Organocatalytic enantioselective Diels-Alder reaction of 4,4,4-trifluorocrotonaldehyde

Article abstract of DOI:10.1016/j.jfluchem.2015.05.011

A highly enantioselective Diels-Alder reaction of 4,4,4-trifluorocrotonaldehyde and dienes was performed with a diarylprolinol silyl ether catalyst. The reaction with cyclopentadiene, 1,3-cyclohexadiene, and 2-substituted 1,3-butadienes yielded the corresponding cycloadducts bearing a trifluoromethylated chiral carbon center with up to 97% ee, whereas the reaction with furan yielded the corresponding Friedel-Crafts adduct with high enantioselectivity.

Full text of DOI:10.1016/j.jfluchem.2015.05.011

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Journal of Fluorine Chemistry xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Organocatalytic enantioselective Diels–Alder reaction of
4,4,4-trifluorocrotonaldehyde
*
Kazutaka Shibatomi , Yohei Kawasaki, Seiji Iwasa
Department of Environmental and Life Sciences, Toyohashi University of Technology, 1-1 Hibarigaoka, Tempaku-cho, Toyohashi 441-8580, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
A
highly enantioselective Diels–Alder reaction of 4,4,4-trifluorocrotonaldehyde and dienes was
Received 15 April 2015
Received in revised form 18 May 2015
Accepted 19 May 2015
Available online xxx
performed with diarylprolinol silyl ether catalyst. The reaction with cyclopentadiene, 1,3-
a
cyclohexadiene, and 2-substituted 1,3-butadienes yielded the corresponding cycloadducts bearing a
trifluoromethylated chiral carbon center with up to 97% ee, whereas the reaction with furan yielded the
corresponding Friedel–Crafts adduct with high enantioselectivity.
ß 2015 Elsevier B.V. All rights reserved.
Keywords:
Asymmetric catalysis
Organocatalyst
Diels–Alder reaction
Trifluoromethyl compounds
Conjugate addition
1. Introduction
affords the corresponding cyclohexenes bearing a trifluoromethy-
lated stereogenic center with high enantioselectivity.
The introduction of fluorinated functional groups into biologi-
cally active compounds is a widely acknowledged method to
improve biological and/or pharmacokinetic properties in drug
discovery [1]. In particular, introducing a trifluoromethyl group
into drug candidates often increases the lipophilicity and
metabolic stability of the original compounds. Indeed, many
pharmaceutical and agricultural agents contain a trifluoromethyl
group(s) in their structure [2]. Furthermore, chiral compounds
bearing a trifluoromethylated stereogenic center have recently
attracted increased attention as drug candidates [3]. Therefore, the
development of efficient methods for the construction of
trifluoromethylated stereogenic centers is as important task in
the field of synthetic organic chemistry. Enantioselective functio-
nalization of trifluoromethylated alkenes is a useful synthetic
method for the preparation of chiral trifluoromethyl compounds
[3–5]. Recently, we developed an efficient method for the
preparation of 4,4,4-trifluorocrotonaldehyde (1) as a versatile
precursor for trifluoromethyl compounds, and successfully applied
it in the organocatalytic enantioselective conjugate addition with
several nucleophiles (Scheme 1) [4u]. Herein, we describe the
application of 1 in the organocatalytic Diels–Alder reaction that
2. Results and discussion
Chiral secondary amines such as MacMillan catalyst 2a and
Jørgensen–Hayashi catalyst 2b efficiently catalyze asymmetric
Diels–Alder reactions of
a,b-unsaturated aldehydes with dienes
via the formation of an iminium cation intermediate [6–
8]. Therefore, we initially attempted the reaction of 1 with
cyclopentadiene in the presence of 10 mol% 2a. In contrast to the
high enantioselectivity obtained in the reaction with crotonalde-
hyde (3) (Table 1, entry 1) [6], this reaction yielded nearly racemic
cycloadduct 4a with poor diastereoselectivity (entry 2) [9]. In this
case the poor selectivity occurs because the Diels–Alder reaction of
1
proceeds in the absence of the organocatalyst at room
temperature due to the increased reactivity induced by the strong
electron withdrawing trifluoromethyl group (entry 3). On the
other hand, conducting the reaction with catalyst 2b (10 mol%) and
HClO4 as the co-catalyst afforded the desired cycloadduct 4a in
high enantio- and diastereoselectivities (entry 5). The use of
diphenylprolinol TMS ether (2c) as the catalyst showed lower
enantioselectivity (entry 6), and the reaction with diarylprolinol
2d yielded nearly racemic products (entry 7). The reaction
proceeded smoothly in either toluene or water (entry 8) [7]. As
we envisioned, lower enantioselectivity was observed with a lower
catalyst loading of 5 mol% (entry 9), whereas the use of 20 mol%
catalyst did not improve the enantioselectivity (entry 10).
*
Corresponding author. Tel.: +81 532446810.
E-mail address: shiba@ens.tut.ac.jp (K. Shibatomi).
http://dx.doi.org/10.1016/j.jfluchem.2015.05.011
0022-1139/ß 2015 Elsevier B.V. All rights reserved.
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Our previous work
Next, we explored different dienes to expand the substrate
*
scope of the Diels–Alder reaction of 1. The results are summarized
in Table 2. The reaction of 1 with cyclohexadiene was very sluggish
and afforded cycloadduct 4b in poor yield (26%), but high
enantioselectivity (entry 1). The highest enantioselectivity was
observed when 2-methyl-1,3-butadiene was employed as the
diene, which afforded 4d in 58% yield as a mixture of regioisomers
(89:11) with 97% ee for the major isomer (entry 3). The reaction of
2-aryl-1,3-butadienes showed moderate enantioselectivity
(entries 4 and 5). On the other hand, when furan was used as
the diene, the Diels–Alder product was not obtained. In this case, a
Friedel–Crafts type 1,4-addition proceeded to afford the 1,4-
adduct with high enantioselectivity, which is similar to our
previous report (Scheme 2) [4u]. The 1,4-adduct with furan was
isolated after reduction of the aldehyde moiety to the primary
alcohol and subsequent benzoylation because of the high volatility
of both the aldehyde and alcohol products.
Nu
*
N
(cat.)
H
CHO
CHO
up to 99% ee
F3C
F3C
Nu-H
1
Nu = Ar, OR, SR
Diverse building block
for chiral CF3 molecules
This work
*
N
CHO
CF3
(cat.)
H
up to 97% ee
+
1
Diels–Alder
Scheme 1. Enantioselective functionalization of 4,4,4-trifluorocrotonaldehyde.
BzCl (1.5 equiv)
Et3N (4 equiv)
DMAP (30 mol%)
2b (10 mol%)
HClO4 (10 mol%)
O
O
NaBH4 (2 equiv.)
+
O
∗
∗
1
CH2Cl2, rt, 1 h
H2O, rt, 4 h
MeOH/CH2Cl2
rt, 15 min
F3C
OH
F3C
OBz
5 equiv.
5
6
52%
71% (2 steps)
94% ee
(determined by 1H NMR)
Scheme 2. Enantioselective Friedel–Crafts arylation of 1.
Table 1
Optimization of the reaction conditions.a
CHO
CF3
CF3
2 (10 mol%)
CHO
1: R = CF3
+
+
R
solvent, rt
CHO
endo-4a
5 equiv.
exo-4a
3: R = CH3
.
Ar
Ar
Ar
Ar
Me
O
•HCl
Ph
N
N
H
N
H
Ph
Me
Me
OTMS
OH
N
H
Bn
N
H
OTMS
Ar = 3,5-(CF3)2C6H3
Ar = 3,5-(CF3)2C6H3
2c
2a
2b
2d
Entry
Catalyst
Dienophile
Solvent
Time
% Yieldb (exo/endo)
% Eec (exo, endo)
1d,e
2
2a
3
1
1
3
1
1
1
1
1
1
MeOH/H2O (95/5)
MeOH/H2O (95/5)
Toluene
H2O
16 h
75 (50/50)
70 (75/25)
79 (80/20)
73 (72/28)
78 (90/10)
91 (89/11)
90 (79/21)
75 (90/10)
89 (85/15)
87 (91/9)
86, 90
4, 9
2a
3.5 h
3
None
30 min
4 h
–
4f
5
2b/HClO4 aq.
2b/HClO4 aq.
2c/HClO4 aq.
2d/HClO4 aq.
2b/HClO4 aq.
2b/HClO4 aq.
2b/HClO4 aq.
99, 99
88, 71
70, 40
2, 1
H2O
15 min
15 min
15 min
15 min
15 min
15 min
6
H2O
7
H2O
8
Toluene
Toluene
Toluene
89, 68
43, 18
90, 69
9e
10g
a
Reactions were carried out with cyclopentadiene (5 equiv.) in the presence of 2a or a combination of 2b/HClO4 (60% aqueous solution) as the catalyst.
b
c
d
e
f
Purified yields are indicated, which may have a small margin of error because of the volatility of 4a. Purified products contained <5% of an inseparable by-product.
Determined by HPLC analysis after reduction of the aldehyde and subsequent benzoylation.
Data is quoted from Ref. [6].
5 mol% catalyst.
Data is quoted from Ref. [7].
20 mol% catalyst.
g
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3
Table 2
Substrate scope of the enantioselective Diels–Alder reaction of 1.a
2b (10 mol%)
HClO4 (10 mol%)
CHO
CHO
CF3
.
+
diene
F3C
H2O, rt
1
5 equiv.
4
Entry
Diene
Product
Time (h)
53
% Yieldb
% Eec (major, minor)
94, 95
1
26 (92/8)d
CF3
CHO
CF3
4b
+
CHO
2
3
4
5
4
10
7
45
76
CHO
4c
CF3
58 (89/11)e
92 (85/15)e
59 (87/13)e
97, 91
52, 20
42, 42
CHO
CHO
+
4d
CF3
CF3
CHO Ph
CHO
4e
4f
+
Ph
Ph
Ar
CF3
CF3
12
CHO
Ar
CHO
+
Ar
CF3
CF3
Ar = 4-Br-C6H4
a
b
c
Reactions were carried out with 5 equiv. of diene in the presence of 10 mol% 2b and HClO4 (60% aqueous solution) as the catalyst.
Purified yields are indicated, but purified product contained <5% of an inseparable by-product.
Determined by HPLC analysis. Ee was measured after the derivatization to primary alcohols or their benzoates, except for entry 4.
Diastereomeric ratio.
d
e
Regioisomeric ratio.
3. Conclusions
Chemical Co., Inc. and used after purification with a Glass Contour
Solvent Dispensing System. Cyclopentadiene was cracked at 160 8C
and redistilled before use. 4,4,4-trifluorocrotonaldehyde (1) was
synthesized by MnO2 oxidation of 4,4,4-trifluorobut-2-en-1-ol in
mesitylene [4u]. The reaction mixture was roughly purified by
distillation to provide 1 containing 5–10% mesitylene, which was
used in the Diels–Alder reaction. We confirmed that the optical
purity of selected products 4a and 4d did not change even after
chromatographic purification using silica gel and subsequent
solvent evaporation [10].
A highly enantioselective Diels–Alder reaction of 4,4,4-trifluor-
ocrotonaldehyde (1) was developed with a diarylprolinol silyl
ether 2b as the catalyst. The reactions afforded the corresponding
cyclohexenes bearing a trifluoromethylated stereogenic center
with up to 97% ee. These cycloadducts are expected to be useful
synthetic intermediates for biologically active molecules.
4. Experimental
4.1. General information
4.2. General procedure for the Diels–Alder reaction of 1
All reactions were magnetically stirred. Thin layer chromatog-
raphy (TLC) was performed on Merck pre-coated silica gel plates
with F254 indicator. Visualization was accomplished using UV
light (254 nm) and potassium permanganate (KMnO4). Flash
column chromatography was performed using silica gel (mesh
A recovery flask was charged with H2O (200 mL), 2b
(0.04 mmol, 10 mol%), 60% HClO4 aqueous solution (0.04 mmol,
10 mol%), and 1 (0.4 mmol). After the solution was stirred for
15 min at room temperature, the diene (2.0 mmol, 5.0 equiv.) was
added to this solution, and the mixture was stirred at the same
temperature for the indicated time as described in Table 2. The
mixture was diluted with a saturated aqueous solution of NaHCO3,
and extracted with Et2O three times. The combined organic layer
was dried over anhydrous MgSO4, and evaporated under reduced
pressure. The crude product was purified by flash chromatography
on silica gel to give the corresponding aldehyde 4 containing <5%
of by-product. Complete purification of the products was
performed after the reduction to the corresponding primary
alcohols 7.
40–100
m F
m) supplied by Kanto Chemical Co., Inc. 1H, 13C, and 19
NMR spectra were recorded on a JEOL JNM-ECX400 (400 MHz 1H,
100 MHz 13C, 376 MHz 19F) or a JEOL JNM-ECX500 (500 MHz 1H,
126 MHz 13C, 470 MHz 19F). Chemical shift values (
d
) are reported
in ppm (tetramethylsilane
d
0.00 ppm for 1H; residual chloroform
d
77.0 ppm for 13C; trichlorofluoromethane
d
0.0 ppm or hexafluor-
obenzene
d
ꢀ162.2 ppm for 19F). High-performance liquid
chromatography (HPLC) analyses were performed on a JASCO
PU-1586 with a UV-1575 UV/VIS detector using a chiral column.
Optical rotations were measured on a JASCO P-1030 polarimeter.
DART mass (negative mode) analyses were performed using a JEOL
the AccuTOF TLC JMS-T100TD. Commercial grade reagents and
solvents were used without further purification unless otherwise
noted. Dry CH2Cl2 and toluene were purchased from Kanto
4.2.1. 3-(Trifluoromethyl)bicyclo[2.2.1]hept-5-ene-2-carbaldehyde
(4a)
The crude product was purified by flash chromatography on
silica gel (15:1 pentane/Et2O) to give 78% yield of 4a as a
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diastereomeric mixture (exo:endo = 90:10). The relative configu-
ration of the diastereomers was estimated based on the reported
diastereoselectivity in a similar reaction with the non-fluorinated
substrate. Correlation of the 1H NMR spectra with those of the non-
fluorinated analogues also support our assignment. The enantio-
meric excess was determined after conversion to benzoate 8a (vide
major regioisomer: 22.0 min (major enantiomer), 28.6 min (minor
enantiomer), minor regioisomer: 53.8 min (major enantiomer),
39.6 min (minor enantiomer). 4e (major regioisomer): 1H NMR
(400 MHz, CDCl3):
1H), 3.08–2.96 (m, 1H), 2.85–2.71 (m, 2H), 2.63–2.50 (m, 3H); 13
NMR (100 MHz, CDCl3): 200.8, 140.4, 134.6, 128.4, 127.5, 127.5
d 9.66 (s, 1H), 7.38–7.24 (m, 5H), 6.14–6.10 (m,
C
d
infra). exo-4a: 1H NMR (400 MHz, CDCl3):
d
9.83 (s, 1H), 6.34–6.29
(q, J = 279.9 Hz), 125.1, 120.8, 44.4, 38.0 (q, J = 26.8 Hz), 24.5 (d,
(m, 1H), 6.21–6.16 (m, 1H), 3.32–3.22 (m, 1H), 3.22 (m, 1H), 3.19
J = 2.9 Hz), 23.8; 19F NMR (376 MHz, CDCl3):
d
ꢀ70.3 (d,
J = 11.6 Hz); HRMS (DART): Anal. for C14H14F3O1 [M+H]+ Calcd.:
+1
(m, 1H), 2.50 (d, J = 5.19 Hz, 1H), 1.49 (d, J = 9.16 Hz, 1H), 1.36 (d,
J = 9.16 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
199.1, 136.3, 135.3,
255.09967, Found: 255.09964.
126.8 (q, J = 277.5 Hz), 54.3, 47.0, 44.6, 43.3, 43.2 (q, J = 26.8 Hz);
19F NMR (376 MHz, CDCl3):
d
ꢀ66.6 (d, J = 11.6 Hz); HRMS (DART):
4.2.6. 40-Bromo-3-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,10-
biphenyl]-4-carbaldehyde (4f)
+1
Anal. for C9H10F3O1
[M+H]+ Calcd.: 191.06837, Found:
191.06856.
The crude product was purified by flash chromatography on
silica gel (1.5:1 hexane/CH2Cl2) to give 59% yield of 4f as a
regioisomeric mixture (87:13). The enantiomeric excess was
determined after conversion to alcohol 7f (vide infra). 4f (major
4.2.2. 3-(Trifluoromethyl)bicyclo[2.2.2]oct-5-ene-2-carbaldehyde
(4b)
The crude product was purified by flash chromatography on
silica gel (10:1 pentane/Et2O) to give 26% yield of 4b as a
diastereomeric mixture (92:8). The enantiomeric excess was
determined after conversion to benzoate 8b (vide infra). 4b (major
diastereomer): 1H NMR (400 MHz, CDCl3):
d 9.71 (s, 1H), 6.43–6.36
(m, 1H), 6.33–6.26 (m, 1H), 3.11 (d, J = 3.36 Hz, 1H), 3.04–2.92 (m,
1H), 2.87 (d, J = 4.27 Hz, 1H), 2.51 (d, J = 6.66 Hz, 1H), 1.60–1.50 (m,
1H), 1.40–1.17 (m, 3H); 13C NMR (100 MHz, CDCl3):
regioisomer): 1H NMR (400 MHz, CDCl3):
d 9.67–9.64 (m, 1H),
7.48–7.42 (m, 2H), 7.25–7.18 (m, 2H), 6.16–6.10 (m, 1H), 3.08–2.97
(m, 1H), 2.83 (ddd, J = 13.66, 6.64, 1.91 Hz, 1H), 2.77–2.67 (m, 1H),
2.61–2.51 (m, 3H); 13C NMR (126 MHz, CDCl3):
d
200.6, 139.2,
133.6, 131.5, 127.4 (q, J = 279.9 Hz), 126.7, 121.5, 121.4, 44.2, 37.8
(q, J = 27.2 Hz), 24.3, 23.7; 19F NMR (376 MHz, CDCl3):
d
ꢀ70.3 (d,
J = 11.6 Hz); HRMS (DART): Anal. for C14H13Br1F3O1 [M+H]+
+1
d
199.8, 133.4,
Calcd.: 333.01019, Found: 333.00992.
132.7, 126.8 (q, J = 278.9 Hz), 52.6, 40.3 (q, J = 26.4 Hz), 29.7, 29.1
(d, J = 1.9 Hz), 25.0, 19.4; 19F NMR (376 MHz, CDCl3):
d
ꢀ71.3 (d,
4.3. General procedure for the reduction of aldehydes 4
J = 11.6 Hz); HRMS (DART): Anal. for C10H12F3O1 [M+H]+ Calcd.:
+1
205.08402, Found: 205.18409.
NaBH4 (0.6 mmol) was added to a solution of 4 (0.3 mmol)
in MeOH/CH2Cl2 (1:1, v/v) (2 mL) at 0 8C, and the mixture
was stirred for 15 min at room temperature. The mixture
was then cooled to 0 8C, a saturated aqueous solution of NH4Cl
was added, and the mixture was extracted with Et2O three
times. The combined organic layer was dried over anhydrous
MgSO4, and concentrated under reduced pressure. The crude
product was purified by flash chromatography on silica gel to
give the corresponding primary alcohols 7 in >90% yield in all
cases.
4.2.3. 3,4-Dimethyl-6-(trifluoromethyl)cyclohex-3-ene-1-
carbaldehyde (4c)
The crude product was purified by flash chromatography on
silica gel (20:1 pentane/Et2O) to give 45% yield of 4c. The
enantiomeric excess was determined after conversion to
benzoate 8c (vide infra). 4c: 1H NMR (400 MHz, CDCl3):
d
9.64–9.49 (m, 1H), 2.86–2.74 (m, 1H), 2.69 (ddd, J = 14.11, 7.25,
2.44 Hz, 1H), 2.31–2.09 (m, 4H), 1.67 (s, 3H), 1.63 (s, 3H); 13C
NMR (100 MHz, CDCl3):
d 201.2, 127.5 (q, J = 279.9 Hz), 123.4,
123.1, 45.7, 38.2 (q, J = 26.5 Hz), 29.3, 28.3 (d, J = 1.9 Hz), 18.7,
4.3.1. (3-(Trifluoromethyl)bicyclo[2.2.1]hept-5-en-2-yl)methanol
(7a)
18.7; 19F NMR (376 MHz, CDCl3):
d
ꢀ70.5 (d, J = 11.6 Hz); HRMS
+1
(DART): Anal. for C10H14F3O1
Found: 207.09946.
[M+H]+ Calcd.: 207.09967,
The crude product was purified by flash chromatography on
silica gel (3:1 hexane/EtOAc) to give 7a as a diastereomeric
mixture. exo-7a: 1H NMR (500 MHz, CDCl3):
d 6.30–6.25 (m, 1H),
4.2.4. 4-Methyl-6-(trifluoromethyl)cyclohex-3-ene-1-carbaldehyde
(4d)
6.09–6.04 (m, 1H), 3.85 (dd, J = 10.65, 5.61 Hz, 1H), 3.61 (dd,
J = 10.30, 8.70 Hz, 1H), 3.07 (brs, 1H), 2.86 (brs, 1H), 2.30 (dddd,
J = 20.04, 10.42, 5.50, 3.21 Hz, 1H), 1.75–1.72 (m, 1H), 1.55–1.46
The crude product was purified by flash chromatography on
silica gel (15:1 pentane/Et2O) to give 58% yield of 4d as a
regioisomeric mixture (89:11). The enantiomeric excess was
determined after conversion to benzoate 8d (vide infra). 4d (major
(m, 2H); 13C NMR (126 MHz, CDCl3):
d
137.6, 133.4, 127.6 (q,
J = 277.5 Hz), 65.8, 46.8, 46.3 (q, J = 25.6 Hz), 44.6, 44.4, 43.2 (d,
J = 2.4 Hz); 19F NMR (470 MHz, CDCl3):
d
ꢀ66.5 (d, J = 7.2 Hz);
isomer): 1H NMR (400 MHz, CDCl3):
(m, 1H), 2.95–2.81 (m, 1H), 2.72–2.65 (m, 1H), 2.41–2.04 (m, 4H),
1.69 (s, 3H); 13C NMR (100 MHz, CDCl3):
201.3, 131.9, 127.5 (q,
d
9.59–9.56 (m, 1H), 5.48–5.43
HRMS (DART): Anal. for C9H15F3N1O1
210.11057, Found: 210.11073.
[M+NH4]+ Calcd.:
+1
d
J = 279.9 Hz), 118.0, 44.5, 37.6 (q, J = 26.8 Hz), 26.6 (d, J = 2.9 Hz),
4.3.2. (3-(Trifluoromethyl)bicyclo[2.2.2]oct-5-en-2-yl)methanol (7b)
The crude product was purified by flash chromatography on
silica gel (3:1 hexane/EtOAc) to give 7b as a diastereomeric
23.2, 23.2; 19F NMR (376 MHz, CDCl3):
d
ꢀ70.6 (d, J = 11.6 Hz);
HRMS (DART): Anal. for C9H12F3O1 [M+H]+ Calcd.: 193.08402,
+1
Found: 193.08421.
mixture. 7b (major diastereomer): 1H NMR (400 MHz, CDCl3):
d
6.40 (dd, J = 7.41, 7.41 Hz, 1H), 6.19 (dd, J = 7.14, 7.14 Hz, 1H),
3.88–3.78 (m, 1H), 3.55 (dd, J = 8.51, 8.51 Hz, 1H), 2.76 (brs, 2H),
1.83–1.68 (m, 3H), 1.53–1.41 (m, 2H), 1.33 (ddt, J = 12.26, 12.26,
3.84, 1H), 1.15 (ddt, J = 12.54, 12.54, 3.59 Hz, 1H); 13C NMR
4.2.5. 3-(Trifluoromethyl)-2,3,4,5-tetrahydro-[1,10-biphenyl]-4-
carbaldehyde (4e)
The crude product was purified by flash chromatography on
silica gel (3:1 hexane/CH2Cl2) to give 92% yield of 4e as a
regioisomeric mixture (85:15). The enantiomeric excess was
determined to be 52% ee (major isomer) and 20% ee (minor
(126 MHz, CDCl3):
45.4 (q, J = 25.2 Hz), 41.3, 29.7, 29.4, 25.7, 17.7; 19F NMR
(376 MHz, CDCl3):
d 135.0, 131.6, 127.4 (q, J = 279.1 Hz), 64.1,
d
ꢀ70.7 (d, J = 8.67 Hz); HRMS (DART):
+1
isomer) by HPLC analysis using
a
Chiralcel OD-H column
Anal. for C10H14F3O1
207.09995.
[M+H]+ Calcd.: 207.09967, Found:
(0.46 cm ꢁ 25 cm, 30:1 hexane/iPrOH, flow rate 0.5 mL/min);
Please cite this article in press as: K. Shibatomi, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.05.011

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FLUOR-8569; No. of Pages 6
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5
4.3.3. (3,4-Dimethyl-6-(trifluoromethyl)cyclohex-3-en-1-
yl)methanol (7c)
purified by flash chromatography on silica gel to give the
corresponding benzoate 8.
The crude product was purified by flash chromatography on
silica gel (2:1 hexane/Et2O) to give 7c. 7c: 1H NMR (500 MHz,
4.4.1. 3-(Trifluoromethyl)bicyclo[2.2.1]hept-5-en-2-yl)methyl
benzoate (8a)
CDCl3):
1.99–1.90 (m, 1H), 1.63 (s, 6H); 13C NMR (126 MHz, CDCl3):
(q, J = 280.3 Hz), 124.9, 122.3, 64.1, 39.5 (q, J = 25.6 Hz), 35.9, 34.0,
30.4 (d, J = 2.4 Hz), 18.7, 18.5; 19F NMR (470 MHz, CDCl3):
ꢀ69.6
d
3.76–3.64 (m, 2H), 2.43–2.31 (m, 1H), 2.23–2.01 (m, 4H),
d
128.1
The crude product was purified by flash chromatography on
silica gel (3:1 hexane/CH2Cl2) to give 81% yield of 8a as a
diastereomeric mixture. The enantiomeric excess was determined
to be 88% ee (exo-8a) and 71% ee (endo-8a) by HPLC analysis using a
Chiralcel OJ-H column (0.46 cm ꢁ 25 cm, 800:1 hexane/iPrOH,
flow rate 1.0 mL/min); exo isomer: 21.8 min (major enantiomer),
25.1 min (minor enantiomer), endo isomer: 12.9 min (major
enantiomer), 11.5 min (minor enantiomer). exo-8a: 1H NMR
d
(d, J = 14.7 Hz); [a]
27 = +55.8 (c 0.6, CHCl3); HRMS (DART): Anal.
D
for C10H16F3O1 [M+H]+ Calcd.: 209.11532, Found: 209.11505.
+1
4.3.4. (4-Methyl-6-(trifluoromethyl)cyclohex-3-en-1-yl)methanol
(7d)
The crude product was purified by flash chromatography on
silica gel (2:1 hexane/Et2O) to give 7d as a regioisomeric mixture.
(400 MHz, CDCl3): d 8.09–8.02 (m, 2H), 7.60–7.54 (m, 1H), 7.49–
7.42 (m, 2H), 6.34–6.29 (m, 1H), 6.13–6.08 (m, 1H), 4.46–4.34 (m,
2H), 3.13 (brs, 1H), 2.87 (brs, 1H), 2.55–2.44 (m, 1H), 2.07–2.00 (m,
1H), 1.61 (d, J = 9.16 Hz, 1H), 1.56 (d, J = 8.24 Hz, 1H); 13C NMR
7d (major isomer): 1H NMR (500 MHz, CDCl3):
d 5.44–5.39 (m, 1H),
3.77–3.63 (m, 2H), 2.51–2.39 (m, 1H), 2.26–2.15 (m, 2H), 2.14–2.00
(m, 2H), 1.99–1.90 (m, 1H), 1.68 (s, 3H), 1.41 (brs, 1H); 13C NMR
(100 MHz, CDCl3):
d 166.5, 137.3, 133.7, 133.1, 129.6, 128.4, 127.3
(126 MHz, CDCl3):
d
130.6, 128.1 (q, J = 280.3 Hz), 120.0, 64.0, 39.0
(q, J = 278.0 Hz), 67.3, 47.0 (q, J = 26.2 Hz), 46.9, 45.0, 43.5 (d,
(q, J = 25.6 Hz), 34.9, 28.5 (d, J = 3.6 Hz), 27.2, 23.0; 19F NMR
J = 1.9 Hz), 41.2; 19F NMR (376 MHz, CDCl3):
d
ꢀ66.3 (d,
J = 11.6 Hz); HRMS (DART): Anal. for C16H16F3O2 [M+H]+ Calcd.:
+1
(470 MHz, CDCl3):
d
ꢀ69.8 (d, J = 10.8 Hz); HRMS (DART): Anal. for
+1
C9H14F3O1 [M+H]+ Calcd.: 195.09967, Found: 195.09978.
297.11024, Found: 297.11005.
4.3.5. (40-Bromo-3-(trifluoromethyl)-2,3,4,5-tetrahydro-[1,10-
biphenyl]-4-yl)methanol (7f)
4.4.2. 3-(Trifluoromethyl)bicyclo[2.2.2]oct-5-en-2-yl)methyl
benzoate (8b)
The crude product was purified by flash chromatography on
silica gel (1.5:1 hexane/Et2O) to give 7f as a regioisomeric mixture.
The enantiomeric excess was determined to be 42% ee (major
isomer) and 42% ee (minor isomer) by HPLC analysis using a
Chiralpak IC-3 column (0.46 cm ꢁ 25 cm, 20:1 hexane/iPrOH, flow
rate 0.5 mL/min); major regioisomer: 14.0 min (major enantio-
mer), 13.1 min (minor enantiomer), minor regioisomer: 16.8 min
(major enantiomer), 18.8 min (minor enantiomer). 7f (major
The crude product was purified by flash chromatography on
silica gel (2:1 hexane/CH2Cl2) to give 75% yield of 8b as a
diastereomeric mixture. The enantiomeric excess was determined
to be 95% ee (exo-8b) and 94% ee (endo-8b) by HPLC analysis using
a Chiralcel OD column (0.46 cm ꢁ 25 cm, 500:1 hexane/iPrOH,
flow rate 0.5 mL/min); endo isomer: 24.3 min (major enantiomer),
36.4 min (minor enantiomer), exo isomer: 21.4 min (major
enantiomer), 27.0 min (minor enantiomer). 8b (major diastereo-
regioisomer): 1H NMR (500 MHz, CDCl3):
d
7.47–7.41 (m, 2H),
mer): 1H NMR (400 MHz, CDCl3):
d 8.06 (d, J = 7.02 Hz, 2H), 7.61–
7.26–7.20 (m, 2H), 6.15–6.08 (m, 1H), 3.82–3.69 (m, 2H), 2.72–2.64
(m, 1H), 2.64–2.49 (m, 2H), 2.49–2.41 (m, 1H), 2.33–2.23 (m, 1H),
7.54 (m, 1H), 7.505–7.41 (m, 2H), 6.45–6.38 (m, 1H), 6.26–6.19 (m,
1H), 4.47–4.29 (m, 2H), 2.83 (brs, 1H), 2.72 (d, J = 3.66 Hz, 1H),
2.10–2.02 (m, 1H), 2.04–1.92 (m, 1H), 1.84–1.75 (m, 1H), 1.62–1.51
(m, 1H), 1.43–1.32 (m, 1H), 1.27–1.14 (m, 1H); 13C NMR (100 MHz,
2.11–2.03 (m, 1H), 1.49 (brs, 1H); 13C NMR (126 MHz, CDCl3):
d
139.7, 132.5, 131.4, 128.0 (q, J = 280.3 Hz), 126.6, 123.9, 121.0,
63.8, 39.0 (q, J = 25.6 Hz), 34.7, 27.9, 26.0 (d, J = 2.4 Hz); 19F NMR
CDCl3):
d 166.4, 134.7, 133.1, 131.6, 129.9, 129.6, 128.4, 127.2 (q,
(376 MHz, CDCl3):
C
d
ꢀ69.6 (d, J = 8.7 Hz); HRMS (DART): Anal. for
J = 278.9 Hz), 65.7, 45.7 (q, J = 25.2 Hz), 38.0, 30.6, 29.4 (d,
14H15Br1F3O1 [M+H]+ Calcd.: 335.02584, Found: 335.02583.
+1
J = 2.9 Hz), 25.5, 17.9; 19F NMR (376 MHz, CDCl3):
d
ꢀ70.7 (d,
J = 11.6 Hz); HRMS (DART): Anal. for C17H18F3O2 [M+H]+ Calcd.:
+1
4.3.6. 4,4,4-Trifluoro-3-(furan-2-yl)butan-1-ol (5)
311.12589, Found: 311.12562.
After the Friedel–Crafts arylation of 1 with furan, NaBH4
(0.8 mmol) and MeOH/CH2Cl2 (1:1, v/v) (2 mL) were added directly
to the reaction mixture. The reduction was performed in a similar
way to the general procedure described above to yield 5. The crude
product was used for benzoylation without further purification. 5:
4.4.3. 3,4-Dimethyl-6-(trifluoromethyl)cyclohex-3-en-1-yl)methyl
benzoate (8c)
The crude product was purified by flash chromatography on
silica gel (2:1 hexane/CH2Cl2) to give 66% yield of 8c. The
enantiomeric excess was determined to be 76% ee by HPLC
analysis using a Chiralpak AD-3 column (0.46 cm ꢁ 25 cm, 100:1
hexane/iPrOH, flow rate 1.0 mL/min); 6.3 min (major enantiomer),
7.0 min (minor enantiomer). 8c: 1H NMR (400 MHz, CDCl3):
9.59–9.56 (m, 1H), 2.88–2.73 (m, 1H), 2.73–2.65 (m, 1H), 2.33–2.06
(m, 4H), 1.67 (s, 3H), 1.63 (s, 3H); 13C NMR (100 MHz, CDCl3):
1H NMR (400 MHz, CDCl3):
d 7.44–7.40 (m, 1H), 6.38 (dd, J = 3.05,
1.83 Hz, 1H), 6.33 (d, J = 3.05 Hz, 1H), 3.83–3.70 (m, 2H), 3.47 (sep,
J = 5.04 Hz, 1H), 2.20 (ddt, J = 14.04, 9.31, 4.43 Hz, 1H), 2.15–2.06
(m, 1H); 13C NMR (100 MHz, CDCl3):
d
147.8 (d, J = 2.3 Hz), 142.8,
d
125.8 (q, J = 280.0 Hz), 110.5, 109.5, 59.1, 40.3 (q, J = 28.7 Hz), 30.1;
19F NMR (376 MHz, CDCl3):
Anal. for C9H10F3O2
d
ꢀ70.7 (d, J = 11.6 Hz); HRMS (DART):
d
[M+H]+ Calcd.: 195.06329, Found:
201.2, 127.5 (q, J = 279.9 Hz), 123.4, 123.1, 45.7, 38.2 (q,
J = 26.8 Hz), 29.3, 28.3 (d, J = 1.9 Hz), 18.7, 18.7; 19F NMR
+1
195.06328.
(376 MHz, CDCl3):
d
ꢀ69.7 (d, J = 11.6 Hz); [
a]
23 = +57.8 (c 1.0,
D
+1
4.4. General procedure for the benzoylation of alcohols 7
CHCl3); HRMS (DART): Anal. for C17H20F3O2 [M+H]+ Calcd.:
313.14154, Found: 313.14173.
Et3N (4.0 equiv.), BzCl (1.5 equiv.), and DMAP (30 mol%) were
added to a solution of 7 (0.2 mmol) in CH2Cl2 (0.8 mL), and the
mixture was stirred for 1 h at room temperature. The reaction
mixture was then cooled to 0 8C, a saturated aqueous solution of
NaHCO3 was added, and the mixture was extracted with Et2O. The
combined organic layer was dried over anhydrous MgSO4, and
concentrated under the reduced pressure. The crude product was
4.4.4. 4-Methyl-6-(trifluoromethyl)cyclohex-3-en-1-yl)methyl
benzoate (8d)
The crude product was purified by flash chromatography on
silica gel (2:1 hexane/CH2Cl2) to give 76% yield of 8d as a
regioisomeric mixture. The enantiomeric excess was determined
to be 97% ee (major isomer) and 91% ee (minor isomer) by HPLC
Please cite this article in press as: K. Shibatomi, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.05.011

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FLUOR-8569; No. of Pages 6
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[4] (a) For recent studies on conjugate addition to trifluoromethylated olefins with
the carbon nucleophile, see: H. Wu, R.-R. Liu, C. Shen, M.-D. Zhang, J. Gao, Y.-X. Jia,
Org. Chem. Front. (2015) 124–126;
analysis using a Chiralcel OJ-H column and Chiralpak IA-3 column
(0.46 cm ꢁ 25 cm, 500:1 hexane/iPrOH, flow rate 0.5 mL/min);
Major regioisomer: 38.8 min (major enantiomer), 42.7 min (minor
enantiomer), Minor regioisomer: 34.7 min (major enantiomer),
37.4 min (minor enantiomer). 8d (major regioisomer): 1H NMR
(b) A. Sanz-Marco, A. Garcia-Ortiz, G. Blay, J.R. Pedro, Chem. Commun. 50 (2014)
2275–2278;
(c) M.-X. Zhao, F.-H. Ji, X.-L. Zhao, Z.-Z. Han, M. Shi, Eur. J. Org. Chem. (2014) 644–
653;
(400 MHz, CDCl3):
7.41 (m, 2H), 5.45–5.40 (m, 1H), 4.37 (ddd, J = 38.15, 11.29, 4.58 Hz,
2H), 2.57–2.43 (m, 1H), 2.39–2.02 (m, 5H), 1.70 (s, 3H); 13C NMR
d 8.06–8.00 (m, 1H), 7.60–7.54 (m, 1H), 7.48–
(d) Q. Chen, G. Wang, X. Jiang, Z. Xu, L. Lin, R. Wang, Org. Lett. 16 (2014) 1394–
1397;
(e) P. Kwiatkowski, A. Cholewiak, A. Kasztelan, Org. Lett. 16 (2014) 5930–5933;
(f) L. Li, J.-Y. Guo, X.-G. Liu, S. Chen, Y. Wang, B. Tan, X.-Y. Liu, Org. Lett. 16 (2014)
6032–6035;
(100 MHz, CDCl3):
d 166.4, 133.1, 131.0, 130.1, 129.6, 128.5, 127.8
(g) E. Boz, Z.P. Has¸ lak, N.S¸ . Tu¨zu¨n, F.A.S. Konuklar, Organometallics 33 (2014)
5111–5119;
(h) H. Wu, R.-R. Liu, Y.-X. Jia, Synlett 25 (2014) 457–460;
(i) Y. Zhao, X.-J. Wang, Y. Lin, C.-X. Cai, J.-T. Liu, Tetrahedron 70 (2014) 2523–
2528;
(q, J = 280.8 Hz), 119.7, 66.1, 40.0 (q, J = 26.2 Hz), 32.4, 28.7, 27.8,
23.1; 19F NMR (376 MHz, CDCl3):
d
ꢀ69.8 (d, J = 11.6 Hz); HRMS
(DART): Anal. for C16H18F3O2 [M+H]+ Calcd.: 299.12589, Found:
+1
299.12599.
(j) L. Wen, L. Yin, Q. Shen, L. Lu, ACS Catal. 3 (2013) 502–506;
(k) H. Kawai, Z. Yuan, T. Kitayama, E. Tokunaga, N. Shibata, Angew. Chem., Int. Ed.
52 (2013) 5575–5579;
4.4.5. 4,4,4-Trifluoro-3-(furan-2-yl)butyl benzoate (6)
The crude product was purified by flash chromatography on
silica gel (1:1 hexane/CH2Cl2) to give 39% yield (3 steps) of 6. The
enantiomeric excess was determined to be 94% ee by HPLC analysis
using a Chiralpak IB-3 column (0.46 cm ꢁ 25 cm, 200:1 hexane/
iPrOH, flow rate 0.5 mL/min); 20.1 min (major enantiomer),
(l) J.-R. Gao, H. Wu, B. Xiang, W.-B. Yu, L. Han, Y.-X. Jia, J. Am. Chem. Soc. 135
(2013) 2983–2986;
(m) K.S. Yang, A.E. Nibbs, Y.E. Tu¨ rkmen, V.H. Rawal, J. Am. Chem. Soc. 135 (2013)
16050–21605;
(n) A.T. Davies, J.E. Taylor, J. Douglas, C.J. Collett, L.C. Morrill, C. Fallan, A.M.Z.
Slawin, G. Churchill, A.D. Smith, J. Org. Chem. 78 (2013) 9243–9257;
(o) S. Harada, T. Morikawa, A. Nishida, Org. Lett. 15 (2013) 5314–5317;
(p) N. Dong, X. Li, F. Wang, J.-P. Cheng, Org. Lett. 15 (2013) 4896–4899;
(q) A. Morigaki, T. Tanaka, T. Miyabe, T. Ishihara, T. Konno, Org. Biomol. Chem. 11
(2013) 586–595;
20.9 min (minor enantiomer). 6: 1H NMR (400 MHz, CDCl3):
d
8.00 (d, J = 7.93 Hz, 2H), 7.62–7.54 (m, 1H), 7.50–7.38 (m, 3H),
6.39–6.33 (m, 2H), 4.40 (dt, J = 11.09, 5.49 Hz, 1H), 4.15 (dt,
J = 14.95, 5.19 Hz, 1H), 3.79–3.64 (m, 1H), 2.40 (m, 2H); 13C NMR
(r) H. Kawai, S. Okusu, E. Tokunaga, H. Sato, M. Shiro, N. Shibata, Angew. Chem.,
Int. Ed. 51 (2012) 4959–4962;
(126 MHz, CDCl3):
d 166.2, 147.1 (d, J = 2.4 Hz), 143.0, 133.1, 129.8,
(s) W. Zhang, D. Tan, R. Lee, G. Tong, W. Chen, B. Qi, K.-W. Huang, C.-H. Tan, Z.
Jiang, Angew. Chem., Int. Ed. 51 (2012) 10069–10073;
(t) H.-P. Deng, Y. Wei, M. Shi, Adv. Synth. Catal. 354 (2012) 783–789;
(u) K. Shibatomi, A. Narayama, Y. Abe, S. Iwasa, Chem. Commun. 48 (2012) 7380–
7382;
129.5, 128.4, 125.6 (q, J = 279.9 Hz), 61.5, 41.1 (q, J = 29.2 Hz), 26.7;
19F NMR (376 MHz, CDCl3):
d
ꢀ70.9 (d, J = 11.6 Hz);
[
C
a
]
26 = ꢀ145.3 (c 1.0, CHCl3); HRMS (DART): Anal. for
D
15H14F3O3 [M+H]+ Calcd.: 299.08950, Found: 299.08972.
+1
(v) H. Kawai, T. Kitayama, E. Tokunaga, T. Matsumoto, H. Sato, M. Shiro, N.
Shibata, Chem. Commun. 48 (2012) 4067–4069;
(w) H. Kawai, Y. Sugita, E. Tokunaga, H. Sato, M. Shiro, N. Shibata, Chem. Commun.
48 (2012) 3632–3634;
Acknowledgements
(x) G. Blay, I. Ferna´ndez, J.R. Pedro, C. Vila, Synthesis 44 (2012) 3590–3594;
(y) Q. Li, C.-H. Ding, X.-H. Li, W. Weissensteiner, X.-L. Hou, Synthesis 44 (2012)
265–271;
(z) Q.-H. Li, Z.-Y. Xue, H.-Y. Tao, C.-J. Wang, Tetrahedron Lett. 53 (2012) 3650–
3653.
This study was supported by Central Glass Co., Ltd. and a Grant-
in-Aid for Scientific Research on Innovative Areas ‘‘Advanced
Molecular Transformations by Organocatalysts’’ from MEXT, Japan.
[5] (a) For recent studies on other C–C bond formations with trifluoromethylated
olefins, see: X. Wang, S.L. Buchwald, J. Org. Chem. 78 (2013) 3429–3433;
(b) D. Grassi, H. Li, A. Alexakis, Chem. Commun. 48 (2012) 11404–11406;
(c) K. Shibatomi, F. Kobayashi, A. Narayama, I. Fujisawa, S. Iwasa, Chem. Commun.
48 (2012) 413–415.
[6] K.A. Ahrendt, C.J. Borths, D.W.C. MacMillan, J. Am. Chem. Soc. 122 (2000) 4243–
4244.
[7] Y. Hayashi, S. Samanta, H. Gotoh, H. Ishikawa, Angew. Chem., Int. Ed. 47 (2008)
6634–6637.
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.2015.
05.011.
[8] For a review on enantioselective organocatalytic Diels–Alder reaction, see: P.
Merino, E. Marque´c-Lo´pez, T. Tejero, R.P. Herrera, Synthesis, (2010) 1–26.
[9] The best reaction conditions described in Ref. [6] were employed without further
optimization.
[10] (a) V.A. Soloshonok, C. Roussel, O. Kitagawa, A.E. Sorochinsky, Chem. Soc. Rev. 41
(2012) 4180–4188;
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Please cite this article in press as: K. Shibatomi, et al., J. Fluorine Chem. (2015), http://dx.doi.org/10.1016/j.jfluchem.2015.05.011