Enantioselective benzylation and allylation of α-trifluoromethoxy indanones under phase-transfer catalysis

Article abstract of DOI:10.3390/molecules24152774

The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral phase transfer catalysts were found to be effective for this transformation, and both enantiomers of α-benzyl-α-trifluoromethoxy indanones were accessed, depended on the use of cinchonidine and cinchonine-derived catalyst. The method was extended to the enantioselective allylation reaction of α-trifluoromethoxy indanones to give the allylation products in moderate yield with good enantioselectivity (up to 76% ee).

Full text of DOI:10.3390/molecules24152774

molecules
Article
Enantioselective Benzylation and Allylation of
α-Trifluoromethoxy Indanones under
Phase-Transfer Catalysis
Yumeng Liang , Mayaka Maeno , Zhengyu Zhao and Norio Shibata 1,2,
1
1
1
*
1
Department of Nanopharmaceutical Sciences, Department of Life Science and Applied Chemistry,
Nagoya Institute of Technology Gokiso, Showa-ku, Nagoya 466-8555, Japan
Institute of Advanced Fluorine-Containing Materials, Zhejiang Normal University, 688 Yingbin Avenue,
Jinhua 321004, China
2
*
Correspondence: nozshiba@nitech.ac.jp; Tel./Fax: +81-52-735-7543
ꢀ
ꢁꢂꢀꢃꢄꢅꢆꢇ
ꢀ
ꢁꢂꢃꢄꢅꢆ
Received: 5 July 2019; Accepted: 29 July 2019; Published: 30 July 2019
Abstract: The organo-catalyzed enantioselective benzylation reaction of α-trifluoromethoxy indanones
afforded α-benzyl-α-trifluoromethoxy indanones with a tetrasubstituted stereogenic carbon center
in excellent yield with moderate enantioselectivity (up to 57% ee). Cinchona alkaloid-based chiral
phase transfer catalysts were found to be effective for this transformation, and both enantiomers of
α
-benzyl-
cinchonine-derived catalyst. The method was extended to the enantioselective allylation reaction
of -trifluoromethoxy indanones to give the allylation products in moderate yield with good
α-trifluoromethoxy indanones were accessed, depended on the use of cinchonidine and
α
enantioselectivity (up to 76% ee).
Keywords: trifluoromethoxy; fluorine; enantioselective; phase-transfer catalyst; organo-catalysis
1
. Introduction
The role of fluorine in medicinal chemistry is expanding rapidly after it was discovered that
the introduction of fluorine into an organic molecule could productively influence its physical and
chemical properties [ 14]. In particular, the trifluoromethoxy (OCF ) functional group has received
1–
3
extensive attention in recent years in the fields of pharmaceuticals and agrochemicals, owing to its
unique three-dimensional electronic properties, suitable lipophilic properties, and good metabolic
stability [15
compounds according to a check of the PubChem database in June 2019 [21
trifluoromethyl (CF3; x = 0.88), methyl (CH3; x = 0.52) and methoxy (OCH ) groups (
the OCF group has the highest lipophilicity value (
–20]. In fact, the OCF group is present in more than 1393 biologically active organic
3
–
23]. Compared to
x = 0.02),
x = 1.04) [24–29] resulting in the potential
π
π
π
−
3
π
3
improvement of metabolic profiles, including permeability and absorption, when it is introduced into
the appropriate position of parent molecules.
In contrast to the requirement of OCF -containing drug candidates in medicinal chemistry,
3
the synthesis of OCF -containing organic compounds is relatively problematic. The OCF unit
3
3
is traditionally synthesized from its chlorinated precursor, the trichloromethoxy (OCCl ) moiety,
3
by a chlorine/fluorine exchange reaction under harsh reaction conditions [30
–
35]. The OCF anion
3
−
is unstable and decomposes rapidly into difluorophosgene (O=CF ) and a fluoride anion (F ),
2
which can make nucleophilic trifluoromethylation difficult [36]. The electrophilic trifluoromethylation
of hydroxyl compounds is another strategy, but the method is somewhat limited. While the
synthesis of OCF -containing organic compounds has improved dramatically over the last five
3
years [37–42], a method that can be used to construct a chiral “C*–OCF ” unit is still extremely
3
Molecules 2019, 24, 2774; doi:10.3390/molecules24152774
www.mdpi.com/journal/molecules

Molecules 2019, 24, 2774
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scarce. This should be one of the reasons of no pharmaceuticals with chiral, aliphatic “C*–OCF ” unit
3
reported. In 2017, Tang and co-workers reported the enantioselective bromo-trifluoromethoxylation
of olefins by trifluoromethyl arylsulfonate (TFMS) under silver catalysis in the presence of
1,3-dibromo-5,5-dimethylhydantoin (DBDMH; Scheme 1a) [43]. Later, Shen and co-workers reported
a method to construct chiral trifluoromethoxyl compounds by the Ni-catalyzed enantioselective
Suzuki–Miyaura coupling of secondary benzyl bromides in good to high enantioselectivity
(
Scheme 1b) [44]. We developed a strategy for the synthesis of chiral, non-racemic
a tetrasubstituted carbon center via a Pd-catalyzed enantioselective Tsuji-allylation reaction with high
enantioselectivity (Scheme 1c) [45 46]. Very recently, Liu and co-workers reported the Pd-catalyzed
enantioselective intramolecular trifluoromethoxylation reaction of alkenes using CsOCF to furnish
α-OCF -ketones with
3
,
3
OCF -compounds with a chiral stereogenic center (Scheme 1d) [47]. While these methods have
3
broad substrate scopes with high enantioselectivity, all the methods require transition metal catalysts.
Herein, we report the first example of constructing molecules with an OCF chiral center under
3
non-metallic, organocatalytic conditions. The
presence of a cinchona alkaloid-derived chiral phase-transfer catalyst (PTC) to afford enantioenriched
-benzyl- -OCF indanones in high yield with up to 57% ee. Access to both (R)- and (S)-enantiomers
of -benzyl-
enantioselective allylation reaction with allyl bromide to provide -allyl-α-OCF indanones with up to
3
α-OCF indanones react with benzyl bromides in the
3
α
α
3
α
α-OCF indanones can be controlled by the catalysts. The method was expanded to the
3
α
7
6% ee (Scheme 1e).
Scheme 1. Enantioselective synthesis of trifluoromethoxy-containing compounds.
2
. Results and Discussion
The enantioselective benzylation of
was first examined (Table 1). The screening of representative cinchonine-derived PTCs, CN-1–CN-8
entries 1–8) in toluene revealed that N-[4-(trifluoromethyl)benzyl]cinchoninium bromide CN-4
α
-OCF -substituted indanone 1a with benzyl bromide (2a)
3
(

Molecules 2019, 24, 2774
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exhibited potential performance with 88% yield with 26% ee of (+)-3aa. We next examined
solvents (n-hexane, dichloromethane (DCM), tetrahydrofuran (THF), diethyl ether (Et O) and
2
N,N-dimethylformamide (DMF)), but no satisfying consequences were observed (entries 9–13).
Bases were next examined (potassium carbonate (K CO ), sodium hydroxide (NaOH), cesium
2
3
hydroxide monohydrate (CsOH
acetate (KOAc), dipotassium phosphate (K HPO ) potassium tert-butoxide (KOtBu) and potassium
·
H O), lithium hydroxide (LiOH), sodium hydride (NaH), potassium
2
2
4
methoxide (KOMe; entries 14–22). A 50% KOH aqueous solution and the addition 2 equiv water
with KOH were also tested (entries 23–24), the results showed H O could not increase yield or
2
enantioselectivity. Among these, CsOH
ee of (+)-3aa. Additional solvent screening using CsOH
·
H O exhibited the best performance (83% yield) with 43%
2
·
H O (benzotrifluoride (PhCF ), toluene:
2 3
CHCl = 7:3; entries 25–26) revealed no improvement in the results. Additional catalyst CN-9 was
3
used, racemic product was obtained (entry 27). This result indicated that a free-OH group on
the phase-transfer catalyst should play an important role for the induction of enantioselectivity,
such as hydrogen bonding. The concentration of the reaction (0.1 M to 0.02 M) and the temperature
affected selectivity (entries 28–29), and the best results obtained were 80% yield with 54% ee (entry
3
0). The product with an opposite configuration, ( )-3aa was obtained in 75% yield with 50% ee
−
using CD-4 (entry 32). More optimization results using other PTC were shown in the supporting
information (SI; Table S1, in SI).
Table 1. Optimal condition screening 1.
Entry
Cat.
Base
Solvent
Time
Yield (%) 7
ee (%) 8
1
2
3
CN-1
CN-2
CN-3
KOH
KOH
KOH
Toluene
Toluene
Toluene
15
15
15
73
75
82
1
3
14

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Table 1. Cont.
Entry
Cat.
Base
Solvent
Time
Yield (%) 7
ee (%) 8
4
5
6
7
8
9
CN-4
CN-5
CN-6
CN-7
CN-8
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-4
CN-9
CN-4
CN-4
CN-4
CN-4
CD-4
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
KOH
Toluene
Toluene
Toluene
Toluene
Toluene
n-hexane
DCM
15
15
15
15
15
24
24
24
24
15
48
48
15
48
48
48
48
24
24
15
15
15
24
15
15
15
15
72
15
88
82
89
67
78
38
65
68
40
20
11
58
83
NR
57
NR
NR
26
6
44
68
96
39
77
92
83
80
75
75
26
14
0
0
0
2
5
5
19
1
n.d.
4
43
-
0
-
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
1
1
1
1
1
1
1
1
1
2
2
2
2
THF
Et O
2
DMF
K CO
2
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
PhCF3
3
NaOH
CsOH·H O
2
LiOH
NaH
KOAc
K HPO
-
2
4
KOtBu
KOMe
50% KOH (aq)
17
n.d.
6
24
9
2
2
4
KOH
25
26
27
CsOH·H O
2
CsOH·H O
Toluene:CHCl = 7:3
35
1
2
3
CsOH·H O
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
2
3
2
2
3
3
3
8
9
0
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
CsOH·H2O
49
50
54
57
−50
4
5
5
,6
1
2 5
1
Reaction conditions: 1a (0.1 mmol, 1.0 equiv), BnBr 2a (0.15 mmol 1.5 equiv), base (0.2 mmol, 2.0 equiv) and
cat. (10.0 mol%) were stirred in 1.0 mL of anhydrous toluene at room temperature.
.0 mL of toluene was used. 3.0 mL of toluene was used. 5.0 mL of toluene was used. Stirred at 0 C.
Isolated yields. ee was determined by chiral HPLC. CN = cinchonine, CD = cinchonidine.
2
2
H O (2.0 equiv) was added.
3
4
5
6
◦
7
2
8
With the optimal reaction conditions in hand (Table 1, entry 30), we explored the substrate scope of
this enantioselective catalytic benzylation of -OCF indanones 1 (Scheme 2). With a variety of benzyl
α
3
bromides 2b–2g under the optimal conditions, the desired OCF indanones (+)-3ab–3ah were obtained
3
in good to high yield (63%–85%) with moderate ee (24%–53%). Indanones with an electron-withdrawing
group on the aromatic ring (1b–1d) gave the desired products (+)-3ba–3da in high to excellent yield
(
(
73%–93%) with good ee (51%–57%). On the other hand, indanones with an electron-donating group
1e–1g) furnished products (+)-3ea–3ga in high to excellent yield, but the ee decreased (13%–33% ee).
The method was unsuitable for the benzylation of
the corresponding product 3ha was detected in 51% yield with 8% ee.
The substrate scope of the enantioselective benzylation of -OCF indanones
CN-4, under the same reaction conditions furnished ( )- ((S)-
in similar yield and up to 50% ee (Scheme 3). The absolute stereochemistry of the (+)-
α-OCF tetralone 1h under the same conditions;
3
α
1
using a catalyst,
was temporality
3
−
3
3) with an opposite configuration
3
assigned to be (R) based on the results for the enantioselective allylation of
1 with allyl bromide (2i) as
discussed below (see the later part of this paper, Scheme 4).

Molecules 2019, 24, 2774
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Scheme 2. The enantioselective benzylation of α-trifluoromethoxy ketones 1 under CN-4 catalysis.
Scheme 3. The enantioselective benzylation of α-trifluoromethoxy indanones 1 under CD-4 catalysis.

Molecules 2019, 24, 2774
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It should be noted that the method could be applied for the enantioselective allylation of
-OCF indanones with allyl bromide (2i) under CN-4 or CD-4 catalysis. The desired (+)- and
-OCF indanones 3ai were obtained in moderate yield with up to 70% ee and 76% ee,
α
1
3
(
−
)-
respectively (Scheme 4). The absolute configurations of 3ai were determined to be the (R)-configuration
for (+)-3ai and the (S)-configuration for ( )-3ai by comparing to the optical rotation of reported (S)-3ai
22.5) [45]. The higher enantioselectivity with allylic substrates is most likely due to the less
α-allyl-α
3
−
2
5
(
[α]
=
−
D
steric hindrance than benzyl bromides.
Scheme 4. The enantioselective allylation of α-trifluoromethoxy indanones 1 under CN-4 or CD-4
catalysis. For (R)-3, CN-4 was used. For (S)-3, CD-4 was used.
3
. Materials and Methods
3
.1. General Information
All reagents were used as received from commercial sources, unless specified otherwise.
All reactions were performed in oven-dried glassware under a positive pressure of nitrogen. Solvents
were transferred via syringe and were introduced into the reaction vessels though a rubber septum.
All reactions were monitored by thin-layer chromatography (TLC) carried out on 0.25 mm Merck
silica-gel (60-F254) (Kenilworth, NJ, USA). The TLC plates were visualized with UV light (254 nm)
(
Tokyo, Japan) and p-Anisaldehyde in ethanol/heat. Column chromatography was carried out on
1
a column packed with silica-gel 60N spherical neutral size 63–210
µm or 40–63
µm. The H-NMR
1
9
13
(
300 MHz), F-NMR (282 MHz) and C-NMR (126 MHz) spectra for solution in CDCl were recorded
3
on a Bruker Avance 500 (Karlsruhe, Germany), Varian Mercury 300 (Palo Alto, CA, USA). Chemical
shifts ( ) are expressed in ppm downfield from tetramethylsilane (δH = 0.00 ppm) or tetramethylsilane
C = 0.00 ppm) or hexafluorobenzene ( F = 162.20 ppm). Optical rotations were measured with
a Horiba SEPA-300 operating at 589 nm (Kyoto, Japan). Mass spectra were recorded on an LCMS-2020EV
ESI-MS) system (Shimadzu Corporation, Kyoto, Japan). High resolution mass spectrometry (HRMS)
was recorded on a Waters Synapt G2 HDMS (ESI-MS) (Milford, MA, USA). The wave numbers
δ
(δ
δ
−
(
−
1
(ν) of recorded IR-signals are quoted in cm on a JASCO FT/IR-4100 spectrometer (Tokyo, Japan).
HPLC analyses were performed on a JASCOLC-2000 Plus series (Tokyo, Japan) using 4.6
CHIRALCEL series or CHIRALPAK series (Tokyo, Japan). The melting point was recorded on
×
250 mm
®
1
a BUCHI M-565 (Flawil, Switzerland). All solvents were dried and distilled before use. The H,
13
19
C and F-NMR spectra of compounds
Supplementary Material.
3 and HPLC data of compounds 3 are available in the

Molecules 2019, 24, 2774
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3
.2. Preparation of α-OCF -Substituted Indanones (General Procedure)
3
All the substrates, α-OCF -indanones 1, were prepared by following a reported procedure [45].
3
General Procedure:
A mixture of the indanone (1.0 equiv) and KOH (3.0 equiv) in MeOH (0.4 M) was stirred for 15 min
◦
at 0 C, and PhI(OAc) (1.1 equiv) was added in 4–5 portions during 5 min. The mixture was stirred at
2
the same temperature for 1 h, then warmed to room temperature and stirred overnight. The mixture
was concentrated, dissolved in Et O, washed with NaHCO aq., dried over Na SO and concentrated,
2
3
2
4
then purified by silica-gel column chromatography. The pure product was then dissolved in EtOH
0.3 M), and 3N HCl aq. (1.0 M) was added. After stirring for 0.5 h at room temperature, the resulting
mixture was extracted with Et O, and the combined organic layer was washed with sat. NaHCO
(
2
3
aq. and brine, then dried over Na SO . The residue can be used without further purification for the
2
4
next reaction.
A flask was charged with hydroxyketone, AgOTf (3.0 equiv), KF (4.0 equiv) and Selectfluor®
1.5 equiv) in a nitrogen-filled glovebox. Then ethyl acetate (0.2 M), 2-fluoropyridine (3.0 equiv) and
(
Me SiCF (3.0 equiv) were added successively under an Ar atmosphere. The resulting mixture was
3
3
stirred overnight at room temperature. The reaction mixture was filtered through a pad of silica-gel
and concentrated. The residue was purified by flash silica-gel column chromatography.
2
-(Trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (1a). The reaction was run according to the general
1
procedure, and the product was consistent with previously reported characterization data [45]. H-NMR
(
3
300 MHz, CDCl3)
δ
: 7.82 (d, J = 6.9 Hz, 1H), 7.71–7.66 (m, 1H), 7.49–7.42 (m, 2H), 4.98–4.91 (m, 1H),
.68 (dd, J = 17.0, 7.9 Hz, 1H) and 3.26 (dd, J = 17.0, 5.0 Hz, 1H) ppm. 1 F-NMR (282 MHz, CDCl3)
9
δ:
−
59.66 (s, 3F) ppm.
5-Bromo-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (1b). The reaction was run according to the
general procedure, and the product was consistent with previously reported characterization data [45].
1
H-NMR (300 MHz, CDCl3) δ: 7.70–7.58 (m, 3H), 4.94–4.90 (m, 1H), 3.66 (dd, J = 17.2, 7.9 Hz, 1H) and
19
3
.25 (dd, J = 17.2, 4.9 Hz, 1H) ppm. F-NMR (282 MHz, CDCl ) δ: −59.82 (s, 3F) ppm.
3
5-Fluoro-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (1c). The reaction was run according to the
general procedure, and the product was consistent with previously reported characterization data [45].
1
H-NMR (300 MHz, CDCl3)
H), 3.67 (dd, J = 17.3, 7.9 Hz, 1H) and 3.26 (dd, J = 17.3, 4.9 Hz, 1H) ppm. 19F-NMR (282 MHz, CDCl3)
δ: −59.81 (s, 3F) and −99.41 (q, J = 8.1 Hz, 1F) ppm.
δ: 7.85 (dd, J = 9.2, 5.4 Hz, 1H), 7.19–7.13 (m, 2H), 4.94 (dd, J = 7.9, 4.8 Hz,
1
6
-Fluoro-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (1d). The reaction was run according to the
1
general procedure. H-NMR (300 MHz, CDCl )
δ
: 7.48–7.37 (m, 3H), 4.96 (dd, J = 8.0, 4.8 Hz, 1H), 3.66
3
19
(
3
dd, J = 16.8, 7.9 Hz, 1H), 3.22 (dd, J = 16.8, 5.0 Hz, 1H) ppm. F-NMR (282 MHz, CDCl3)
F), 111.30– : 196.73 (d, J = 3.0 Hz), 162.72 (d,
112.37 (m, 1F) ppm. 13C-NMR (126 MHz, CDCl3)
J = 250.2 Hz), 145.06 (d, J = 2.4 Hz), 135.29 (d, J = 7.7 Hz), 128.34 (d, J = 7.8 Hz), 124.25 (d, J = 23.8 Hz),
21.88 (q, J = 256.9 Hz), 110.70 (d, J = 22.3 Hz), 76.85 (q, J = 2.5 Hz) and 33.19 ppm. MS (ESI): m/z 233
δ
:
−
59.85 (s,
−
−
δ
1
−
◦
[M − H] . m.p.: 93.4–95.1 C.
6-Methyl-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (1e). The reaction was run according to the
general procedure, and the product was consistent with previously reported characterization data [45].
1
H-NMR (300 MHz, CDCl3)
H), 3.67 (dd, J = 17.3, 7.9 Hz, 1H) and 3.26 (dd, J = 17.3, 4.9 Hz, 1H) ppm. 19F-NMR (282 MHz, CDCl3)
δ: −59.72 (s, 3F) ppm.
δ: 7.62 (s, 1H), 7.50 (d, J = 7.5, 1H), 7.35 (d, J = 7.9, 1H), 4.92 (dd, J = 7.9 Hz,
1
6
-Methoxy-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (1f). The reaction was run according to the
general procedure, and the product was consistent with previously reported characterization data [45].
1
H-NMR (300 MHz, CDCl3) δ: 7.37 (d, J = 8.3, 1H), 7.29–7.23 (m, 2H), 4.97–4.92 (m, 1H), 3.86 (s, 3H),

Molecules 2019, 24, 2774
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3
.61 (dd, J = 16.6, 7.8 Hz, 1H) and 3.18 (dd, J = 16.6, 4.7 Hz, 1H) ppm. 19F-NMR (282 MHz, CDCl3)
δ:
−
59.73 (s, 3F) ppm.
5
,6-Dimethoxy-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (1g). The reaction was run according to
1
the general procedure. H-NMR (300 MHz, CDCl )
δ: 7.24 (d, J = 14.6, 1H), 4.90 (dd, J = 7.6, 4.3 Hz,
3
1
H), 3.99 (s, 3H), 3.92 (s, 3H), 3.58 (dd, J = 16.8, 7.6 Hz, 1H) and 3.17 (dd, J = 16.8, 4.3 Hz, 1H) ppm.
19
13
F-NMR (282 MHz, CDCl3)
δ:
−
59.61 (s, 3F) ppm. C-NMR (126 MHz, CDCl3) δ: 195.90, 156.89,
1
50.23, 145.38, 126.50, 121.97 (q, J = 256.5 Hz), 107.30, 104.91, 76.51 (q, J = 2.3 Hz), 56.44, 56.22 and 33.54
+
◦
ppm. MS (ESI): m/z 277 [M + H] . m.p.: 136.9–138.0 C.
2
-(Trifluoromethoxy)-3,4-dihydronaphthalen-1(2H)-one (1h). The reaction was run according to the general
1
procedure, and the product was consistent with previously reported characterization data [45]. H-NMR
(
4
−
300 MHz, CDCl3)
.8 Hz, 1H), 3.16 (dd, J = 8.1, 4.4 Hz, 2H) and 2.57–2.36 (m, 2H) ppm. 19F-NMR (282 MHz, CDCl3)
59.05 (s, 3F) ppm.
δ: 8.07 (d, J = 7.9, 1H), 7.54 (t, J = 7.4, 1H), 7.37 (t, J = 7.7, 1H), 4.85 (dd, J = 12.1,
δ:
3
.3. Representative Procedure for the Enantioselective Catalytic Phase Transfer Benzylation
A flask was charged with -OCF -indanone (0.10 mmol, 1.0 equiv), CsOH H O (0.20 mmol,
.0 equiv) and cat. (0.010 mmol, 10.0 mol%) in a nitrogen-filled glovebox. Then anhydrous toluene
(0.15 mmol, 1.5 equiv) was added under an Ar atmosphere. The resulting
α
1
·
3
2
2
4
(5.0 mL, 0.02 M) and
2
mixture was stirred overnight or 48 h at room temperature. After that, the solvent was removed under
reduced pressure and the residue was purified by flash silica-gel column chromatography.
(+)-2-Benzyl-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3aa). The reaction was run according to
the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow oil; 24.5 mg; 80% yield.
®
The enantiomeric excess (54% ee) was determined by chiral HPLC using CHIRALCEL OJ-H column
(
1
n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min,
λ
= 254 nm) t (major) = 16.525 min, t (minor) =
25
1
1.367 min). [α] = +37.7 (CH Cl , c = 0.62). H-NMR (300 MHz, CDCl ) : 7.78 (d, J = 7.7 Hz, 1H), 7.59
δ
3
D
2
2
(
t, J = 7.4 Hz, 1H), 7.40–7.32 (m, 2H), 7.22–7.17 (m, 5H), 3.43 (s, 2H), 3.31 (d, J = 13.8 Hz, 1H) and 3.01 (d,
J = 13.8 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
: 200.07, 149.53, 136.16, 133.82, 133.42, 130.51,
28.31, 128.25, 127.38, 126.27, 124.97, 121.14 (q, J = 258.8 Hz), 87.04, 42.22 and 35.52 ppm. F-NMR (282
MHz, CDCl ) 51.67 (s, 3F) ppm. IR (NaCl): = 3033, 2929, 1730, 1608, 1496, 1456, 1265, 1043, 757
δ
19
1
δ:
−
ν
3
−
1
+
+
and 701 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO 329.0760; found 329.0765.
17
13
3
2
(
+)-2-(4-Fluorobenzyl)-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ab). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow oil; 26.9 mg;
3% yield. The enantiomeric excess (53% ee) was determined by chiral HPLC using CHIRALCEL®
OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min, = 254 nm) t (major) = 19.383 min, t
minor) = 11.833 min). [α] = +29.6 (CH Cl , c = 0.76). H-NMR (300 MHz, CDCl ) : 7.77 (d, J = 7.7
8
λ
2
5
1
(
δ
3
D
2
2
Hz, 1H), 7.61 (t, J = 7.5 Hz, 1H), 7.41–7.33 (m, 2H), 7.17–7.12 (m, 2H), 6.91 (t, J = 8.4 Hz, 2H), 3.48–3.35
m, 2H), 3.27 (d, J = 14.0 Hz, 1H) and 3.00 (d, J = 14.0 Hz, 1H) ppm. 1 C-NMR (126 MHz, CDCl3)
3
δ:
(
1
1
99.84, 162.16 (d, J = 246.2 Hz), 149.37, 136.30, 133.36, 132.02 (d, J = 8.0 Hz), 129.50 (d, J = 3.2 Hz), 128.38,
26.29, 124.98, 121.12 (q, J = 258.8 Hz), 115.24 (d, J = 21.4 Hz), 86.87, 41.50 and 35.56 ppm. 19F-NMR
(
1
282 MHz, CDCl3)
δ
:
−
51.72 (s, 3F) and
−
115.49–
−
115.59 (m, 1F) ppm. IR (NaCl):
ν
= 3045, 2931, 1730,
−
1
+
+
606, 1512, 1469, 1265, 1159, 838 and 744 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO
17
12
4
2
3
47.0666; found 347.0669.
(
+)-2-(4-Bromobenzyl)-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ac). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow semi-solid;
2
8.9 mg; 75% yield. The enantiomeric excess (41% ee) was determined by chiral HPLC using
®
CHIRALCEL OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min,
λ = 254 nm) t (major) =
25
1
3
7
3.433 min, t (minor) = 13.825 min). [α] = +22.8 (CH Cl , c = 0.84). H-NMR (300 MHz, CDCl ) δ:
D
2 2 3
.79 (d, J = 7.7 Hz, 1H), 7.62 (t, J = 7.5 Hz, 1H), 7.43–7.34 (m, 4H), 7.07 (d, J = 8.2, 2H), 3.47–3.33 (m, 2H),

Molecules 2019, 24, 2774
9 of 14
3
.25 (d, J = 14.0 Hz, 1H) and 2.95 (d, J = 14.0 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
δ
: 199.66,
1
8
2
49.29, 136.37, 133.22, 132.86, 132.16, 131.47, 128.45, 126.35, 125.07, 121.61, 121.08 (q, J = 259.0 Hz),
6.63, 41.65 and 35.54 ppm. 19F-NMR (282 MHz, CDCl3)
δ
:
−
51.75 (s, 3F) ppm. IR (NaCl): ν = 3074,
−1
+
929, 1730, 1608, 1489, 1265, 1201, 1153, 1012 and 519 cm . HRMS (ESI) m/z: [M + Na] Calcd. for
+
C H BrF NaO 406.9865; found 406.9865.
17
12
3
2
(
+)-2-(Trifluoromethoxy)-2-(4-(trifluoromethyl)benzyl)-2,3-dihydro-1H-inden-1-one ((+)-3ad). The reaction
was run according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow
oil; 23.6 mg; 63% yield. The enantiomeric excess (40% ee) was determined by chiral HPLC using
®
CHIRALCEL OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min,
λ = 254 nm) t (major) =
25
1
4
7
3
8.208 min, t (minor) = 33.525 min). [α] = +18.8 (CH Cl , c = 0.50). H-NMR (300 MHz, CDCl ) δ:
D
2 2 3
.80 (d, J = 7.7 Hz, 1H), 7.63 (t, J = 7.5, 1H), 7.51 (d, J = 8.0 Hz, 2H), 7.42 (t, J = 7.4 Hz, 1H), 7.39–7.32 (m,
H), 3.49–3.34 (m, 3H) and 3.04 (d, J = 13.9 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
δ: 199.42, 149.15,
1
(
38.06, 136.45, 133.13, 130.87, 129.72 (q, J = 32.5 Hz), 128.54, 126.39, 125.25 (q, J = 3.7 Hz), 125.15, 124.00
q, J = 272.1 Hz), 121.07 (q, J = 259.2 Hz), 86.57, 42.03 and 35.65 ppm. 1 F-NMR (282 MHz, CDCl3)
9
δ
:
−
51.82 (s, 3F) and
−
63.14 (s, 3F) ppm. IR (NaCl):
ν
= 3076, 2937, 1732, 1610, 1419, 1327, 1267, 1162, 1068
−1
+
+
and 748 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO 397.0634; found 397.0638.
18
12
6
2
(
+)-2-(3-Fluorobenzyl)-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ae). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow oil; 24.3 mg;
5% yield. The enantiomeric excess (47% ee) was determined by chiral HPLC using CHIRALCEL®
OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min, = 254 nm) t (major) = 14.050 min, t
minor) = 8.758 min). [α] = +26.8 (CH Cl , c = 0.19). H-NMR (300 MHz, CDCl ) : 7.80 (d, J = 7.9
Hz, 1H), 7.65–7.59 (m, 1H), 7.43–7.35 (m, 2H), 7.25–7.17 (m, 1H), 6.98–6.89 (m, 3H), 3.50–3.36 (m, 2H),
.31 (d, J = 13.9 Hz, 1H) and 2.99 (d, J = 13.9 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
: 199.66,
7
λ
2
5
1
(
δ
3
D
2
2
3
δ
1
62.49 (d, J = 246.1 Hz), 149.33, 136.33, 136.27 (d, J = 7.4 Hz), 133.26, 129.79 (d, J = 8.4 Hz), 128.42,
26.34, 126.25 (d, J = 2.9 Hz), 125.07, 121.09 (q, J = 258.9 Hz), 117.40 (d, J = 21.6 Hz), 114.43 (d, J = 20.9
1
Hz), 86.72, 41.90 and 35.58 ppm. 19F-NMR (282 MHz, CDCl3)
δ:
−51.75 (s, 3F) and
−
113.50–
−
113.58 (m,
−
1
1
F) ppm. IR (NaCl): ν = 3070, 2931, 1732, 1610, 1489, 1448, 1265, 1149 and 785 cm . HRMS (ESI) m/z:
+
+
[M + Na] Calcd. for C H F NaO 347.0666; found 347.0672.
17 12 4 2
0
(
+)-2-([1,1 -Biphenyl]-4-ylmethyl)-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3af). The reaction
was run according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow
oil; 31.0 mg; 81% yield. The enantiomeric excess (41% ee) was determined by chiral HPLC using
®
CHIRALPAK ID (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min,
1
λ
= 254 nm) t (major) =
: 7.80
d, J = 7.7 Hz, 1H), 7.62–7.31 (m, 10H), 7.27–7.25 (m, 2H), 3.47 (s, 2H), 3.36 (d, J = 13.9 Hz, 1H) and 3.05
d, J = 13.9 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
: 200.04, 149.54, 140.49, 140.19, 136.21, 133.38,
32.89, 130.93, 128.75, 128.30, 127.34, 126.99, 126.96, 126.33, 125.01, 121.16 (q, J = 258.8 Hz), 87.06, 41.88
and 35.61 ppm. 19F-NMR (282 MHz, CDCl )
51.64 (s, 3F) ppm. IR (NaCl): = 3032, 2937, 1730,
25
1
0.408 min, t (minor) = 8.192 min). [α] = +27.3 (CH Cl , c = 0.84). H-NMR (300 MHz, CDCl ) δ
D
2 2 3
(
(
δ
1
δ:
−
ν
3
−
608, 1487, 1265, 1201, 1151 and 748 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO
23 17 3 2
05.1073; found 405.1077.
1
+
+
1
4
(
+)-2-(Naphthalen-2-ylmethyl)-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ag). The reaction
was run according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow
oil; 30.3 mg; 85% yield. The enantiomeric excess (24% ee) was determined by chiral HPLC using
®
CHIRALPAK ID (n-hexane/isopropanol = 99.5/0.5, flow rate 1.0 mL/min,
λ = 254 nm) t (major) =
25
1
9
7
2
.708 min, t (minor) = 8.233 min). [α] = +18.1 (CH Cl , c = 0.77). H-NMR (300 MHz, CDCl )
.82–7.26 (m, 11H), 3.54–3.39 (m, 3H) and 3.16 (d, J = 13.9 Hz, 1H) ppm. C-NMR (126 MHz, CDCl3)
00.07, 149.55, 136.21, 133.33, 133.10, 132.47, 131.57, 129.53, 128.39, 128.29, 127.98, 127.65, 127.56, 126.33,
26.14, 125.95, 125.02, 121.16 (q, J = 258.9 Hz), 87.15, 42.26 and 35.50 ppm. 19F-NMR (282 MHz, CDCl3)
δ
:
:
D
2
2
3
13
δ
1

Molecules 2019, 24, 2774
10 of 14
δ
:
−
51.64 (s, 3F) ppm. IR (NaCl):
ν
= 3057, 2927, 1730, 1608, 1509, 1468, 1263, 1153, 1162, 1045 and
−
42 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO 379.0916; found 379.0917.
21 15 3 2
1
+
+
7
(
+)-2-(3,5-di-tert-Butylbenzyl)-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ah). The reaction was
run according to the general procedure. Eluent (n-hexane/ethyl acetate = 20/1). Yellow oil; 33.1 mg;
9% yield. The enantiomeric excess (37% ee) was determined by chiral HPLC using CHIRALPAK® IF
column (n-hexane/TBME = 95.0/5.0, flow rate 0.5 mL/min, = 254 nm) t (major) = 12.842 min, t (minor)
11.972 min). [α] = +24.3 (CH Cl , c = 0.87). H-NMR (300 MHz, CDCl ) : 7.69 (d, J = 7.8 Hz, 1H),
.51 (t, J = 7.5 Hz, 1H), 7.32–7.15 (m, 3H), 6.94 (s, 2H), 3.45 (s, 2H), 3.30 (d, J = 13.3 Hz, 1H), 3.14 (d,
J = 13.3 Hz, 1H) and 1.22 (s, 18H) ppm. 13C-NMR (126 MHz, CDCl3)
: 200.38, 150.55, 149.71, 135.88,
33.85, 132.40, 127.95, 125.99, 124.70, 124.59, 121.26 (q, J = 258.5k Hz), 120.95, 87.41, 43.01, 35.97, 35.96,
7
λ
2
5
1
=
δ
3
D
2
2
7
δ
1
3
2
4.61 and 31.30 ppm. 19F-NMR (282 MHz, CDCl3)
359, 2336, 1730, 1465, 1368, 1263, 1199, 1153 and 830,720 cm . MS (ESI): m/z 436 [M + NH ] .
δ
:
−51.56 (s, 3F) ppm. IR (NaCl): ν = 2961, 2867,
−
1
+
4
(
+)-2-Benzyl-5-bromo-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ba). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow solid; 35.8
mg; 93% yield. The enantiomeric excess (57% ee) was determined by chiral HPLC using CHIRALCEL®
OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min,
λ
= 254 nm) t (major) = 13.833 min,
t (minor) = 18.725 min). [α] = +12.5 (CH Cl , c = 0.31). H-NMR (300 MHz, CDCl3) : 7.63 (d,
J = 8.4 Hz, 1H), 7.53–7.51 (m, 2H), 7.32–7.06 (m, 5H), 3.41 (s, 2H), 3.30 (d, J = 13.8 Hz, 1H) and 3.02 (d,
J = 13.8 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
: 198.92, 151.00, 133.42, 132.26, 131.99, 131.66,
30.47, 129.58, 128.43, 127.55, 126.09, 121.09 (q, J = 259.1 Hz), 86.77, 42.15 and 35.21 ppm. F-NMR (282
MHz, CDCl )) 51.71 (s, 3F) ppm. IR (NaCl): = 3031, 2929, 1734, 1263, 1203, 1151, 1058, 704 and
25
1
δ
D
2
2
δ
19
1
δ
:
−
ν
3
−
73 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H BrF NaO 406.9865; found 406.9864. m.p.:
17 12 3 2
1
+
+
5
5
◦
3.6–55.8 C.
(
+)-2-Benzyl-5-fluoro-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ca). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow oil; 23.0 mg;
1% yield. The enantiomeric excess (51% ee) was determined by chiral HPLC using CHIRALCEL®
OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min, = 254 nm) t (major) = 28.833 min, t
minor) = 27.167 min). [α] = +27.0 (CH Cl , c = 0.77). H-NMR (300 MHz, CDCl ) : 7.81–7.76 (m,
H), 7.23–7.17 (m, 5H), 7.07 (t, J = 8.8 Hz, 1H), 6.99 (d, J = 8.2 Hz, 1H), 3.42 (s, 2H), 3.31 (d, J = 13.8 Hz,
H) and 3.05 (d, J = 13.8 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
: 198.16, 167.78 (d, J = 259.1 Hz),
52.48 (d, J = 10.5 Hz), 133.47, 130.46, 129.94 (d, J = 1.9 Hz), 128.39, 127.51, 127.48 (d, J = 10.5 Hz), 121.12
7
λ
2
5
1
(
δ
3
D
2
2
1
1
1
(
(
δ
q, J = 259.0 Hz), 116.73 (d, J = 23.7 Hz), 113.09 (d, J = 22.7 Hz), 86.97, 42.20 and 35.58 ppm. 19F-NMR
282 MHz, CDCl3)
δ
:
−
51.72 (s, 3F) and
−
99.80 (q, J = 7.1 Hz, 1F) ppm. IR (NaCl):
ν
= 3028, 2929, 1734,
−
616, 1595, 1263, 1200, 1151 and 702 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO
17 12 4 2
1
+
+
1
3
47.0666; found 347.0672.
(
+)-2-Benzyl-6-fluoro-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3da). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow oil; 26.6 mg;
2% yield. The enantiomeric excess (56% ee) was determined by chiral HPLC using CHIRALCEL®
OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min, = 254 nm) t (major) = 13.792 min,
t (minor) = 9.725 min). [α] = +22.2 (CH Cl , c = 0.80). H-NMR (300 MHz, CDCl3) : 7.40 (d,
J = 7.0 Hz, 1H), 7.29 (d, J = 5.1 Hz, 2H), 7.23–7.14 (m, 5H), 3.40 (s, 2H), 3.30 (d, J = 13.8 Hz, 1H) and
.05 (d, J = 13.7 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
: 199.35, 162.43 (d, J = 249.8 Hz), 145.02
d, J = 2.3 Hz), 135.14 (d, J = 7.5 Hz), 133.45, 130.44, 128.38, 127.84 (d, J = 7.8 Hz), 127.51, 123.92 (d,
J = 23.7 Hz), 121.12 (q, J = 258.9 H z), 110.69 (d, J = 22.2 Hz), 87.49, 42.27 and 35.10 ppm. 19F-NMR
8
λ
2
5
1
δ
D
2
2
3
(
δ
(
1
282 MHz, CDCl3)
δ
:
−
51.73 (s, 3F) and
−
112.86 (q, J = 6.9 Hz, 1F) ppm. IR (NaCl):
ν
= 3033, 2947, 1736,
−1
+
+
614, 1489, 1265, 1200, 1155, 775 and 702 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO
17
12
4
2
3
47.0666; found 347.0671.

Molecules 2019, 24, 2774
11 of 14
(
+)-2-Benzyl-6-methyl-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ea). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 15/1). Slightly yellow oil; 27.2 mg;
5% yield. The enantiomeric excess (29% ee) was determined by chiral HPLC using CHIRALCEL®
OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min, = 254 nm) t (major) = 17.217 min, t
minor) = 8.958 min). [α] = +20.0 (CH Cl , c = 0.82). H-NMR (300 MHz, CDCl ) : 7.58 (s, 1H), 7.41
d, J = 7.8 Hz, 1H), 7.26–7.17 (m, 6H), 3.37 (s, 2H), 3.30 (d, J = 13.8 Hz, 1H), 2.98 (d, J = 13.9 Hz, 1H) and
.38 (s, 3H) ppm. 13C-NMR (126 MHz, CDCl3)
: 200.12, 146.90, 138.35, 137.45, 133.98, 133.47, 130.54,
28.29, 127.33, 125.98, 124.84, 121.14 (q, J = 258.5 Hz), 87.37, 42.22, 35.14 and 21.11 ppm. F-NMR (282
8
λ
2
5
1
(
(
2
δ
3
D
2
2
δ
19
1
−1
MHz, CDCl3)
δ:
−
51.68 (s, 3F) ppm. IR (NaCl): ν = 3034, 2929, 1727, 1495, 1265, 1153 and 702 cm .
+
+
HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO 343.0916; found 343.0913.
18
15
3
2
(
+)-2-Benzyl-6-methoxy-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3fa). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 10/1). Yellow solid; 30.9 mg; 92%
yield. The enantiomeric excess (33% ee) was determined by chiral HPLC using CHIRALCEL® OJ-H
(
1
n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min,
λ
= 254 nm) t (major) = 26.942 min, t (minor) =
25
1
6.517 min). [α] = +29.2 (CH Cl , c = 0.67). H-NMR (300 MHz, CDCl ) : 7.26–7.17 (m, 8H), 3.83
δ
3
D
2
2
13
(
s, 3H), 3.35 (s, 2H), 3.30 (d, J = 13.8 Hz, 1H) and 3.00 (d, J = 13.8 Hz, 1H) ppm. C-NMR (126 MHz,
CDCl3) : 200.13, 159.80, 142.42, 134.48, 133.91, 130.50, 128.29, 127.37, 127.09, 125.69, 121.14 (q, J = 258.8
Hz), 105.79, 87.65, 55.64, 42.33 and 34.87 ppm. F-NMR (282 MHz, CDCl3)
δ
19
δ
1
:
−
51.73 (s, 3F) ppm. IR
−
◦
(
NaCl): ν = 3032, 2945, 1728, 1618, 1493, 1435, 1271, 1028, 769 and 702 cm . HRMS (ESI) m/z: [M +
+
+
Na] Calcd. for C H F NaO 359.0866; found 359.0869. m.p.: 93.5–95.7 C.
18
15
3
3
(
+)-2-Benzyl-5,6-dimethoxy-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one ((+)-3ga). The reaction was
run according to the general procedure. Eluent (n-hexane/ethyl acetate = 5/1). Orange solid; 24.9 mg;
8% yield. The enantiomeric excess (13% ee) was determined by chiral HPLC using a series of
6
®
®
CHIRALPAK IF and CHIRALPAK IA-3 (n-hexane/isopropanol = 90.0/10.0, flow rate 1.0 mL/min,
=
λ
254 nm) t (major) = 15.475 min, t (minor) = 23.808 min). [α]2
5
= 4.5 (CH Cl , c = 0.83). H-NMR
−
1
D
2 2
(
(
300 MHz, CDCl )
δ
: 7.27–7.18 (m, 6H), 6.72 (s, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.34–3.29 (m, 3H) and 3.02
d, J = 13.8 Hz, 1H) ppm. 13C-NMR (126 MHz, CDCl3)
: 198.42, 156.63, 149.97, 145.30, 134.08, 130.51,
28.27, 127.32, 126.22, 121.16 (q, J = 258.5 Hz), 107.02, 104.96, 87.37, 56.34, 56.14, 42.31 and 35.24 ppm.
51.72 (s, 3F) ppm. IR (NaCl): ν = 3030, 2939, 1716, 1591, 1502, 1268,
196, 1146, 782 and 702 cm . HRMS (ESI) m/z: [M + Na] Calcd. for C H F NaO 389.0971; found
3
δ
1
1
9
F-NMR (282 MHz, CDCl )
δ:
−
3
−
1
+
+
1
3
19
17
3
4
◦
89.0976. m.p.: 101.4–105.2 C.
(
+)-2-Benzyl-2-(trifluoromethoxy)-3,4-dihydronaphthalen-1(2H)-one ((+)-3ha). The reaction was run
according to the general procedure. Eluent (n-hexane/ethyl acetate = 10/1). Slightly yellow oil; 16.3 mg;
1% yield. The enantiomeric excess (8% ee) was determined by chiral HPLC using CHIRALCEL®
OJ-H (n-hexane/isopropanol = 99.0/1.0, flow rate 1.0 mL/min, =254 nm) t (major) = 22.442 min, t
0.1 (CH Cl , c = 0.30). H-NMR (300 MHz, CDCl ) : 8.13 (dd, J = 7.8,
.5 Hz, 1H), 7.55 (td, J = 7.5, 1.5 Hz, 1H), 7.38 (t, J = 7.5 Hz, 1H), 7.35–7.26 (m, 6H), 3.29–3.16 (m, 2H),
5
λ
minor) = 8.583 min). [α]2
5
D
=
−
1
δ
3
(
1
3
(
1
2
2
13
.11 (t, J = 6.3 Hz, 2H), 2.49 (dt, J = 14.1, 7.1 Hz, 1H) and 2.14 (dt, J = 13.7, 5.1 Hz, 1H) ppm. C-NMR
: 192.65, 142.15, 134.27, 134.25, 130.68, 130.63, 128.71, 128.68, 128.38, 127.33, 127.25,
21.09 (q, J = 258.4 Hz), 85.72, 39.78, 30.41 and 26.01 ppm. 19F-NMR (282 MHz, CDCl )
50.57 (s, 3F)
126 MHz, CDCl3) δ
δ:
−
3
−1
ppm. IR (NaCl):
[
ν
= 3032, 2949, 1699, 1603, 1454, 1273, 1201, 1146, 908 and 706 cm . HRMS (ESI) m/z:
+
+
M + Na] Calcd. for C H F NaO 343.0916; found 343.0922.
18
15
3
2
(
R)-2-Allyl-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (3ai). The reaction was run according to the
general procedure, and the product is consistent with previously reported characterization data [46].
Eluent (n-hexane/ethyl acetate = 15/1). Colorless oil; 11.0 mg; 43% yield. The enantiomeric excess (68%
ee) was determined by chiral HPLC using a CHIRALCEL® OJ-H column (n-hexane/isopropanol =
5
9
8.0/2.0, flow rate 0.5 mL/min,
λ
= 254 nm) t (major) = 11.167 min, t (minor) = 9.975 min). [α]2
=
D
1
+16.5 (CHCl , c = 0.37). H-NMR (300 MHz, CDCl )
δ
: 7.82 (d, J = 7.7 Hz, 1H), 7.68 (t, J = 7.5 Hz, 1H),
3
3

Molecules 2019, 24, 2774
12 of 14
7
3
.46–7.42 (m, 2H), 5.67 (ddt, J = 17.3, 10.4, 7.2 Hz, 1H), 5.19–5.11 (m, 2H), 3.54 (d, J = 17.8 Hz, 1H),
.41 (d, J = 17.8 Hz, 1H), 2.75 (dd, J = 14.0, 6.7 Hz, 1H), 2.55 (dd, J = 14.0, 7.5 Hz, 1H) ppm. F-NMR
19
(
282 MHz, CDCl ) δ: −51.90 (s, 3F) ppm.
3
(R)-2-Allyl-5-fluoro-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (3ci). The reaction was run according
to the general procedure, and the product is consistent with previously reported characterization
data. [46] Eluent (n-hexane/ethyl acetate = 20/1). Colorless oil; 9.6 mg; 35% yield. The enantiomeric
®
excess (70% ee) was determined by chiral HPLC using CHIRALPAK IF column (n-hexane/TBME =
2
5
9
+
5
0.0/10.0, flow rate 0.5 mL/min,
λ
= 254 nm) t (major) = 15.192 min, t (minor) = 13.042 min). [α]D
=
1
19.7 (CH Cl , c = 0.31). H-NMR (300 MHz, CDCl )
δ
: 7.85 (d, J = 4.5 Hz, 1H), 7.18–7.12 (m, 2H),
.67–5.60 (m, 1H), 5.21–5.12 (m, 2H), 3.53 (d, J = 18.0 Hz, 1H), 3.40 (d, J = 18.1 Hz, 1H), 2.79–2.72 (m, 1H),
2
2
3
2
.60–2.52 (m, 1H) ppm. 19F-NMR (282 MHz, CDCl3)
δ:
−
51.95 (s, 3F) and 99.62– 99.73 (m, 1F) ppm.
−
−
(
R)-2-Allyl-6-methyl-2-(trifluoromethoxy)-2,3-dihydro-1H-inden-1-one (3ei). The reaction was run according
to the general procedure, and the product was consistent with previously reported characterization
data [46]. Eluent (n-hexane/ethyl acetate = 15/1). Colorless oil; 14.0 mg; 52% yield. The enantiomeric
®
excess (45% ee) was determined by chiral HPLC using CHIRALPAK IF column (n-hexane/TBME =
2
5
9
+
7
0.0/10.0, flow rate 0.5 mL/min,
λ
= 254 nm) t (major) = 15.992 min, t (minor) = 13.083 min). [α]D
=
1
16.2 (CH Cl , c = 0.46). H-NMR (300 MHz, CDCl )
δ
: 7.61 (s, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.32 (d, J =
.7 Hz, 1H), 5.70–5.59 (m, 1H), 5.18– 5.10 (m, 2H), 3.48 (d, J = 17.7 Hz, 1H), 3.35 (d, J = 17.5 Hz, 1H),
2
2
3
19
2.76–2.69 (m, 1H), 2.57–2.50 (m, 1H) and 2.41 (s, 3H) ppm. F-NMR (282 MHz, CDCl3)
δ:
−
51.90 (s,
3
F) ppm.
4
. Conclusions
In conclusion, we disclose the organo-catalytic enantioselective benzylation reaction of
-OCF -indanones -Benzyl- -OCF -indanones was synthesized in good to high yield with
could be accessed by the selection
of chiral PTC, CN-4 or CD-4. The method was extended to the enantioselective allylation of
and both enantiomers of -allyl- -OCF -indanones were also obtained in moderate yield with good
ee, as much as 76% ee. To our knowledge, this is the first example of the asymmetric synthesis of
trifluoromethoxylated compounds with a stereogenic OCF -carbon center, without the use of transition
α
1.
α
α
3
3
3
moderate enantioselectivity, up to 57% ee, and both enantiomers of
3
1,
α
α
3
3
metals. Extension of this methodology to other OCF ketones is underway, and will be reported
3
in due course [48].
Supplementary Materials: The following are available online, 1H, 13C and 19F-NMR spectra for desired
compounds 3 and HPLC data for desired compounds 3.
Author Contributions: N.S. conceived and designed the experiments and directed the project; M.M. Y.L. and Z.Z.
performed the experiments; Y.L. analyzed the data; N.S. and Y.L. wrote the paper.
Funding: This work was supported by JSPS KAKENHI grants JP 18H02553 (KIBAN B) and JP 18H04401 (Middle
Molecular Strategy).
Conflicts of Interest: The authors declare no conflicts of interest.
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Sample Availability: Samples of the compounds 1a and 3aa are available from the authors.
©
2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access
article distributed under the terms and conditions of the Creative Commons Attribution
CC BY) license (http://creativecommons.org/licenses/by/4.0/).
(