H, CHH′).
HPLC: DAICEL CHIRALCEL OJ–H (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(1000:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 17.2 min (minor),
tR = 38.8 min (major).
IR (NaCl): 3089, 3064, 3033, 2933, 1698, 1597, 1449, 1265, 1134, 941,
13C NMR (CD3OD, 126 MHz):  = 189.6 (CO), 170.2 (COO), 144.2 (CAr),
135.6 (CAr), 130.7 (CAr), 130.1 (CAr), 129.4 (CAr), 128.2 (CAr), 67.0 (CBr),
37.2 (PhCH2), 27.7 (CH2).
HRMS (DART): m/z [M + H]+ calcd for C11H10BrO3: 268.9813; found:
268.9810.
892, 749, 698, 663, 593 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 7.33–7.28 (m, 3 H, HAr), 7.26–7.24 (m,
2 H, HAr), 3.59 (dd, J = 24.9, 14.5 Hz, 1 H, CHH′), 3.50 (dd, J = 19.7, 14.7
Hz, 1 H, CHH′), 2.24 (d, J = 3.8 Hz, 3 H, CH3).
13C NMR (CDCl3, 126 MHz):  = 199.0 (d, J = 32.4 Hz, CO), 132.3 (CAr),
130.8 (CAr), 128.4 (CAr), 127.7 (CAr), 109.3 (d, J = 259.1 Hz, CF), 44.1 (d,
J = 20.4 Hz, CH2), 24.0 (CH3).
2-Bromo-2-chloro-3,4-dihydronaphthalen-1(2H)-one (6)
Amine catalyst C1 (22 mg, 0.0296 mmol, 10 mol%) and NCS (59 mg,
0.444 mmol, 1.5 equiv) were added to a stirred solution of 5 (80 mg,
0.296 mmol) in toluene (1.5 mL) at –20 °C, and the reaction mixture
was stirred for 46 h. The mixture was directly subjected to flash col-
umn chromatography on silica gel (hexane/CH2Cl2 1:1) to give 6;
yield: 75.4 mg (98%, 90% ee); brown solid; Rf = 0.63 (hexane/CH2Cl2
1:1); mp 67.6 °C; []D27.6 –21.45 (c 1.07, CHCl3).
19F NMR (CDCl3, 470 MHz):  = –119.2 (t, J = 22.0 Hz).
HRMS (DART): m/z [M + NH4]+ calcd for C10H14ClFON: 218.0748;
found: 218.0747.
-Bromo--chloro Ketone 6
HPLC: DAICEL CHIRALPAK IA–3 (0.46 cm ϕ × 25 cm); hexane/i-PrOH
(150:1), flow rate = 1.0 mL/min,  = 254 nm; tR = 10.0 min (minor),
tR = 10.8 min (major).
tert-Butyl 2-Bromo-1-oxo-1,2,3,4-tetrahydronaphthalene-2-car-
boxylate (4)
tert-Butyl 1-oxo-1,2,3,4-tetrahydronaphthalene-2-carboxylate (900
mg, 3.65 mmol) was added to a stirred suspension of NaH (60% in oil,
washed with hexane and dried in vacuo, 0.123 g, 5.11 mmol, 1.4
equiv) in THF (20 mL) at 0 °C, and the mixture was stirred at 0 °C for
30 min. Subsequently, NBS (910 mg, 5.11 mmol, 1.4 equiv) was added
in one portion, and the reaction mixture was stirred at r.t. for 30 min.
The mixture was quenched by adding sat. aq NH4Cl at 0 °C, and then
extracted with CH2Cl2. The combined extracts were dried (anhyd
Na2SO4), concentrated, and the residue was purified by flash column
chromatography on silica gel (hexane/EtOAc 10:1 to 7:1) to yield 4;
yield: 1090 mg (92%); white solid; Rf = 0.27 (hexane/EtOAc 20:1); mp
44.3 °C.
IR (NaCl): 3067, 2956, 2938, 1703, 1599, 1454, 1292, 1220, 886, 807,
742, 628, 577, 464 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 8.16 (dd, J = 8.0, 1.2 Hz, 1 H, HAr), 7.56
(dt, J = 7.5, 1.2 Hz, 1 H, HAr), 7.39 (t, J = 7.6 Hz, 1 H, HAr), 7.28 (d, J = 7.6
Hz, 1 H, HAr), 3.25 (ddd, J = 17.3, 10.0, 4.2 Hz, 1 H, PhCHH′), 3.09 (dt,
J = 17.2, 4.6 Hz, 1 H, PhCHH′), 3.03 (dt, J = 14.5, 4.6 Hz, 1 H, CHH′), 2.85
(ddd, J = 19.1, 9.9, 4.6 Hz, 1 H, CHH′).
13C NMR (CDCl3, 126 MHz):  = 184.1 (CO), 141.9 (CAr), 134.5 (CAr),
129.8 (CAr), 128.6 (CAr), 127.8 (CAr), 127.5 (CAr), 77.7 (CBr), 44.2
(PhCH2), 28.5 (CH2).
HRMS (DART): m/z [M + NH4]+ calcd for C10H12BrClON: 275.9791;
found: 275.9793.
IR (NaCl): 2978, 2933, 1751, 1725, 1686, 1455, 1369, 1295, 1254,
1153, 735, 403 cm–1
.
1H NMR (CDCl3, 500 MHz):  = 8.09 (d, J = 7.6 Hz, 1 H, HAr), 7.53 (t,
J = 7.6 Hz, 1 H, HAr), 7.36 (t, J = 7.6 Hz, 1 H, HAr), 7.27 (d, J = 7.6 Hz, 1 H,
HAr), 3.20 (ddd, J = 17.2, 9.0, 4.8 Hz, 1 H, PhCHH′), 3.03 (dt, J = 17.2, 5.2
Hz, 1 H, PhCHH′), 2.95 (ddd, J = 14.1, 9.2, 5.2 Hz, 1 H, CHH′), 2.56 (dt,
J = 14.1, 5.4 Hz, 1 H, CHH′), 1.47 (s, 9 H, C3H9).
Funding Information
This study was supported by the Grants-in-Aid for Scientific Research
(B) (18H01974) and the Grant-in-Aid for Research Fellow of JSPS
(18J12369), and Tatematsu Foundation.
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© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H

H
K. Kitahara et al.
Special Topic
Synthesis
Supporting Information
413. (f) Narayama, A.; Shibatomi, K.; Soga, Y.; Muto, T.; Iwasa, S.
Synlett 2013, 24, 375. (g) Shibatomi, K.; Kawasaki, Y.; Iwasa, S.
J. Fluorine Chem. 2015, 179, 77. (h) Shibatomi, K.; Kitahara, K.;
Okimi, T.; Abe, Y.; Iwasa, S. Chem. Sci. 2016, 7, 1388.
(5) Earlier and/or representative studies on the asymmetric syn-
thesis of -chloro--fluorocarbonyl compounds, see: (a) Frantz,
R.; Hintermann, L.; Perseghini, M.; Broggini, D.; Togni, A. Org.
Lett. 2003, 5, 1709. (b) Cho, M. J.; Kang, Y. K.; Lee, N. R.; Kim, D.
Y. Bull. Korean Chem. Soc. 2007, 28, 2191. (c) Kanga, S. H.; Kim,
D. Y. Adv. Synth. Catal. 2010, 352, 2783. (d) Yi, W.-B.; Huang, X.;
Zhang, Z.; Zhu, D.-R.; Cai, C.; Zhang, W. Beilstein J. Org. Chem.
2012, 8, 1233. (e) Hayes, M. D.; Rodriguez-Alvarado, M.;
Brenner-Moyer, S. E. Tetrahedron Lett. 2015, 56, 4718.
(6) (a) Shibatomi, K.; Kitahara, K.; Sasaki, N.; Kawasaki, Y.;
Fujisawa, I.; Iwasa, S. Nat. Commun. 2017, 8, 15600. (b) See ref.
4h for the synthesis of chiral primary amine catalyst C1.
(7) Naruse, A.; Kitahara, K.; Iwasa, S.; Shibatomi, K. Asian J. Org.
Chem. 2019, 8, 691.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0039-1690009.
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References
(1) (a) Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biol-
ogy; Wiley-Blackwell: Chichester, 2009. (b) Wang, J.; Sánchez-
Roselló, M.; Aceña, J. L.; del Pozo, C.; Sorochinsky, A. E.; Fustero,
S.; Soloshonok, V. A.; Liu, H. Chem. Rev. 2013, 114, 2432.
(2) Zhu, Y.; Han, J.; Wang, J.; Shibata, N.; Sodeoka, M.; Soloshonok,
V. A.; Coelho, J. A. S.; Toste, F. D. Chem. Rev. 2018, 118, 3887.
(3) (a) Shibatomi, K.; Yamamoto, H. Angew. Chem. Int. Ed. 2008, 47,
5796. (b) Shibatomi, K.; Narayama, A.; Soga, Y.; Muto, T.; Iwasa,
S. Org. Lett. 2011, 13, 2944. (c) Shibatomi, K.; Okimi, T.; Abe, Y.;
Narayama, A.; Nakamura, N.; Iwasa, S. Beilstein J. Org. Chem.
2014, 10, 323.
(4) (a) Shibatomi, K.; Tsuzuki, Y.; Nakata, S.-I.; Sumikawa, Y.; Iwasa,
S. Synlett 2007, 551. (b) Shibatomi, K.; Tsuzuki, Y.; Iwasa, S.
Chem. Lett. 2008, 37, 1098. (c) Shibatomi, K.; Futatsugi, K.;
Kobayashi, F.; Iwasa, S.; Yamamoto, H. J. Am. Chem. Soc. 2010,
132, 5625. (d) Shibatomi, K.; Narayama, A.; Abe, Y.; Iwasa, S.
Chem. Commun. 2012, 48, 7380. (e) Shibatomi, K.; Kobayashi, F.;
Narayama, A.; Fujisawa, I.; Iwasa, S. Chem. Commun. 2012, 48,
(8) Wang, X.; Lan, Q.; Shirakawa, S.; Maruoka, K. Chem. Commun.
2010, 46, 321.
(9) Deng, Q.-H.; Wadepohl, H.; Gade, L. H. Chem. Eur. J. 2011, 17,
14922.
(10) Hamashima, Y.; Yagi, K.; Takano, H.; Tamás, L.; Sodeoka, M.
J. Am. Chem. Soc. 2002, 124, 14530.
(11) Ding, C.; Maruoka, K. Synlett 2009, 664.
© 2019. Thieme. All rights reserved. — Synthesis 2019, 51, A–H