The enantioselective trifluoromethylation of aromatic aldehydes by quaternary ammonium bromide and (IPr)CuF at low catalyst loading

Article abstract of DOI:10.1016/j.jfluchem.2013.01.027

A general catalytic enantioselective trifluoromethylation of aromatic aldehydes using (IPr)CuF and quinidine-derived quaternary ammonium salt as catalysts has been developed. A wide range of aromatic aldehydes are converted to the corresponding products in up to 92% yield and 81% ee at 2 mol% of catalyst loading.

Full text of DOI:10.1016/j.jfluchem.2013.01.027

Journal of Fluorine Chemistry 148 (2013) 19–29
Contents lists available at SciVerse ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
The enantioselective trifluoromethylation of aromatic aldehydes by quaternary
ammonium bromide and (IPr)CuF at low catalyst loading
*
Shaoxiang Wu, Jiyi Guo, Muhammad Sohail, Chengyao Cao, Fu-Xue Chen
Department of Applied Chemistry, School of Chemical Engineering & the Environment, Beijing Institute of Technology, No. 5 South Zhongguancun Street, Haidian District,
Beijing 100081, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
A general catalytic enantioselective trifluoromethylation of aromatic aldehydes using (IPr)CuF and
quinidine-derived quaternary ammonium salt as catalysts has been developed. A wide range of aromatic
aldehydes are converted to the corresponding products in up to 92% yield and 81% ee at 2 mol% of
catalyst loading.
Received 11 December 2012
Received in revised form 25 January 2013
Accepted 26 January 2013
Available online 5 February 2013
ß 2013 Elsevier B.V. All rights reserved.
Keywords:
Aldehyde
Asymmetric catalysis
Carbene copper species
Quaternary ammonium salt
Trifluoromethylation
1. Introduction
Kobayashi and coworkers firstly selected N-[4-(trifluoro-
methyl)benzyl]cinchonium fluoride as catalyst for the reaction
Due to their unique properties and unusual reactivities,
fluorinated compounds have found extensive applications in the
fields of materials, pharmaceuticals, and agrochemicals [1].
Trifluoromethylated organic compounds have recently emerged
expansively as promising biologically active motifs for drug design
[2]. As a consequence, many groups are committed to the
introduction of trifluoromethyl group into organic compounds
[3]. Another point of interest in medicinal chemistry is the fact that
thenumberofchiraldrugsonthemarkethas beenrapidlyincreasing
[4]. These lead us to explore efficient method for constructing
optically pure trifluoromethylated compounds to provide attractive
surrogates for drug candidates [5,1d]. Among them, direct
trifluoromethylation is simple and therefore promising as an
industrial process. Indeed, after the initial discovery of trifluor-
omethylation reaction of carbonyl compounds with Me3SiCF3
(Ruppert–Prakash reagent) by Prakash group [6], considerable
efforts have been devoted to the development of different catalytic
systems to activate Me3SiCF3. Although synthesis of racemic
trifluoromethylated alcohols with Me3SiCF3 has been competitively
studied inrecent years, highlyenantioselectivetrifluoromethylation
of aromatic aldehydes is difficult to be achieved [7].
and the corresponding trifluoromethylated alcohols were provided
in ee values of 40–50% in 1994 [8]. Following this work, a lot of
stereo-selective variants were developed in recent years [9], such
as chiral ammonium salts and triaminosulfonium salts. However,
enantioselectivities were low to moderate. Furthermore, Feng
discovered that a combination of disodium (R)-binaphtholate and
cinchona alkaloid-derived quaternary ammonium salts afforded
the products of trifluoromethylation of aromatic aldehydes in up to
71% ee by 10 mol% of catalyst [10], while the enantioselectivities
were low around 40% ee for electron-rich aromatic aldehydes.
The subsequently developed asymmetric approaches were docu-
mented by Shibata [11]. They used 1 mol% of chiral crown ether
and 10 mol% base as the catalyst. But the ee values just reached
44%. In contrast to the enantioselective trifluoromethylation of
aromatic aldehydes, better results of ketones were acquired [12].
In the later papers, the best enantioselectivity for ketones was
recorded as 94% ee by Shibata, while aryl aldehyde only got 41% ee
using 10 mol% of the same catalyst cinchona alkaloid-derived
ammonium bromide salt and Me4N+Fꢀ. The enantioselective
trifluoromethylation of aromatic aldehydes is still improvable.
Previously, we communicated an enantioselective trifluoromethy-
lation reaction of aromatic aldehydes with (IPr)CuF (IPr = 1,3-
bis(20,60-di-iso-propylphenyl)imidazol-2-ylidene) and quaternary
ammonium salt [13]. Herein, the effects of catalyst structure (1a–g,
2, 3, 4a–d), reaction parameters, structure of substrates (5a–u)
* Corresponding author. Tel.: +86 10 68918932; fax: +86 10 68918296.
E-mail address: fuxue.chen@bit.edu.cn (F.-X. Chen).
0022-1139/$ – see front matter ß 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.jfluchem.2013.01.027

20
S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
benzyl group at the nitrogen atom of quinidine was used, the
reaction afforded 6a in 90% yield and 35% ee (entry 2). It was
noteworthy that 1c bearing a hindering N-9-anthrylmethylene
group gave nearly racemic product (entry 3). Better enantioselec-
tivities were obtained with catalyst 1d and 1e bearing electron-
withdrawing groups (entries 4 and 5). Additionally, both bulky
substituent at the nitrogen atom and enhanced electron-with-
drawing strength caused a significant improvement in enantios-
electivity. Accordingly, catalyst 1f and 1g greatly increased the ee
values to 69% and 63%, respectively (entries 6 and 7). However, C2-
symmetric dimeric catalyst 2 derived from quinidine gave a
disappointing result of 45% yield and 21% ee (entry 8).
Scheme 1. Enantioselective trifluoromethylation of aldehydes catalyzed by
quaternary ammonium bromide and (IPr)CuF.
including the heterocyclic aromatic aldehyde (5d), and the
plausible catalytic cycle are described in full length (Scheme 1).
The steric effect of substituent at C-6 was also evaluated. As
shown in Table 2, both 3 with a small H at C-6 derived from
cinchonine and 4a with a bulky cyclopentyloxyl instead gave lower
ee values than methoxy group (Table 2, entries 1–2 vs. entry 6 of
Table 1). Modification of the catalyst motif revealed that the C-9
hydroxyl group had to be unprotected to maintain good chiral
inductive capability. Thus, C-9-protected 4b led to a decreased
yield and 45% ee (entry 3), suggesting a live hydrogen bond and a
2. Results and discussion
The model reaction was conducted with 2-naphthaldehyde (5a)
and Me3SiCF3 (2 equiv.) in toluene at ꢀ78 8C. Initially, a variety of
quinidine-derived quaternary ammonium salts (1a–g, 2) were
examined with different N-substituent at 10 mol% catalyst loading
with results shown in Table 1. N-(4-Methylbenzyl) ammonium
bromide salt (1a) led to the desired product in 20% ee albeit in good
yield (Table 1, entry 1). When 1b possessing a 4-trifluoromethyl
possible
p–p stacking between the benzyl moiety of catalyst and
the aromatic portion of substrate as well [14]. Considering the
indispensability of free hydroxyl group of the quinidine for
achieving high enantiocontrol, deprotection of O-methyl yielded
4c. However, the result was disappointing with it (entry 4), which
indicated that one more free hydroxyl group at C-6 disturbed the
Table 1
Effect of N-substituents of quinidine-derived quaternary ammonium salts on the
enantioselectivity.a
hydrogen bond of C-9-OH and
p–p stacking interactions.
Furthermore, C-6-OH and C-9-O-benzylated catalyst 4d decreased
the enantioselectivity to 21% ee (entry 5). Based on the results of
catalyst screening, 1f gave the highest enantioselectivity.
In view of the role of H-bond in this cooperative catalyst, other
additives were introduced into the reaction mixture with results
listed in Table 3. Without any proton additive, the ee value was up
to 69% (Table 1, entry 6). Proton sources such as (R)-BINOL ((R)-
1,10-binaphthalen-2,20-diol) and (R)-2,2,2-trifluoro-1-(naphtha-
len-2-yl)ethanol gave no conversion (Table 3, entries 1–2). When
Table 2
Effect of hydroxy groups at C-6 and C-9 on the enantioselectivity.a
Entry
Ammonium
salt (mol%)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
1a (10)
1b (10)
1c (10)
1d (10)
1e (10)
1f (10)
1g (10)
2 (10)
1
1
1
1
1
1
1
4
87
90
90
89
93
92
86
45
20 (R)d
35
2
53
Entry
Ammonium
salt (mol%)
Time (h)
Yieldb (%)
eec (%)
57
69
63
1
2
3
4
5
3 (10)
2
1
83
90
85
43
37
20
46
45
17
21
21
4a (10)
4b (10)
4c (10)
4d (10)
1
a
Reaction conditions: 5a (0.2 mmol), (IPr)CuF (10 mol%), Me3SiCF3 (0.4 mmol,
2 equiv.), [5a] = 0.25 mol Lꢀ1 in toluene (0.8 mL), ꢀ78 8C, stirring under Ar
atmosphere.
12
12
b
a
Isolated yield.
Reaction conditions: 5a (0.2 mmol), (IPr)CuF (10 mol%), Me3SiCF3 (0.4 mmol,
2 equiv.), [5a] = 0.25 mol Lꢀ1 in toluene (0.8 mL), ꢀ78 8C, stirring under Ar
atmosphere.
c
Determined by chiral HPLC on Chiralcel OJ-H.
d
The absolute configuration of the 6a was assigned by comparing HPLC retention
b
time and the sign of optical rotation value with that of literature [Ref. 12b].
TBAF = tetrabutylammonium fluoride.
Isolated yield.
c
Determined by chiral HPLC on Chiralcel OJ-H.

S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
21
Table 3
Table 5
Effect of additive on the model reaction.a
Effects of solvent on the model reaction.a
Yieldb (%)
eec (%)
Entry
Solvent
Temp (8C)
Time (h)
Yieldb (%)
eec (%)
Entry
Additive (mol%)
Time (h)
1
2
3
4
5
6
7
Toluene
2-Chlorotoluene
Et2O
ꢀ78
ꢀ20
ꢀ78
ꢀ78
ꢀ78
ꢀ20
ꢀ78
1
2
4
4
2
2
1
90
92
41
37
88
85
87
75
35
37
6
1
2
(R)-BINOL (10)
12
4
–
–
–
–
(R)-2,2,2-trifluoro-1-
(naphthalen-2-yl)ethanol (10)
(R)-BNPH (10)
Hexane
THF
3
4
5d
12
2
Trace
–
ND
–
29
0
Me3SiCl (100)
CH3CN
˚
4 A MS
1
92
68
CH2Cl2
40
a
Reaction conditions: 5a (0.2 mmol), (IPr)CuF (0.02 mmol, 10 mol%), 1f
(0.02 mmol, 10 mol%), Me3SiCF3 (0.4 mmol, 2 equiv.), [5a] = 0.25 mol Lꢀ1 in toluene
(0.8 mL), ꢀ78 8C, stirring under Ar atmosphere.
a
Reaction conditions: 5a (0.2 mmol), Me3SiCF3 (0.4 mmol, 2 equiv.), (IPr)CuF
(0.004 mmol, 2 mol%), 1f (0.004 mmol, 2 mol%), [5a] = 0.33 mol Lꢀ1, stirring under Ar
atmosphere.
b
Isolated yield.
b
c
Isolated yield.
Determined by chiral HPLC on Chiralcel OJ-H.
c
d
Determined by chiral HPLC on Chiralcel OJ-H.
˚
10 mg 4 A MS was used. ND = not detected.
the protonic acid (R)-BNPH ((R)-1,10-binaphthyl-2,20-diyl phospho-
ric acid) was added, only trace product was obtained (entry 3).
Protonadditivesdestroyedthecatalyticcapabilityofthecooperative
catalysts. Me3SiCl suppressed the reaction completely (entry 4).
Molecular sieves had no effect on the catalyst efficiency (entry 5).
To obtain the optimum reaction condition further optimization
on catalyst loading, reaction temperature substrate concentration
and other copper complexes was performed (Table 4). Reasonably,
as reducing the catalyst loading from 10 mol% to 2 mol% at
0.25 mol Lꢀ1 of 2-naphthaldehyde, the yields and ee values of
product 6a had no significant effect (entries 1 and 2). Further
decrease of the catalyst loading to 1 mol% resulted in a deleterious
effect on the reaction conversion even at higher concentration of
0.5 mol Lꢀ1 and longer reaction time, but without decrease of
enantioselectivity (entries 3–4). To our delight, when the reaction
was run at 0.33 mol Lꢀ1 of aldehyde concentration, better
enantioselectivity 75% ee was afforded at 2 mol% of catalyst
loading (entry 5). Higher concentration of the substrate
Table 6
Scope of substrate.a
Table 4
Effect of catalyst loading, reaction temperature and concentration on the model
reaction.a
Entry
5
Ar
Time (h)
Yieldb (%)
eec (%)
1
2
5a
5b
5c
5d
5e
5f
2-Naphthyl
1-Naphthyl
C6H5
1
2
2
2
2
2
2
2
2
2
1
1
1
1
1
1
2
2
2
2
2
90
88
80
89
81
82
83
83
79
87
88
90
87
85
89
88
83
92
92
80
85
75 (98)d
60
3e
4
60
2-Pyridyl
42
5
4-BrC6H4
57
6
3-BrC6H4
52
7e
8e
9e
10e
11
12
13
14
15
16
17
18
19
20
21
5g
5h
5i
4-ClC6H4
51
.
3-ClC6H4
51
Entry
Ammonium
salt (mol%)
(IPr)CuF
(mol%)
Concnb
(mol Lꢀ1
Yieldc (%)
eed (%)
4-FC6H4
45
)
5j
3-FC6H4
51
1
2
1f (5)
1f (2)
1f (1)
1f (1)
1f (2)
1f (2)
1f (2)
1f (2)
1f (10)
1f (10)
5
2
1
1
2
2
2
2
–
–
0.25
0.25
0.25
0.50
0.33
0.50
0.33
0.33
0.33
0.33
89
92
52
50
90
89
92
87
86
NR
67
68
66
67
75
67
47
24
53
-
5k
5l
4-MeC6H4
68
4-PhC6H4
66
3e
4
5m
5n
5o
5p
5q
5r
5s
5t
3-PhOC6H4
4-MeOC6H4
3-MeOC6H4
2-MeOC6H4
6-MeO-2-naphthyl
3,4-O(CH2)C6H3
3,4-O(CH2)2C6H3
4-(C3H5O)C6H4
4-C2H5SC6H4
60
67
5
74
6
7f
8g
9h
10i,j
73
53
81
79
67
5u
73
a
Reaction conditions: 5a (0.2 mmol), Me3SiCF3 (0.4 mmol, 2 equiv.), ꢀ78 8C,
a
stirring under Ar atmosphere.
b
Reaction conditions: 5a–u (0.2 mmol), (IPr)CuF (0.004 mmol, 2 mol%), 1f
(0.004 mmol, 2 mol%), Me3SiCF3 (0.4 mmol, 2 equiv.), [5] = 0.33 mol Lꢀ1 in toluene
(0.6 mL), ꢀ78 8C, stirring under Ar atmosphere.
Concentration of 5a.
c
Isolated yield.
d
b
Determined by chiral HPLC on Chiralcel OJ-H.
Isolated yield.
e
c
The reaction time was 4 h.
Determined by HPLC analysis (Chiralcel OJ-H, OD-H, AD-H, and AS-H). The
f
The reaction was carried out at ꢀ40 8C.
absolute configuration of 6a was assigned by comparing HPLC retention time and
the sign of optical rotation value with that of literature [Ref. 12b]. Others (6b–u)
were assumed by analogy.
g
The reaction was carried out at ꢀ20 8C.
h
CuF(PPh3)3 (10 mol%) instead of (IPr)CuF was used.
i
d
CuF2 (10 mol%) and (S)-BINAP (10 mol%) instead of (IPr)CuF was used.
The ee value in parentheses was obtained after recrystallization.
j
e
The reaction was carried out at 0 8C.
The reaction was carried out at ꢀ20 8C.

22
S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
Scheme 2. Proposed catalytic cycle.
(0.5 mol Lꢀ1) eroded the enantioselectivity obviously to 67% ee.
Elevation of the reaction temperature from ꢀ78 8C to ꢀ40 8C and
ꢀ20 8C decreased enantioselectivity stepwise from 75% ee to 47%
ee and 24% ee, respectively (entries 7 and 8). Other copper
complexes were also tested and the results were summarized in
entry 9 and 10. CuF(PPh3)3 and 1f led to relative lower ee values
while CuF2/(S)-BINAP and 1f gave no conversion.
With 1f as the catalyst, the solvent effect on the model reaction
was subsequently investigated. Solvents exhibited strong effect on
the catalyst capability. As shown in Table 5, when toluene was
used, the reaction was furnished in 75% ee (entry 1). 2-
Chlorotoluene and Et2O gave poor results (entries 2 and 3). In
hexane, the cooperative catalyst nearly lost its enantioselective
capability (entry 4). THF, CH3CN and CH2Cl2 afforded 6a with
excellent yields, however, the ee values were decreased sharply
(entries 5–7). Consequently, the optimal reaction conditions are as
follows: 2 mol% of (IPr)CuF, 2 mol% of 1f, substrate concentration
0.33 mol Lꢀ1 in toluene, and ꢀ78 8C.
With the optimal reaction condition in hands, the substrate
generality was evaluated (Table 6). For aldehydes (5a–c) without
substituent, almost all of the corresponding products could be
obtained in high yields and high enantioselectivities (entries 1–3).
After a simple recrystallization the enantiopurity of 6a was
increased from 75% to 98% ee easily (entry 1). The heterocyclic
aromatic aldehyde (5d) gave lower ee value and good yield (entry
4). This is the first report of directly enantioselective trifluor-
omethylation of heterocyclic aromatic aldehydes up to date. On the
other hand, F, Cl, Br-substituted aldehydes (5e–j) worked well for
this reaction and provided the products in moderate enantios-
electivities (entries 5–10).
Table 7
Control experiments.a
Entry
Ammonium salt (mol%)
(IPr)CuX (mol%)
Time (h)
Yieldb (%)
eec (%)
1
2
1f (2)
–
–
4
4
NR
Trace
90
–
(IPr)CuF (2)
(IPr)CuF (2)
(IPr)Cu(Ot-Bu) (2)
(IPr)CuCl (2)
–
ND
75
45
–
3
1f (2)
1f (2)
1f (2)
1f0 (5)
1f0 (5)
1f (5)
1f (5)
1
4
4
57
5
4
NR
87
6
36
48
12
12
57
67
52
59
7
(IPr)CuCl (5)
–
84
8d
9d
76
(IPr)CuF (5)
79
a
Reaction conditions: 5a (0.2 mmol), Me3SiCF3 (0.4 mmol, 2 equiv.), toluene (0.6 mL), ꢀ78 8C, stirring under Ar atmosphere.
Isolated yield.
b
c
Determined by HPLC analysis on Chiralcel OJ-H.
d
Sodium salt of (R)-6a (99% ee, 10 mol%) was added. ND = not detected. NR =no reaction.

S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
23
To our satisfaction, electron-donating aromatic aldehydes
reacted very well under the optimal reaction condition to give
6k–u with good to high enantioselectivities (entries 11–21). For
aldehydes (5n–p) with methoxy group on different positions of
the phenyl ring were well tolerated in the present system with
good to high enantioselectivities (67–74% ee) (entries 14–16).
Significantly, we were pleased to find that epoxy replaced
aromatic substrates (5r–s) were trifluoromethylated with
excellent yields and good enantioselectivities (81% ee and 79%
ee, respectively, entries 18–19). The highest enantioselectivity
81% ee (entry 18) was recorded in the case of 5r compared to 46%
ee in the literature [10]. It should be mentioned that functional
aldehydes and hetero-substitutional were also suitable to the
reaction. 4-(Allyloxy)benzaldehyde (5t) and 4-(ethylthio)ben-
zaldehyde (5u) were converted into the alcohols in 67% ee and
73% ee, respectively (entries 20 and 21). To the best of our
knowledge, this represents the most general process for the
catalytic enantioselective trifluoromethylation of aromatic alde-
hydes to date.
To gain more information about the reaction mechanism and
fundamental catalytic steps, a family of (IPr)CuX were applied to
the model reaction under optimum reaction conditions as
controlled reactions (Table 7). Neither (IPr)CuF nor the chiral
quaternary ammonium salt was sufficiently effective to promote
the addition of Me3SiCF3 to aldehyde even after 4 h (entries 1, 2 vs.
entry 3). However, in the presence of 1f (IPr)Cu(Ot-Bu) produced
6a with 45% ee while (IPr)CuCl and 1f gave no product (entries 4
and 5). Nevertheless, quaternary ammonium fluoride salt 1f0 gave
the product in 87% yield and 57% ee (entry 6). In combination with
(IPr)CuCl, the enantioselectivity increased to 67% ee (entry 7). We
supposed that the fluoride ion might act as an initiator to generate
the active [(IPr)CuCF3] and other copper species. Considering the
generation of carbene copper alkoxides in the catalytic cycle [15],
in the absence of (IPr)CuF, the (R)-sodium 2,2,2-trifluoro-1-
(naphthalen-2-yl)ethanolate was added to enhance the enantios-
electivity. However, the ee value decreased to 52% (entry 8). After
the (IPr)CuF was used together, the ee value increased to 59%
(entry 9). These observations indicated (IPr)CuF was the key factor
for the high performance of the cooperative catalyst.
salts has a significant influence on the yield and enantioselectivity.
Moreover, The reaction requires only 2 mol% of the (IPr)CuF and
chiral ammonium salt, to the best of our knowledge, the lowest
catalyst loading for the enantioselective trifluoromethylation of
aromatic aldehydes up to date. Further investigations would be
directed toward extension of this cooperative catalyst in other
asymmetric reactions.
4. Experimental
All reactions were carried out under argon atmosphere using
typical vacuum-line techniques unless otherwise noted. The 1H
NMR (400 MHz) spectra for solution in CDCl3 and DMSO-d6 were
recorded on Bruker Avance 400 or Varian Mercury 400. Chemical
shifts were reported downfield in ppm from tetramethylsilane
(CDCl3,
d
= 7.26; DMSO-d6,
d = 2.50). Spectra were reported as
follows: chemical shift (
d
ppm), multiplicity (s = singlet, d = doublet,
t = triplet, q = quartet, m = multiplet), coupling constant (Hz),
integration and assignment. 13C NMR spectra were collected on a
Bruker Avance 400 or a Varian Mercury 400 (100 MHz) with
complete proton decoupling. Chemical shifts were reported in ppm
from the tetramethylsilane (CDCl3, d = 77.0; DMSO-d6, d = 39.5). The
IR spectra were recorded on Thermo Scientific Nicolet iS10 with KBr
pellets. Elemental analyses were performed on an Elementar Vario
MICRO CUBE instrument. Enantiomeric excesses were determined
by HPLC on Shimadzu LC-20A apparatus with Chiralpak OJ-H, AS-H,
OD-H and AD-H. Optical rotations were measured on a Kru¨ss P8000
polarimeter. HRMS was recorded on Bruker Apex IV FTMS. All
melting points were determined on a XT4A melting point apparatus
without correction. Analytical thin layer chromatography (TLC) was
performed using F254 pre-coated silica gel plate. Column chroma-
tography was performed with silica gel (200–300 mesh). Petroleum
ether (PE) had a boiling point range of 60–90 8C.
4.1. Enantioselective trifluoromethylation reaction of aldehydes;
general procedure
To a stirred solution of (IPr)CuF (1.9 mg, 0.004 mmol, 2 mol%)
and N-(3,5-ditrifluoromethylbenzyl)quinidinium bromide (1f)
(2.6 mg, 0.004 mmol, 2 mol%) in toluene (0.6 mL) was added aryl
aldehydes (5a–u, 0.2 mmol) at ꢀ78 8C under argon atmosphere.
Then this mixture was kept at ꢀ78 8C for 10 min. After that,
Based on the experimental observations, the plausible catalytic
cycle was proposed (Scheme 2). First, aldehyde was effectively
activated by the chiral N+ cation. At the same time, (IPr)CuF reacted
with Me3SiCF3 to transfer a CF3 group to copper and furnished the
active [(IPr)CuCF3] which underwent nucleophilic attack to the
activated carbonyl group forming intermediate A. The presence of
copper species may further enhance the chiral communications
between the quaternary ammonium salt and the substrates. The
formation of alkoxide intermediate A, subsequent association and
thus activation of Me3SiCF3 arranged the new transition state B
effectively allowing the release of product C and regeneration of A
simultaneously.
Me3SiCF3 (60
mL, 0.4 mmol, 2 equiv.) was added drop-wise. After
stirring for 1–2 h at ꢀ78 8C, the reaction was quenched with water.
Aqueous layer was extracted with EtOAc (15 mL ꢁ 3), and the
combined organic layer was washed with brine, dried over Na2SO4
and concentrated under reduced pressure. The crude product O-
TMS ether was treated with n-Bu4NF (0.2 mL, 1 M in THF,
0.2 mmol) in THF (2.0 mL) at room temperature until full
conversion to the final product. The resulting mixture was
concentrated under reduced pressure, and purified by column
chromatography with silica gel (PE/EtOAc = 20/1, V/V) to give
trifluoromethylated alcohols (6a–u).
3. Conclusion
In conclusion, a general catalytic enantioselective trifluoro-
methylation of aromatic aldehydes using (IPr)CuF and quinidine-
derived quaternary ammonium salts as the catalyst as well as the
plausible catalytic cycle have been developed. This process
proceeds through [(IPr)CuCF3] and (IPr)Cu-alkoxide to give the
product. It furnishes a wide range of substrates to the correspond-
ing products with the highest levels of enantiomeric excess
recorded in the literature thus far including the first example of
directly enantioselective trifluoromethylation of heterocyclic
aromatic aldehydes. In particular, the results obtained with
electron-donating aldehydes are remarkable. On the other hand,
the hydroxy group at the position of C-9 of quaternary ammonium
4.2. (R)-2,2,2-Trifluoro-1-(naphthalen-2-yl)ethanol [10] (6a)
25
Yield: 90%; white solid; mp 76–78 8C; [
a
]
D
ꢀ24.7 (c 0.21,
CH2Cl2) [lit.10
3062, 1602, 1507, 1341, 1247, 1262, 1193, 1124, 1085, 822, 792,
763, 752, 702, 486 cmꢀ1; 1H NMR (400 MHz, CDCl3):
= 7.96–7.86
(m, 4H), 7.59–7.51 (m, 3H), 5.19 (m, 1H), 2.77 (d, J = 4.4 Hz, 1H); 13
NMR (100 MHz, CDCl3): = 133.8, 132.9, 131.3, 128.5, 128.3, 127.8,
[a
]
D
ꢀ23.7 (c 0.16, CH2Cl2, 71% ee)]; IR (KBr): 3374,
20
d
C
d
127.4, 126.9, 126.6, 124.4 (q, J = 281.2 Hz), 124.3, 73.0 (q,
J = 31.9 Hz). The ee was determined by HPLC on Chiralpak OJ-H
(n-hexane/i-PrOH = 80/20, V/V, 1.0 mL/min, 254 nm), tR(ma-
jor) = 10.7 min, tS(minor) = 15.4 min, 75% ee.

24
S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
4.3. (R)-2,2,2-Trifluoro-1-(naphthalen-1-yl)ethanol [12b] (6b)
NMR (400 MHz, CDCl3):
d
= 7.43–7.38 (m, 4H), 5.04–4.98 (m, 1H),
= 135.7,
2.72 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
25
Yield: 88%; colorless oil; [a D
]
ꢀ14.6 (c 0.47, CH2Cl2); IR (KBr):
132.4, 129.0, 128.9, 124.1 (q, J = 281.1 Hz), 72.3 (q, J = 32.1 Hz); The
ee was determined by HPLC on Chiralpak OD-H (n-hexane/i-
PrOH = 95/5, V/V, 1.0 mL/min, 254 nm), tR(major) = 8.0 min, tS(mi-
nor) = 10.9 min, 52% ee.
3421, 3046, 2927, 2847, 1515, 1399, 1355, 1264, 1167, 1126, 1093,
1030, 877, 781, 698, 632, 538 cmꢀ1 1H NMR (400 MHz, CDCl3):
= 8.06 (d, J = 8.4 Hz, 1H), 7.93–7.91 (m, 2H), 7.84 (d, J = 7.2 Hz, 1H),
7.60–7.53 (m, 3H), 5.90 (m, 1H), 2.78 (d, J = 4.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): = 131.1, 130.3, 129.1, 126.1, 125.8, 125.2, 124.7
;
d
d
4.9. (R)-1-(3-Chlorophenyl)-2,2,2-trifluoroethanol [10] (6h)
(q, J = 281.7 Hz), 122.8, 69.0 (q, J = 32.0 Hz). The ee was determined
by HPLC on Chiralpak AS-H (n-hexane/i-PrOH = 98/2, V/V, 1.0 mL/
min, 254 nm), tR(major) = 16.7 min, tS(minor) = 19.8 min, 60% ee.
19
Yield: 83%; colorless oil; [
a
]
ꢀ6.5 (c 0.09, CH2Cl2) [lit.10
D
20
[a
]
ꢀ7.3 (c 0.22, CH2Cl2, 56% ee)]; IR (KBr): 3407, 3066, 2925,
D
1601, 1578, 1477, 1433, 1412, 1355, 1267, 1177, 1131, 907, 742,
722, 696, 631, 535 cmꢀ1 1H NMR (400 MHz, CDCl3):
= 7.52 (s,
1H), 7.43–7.29 (m, 3H), 5.02 (m, 1H), 2.98 (t, J = 4.0 Hz, 1H); 13C
NMR (100 MHz, CDCl3): = 135.8, 134.7, 129.9, 129.8, 127.7, 125.7,
4.4. (R)-2,2,2-Trifluoro-1-phenylethanol [10] (6c)
;
d
Yield: 80%; colorless oil; [
a
]
D
ꢀ13.1 (c 0.28, CH2Cl2) [lit.10
d
25
20
[
a
]
D
ꢀ12.5 (c 0.40, CH2Cl2, 56% ee)]; IR (KBr): 3410, 2927, 2851,
124.0 (q, J = 281.1 Hz), 72.2 (q, J = 32.2 Hz). The ee was determined
by HPLC on Chiralpak OD-H (n-hexane/i-PrOH = 95/5, V/V, 1.0 mL/
min, 254 nm), tR(major) = 8.2 min, tS(minor) = 11.4 min, 50% ee.
2360, 2342, 1457, 1206, 1171, 1127, 1093, 1063, 1029, 860, 760,
705, 633 cmꢀ1 1H NMR (400 MHz, CDCl3):
= 7.48–7.47 (m, 2H),
7.42–7.40 (m, 3H), 5.10 (q, J = 6.6 Hz, 1H), 2.73 (s, 1H); 13C NMR
(100 MHz, CDCl3): = 134.0, 129.6, 128.7, 127.5, 124.3 (q,
;
d
d
4.10. (R)-2,2,2-Trifluoro-1-(4-fluorophenyl)ethanol [10] (6i)
J = 281.0 Hz), 72.9 (q, J = 32.0 Hz). The ee was determined by HPLC
on Chiralpak OJ-H (n-hexane/i-PrOH = 95/5, V/V, 1.0 mL/min,
254 nm), tR(major) = 21.3 min, tS(minor) = 29.4 min, 60% ee.
19
Yield: 79%; colorless oil; [
a]
ꢀ11.5 (c 0.07, CH2Cl2) [lit.10
D
20
[
a
]
ꢀ20 (c 0.02, CH2Cl2, 57% ee)]; IR (KBr): 3415, 2925, 1609,
D
1514, 1358, 1271, 1232, 1174, 1128, 1074, 873, 855, 821, 693,
575 cmꢀ1; 1H NMR (400 MHz, CDCl3):
= 7.48–7.44 (m, 2H), 7.12–
7.07 (m, 2H), 5.00 (m, 1H), 3.07 (s, 1H); 13C NMR (100 MHz, CDCl3):
= 163.6 (d, J = 247.5 Hz), 129.9 (d, J = 1.9 Hz), 129.4 (d, J = 8.5 Hz),
4.5. (R)-2,2,2-Trifluoro-1-(pyridin-2-yl)ethanol [16] (6d)
d
19
Yield: 89%; colorless oil; [
a
]
ꢀ7.1 (c 0.10, CH2Cl2); IR (KBr):
d
D
3092, 2863, 1622, 1421, 1354, 1271, 1228, 1203, 1119, 1081, 1068,
717, 653, 549 cmꢀ1 1H NMR (400 MHz, CDCl3):
= 8.64 (d,
J = 4.4 Hz, 1H), 7.80 (dt, J = 8.0, 1.6 Hz, 1H), 7.45–7.38 (m, 2H), 5.04
(q, J = 6.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
= 151.0, 148.3,
124.2 (q, J = 280.9 Hz), 115.6 (d, J = 21.7 Hz), 72.2 (q, J = 32.0 Hz).
The ee was determined by HPLC on Chiralpak OD-H (n-hexane/i-
PrOH = 95/5, V/V, 1.0 mL/min, 254 nm), tR(major) = 14.7 min,
tS(minor) = 20.2 min, 45% ee.
;
d
d
137.3, 124.5, 124.1 (q, J = 281.8 Hz), 122.7, 70.7 (q, J = 31.9 Hz). The
ee was determined by HPLC on Chiralpak OD-H (n-hexane/i-
PrOH = 95/5, V/V, 1.0 mL/min, 254 nm), tS(minor) = 17.1 min,
tR(major) = 23.2 min, 42% ee.
4.11. (R)-2,2,2-Trifluoro-1-(3-fluorophenyl)ethanol [19] (6j)
Yield: 87%; colorless oil; [
a
]
ꢀ19.3 (c 0.13, CH2Cl2) [lit.19
19
D
26
[
a
]
ꢀ18.6 (c 0.5, CHCl3, 47% ee)]; IR (KBr): 3421, 2923, 1610,
D
4.6. (R)-1-(4-Bromophenyl)-2,2,2-trifluoroethanol [17] (6e)
1491, 1296, 1258, 1128, 841, 788, 718 cmꢀ1
CDCl3): = 7.40–7.35 (m, 1H), 7.24 (t, J = 8.0 Hz, 2H), 7.13–7.08 (m,
1H), 5.02 (m, 1H), 2.93 (s, 1H); 13C NMR (100 MHz, CDCl3):
= 162.8 (d, J = 245.9 Hz), 136.3, 130.2 (d, J = 8.2 Hz), 124.1 (q,
;
1H NMR (400 MHz,
d
Yield: 81%; colorless oil; [
a
]
D
ꢀ11.5 (c 0.24, CH2Cl2) [lit.17
25
20
[
a
]
D
ꢀ1.3 (c 1.04, EtOH, 12% ee)]; IR (KBr): 3420, 2921, 2353,
d
1596, 1491, 1406, 1356, 1267, 1097, 1012, 871, 847, 807, 726, 667,
586 cmꢀ1 1H NMR (400 MHz, CDCl3):
= 7.55–7.52 (m, 2H), 7.34
(d, J = 8.4 Hz, 2H), 4.97 (q, J = 6.4 Hz, 1H), 2.98 (s, 1H); 13C NMR
(100 MHz, CDCl3): = 132.8, 131.9, 129.1, 124.0 (q, J = 281.1 Hz),
J = 281.1 Hz), 123.2, 116.5 (d, J = 21.0 Hz), 114.6 (d, J = 23.0 Hz),
72.2 (q, J = 32.1 Hz); The ee was determined by HPLC on Chiralpak
OD-H (n-hexane/i-PrOH = 95/5, V/V, 1.0 mL/min, 254 nm), tR(ma-
jor) = 7.7 min, tS(minor) = 9.5 min, 52% ee.
;
d
d
123.8, 72.2 (q, J = 32.1 Hz). The ee was determined by HPLC on
Chiralpak OD-H (n-hexane/i-PrOH = 95/5, V/V, 1.0 mL/min,
254 nm), tR(major) = 9.1 min, tS(minor) = 12.6 min, 57% ee.
4.12. (R)-2,2,2-Trifluoro-1-(p-tolyl)ethanol [10] (6k)
Yield: 88%; colorless oil; [
a
]
D
ꢀ12.7 (c 0.18, CH2Cl2) [lit.10
25
20
4.7. (R)-1-(3-Bromophenyl)-2,2,2-trifluoroethanol [18] (6f)
[
a
]
ꢀ18.4 (c 0.43, CH2Cl2, 60% ee)]; IR (KBr): 3421, 3046, 2927,
D
2847, 1515, 1399, 1355, 1264, 1167, 1126, 1093, 1030, 1001, 877,
781, 698, 632, 538, 525, 455 cmꢀ1 1H NMR (400 MHz, CDCl3):
= 7.36 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 4.97 (m, 1H), 2.73
(s, 1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3):
= 139.6, 131.1,
25
Yield: 82%; colorless oil; [
a
]
D
ꢀ7.3 (c 0.11, CH2Cl2).
;
IR (KBr): 3409, 3062, 2925, 1574, 1430, 1355, 1255, 1178, 1100,
1076, 997, 838, 784, 677, 630, 532, 453 cmꢀ1 1H NMR (400 MHz,
CDCl3): = 7.64 (s, 1H), 7.55–7.52 (m, 1H), 7.40–7.38 (d, J = 7.6 Hz,
1H), 7.27 (t, J = 7.8 Hz, 1H), 5.00–4.95 (m, 1H), 3.01 (d, J = 4.4 Hz,
1H); 13C NMR (100 MHz, CDCl3):
= 136.3, 130.3, 124.0 (q,
d
;
d
d
129.4, 127.4, 124.3 (q, J = 280.9 Hz), 72.8 (q, J = 31.9 Hz), 21.3. The
ee was determined by HPLC on Chiralpak OD-H (n-hexane/i-
PrOH = 97/3, V/V, 1.0 mL/min, 254 nm), tR(major) = 13.3 min,
tS(minor) = 17.7 min, 68% ee.
d
J = 281.1 Hz), 123.2, 116.7, 114.7, 114.5, 72.2 (q, J = 32.1 Hz). The
ee was determined by HPLC on Chiralpak OD-H (n-hexane/i-
PrOH = 95/5, V/V, 1.0 mL/min, 254 nm), tR(major) = 8.8 min, tS(mi-
nor) = 14.4 min, 51% ee.
4.13. (R)-1-([1,10-Biphenyl]-4-yl)-2,2,2-trifluoroethanol [10] (6l)
28
Yield: 90%; white solid; mp 113–114 8C; [
a
]
ꢀ18.5 (c 0.40,
D
CH2Cl2) [lit.10
3364, 1490, 1408, 1352, 1256, 1198, 1173, 1158, 1130, 1075,
1006, 855, 823, 764, 743, 726, 696 cmꢀ1 1H NMR (400 MHz,
CDCl3): = 7.65–7.54 (m, 6H), 7.47–7.43 (m, 2H), 7.39–7.35 (m,
1H), 5.07 (m, 1H), 2.70 (d, J = 4.4 Hz, 1H); 13C NMR (100 MHz,
[
a
]
ꢀ7.1 (c 0.14, CH2Cl2, 56% ee)]; IR (KBr):
20
4.8. (R)-1-(4-Chlorophenyl)-2,2,2-trifluoroethanol [10] (6g)
D
25
Yield: 83%; colorless oil; [
a
]
D
ꢀ8.3 (c 0.13, CH2Cl2) [lit.10
;
20
[
a
]
D
ꢀ8.8 (c 0.10, CH2Cl2, 50% ee)]; IR (KBr): 3431, 2919, 1576,
d
1492, 1346, 1267, 1197, 1097, 870, 847, 811, 667, 586 cmꢀ1 1H
;

S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
25
CDCl3):
d
= 142.5, 140.3, 132.9, 128.9, 127.9, 127.7, 127.4, 127.2,
5.13 (m, 1H), 3.92 (s, 3H), 2.80 (d, J = 4.4 Hz, 1H); 13C NMR
(100 MHz, CDCl3): = 158.4, 135.1, 129.8, 129.1, 128.4, 127.4,
127.2, 125.9, 124.4 (q, J = 281.1 Hz), 119.5, 105.7, 73.0 (q,
J = 31.9 Hz), 55.4. The ee was determined by HPLC on Chiralpak
OD-H (n-hexane/i-PrOH = 90/10, V/V, 1.0 mL/min, 254 nm), tR(ma-
jor) = 10.3 min, tS(minor) = 20.6 min, 51% ee.
124.3 (q, J = 281.0 Hz), 72.7 (q, J = 32.0 Hz). The ee was
determined by HPLC on Daicel Chiralpak OD-H (n-hexane/i-
PrOH = 90/10, V/V, 1.0 mL/min, 254 nm), tR(major) = 10.0 min,
tS(minor) = 12.8 min, 66% ee.
d
4.14. (R)-2,2,2-Trifluoro-1-(3-phenoxyphenyl)ethanol [20] (6m)
4.19. (R)-1-(Benzo[d][1,3]dioxol-5-yl)-2,2,2-trifluoroethan-ol [10]
(6r)
25
Yield: 87%; colorless oil; [
a
]
ꢀ8.8 (c 0.50, CH2Cl2); IR (KBr):
D
3447, 2926, 2843, 2357, 1606, 1491, 1458, 1438, 1262, 1170, 1126,
1044, 839, 788, 710, 631, 556 cmꢀ1 1H NMR (400 MHz, CDCl3):
= 7.37–7.32 (m, 3H), 7.18 (d, J = 8.0 Hz, 1H), 7.14–7.10 (m, 2H),
7.04–7.00 (m, 3H), 4.96 (m, 1H), 2.75 (d, J = 4.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): = 157.3, 156.4, 135.6, 129.7, 129.6, 123.8 (q,
J = 281.0 Hz), 123.4, 121.8, 119.3, 118.8, 117.5, 72.2 (q, J = 32.0 Hz).
The ee was determined by HPLC on Chiralpak OD-H (n-hexane/i-
PrOH = 95/5, V/V, 1.0 mL/min, 254 nm), tR(major) = 13.9 min,
tS(minor) = 28.6 min, 60% ee.
25
;
Yield: 92%; colorless oil; [
a
]
ꢀ16.7 (c 0.48, CH2Cl2) [lit.10
D
20
d
[a
]
D
ꢀ7.8 (c 0.55, CH2Cl2, 46% ee)]; IR (KBr): 3454, 2906, 2772,
1855, 1602, 1506, 1492, 1448, 1351, 1251, 1170, 1124, 1040, 930,
872, 810, 793, 730, 704, 636, 654, 560 cmꢀ1 1H NMR (400 MHz,
CDCl3): = 6.96 (s, 1H), 6.91 (d, J = 8.4 Hz, 1H), 6.81 (d, J = 8.0 Hz,
1H), 5.97 (s, 2H), 4.90 (m, 1H), 2.90 (d, J = 2.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3): = 148.6, 148.0, 127.8, 124.3 (q, J = 281.0 Hz),
d
;
d
d
121.6, 108.3, 107.7, 101.4, 72.6 (q, J = 32.0 Hz). The ee was
determined by HPLC on Chiralpak OD-H (n-hexane/i-PrOH = 97/
3, V/V, 1.0 mL/min, 254 nm), tR(major) = 27.9 min, tS(mi-
nor) = 34.7 min, 81% ee.
4.15. (R)-2,2,2-Trifluoro-1-(4-methoxyphenyl)ethanol [10] (6n)
25
Yield: 85%; colorless oil; [
a
]
ꢀ13.6 (c 0.27, CH2Cl2) [lit.10
D
20
[
a
]
ꢀ8.9 (c 1.00, CH2Cl2, 41% ee)]; IR (KBr): 3445, 3008, 2918,
4.20. (R)-1-(2,3-Dihydrobenzo[b][1,4]dioxin-6-yl)-2,2,2-tri-
fluoroethanol [22] (6s)
D
2842, 1614, 1587, 1517, 1465, 1444, 1356, 1252, 1207, 1171,
1127, 1075, 1031, 850, 819, 695, 589, 520 cmꢀ1 1H NMR
(400 MHz, CDCl3): = 7.40 (d, J = 8.4 Hz, 2H), 6.93 (d, J = 8.4 Hz,
2H), 4.97 (q, J = 3.2 Hz, 1H), 3.82 (s, 3H), 2.58 (s, 1H); 13C NMR
(100 MHz, CDCl3): = 160.5, 128.8, 126.2, 124.4 (q, J = 281.0 Hz),
;
25
d
Yield: 92%; colorless oil; [
a
]
D
ꢀ16.3 (c 0.54, CH2Cl2); IR (KBr):
3458, 2928, 1539, 1511, 1461, 1437, 1314, 1291, 1260, 1171, 1125,
1067, 921, 888, 846, 816, 725, 703, 664 cmꢀ1 1H NMR (400 MHz,
CDCl3): = 7.00 (s, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.88 (d, J = 8.4 Hz,
1H), 4.90 (m, 1H), 4.27 (s, 4H), 2.90 (d, J = 4.0 Hz, 1H); 13C NMR
(100 MHz, CDCl3): = 144.6, 143.6, 127.2, 124.3 (q, J = 281.0 Hz),
d
;
114.1, 72.5 (q, J = 32.0 Hz), 55.3. The ee was determined by HPLC
on Chiralpak OJ-H (n-hexane/i-PrOH = 95/5, V/V, 1.0 mL/min,
254 nm), tR(major) = 34.8 min, tS(minor) = 38.5 min, 67% ee.
d
d
120.6, 117.5, 116.6, 72.4 (q, J = 32.0 Hz), 64.4, 64.3. The ee was
determined by HPLC on Chiralpak OD-H (n-hexane/i-PrOH = 97/3,
V/V, 1.0 mL/min, 254 nm), tS(minor) = 44.9 min, tR(major) = 50.4 -
min, 79% ee.
4.16. (R)-2,2,2-Trifluoro-1-(3-methoxyphenyl)ethanol [21] (6o)
25
Yield: 89%; colorless oil; [
a
]
D
ꢀ13.6 (c 0.13, CH2Cl2); IR (KBr):
3442, 2926, 2843, 1357, 1605, 1589, 1491, 1458, 1438, 1262, 1170,
1126, 1044, 933, 839, 788, 760, 710, 631, 556 cmꢀ1 1H NMR
(400 MHz, CDCl3): = 7.38–7.30 (m, 1H), 7.04 (d, J = 7.6 Hz, 2H),
6.95–6.92 (m, 1H), 4.98 (m, 1H), 3.82 (s, 3H), 2.93 (s, 1H); 13C NMR
(100 MHz, CDCl3): = 159.8, 135.5, 129.7, 124.2 (q, J = 281.1 Hz),
;
4.21. (R)-1-(4-(Allyloxy)phenyl)-2,2,2-trifluoroethanol (6t)
d
25
Yield: 80%; white solid; mp 49–50 8C; [
a
]
ꢀ19.3 (c 0.20,
D
d
CH2Cl2); IR (KBr): 3408, 2929, 2863, 1888, 1614, 1515, 1428,
1324, 1305, 1247, 1178, 1117, 1070, 1013, 940, 871, 802, 693,
; d = 7.38 (d, J = 8.4 Hz, 2H),
589 cmꢀ1 1H NMR (400 MHz, CDCl3):
119.8, 115.1, 113.0, 72.8 (q, J = 31.8 Hz), 55.4. The ee was
determined by HPLC on Chiralpak OD-H (n-hexane/i-PrOH = 95/
5, V/V, 1.0 mL/min, 254 nm), tR(major) = 20.7 min, tS(mi-
nor) = 28.0 min, 74% ee.
6.95–6.92 (m, 2H), 6.10–6.00 (m, 1H), 5.41 (qd, J = 1.6, 17.2 Hz,
1H), 5.29 (qd, J = 1.2, 10.8 Hz, 1H), 4.98–4.92 (m, 1H), 4.54 (td,
J = 1.6, 5.2 Hz, 2H), 2.61 (br, 1H); 13C NMR (100 MHz, CDCl3):
4.17. (R)-2,2,2-Trifluoro-1-(2-methoxyphenyl)ethanol [12b] (6p)
d = 159.5, 133.0, 128.8, 126.3, 124.4 (q, J = 281.0 Hz), 117.9,
114.9, 72.5 (q, J = 32.0 Hz), 68.9; Anal. Calcd for C11H11F3O2: C,
56.90; H, 4.77. Found: C, 57.12; H, 4.87. The ee was determined
by HPLC on Chiralpak AD-H (n-hexane/i-PrOH = 97/3, V/V,
1.0 mL/min, 254 nm), tS(minor) = 18.0 min, tR(major) = 20.2 min,
66% ee.
25
Yield: 88%; colorless oil; [
a
]
D
ꢀ11.7 (c 0.24, CH2Cl2); IR (KBr):
3441, 3012, 2946, 2845, 1605, 1591, 1496, 1466, 1442, 1358, 1249,
1171, 1131, 1027, 871, 829, 781, 627, 593, 574, 538, 498 cmꢀ1; 1H
NMR (400 MHz, CDCl3):
1.2 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 5.27 (m, 1H), 3.86 (s, 3H), 3.75
(q, J = 4.0 Hz, 1H); 13C NMR (100 MHz, CDCl3):
= 157.6, 130.6,
d = 7.39–7.34 (m, 2H), 7.00 (dt, J = 7.6,
d
4.22. (R)-1-(4-(Ethylthio)phenyl)-2,2,2-trifluoroethanol (6u)
129.3, 124.7 (q, J = 282.0 Hz), 122.1, 121.1, 111.3, 69.9 (q,
J = 32.5 Hz), 55.8. The ee was determined by HPLC on Chiralpak
OJ-H (n-hexane/i-PrOH = 97/3, V/V, 1.0 mL/min, 254 nm), tS(mi-
nor) = 23.5 min, tR(major) = 27.4 min, 74% ee.
25
Yield: 85%; white solid; mp 47–49 8C; [
a
]
ꢀ16.7 (c 0.63,
D
CH2Cl2); IR (KBr): 3356, 2974, 2928, 2873, 1601, 1496, 1406,
1351, 1255, 1135, 1093, 1071, 1013, 868, 848, 811, 793, 680,
; d = 7.37 (d, J = 8.4 Hz,
586, 496 cmꢀ1 1H NMR (400 MHz, CDCl3):
4.18. (R)-2,2,2-Trifluoro-1-(6-methoxynaphthalen-2-yl)-ethanol
[20] (6q)
2H), 7.32 (d, J = 8.8 Hz, 2H), 4.93–4.50 (m, 1H), 2.96 (q, J = 7.2 Hz,
2H), 2.70 (s, 1H), 1.33 (t, J = 7.4 Hz, 3H); 13C NMR (100 MHz,
CDCl3):
d = 138.9, 131.1, 128.3, 127.9, 124.2 (q, J = 281.0 Hz),
25
Yield: 88%; white solid; m.p. 85–87 8C; [
a
]
D
ꢀ13.9 (c 0.11,
72.5 (q, J = 32.0 Hz), 27.1, 14.2; Anal. Calcd for C10H11F3OS: C,
50.84; H, 4.69. Found: C, 51.23; H, 4.76. The ee was determined
by HPLC on Chiralpak OJ-H (n-hexane/i-PrOH = 95/5, V/V,
1.0 mL/min, 254 nm), tR(major) = 26.2 min, tS(minor) = 30.2 min,
73% ee.
CH2Cl2); IR (KBr): 3265, 2924, 2838, 1632, 1509, 1489, 1468, 1267,
1173, 1128, 1080, 1033, 1018, 859, 727, 690, 474 cmꢀ1 1H NMR
(400 MHz, CDCl3): = 7.85 (s, 1H), 7.75 (t, J = 7.8 Hz, 2H), 7.52 (d,
J = 8.4 Hz, 1H), 7.17 (dd, J = 8.8, 2.6 Hz, 1H), 7.13 (d, J = 2.8 Hz, 1H),
;
d

26
S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
4.23. (IPr)CuF preparation; general procedure
1353, 1255, 1239, 1227, 1125, 1037, 1002, 928, 931, 816 cmꢀ1; 1H
NMR (400 MHz, DMSO-d6): = 8.81 (d, J = 4.4 Hz, 1H), 8.02 (d,
d
4.23.1. [1,3-Bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]
copper(I) chloride, (IPr)CuCl [23]
J = 5.2 Hz,1H), 7.77(d, J = 4.4 Hz, 1H), 7.60(t,J = 3.8 Hz,2H), 7.50(dd,
J = 9.2, 2.0 Hz, 1H), 7.44 (s, 1H), 7.38 (d, J = 7.6 Hz, 2H), 6.84 (s, 1H),
6.53 (s, 1H), 6.03 (ddd, J = 17.6, 10.0, 7.2 Hz, 1H), 5.25 (s, 1H), 5.22 (d,
J = 6.0 Hz, 1H), 5.00 (d, J = 12.8 Hz, 1H), 4.72 (d, J = 12.8 Hz, 1H),
4.23–4.19 (m, 1H), 4.07 (s, 3H), 3.96–3.94 (m, 1H), 3.85 (t, J = 9.2 Hz,
1H), 3.48(t,J = 11.4 Hz, 1H), 2.90(q, J = 9.6 Hz, 1H), 2.66(q, J = 8.4 Hz,
1H), 2.39 (s, 4H), 1.89 (s, 1H), 1.76 (t, J = 8.8 Hz, 2H), 1.12–1.05 (m,
An oven-dried Schlenk flask containing 1,3-bis(2,6-di-iso-pro-
pylphenyl) imidazolium chloride (849.0 mg, 2.00 mmol), CuCl
(198.0 mg, 2.00 mmol), NaOt-Bu (192.0 mg, 2.00 mmol) was evacu-
ated and refilled with argon three times. THF (10 mL) were added to
this Schlenk flask. The resulting suspension was stirred at room
temperature for 4 h. Then, it was filtered through Celite in glovebox.
Yield: 81%; white powder; IR (KBr): 3160, 3137, 3070, 2968,
2926, 2869, 1963, 1577, 1469, 1456, 1405, 1383, 1327, 1114, 1104,
1212, 1058, 937, 946, 809, 765, 742, 699 cmꢀ1; 1H NMR (400 MHz,
1H); 13C NMR (100 MHz, DMSO-d6):
d = 157.9, 147.9, 144.2, 144.0,
140.4, 137.7, 134.0, 131.9, 130.1, 125.9, 125.2, 121.9, 120.8, 117.5,
102.8, 67.7, 65.1, 63.6, 56.4, 56.1, 54.2, 37.2, 26.9, 23.6, 21.4, 21.1;
HRMS calcd for [C28H33N2O2]+: 429.2536, found 429.2540.
CDCl3):
d = 7.48 (t, J = 8.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 4H), 7.11 (s,
2H), 2.53–2.60 (m, 4H), 1.30 (d, J = 12 Hz, 12H), 1.22 (d, J = 6.8 Hz,
4.24.2. N-(4-Trifluoromethylbenzyl)quinidinium bromide (1b) [25]
12H); 13C NMR (100 MHz, CDCl3):
124.2, 123.2, 28.8, 24.9, 23.9.
d
= 180.6, 145.6, 134.4, 130.6,
Yield: 87%; white solid; mp 218 8C (decomp.); [a D
]
+184.2 (c
28
0.15, CH3OH); IR (KBr): 3398, 3209, 2954, 1621, 1589, 1509, 1373,
1427, 1325, 1227, 1241, 1170, 1125, 1068, 1021, 1003, 934, 864,
832 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d = 8.82 (d, J = 4.4 Hz, 1H),
4.23.2. [1,3-Bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]-
copper(I) tert-butoxide, (IPr)Cu(Ot-Bu) [24]
8.02 (d, J = 9.2 Hz, 1H), 7.97 (dd, J = 10.4, 9.2 Hz, 4H), 7.77 (d,
J = 4.4 Hz, 1H), 7.51 (dd, J = 9.2, 2.4 Hz, 1H), 7.44 (d, J = 2.4 Hz, 1H),
6.84 (d, J = 3.6 Hz, 1H), 6.52 (s, 1H), 6.03 (ddd, J = 17.4, 10.5, 6.9 Hz,
1H), 5.25 (s, 1H), 5.10 (d, J = 8.4 Hz, 2H), 4.85 (d, J = 12.8 Hz, 1H), 4.28–
4.22 (m, 1H), 4.06 (s, 3H), 4.02–4.00 (m, 1H), 3.86 (t, J = 9.4 Hz, 1H),
3.50 (t, J = 11.4 Hz, 1H), 3.00–2.90 (m, 1H), 2.69–2.63 (m, 1H), 2.40 (t,
J = 11.4 Hz, 1H), 1.91 (s, 1H), 1.79–1.75 (m, 2H), 1.15–1.07 (m, 1H).
In a glovebox, a 30 mL round-bottom flask was charged with
(IPr)CuCl (969.0 mg, 2.00 mmol) and NaOt-Bu (192.0 mg,
2.00 mmol). Anhydrous THF (12.0 mL) was added. The resulting
opaque brown solution was stirred for 2.0 h. It was filtered through
Celite in glovebox and concentrated in vacuo.
Yield: 79%; off-white powder; IR (KBr): 3396, 3136, 3073, 2263,
2927, 2869, 1593, 1470, 1407, 1385, 1364, 1330, 1213, 1060, 935,
13C NMR (100 MHz, DMSO-d6):
d = 158.0, 147.9, 144.2, 143.8,
805, 758, 745 cmꢀ1
;
1H NMR (400 MHz, CDCl3):
d
= 7.48 (t,
137.7, 135.1, 133.0, 131.9, 130.9 (q, J = 31.8 Hz), 126.4, 126.3,
125.9, 123.1, 121.7, 120.8, 117.5, 103.0, 68.1, 65.2, 62.9, 56.5, 56.2,
54.5, 37.2, 26.8, 23.6, 21.1.
J = 8.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 4H), 7.11 (s, 2H), 2.53–2.60
(m, 4H), 1.30 (d, J = 6.8 Hz, 12H), 1.26 (s, 9H), 1.22 (d, J = 6.8 Hz,
12H); 13C NMR (100 MHz, CDCl3):
124.2, 123.2, 31.2, 28.8, 24.9, 23.9.
d = 180.6, 145.6, 134.4, 130.6,
4.24.3. N-(9-Anthrylmethyl)quinidinium chloride (1c) [26]
Yield: 80%; light yellow solid; m.p. 161 8C (decomp.) (lit.26 mp
28
4.23.3. [1,3-Bis(2,6-di-iso-propylphenyl)imidazol-2-ylidene]-
copper(I) fluoride, (IPr)CuF [15f]
160 8C, decomp.); [
a
]
D
+390.0 (c 0.12, CH3OH); IR (KBr): 3394,
3183, 1621, 1508, 1458, 1473, 1431, 1258, 1362, 1240, 1227, 1029,
922, 864, 744 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
= 8.98 (s, 1H),
In glovebox, (IPr)CuOt-Bu (1043 mg, 2.00 mmol) and benzene
(18 mL) were added to a 50 mL round-bottom flask equipped with
a Teflon-coated stirbar. The flask was sealed with a rubber septum
and took out from the glovebox. Triethylamine tris(hydrofluoride)
d
8.86 (d, J = 4.4 Hz, 1H), 8.79 (d, J = 9.2 Hz, 1H), 8.70 (d, J = 9.2 Hz,
1H), 8.28 (dd, J = 8.2, 3.0 Hz, 2H), 8.05 (d, J = 9.2 Hz, 1H), 7.90 (d,
J = 4.4 Hz, 1H), 7.82–7.74 (m, 3H), 7.69–7.64 (m, 3H), 7.53 (dd,
J = 7.6, 2.4 Hz, 1H), 6.98 (s, 1H), 6.33 (d, J = 14.4 Hz, 1H), 6.03 (ddd,
J = 17.2, 10.2, 7.2 Hz, 1H), 5.88 (d, J = 14.0 Hz, 1H), 5.18 (d,
J = 10.4 Hz, 1H), 5.08 (d, J = 17.2 Hz, 1H), 4.46 (t, J = 9.2 Hz, 2H),
4.21 (s, 4H), 3.18 (t, J = 11.2 Hz, 1H), 2.62–2.54 (m, 1H), 2.46–2.35
(m,2H), 1.78 (s, 1H), 1.69 (d, J = 8.4 Hz, 1H), 1.56–1.53 (m, 1H),
1.10–1.04 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d = 157.9, 147.9,
144.3, 137.9, 133.5, 133.3, 132.5, 131.8, 131.7, 131.6, 130.2, 128.3,
128.0, 126.1, 126.0, 125.3, 125.0, 122.3, 121.0, 119.3, 117.5, 103.2,
67.9, 65.7, 56.5, 56.1, 55.8, 55.6, 37.7, 26.1, 24.2, 21.6.
(110.0
mL, 0.67 mmol, 0.33 equiv.) was added via a syringe. The
resulting white suspension was stirred for 6 h at room tempera-
ture. The solvent was removed under reduced pressure. In the
glovebox, the white solid was suspended in hexane (5 mL), filtered,
and washed with hexane (5 mL).
Yield: 85%; white powder; IR (KBr): 3166, 3138, 3076, 3031,
1963, 2926, 2869, 1591, 1467, 1402, 1362, 1329, 1276, 1209, 1181,
1061, 944, 807, 766, 744, 699, 560, 542 cmꢀ1 1H NMR (400 MHz,
;
CDCl3):
d = 7.48 (t, J = 8.0 Hz, 2H), 7.29 (d, J = 7.6 Hz, 4H), 7.14 (s,
2H), 2.51–2.58 (m, 4H), 1.30 (d, J = 6.8 Hz, 12H), 1.22 (d, J = 6.8 Hz,
12H); 13C NMR (100 MHz, CDCl3):
124.2, 123.2, 28.8, 24.7, 24.0.
d
= 180.5, 145.6, 134.6, 130.5,
4.24.4. N-(2-F-4-Br-benzyl)quinidinium bromide (1d)
28
Yield: 79%; white solid; m.p. 174–176 8C (decomp.); [a]
D
+143.3 (c 0.14, CH3OH); IR (KBr): 3387, 3198, 3006, 1621, 1520,
4.24. Ammonium bromides of cinchona alkaloids; general procedure
1473, 1460, 1431, 1338, 1259, 1241, 1205, 1113, 1026, 851, 828,
; d = 8.81 (d, J = 4.4 Hz,
719 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
Toa flame-dried flask equipped witha magneticstirring bar and a
condenser was added with cinchona alkaloids (1 mmol), toluene
(5 mL), and benzyl bromide derivatives (1.2 mmol, 1.2 equiv.). The
mixture was heated at 80 8C until a TLC analysis showing that the
starting material was completely consumed. Cooled to room
temperature and poured onto Et2O (30 mL) with stirring, the
resultingsuspension was stirredfor another 1 h. Then the precipitate
was purified by flash chromatography (MeOH/EtOAc = 1/10, V/V).
1H), 8.02 (d, J = 9.2 Hz, 1H), 7.87–7.76 (m, 3H), 7.67 (dd, J = 8.4,
1.6 Hz, 1H), 7.50 (dd, J = 9.2, 2.0 Hz, 1H), 7.41 (d, J = 2.4 Hz, 1H),
6.86 (d, J = 2.8 Hz, 1H), 6.51 (s, 1H), 6.03 (ddd, J = 17.2, 10.4, 6.8 Hz,
1H), 5.25–5.23 (m, 2H), 5.06 (d, J = 12.4 Hz, 1H), 4.77 (d, J = 12.4 Hz,
1H), 4.19 (t, J = 9.6 Hz, 1H), 4.06 (s, 3H), 3.97–3.85 (m, 2H), 3.44 (t,
J = 11.2 Hz, 1H), 3.12 (q, J = 10.0 Hz, 1H), 2.68–2.62 (m,1H), 2.36 (t,
J = 11.2 Hz, 1H), 2.00 (s, 1H), 1.82–1.75 (m, 2H), 1.10–1.03 (m, 1H);
13C NMR (100 MHz, DMSO-d6):
d = 162.1 (d, J = 252.2 Hz), 157.9,
147.9, 144.2, 143.8, 137.6, 131.9, 129.0, 125.8, 125.5 (d,
J = 10.1 Hz), 121.9, 120.7, 120.3 (d, J = 25.7 Hz), 117.5, 115.4 (d,
J = 13.7 Hz), 102.8, 67.9, 65.3, 56.8, 56.1, 54.7, 37.4, 26.6, 23.7, 21.0;
HRMS calcd for [C33H35F6N2O2]+: 511.1391, found 511.1398.
4.24.1. N-(4-Methylbenzyl)quinidinium bromide (1a)
Yield: 80%; white solid; mp 240 8C (decomp.); [a D
0.35, CH3OH); IR (KBr): 3406, 3054, 1620, 1585, 1508, 1467, 1417,
28
]
+154.3 (c

S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
27
4.24.5. N-(2,4,5-Trifluorobenzyl)quinidinium bromide (1e)
Yield: 69%; white solid; m.p. 182–185 8C (decomp.); [
+194.8 (c 0.19, CH3OH); IR (KBr): 3394, 3198, 3006, 1621, 1520,
precipitate was purified by flash chromatography (MeOH/
EtOAc = 1/10, V/V).
28
D
a]
Yield: 75%; white solid; mp 218 8C (decomp.); [a]
28 +197.2 (c
D
1473, 1469, 1431, 1338, 1259, 1241, 1226, 1205, 1158, 1113, 1026,
0.14, CH3OH); IR (KBr): 3386, 2951, 2361, 1621, 1590, 1509, 1473,
1459, 1431, 1358, 1241, 1227, 1207, 1026, 1001, 934, 866, 828,
851, 828, 719 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d = 8.82 (d,
J = 4.4 Hz, 1H), 8.16–8.10 (m, 1H), 8.02 (d, J = 9.2 Hz, 1H), 7.91–7.85
(m, 1H), 7.76 (d, J = 4.4 Hz, 1H), 7.50 (dd, J = 9.6, 2.8 Hz, 1H), 7.40 (d,
J = 2.4 Hz, 1H), 6.84 (d, J = 2.8 Hz, 1H), 6.50 (s, 1H), 6.03 (ddd,
J = 17.2, 10.4, 6.8 Hz, 1H), 5.26–5.21 (m, 2H), 5.01 (d, J = 12.8 Hz,
1H), 4.77 (d, J = 13.6 Hz, 1H), 4.23–4.18 (m, 1H), 4.06 (s, 3H), 3.94–
3.82 (m, 2H), 3.49 (t, J = 11.4 Hz, 1H), 3.22–3.15 (m, 1H), 2.67–2.60
(m, 1H), 2.36 (t, J = 11.8 Hz, 1H), 1.90 (s, 1H), 1.84–1.75 (m, 2H),
717, 855 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d = 8.82 (d,
J = 4.0 Hz, 2H), 8.07 (s, 1H), 8.03 (d, J = 8.8 Hz, 2H), 7.90 (d,
J = 7.6 Hz, 2H), 7.78 (d, J = 4.4 Hz, 2H), 7.74 (d, J = 7.6 Hz, 1H), 7.52
(d, J = 2.0 Hz, 1H), 7.50 (d, J = 2.0 Hz, 1H), 7.44 (d, J = 2.0 Hz, 2H),
6.83 (d, J = 3.2 Hz, 2H), 6.56 (s, 2H), 6.03 (ddd, J = 16.8, 10.4, 6.8 Hz,
2H), 5.22–5.12 (m, 6H), 4.82 (d, J = 12.4 Hz, 2H), 4.24–4.19 (m, 2H),
4.09–3.99 (m, 8H), 3.85–3.80 (m, 2H), 3.53–3.47 (m, 2H), 3.27–3.22
(m, 2H), 2.77–2.70 (m, 2H), 2.42 (t, J = 11.4 Hz, 2H), 1.91 (s, 2H),
1.76–1.74 (m, 4H), 1.16–1.12 (m, 2H); 13C NMR (100 MHz, DMSO-
1.10–1.05 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
d = 158.0 (ddd,
J = 244.1, 9.9, 2.3 Hz), 157.9, 151.5 (dt, J = 251.2, 13.6 Hz), 147.9,
146.7 (ddd, J = 241.8, 12.6, 2.4 Hz), 144.2, 143.7, 137.7, 131.9,
125.9, 123.8 (dd, J = 19.1, 2.7 Hz), 122.0, 120.7, 117.6, 112.8 (dt,
J = 17.0, 5.6 Hz), 107.5 (dd, J = 29.5, 21.4 Hz), 102.7, 68.0, 65.3, 56.4,
56.1, 56.0, 54.7, 37.5, 26.6, 23.7, 21.0; HRMS calcd for
[C27H28F3N2O2]+: 469.2097, found 469.2098.
d6): d = 158.0, 147.9, 144.2, 143.9, 139.2, 137.7, 135.7, 131.9, 130.2,
129.0, 125.9, 121.8, 120.9, 117.5, 102.8, 68.0, 65.1, 63.3, 56.2, 54.1,
37.3, 26.9, 23.5, 21.1.
4.24.9. N-(3,5-Ditrifluoromethylbenzyl)cinchonium bromide (3) [27]
Yield 72%; white solid; m.p. 237 8C (decomp.); [
0.12, CH3OH); IR (KBr): 3411, 3220, 3018, 2956, 1510, 1460, 1372,
1279, 1238, 1179, 1135, 920, 763, 710, 683 cmꢀ1 1H NMR
(400 MHz, DMSO-d6): = 9.00 (d, J = 4.4 Hz, 1H), 8.59 (s, 2H), 8.37
a]
D
28 +153.1 (c
4.24.6. N-(3,5-Ditrifluoromethylbenzyl)quinidinium bromide (1f)
[27]
;
Yield: 85%; white solid; mp 177 8C (decomp.); [
a
]
D
28 +176.1 (c
d
0.19, CH3OH); IR (KBr): 3394, 3201, 2954, 2664, 1622, 1509, 1473,
1432, 1374, 1281, 1214, 1226, 1178, 1135, 1027, 1005, 866, 905,
(d, J = 4.8 Hz, 1H), 8.34 (s, 1H), 8.12 (d, J = 8.4 Hz, 1H), 7.87 (d,
J = 6.8 Hz, 1H), 7.84 (d, J = 4.4 Hz 1H), 7.77 (t, J = 7.6 Hz, 1H), 6.76 (d,
J = 3.6 Hz, 1H), 6.50 (s, 1H), 6.01 (ddd, J = 17.4, 10.2, 7.2 Hz, 1H),
5.32 (d, J = 12.4 Hz, 1H), 5.28 (s, 1H), 5.24 (d, J = 3.2 Hz, 1H), 5.14 (d,
J = 12.4 Hz, 1H), 4.34 (t, J = 9.6 Hz, 1H), 4.04 (t, J = 7.6 Hz, 1H), 3.90
(t, J = 9.2 Hz, 1H), 3.50 (t, J = 11.2 Hz, 1H), 3.03 (q, J = 10.0 Hz, 1H),
2.62 (q, J = 8.4 Hz, 1H), 2.32 (t, J = 11.6 Hz, 1H), 1.89 (s, 1H), 1.80–
1.75 (m, 2H), 1.13–1.06 (m, 1H); 13C NMR (100 MHz, DMSO-d6):
843, 828, 709, 682 cmꢀ1; 1H NMR (400 MHz, DMSO-d6):
d = 8.82 (d,
J = 4.8 Hz, 1H), 8.56 (s, 2H), 8.38 (s, 1H), 8.04 (d, J = 9.2 Hz, 1H), 7.77
(d, J = 4.4 Hz, 1H), 7.53 (dd, J = 7.2, 2.4 Hz 1H), 7.44 (d, J = 2.4 Hz,
1H), 6.78 (d, J = 3.2 Hz, 1H), 6.48 (s, 1H), 6.04 (ddd, J = 17.4, 10.2,
7.2 Hz, 1H), 5.28 (d, J = 2.8 Hz, 1H), 5.22 (d, J = 12.4 Hz, 2H), 5.01 (d,
J = 12.8 Hz, 1H), 4.34 (t, J = 10.0 Hz, 1H), 4.10–4.13 (m, 1H), 4.06 (s,
3H), 3.80 (t, J = 9.4 Hz, 1H), 3.48 (t, J = 11.4 Hz, 1H), 3.04 (q,
J = 9.6 Hz, 1H), 2.62 (q, J = 8.4 Hz, 1H), 2.42 (t, J = 11.6 Hz, 1H), 1.91
(s, 1H), 1.85–1.72 (m, 2H), 1.20–1.13 (m, 1H); 13C NMR (100 MHz,
d
= 147.9, 144.2, 143.7, 137.7, 135.1, 131.9, 131.7, 131.3 (q,
J = 33.0 Hz), 127.7, 125.1, 123.7 (q, J = 271.3 Hz), 121.4, 120.9,
117.6, 103.1, 68.5, 65.2, 61.8, 56.2, 54.7, 37.4, 26.9, 23.6, 21.0.
DMSO-d6):
d = 158.1, 147.9, 144.2, 143.7, 137.8, 135.1, 132.0,
131.7, 131.3 (q, J = 33.1 Hz), 130.1, 126.0, 125.0, 124.6 (q,
J = 4.1 Hz), 123.7 (q, J = 271.3 Hz), 121.5, 120.9, 117.6, 103.1,
68.4, 65.2, 61.8, 56.3, 56.2, 54.7, 37.4, 26.9, 23.6, 21.1.
4.24.10. N-(3,5-Ditrifluoromethylbenzyl)-60-(cyclopentyloxy)-
quinidinium bromide (4a)
28
Yield: 62%; white solid; m.p. 165–169 8C (decomp.); [a D
]
+
116.5 (c 0.17, CH2Cl2); IR (KBr): 3427, 3201, 2961, 1712, 1619, 1507,
4.24.7. N-(3,300,5,500-Tetrakis(trifluoromethyl)-1,10:30,100-
terbenzyl)quinidinium bromide (1g) [27]
1461, 1373, 1281, 1239, 1223, 1177, 1138 cmꢀ1; 1H NMR (400 MHz,
CDCl3):
d = 8.42 (d, J = 4.8 Hz, 1H), 8.31 (s, 2H), 7.85 (s,1H), 7.80 (d,
Yield: 71%; white solid; mp 186 8C (decomp.); [
a
]
D
28 +129.5 (c
J = 9.2 Hz, 1H), 7.73 (d, J = 4.8 Hz, 1H), 7.67 (d, J = 2.4 Hz, 1H), 7.05
(dd, J = 9.8, 2.4 Hz, 1H), 6.66 (d, J = 6.0 Hz, 1H), 6.47 (s, 1H), 6.23 (d,
J = 12.4 Hz, 1H), 6.02 (d, J = 12.4 Hz, 1H), 5.87 (ddd, J = 17.6, 10.4,
7.2 Hz, 1H), 5.25(d, J = 9.6 Hz, 1H), 5.20(s, 1H), 4.79(t,J = 5.6 Hz,1H),
4.64 (m, 1H), 4.23 (t, J = 9.6 Hz, 2H), 3.19 (t, J = 11.6, 1H), 3.09 (q,
J = 7.2 Hz, 1H), 2.73 (q, J = 9.6 Hz, 1H), 2.42 (q, J = 8.8 Hz, 1H), 2.31 (t,
J = 12.8 Hz, 1H), 1.90–1.82 (m, 8H), 1.65–1.63 (m, 2H), 1.00–0.94 (m,
0.14, CH3OH); IR (KBr): 3402, 3196, 2946, 1711, 1621, 1509, 1432,
1280, 1239, 1226, 1176, 1134, 1029, 1002, 900, 885, 844, 827, 718,
704, 683, 640 cmꢀ1
; d = 8.39 (d,
1H NMR (400 MHz, CDCl3):
J = 4.4 Hz, 1H), 8.29 (s, 2H), 8.00 (s, 4H), 7.84 (s, 2H), 7.69 (d,
J = 6.0 Hz, 2H), 7.60 (s, 1H), 7.42 (s, 1H), 6.94 (d, J = 8.8 Hz, 1H), 6.71
(d, J = 5.6 Hz, 1H), 6.44 (s, 1H), 6.00 (s, 2H), 5.88 (ddd, J = 17.0, 10.2,
7.0 Hz, 1H), 5.23–5.17 (m, 2H), 4.66 (t, J = 10.0 Hz, 1H), 4.36 (t,
J = 10.0 Hz, 1H),4.10 (t, J = 9.0 Hz, 1H), 3.77 (s, 3H), 3.34 (t, J = 11.2,
1H), 2.98 (q, J = 10.0 Hz, 1H), 2.28–2.43 (m, 2H), 1.82 (s, 1H), 1.78
(d, J = 8.4 Hz, 2H), 0.90–0.83 (m, 1H); 13C NMR (100 MHz, DMSO-
1H); 13C NMR (100 MHz, CDCl3):
d = 156.5, 146.7, 143.6, 142.0,
134.8, 133.8, 132.0 (q, J = 33.9 Hz), 131.3, 130.4, 126.3, 122.6 (q,
J = 271.9 Hz), 121.1, 120.4, 118.5, 105.2, 79.9, 68.6, 67.7, 60.3, 56.6,
54.5, 46.1, 37.9, 32.9, 27.1, 24.2, 23.9, 21.9; HRMS calcd for
[C33H35F6N2O2]+: 605.2597, found 605.2598.
d6):
d = 157.8, 147.0, 143.9, 142.1, 139.8, 135.1, 133.1, 132.5 (q,
J = 33.4 Hz), 131.5, 130.2, 127.3, 127.2, 127.1, 126.0, 123.1 (q,
J = 272.0 Hz), 122.1 (q, J = 3.4 Hz), 120.4, 120.1, 118.4, 102.8, 68.2,
66.8, 61.5, 56.9, 56.3, 54.5, 38.1, 27.1, 24.0, 21.7.
4.24.11. N-(3,5-Ditrifluoromethyl)benzyl-O(9)-(3,5-ditrifluoro-
methylbenzyl)quinidinium bromide (4b)
To a suspension of N-(3,5-ditrifluoromethylbenzyl)-quinidi-
nium bromide (632.5 mg, 1.0 mmol) in dichloromethane (3 mL)
4.24.8. 1,3-Bis(quinidinium-N-methylene)benzene dibromide (2)
[27]
was added 3,5-ditrifluoro-methylbenzyl bromide (920.0
mL,
A mixture of quinidine (324.4 mg, 1.0 mmol) with
a
,
a0
-
5.0 mmol) and 50% aqueous KOH (560.0 L, 5.0 mmol). The
m
dibromo-m-xylene (132.0 mg, 0.5 mmol) in a mixture of ethanol
(1 mL), DMF (1.2 mL), and chloroform (0.4 mL) was stirred at
100 8C for 8 h. After cooling the reaction mixture to room
temperature, the reaction mixture was diluted with methanol
(40 mL) and then added to ether (200 mL) dropwise with
stirring. The solid precipitated was filtered. The resulting
resulting mixture was stirred vigorously at room temperature
for 4 h. The mixture was diluted with water (5 mL) and extracted
with dichloromethane (3ꢁ 20 mL). The combined organic extracts
were dried over Na2SO4, filtered and concentrated in vacuo. The
crude solid was purified by flash chromatography (MeOH/
EtOAc = 1/10, V/V).

28
S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
Yield: 63%; white solid; mp 150 8C (decomp.); [
a
]
28 +78.1 (c
chromatography (MeOH/EtOAc = 1/20, V/V). The product was
obtained as pale white solid.
D
0.31, CH2Cl2); IR (KBr): 3420, 2961, 1622, 1508, 1475, 1433,
1372, 1280, 1241, 1227, 1177, 1135, 1030, 902, 843, 828, 707,
Yield 46%; pale white solid; mp 246 8C (decomp.); [a]
28 +68.9
D
683 cmꢀ1
;
1H NMR (400 MHz, DMSO-d6):
d
= 8.80 (d, J = 2.8 Hz,
(c 0.33, CH3OH); IR (KBr): 3462, 2950, 1622, 1601, 1497, 1463,
1H), 8.53 (s, 2H), 8.39 (s, 1H), 8.27 (s, 2H), 8.09 (s, 1H), 8.04 (d,
J = 9.2 Hz, 1H), 7.75 (d, J = 1.2 Hz, 1H), 7.56–7.48 (m, 2H), 6.57 (s,
1H), 6.01–5.96 (m, 1H), 5.19–5.02 (m, 5H), 4.68 (d, J = 12.0 Hz,
1H), 4.07 (s, 4H), 3.86–3.83 (m, 1H), 3.58–3.52 (m, 1H), 3.00–
2.93 (m, 1H), 2.64 (d, J = 9.2 Hz, 2H), 1.98 (s, 1H), 1.81–1.74 (m,
2H),1.45–1.42 (m, 1H), 0.86–0.74 (m, 1H); 13C NMR (100 MHz,
1427, 1375, 1280, 1245, 1181, 1135, 1083, 903, 845, 748, 683,
483 cmꢀ1 1H NMR (400 MHz, CDCl3):
; d = 9.26 (s, 1H), 8.83 (d,
J = 3.6 Hz, 1H), 8.27 (s, 1H), 8.05 (d, J = 9.2 Hz, 2H), 7.97 (s,1H),
7.72–7.70 (m, 1H), 7.58–7.39 (m, 7H), 6.34 (d, J = 12.0 Hz, 1H), 6.05
(s, 1H), 5.93 (ddd, J = 17.0, 10.0, 7.2 Hz, 1H), 5.37 (d, J = 10.4 Hz, 1H),
5.24–5.13 (m, 2H), 5.07 (d, J = 12.4 Hz, 1H), 4.53 (t, J = 9.4 Hz, 1H),
4.33–4.29 (m, 2H), 4.16–4.11 (m, 1H), 3.75 (d, J = 12.0 Hz, 1H), 3.06
(t, J = 11.4 Hz, 1H), 2.75–2.67 (m, 1H), 2.51–2.36 (m, 2H), 2.02 (s,
1H), 1.95 (t, J = 10.4 Hz, 1H), 1.17–1.12 (m, 1H); 13C NMR
CDCl3):
d = 184.6, 158.8, 146.7, 146.6, 146.5, 145.0, 141.3, 139.4,
137.8, 137.7, 134.9, 134.5, 134.4, 134.3, 132.5 (q, J = 33.0 Hz),
131.6, 130.2, 128.2 (q, J = 33.0 Hz), 124.6, 124.5, 124.4, 123.1 (q,
J = 271.7 Hz), 122.7 (q, J = 271.9 Hz), 122.3 (q, J = 2.8 Hz), 118.2,
101.7, 73.1, 69.4, 67.5, 61.5, 61.4, 56.1, 55.1, 37.7, 26.9, 23.6,
21.9, 11.0; HRMS calcd for [C38H33F12N2O2]+: 777.2344, found
777.2331.
(100 MHz, CDCl3):
d = 167.7, 157.4, 146.4, 144.1, 136.7, 135.8,
134.9, 134.0, 132.6 (q, J = 34.3 Hz), 132.3, 131.9, 130.9, 129.9,
129.8, 129.5, 129.4, 128.9, 125.9, 123.8, 122.7 (q, J = 272.4 Hz),
118.7, 104.8, 73.5, 72.0, 66.5, 59.4, 56.1, 54.4, 37.7, 27.0, 23.5, 21.7;
HRMS calcd for [C35H33F6N2O2]+: 627.2440, found 627.2434.
4.24.12. N-(3,5-Ditrifluoromethyl)benzyl-60-hydroxyquinidi-nium
bromide (4c)
4.24.14. N-(3,5-Ditrifluoromethylbenzyl)quinidinium fluoride (1f0)
The column of Amberlyst A-26 (OHꢀ form, 500 mg) was washed
with methanol. A solution of the N-(3,5-ditrifluoromethylbenzyl)-
quinidinium bromide (126.2 mg, 0.2 mmol) in methanol (5 mL)
was slowly passed through the column and the column then
washed with methanol. The eluent was neutralized until pH = 7
with HF and the solvents were removed in vacuo. The residue was
coevaporated with toluene three times and dried under vacuum
overnight and the chiral ammonium fluoride was used without
Ethanethiol (2.30 mL, 30.8 mmol) was added under argon
atmosphere to a stirred suspension of sodium hydride (370.0 mg,
15.4 mmol) in dry DMF (15 mL). Quinidine (500 mg, 1.5 mmol) in
dry DMF (7.5 mL) was added dropwise and the reaction mixture
was stirred at 110 8C for 13 h. The solvent and excess ethanethiol
were removed under reduced pressure. Then the 3,5-ditrifluor-
omethylbenzyl bromide (675.4 mg, 2.2 mmol) was added in THF
(9 mL). The reaction mixture was refluxed and monitored by TLC
analysis. The solvent was removed under reduced pressure and the
residue was purified by flash chromatography (MeOH/EtOAc = 1/
further purification.
28
Yield: 89%; light yellow solid; mp 190 8C (decomp.); [a]
D
20, V/V).
+127.2 (c 0.14, CH3OH); IR (KBr): 3462, 2950, 1622, 1601, 1497,
1463, 1427, 1375, 1280, 1245, 1181, 1135, 1083, 903, 845, 748,
683, 483 cmꢀ1 1H NMR (400 MHz, DMSO-d6):
; d = 8.83 (d,
28
Yield 52%; white solid; mp 258 8C (decomp.); [
a
]
D
+182.3 (c
0.16, CH3OH); IR (KBr): 3369, 3234, 1622, 1531, 1469, 1217, 1181,
1135, 1003, 927, 905, 864, 842, 736, 709, 683 cmꢀ1 1H NMR
(400 MHz, DMSO-d6): = 10.06 (s, 1H), 8.75 (d, J = 4.4 Hz, 1H), 8.63
(s, 2H), 8.37 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 4.4 Hz, 1H),
7.67 (d, J = 2.4 Hz, 1H), 7.38 (dd, J = 9.0, 2.2 Hz, 1H), 6.68 (d,
J = 3.6 Hz, 1H), 6.32 (s, 1H), 6.02 (ddd, J = 17.4, 10.5, 6.9 Hz, 1H),
5.38 (d, J = 12.4 Hz, 1H), 5.26–5.19 (m, 3H), 4.32 (t, J = 9.6 Hz, 1H),
4.13 (t, J = 9.6 Hz, 1H), 3.92 (t, J = 9.6 Hz, 1H), 3.49 (t, J = 11.2 Hz,
1H), 3.12–3.05 (m, 1H), 2.65–2.59 (m, 1H), 2.33 (t, J = 11.6 Hz, 1H),
1.89 (s, 1H), 1.83–1.78 (m, 2H), 1.17–1.09 (m, 1H); 13C NMR
;
J = 4.4 Hz, 1H), 8.53 (s, 2H), 8.38 (s,1H), 8.05 (d, J = 9.2 Hz, 1H),
7.78 (d, J = 4.4 Hz, 1H), 7.55 (dd, J = 9.2, 2.4 Hz, 1H), 7.44 (d,
J = 2.4 Hz, 1H), 6.75 (d, J = 2.8 Hz, 1H), 6.46 (s, 1H), 6.05 (ddd,
J = 17.6, 10.4, 7.2 Hz, 1H), 5.24–5.29 (m, 2H), 5.14 (d, J = 12.8 Hz,
1H), 4.97 (d, J = 12.8 Hz, 1H), 4.32 (t, J = 9.2 Hz, 1H), 4.05 (s, 3H),
4.03 (t, J = 12.0, 1H), 3.78 (t, J = 10.0 Hz, 1H), 3.49 (t, J = 11.4, 1H),
3.13–2.99 (m, 1H), 2.62 (q, J = 2.4 Hz, 1H), 2.43 (t, J = 11.4 Hz, 1H),
1.92 (s, 1H), 1.83–1.76 (m, 2H), 1.46–1.20 (m, 1H); 13C NMR
d
(100 MHz, DMSO-d6):
d = 158.1, 147.9, 144.1, 143.8, 137.7, 135.1,
(100 MHz, DMSO-d6):
d
= 156.5, 147.2, 143.4, 143.1, 137.7, 135.2,
132.0, 131.7, 131.3 (q, J = 33.1 Hz), 126.0, 124.7 (q, J = 1.9 Hz),
123.7 (q, J = 271.8 Hz), 121.4, 120.9, 117.6, 103.2, 68.5, 65.3, 61.9,
56.2, 54.8, 46.3, 44.7, 37.4, 26.9, 23.6, 21.0; HRMS calcd for
[C29H29F6N2O2]+: 551.2127, found 551.2135.
131.9, 131.7, 131.2 (q, J = 33.0 Hz), 126.1, 124.6 (q, J = 3.2 Hz),
123.7 (q, J = 271.8 Hz), 122.2, 120.4, 117.6, 105.1, 68.2, 65.3, 60.9,
56.3, 54.7, 37.3, 26.9, 23.6, 21.0; HRMS calcd for [C28H27F6N2O2]+:
537.1971, found 537.1959.
Acknowledgements
4.24.13. N-(3,5-Ditrifluoromethyl)benzyl-9-O-benzyl-60-
hydroxyquinidinium bromide (4d)
We thank National Natural Science Foundation of China
(20972016, 21172018) and Beijing Institute of Technology for
the financial support.
Sodium hydride (96.0 mg, 4.0 mmol) was added to a solution of
quinidine (324.4 mg, 1.0 mmol) in dry DMF (5 mL). Benzyl chloride
(173
mL, 1.5 mmol) was added dropwise. The reaction mixture was
stirred at room temperature for 20 h and quenched by water. The
aqueous phase was extracted with ethyl acetate. The organic layer
was washed with brine, dried over Na2SO4, concentrated in vacuo
to afford yellowish oil, which was used without purification.
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.jfluchem.2013.
01.027.
Ethanethiol (434.0
mL, 5.8 mmol) was added to a stirred suspen-
sion of sodium hydride (139.3 mg, 5.8 mmol) in dry DMF (3 mL).
The yellowish oil (300 mg) in dry DMF (3 mL) was added dropwise
and the reaction mixture was stirred at 110 8C for 15 h. The solvent
and excess ethanethiol were removed under reduced pressure. The
crude product was added the 3,5-ditrifluoromethylbenzyl bromide
(336.2 mg, 1.1 mmol) in THF (6 mL). The reaction mixture was
refluxed and monitored by TLC analysis. The solvent was removed
under reduced pressure and the residue was purified by flash
References
[1] (a) R.E. Banks, B.E. Smart, J.C. Tatlow, Organofluorine Chemistry: Principles and
Commercial Applications, Plenum Press, New York, 1994;
(b) I. Ojima, J.R. McCarthy, J.T. Welch (Eds.), Biomedical Frontiers of Fluorine
Chemistry, American Chemical Society, Washington, DC, 1996;
(c) M. Schlosser, Angew. Chem. Int. Ed. 45 (2006) 5432–5446;

S. Wu et al. / Journal of Fluorine Chemistry 148 (2013) 19–29
29
(d) S. Purser, P.R. Moore, S. Swallow, V. Gouverneur, Chem. Soc. Rev. 37 (2008)
320–330;
[14] (a) W. Nerinckx, M. Vandewalle, Tetrahedron: Asymmetry 1 (1990) 265–276;
´
(b) T. Perrard, J.-C. Plaquevent, J.-R. Desmurs, D. Hebrault, Org. Lett. 2 (2000)
(e) K. Mu¨ller, C. Faeh, F. Diederich, Science 317 (2007) 1881–1886;
(f) K.L. Kirk, Org. Process Res. Dev. 12 (2008) 305–321.
2959–2962;
(c) T. Ooi, K. Doda, K. Maruoka, Org. Lett. 3 (2001) 1273–1276;
(d) T. Ooi, D. Ohara, M. Tamura, K. Maruoka, J. Am. Chem. Soc. 126 (2004)
6844–6845;
[2] For some examples of pharmacophores containing a trifluoromethyl groups, see:
(a) K. Kirk, J. Fluorine Chem. 127 (2006) 1013–1029;
(e) T. Ooi, D. Ohara, K. Fukumoto, K. Maruoka, Org. Lett. 7 (2005) 3195–3197;
(f) S. Jew, J.-H. Lee, B.-S. Jeong, M.-S. Yoo, M.-J. Kim, Y.-J. Lee, J. Lee, S. Choi, K. Lee,
M.S. Lah, H. Park, Angew. Chem. Int. Ed. 44 (2005) 1383–1385;
(g) C. Palomo, M. Oiarbide, A. Laso, R. Lo´pez, J. Am. Chem. Soc. 127 (2005)
17622–17623;
(b) F.M.D. Ismail, J. Fluorine Chem. 118 (2002) 27–35;
(c) L.M. Jackson, C.J. Hawkey, Drugs 59 (2000) 1207–1216;
(d) M.L.P. Price, W.J. Jorgensen, J. Am. Chem. Soc. 122 (2000) 9455–9466;
(e) L. Tan, C.-Y. Chen, R.D. Tillyer, E.J.J. Grabowski, P.J. Reider, Angew. Chem. Int.
Ed. 38 (1999) 711–715.
(h) M. Lian, Z. Li, J. Du, Q. Meng, Z. Gao, Eur. J. Org. Chem. (2010) 6525–6530;
(i) C.D. Fiandra, L. Piras, F. Fini, P. Disetti, M. Moccia, M.F.A. Adamo, Chem.
Commun. (2010) 3863–3865.
[3] (a) G.K.S. Prakash, A.K. Yudin, Chem. Rev. 97 (1997) 757–786;
(b) R.P. Singh, M.J. Shreeve, Tetrahedron 56 (2000) 7613–7632;
(c) J.-A. Ma, D. Cahard, J. Fluorine Chem. 128 (2007) 975–996.
[4] (a) E. Franccotte, W. Lindner, Chirality in Drug Research, Wiley-VCH, Weinheim,
2006;
[15] (a) S. Yamasaki, K. Fujii, R. Wada, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 124
(2002) 6536–6537;
(b) K. Oisaki, Y. Suto, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 125 (2003)
5644–5645;
(b) I.K. Reddy, R. Mehvar, Chirality in Drug Design and Development, Marcel
Dekker, New York, 2004;
(c) R. Wada, K. Oisaki, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 126 (2004)
8910–8911;
(d) D. Tomita, R. Wada, M. Kanai, M. Shibasaki, J. Am. Chem. Soc. 127 (2005)
4138–4139;
(c) C.A. Challener, Chiral Intermediates and Chiral Drugs, Ashgate, Brookfield, 2001.
[5] (a) I. Ojima, Fluorine in Medicinal Chemistry and Chemical Biology, Blackwell,
Oxford, 2009;
(b) C. Isanbor, D.O. Hagan, J. Fluorine Chem. 127 (2006) 303–319;
(e) G.G. Dubinina, H. Furutachi, D.A. Vicic, J. Am. Chem. Soc. 130 (2008)
8600–8601;
(f) J.R. Herron, Z.T. Ball, J. Am. Chem. Soc. 130 (2008) 16486–16487;
(g) T. Fujihara, T. Xu, K. Semba, J. Terao, Y. Tsuji, Angew. Chem. Int. Ed. 50 (2011)
523–527.
´
´
(c) J.-P. Begue, D. Bonnet-Delpon, J. Fluorine Chem. 127 (2006) 992–1012.
[6] G.K.S. Prakash, R. Krishnamurti, G.A. Olah, J. Am. Chem. Soc. 111 (1989) 393–395.
[7] (a) N. Shibata, S. Mizuta, H. Kawai, Tetrahedron: Asymmetry 19 (2008) 2633–
2644;
(b) J.-A. Ma, D. Cahard, Chem. Rev. 108 (2008) PR1–PR43;
[16] C.B. Kelly, M.A. Mercadante, T.A. Hamlin, M.H. Fletcher, N.E. Leadbeater, J. Org.
Chem. 77 (2012) 8131–8141.
[17] S.V. Slungard, T.-A. Krakeli, T.H.K. Thvedt, E. Fuglseth, E. Sundby, B.H. Hoff,
Tetrahedron 67 (2011) 5642–5650.
(c) J. Gawronski, N. Wascinska, J. Gajewy, Chem. Rev. 108 (2008) 5227–5252.
[8] (a) K. Iseki, T. Nagai, Y. Kobayashi, Tetrahedron Lett. 35 (1994) 3137–3139;
(b) K. Iseki, Y. Kobayashi, Rev. Heteroat. Chem. 12 (1995) 211–237.
[9] (a) Y. Kuroki, K. Iseki, Tetrahedron Lett. 40 (1999) 8231–8234;
[18] A. Ohno, H. Yamamoto, S. Oka, J. Am. Chem. Soc. 103 (1981) 2041–2045.
[19] Q. Xu, H. Zhou, X. Geng, P. Chen, Tetrahedron 65 (2009) 2232–2238.
[20] Y. Yamauchi, S. Hara, H. Senboku, Tetrahedron 66 (2010) 473–479.
[21] R.P. Singh, D. Chakraborty, J.M. Shreeve, J. Fluorine Chem. 111 (2001) 153–160.
[22] Y. Fukuda, T. Kanai, Y. Nakasato, K. Kimpara, JP Patent 060654 (2011).
[23] V. Jurkauskas, J.P. Sadighi, S.L. Buchwald, Org. Lett. 5 (2003) 2417–2420.
[24] N.P. Mankad, D.S. Laitar, J.P. Sadighi, Organometallics 23 (2004) 3369–3371.
[25] J.M. Hutzler, J.S. Walker, L.C. Wienkers, Chem. Res. Toxicol. 16 (2003) 450–459.
[26] A. Berkessel, B. Seelig, S. Schwengberg, J. Hescheler, A. Sachinidis, ChemBioChem.
11 (2010) 208–217.
´
(b) S. Caron, N.M. Do, P. Arpin, A. Larivee, Synthesis (2003) 1693–1698;
(c) S. Roussel, T. Billard, B.R. Langlois, L. Saint-James, Chem. Eur. J. 11 (2005) 939–944;
(d) G.K.S. Prakash, J. Hu, in: Soloshonok (Ed.), Fluorine-Containing Synthons; ACS
Symposium Series 911, American Chemical Society, Washington, 2005, p. 16.
[10] H. Zhao, B. Qin, X. Liu, X. Feng, Tetrahedron 63 (2007) 6822–6826.
[11] H. Kawai, A. Kusuda, S. Mizuta, S. Nakamura, Y. Funahashi, H. Masuda, N. Shibata,
J. Fluorine Chem. 130 (2009) 762–765.
[12] (a) S. Mizuta, N. Shibata, S. Akiti, H. Fujimoto, S. Nakamura, T. Toru, Org. Lett. 9
(2007) 3707–3710;
(b) S. Mizuta, N. Shibata, M. Hibino, S. Nagano, S. Nakamura, T. Toru, Tetrahedron
63 (2007) 8521–8528.
[13] S. Wu, W. Zeng, Q. Wang, F.-X. Chen, Org. Biomol. Chem. 10 (2012) 9334–9337.
[27] K. Matoba, H. Kawai, T. Furukawa, A. Kusuda, E. Tokunaga, S. Nakamura, M. Shiro,
N. Shibata, Angew. Chem. Int. Ed. 49 (2010) 5762–5766.