Enantioselective addition of a trifluoromethyl anion to aryl ketones and aldehydes

Article abstract of DOI:10.1055/s-2003-40889

The identification and development of a catalyst for the enantioselective nucleophilic addition of a trifluoromethyl anion to a ketone is described. An easily prepared cinchonine-derived catalyst was used in amounts as low as 4 mol% to afford enantiomeric

Full text of DOI:10.1055/s-2003-40889

PAPER
1693
Enantioselective Addition of a Trifluoromethyl Anion to Aryl Ketones and
Aldehydes
E
nantioselecti
t
é
ition of
a
T
p
rifluorometh
h
yl
A
nion to A
a
r
yl Ketone
n
s
and Aldeh
eydes Caron,* Nga M. Do, Patrice Arpin, Alexandre Larivée
Chemical Research and Development, Pfizer Global Research & Development, Groton MS-8118D-4002, CT 06340, USA
Fax +1(860)7158584; E-mail: stephane_caron@groton.pfizer.com
Received 21 April 2003
achieved using CF3TMS and CsF in DMF to provide the
racemic silylated tertiary alcohol 4 in quantitative yield
(Scheme 2).
Abstract: The identification and development of a catalyst for the
enantioselective nucleophilic addition of a trifluoromethyl anion to
a ketone is described. An easily prepared cinchonine-derived cata-
lyst was used in amounts as low as 4 mol% to afford enantiomeric
excess as high as 92%.
Me
F3C
HO
OTMS
Me
O
AlBr3, AcBr
CH2Cl2
CF3TMS
DMF, CsF
Key words: alkaloids, ketones, aldehydes, asymmetric catalysis,
fluorine, nucleophilic additions, substituent effects
OAc
OAc
95%
100%
OMe
OMe
OMe
2a
The nucleophilic addition of a trifluoromethyl group is not
well precedented due to the difficulty generating a stable
trifluoromethyl anion.1–3 In 1989, Olah described a solu-
tion to this problem by using trimethylsilyltrifluoro-
methane (CF3TMS) as a precursor to the anion, which was
liberated by activation with a fluoride source.4 This meth-
od has proven to be successful for addition to a number of
electrophiles.5,6 Furthermore, an asymmetric variation of
this reaction, using a cinchonine-derived catalyst, has
been described.7 Unfortunately, the method yielded only
modest enantiomeric excess. A chiral triaminosulfonium
salt has also been reported for this transformation.8 We re-
cently were faced with the challenge of preparing diol 1 in
enantiomerically-enriched form. While several approach-
es were considered and evaluated, we found that the de-
sired product could be obtained by addition of a
trifluoromethyl group to a suitably protected acetophe-
none 2, derived from the corresponding phenethyl alcohol
3 (Scheme 1). Herein we describe the development of a
catalyst to accomplish this transformation in a highly
enantioselective fashion.
3
4
Scheme 2
Initial investigations into an asymmetric variant of the tri-
fluoromethyl addition began using a literature procedure7
with cinchonine-derived catalyst 5a. We observed a poor
conversion in toluene, the recommended solvent, whereas
CH2Cl2 was found to yield a 70% conversion and 48%
ee10 (Scheme 3).
HO
+
N
-
Me
F3C
F
OTMS
Me
O
Ar
N
OAc
OAc
5a, Ar = 4-CF3Ph, 20 mol%
CF3TMS, -78 °C
OMe
OMe
Toluene: Low conversion
CH2Cl2: 48% ee, ~70% conversion (R)-4
2a
Scheme 3
Me
F3C
OH
Me
O
To further optimize the reaction, we studied the influence
of the alcohol protecting group, the structure of the cata-
lyst, and the reaction conditions. All factors affected the
enantioselectivity of the reaction. The choice of protecting
group of the primary alcohol altered the enantioselectivity
and the rate of the reaction. The 3,4-dimethoxybenzoate
derivative 2f, a crystalline solid, provided the greatest lev-
el of enantioselectivity (78% ee, Table 1).11
OH
OH
OP
OMe
OMe
OMe
1
3
2
Scheme 1 Retrosynthesis to diol 1
Using 20 mol% of catalyst 5b [Ar = 3,5-(MeO)2C6H3], we
surveyed the effects of reaction conditions. The addition
did not proceed in DMAC, MeCN, toluene, THF or 2-
MeTHF (Table 2, Entries 1–5). While the conversion was
high in DMF, minimal chiral induction was observed (En-
try 6). Fortunately, CH2Cl2 provided acceptable conver-
sion and enantionselective excess up to 80% (Entries 7,
8). It appears that an electron rich protecting group maxi-
We initially prepared the known acetophenone 2a from
commercially available alcohol 3 in 95% yield by modi-
fying a literature Friedel–Crafts acylation procedure.9 The
addition of the trifluoromethyl group was successfully
Synthesis 2003, No. 11, Print: 05 08 2003.
Art Id.1437-210X,E;2003,0,11,1693,1698,ftx,en;M01203SS.pdf.
© Georg Thieme Verlag Stuttgart · New York

1694
S. Caron et al.
PAPER
conditions [CF3TMS (1.5 equiv), CH2Cl2, –78 °C, cata-
lyst (4 mol%)] (Entries 7–13). We were pleased to find
that the 1-methylnaphthyl catalyst 5i provided not only
excellent conversion (97%) but also high enantioselectiv-
ity (92%) (Entry 12). The absolute stereochemistry was
determined by X-ray analysis of the 4-bromobenzoate de-
rivative (6d) which was obtained by hydrolysis of the silyl
ether and 3,4-dimethoxybenzoate with NaOH and acyla-
tion with 4-bromobenzoyl chloride (Figure 1).
Table 1 Alcohol Protecting Group Effect Using Catalyst 5b (20
mol%), CF3TMS (2 equiv) in CH2Cl2 at –78 °C
Substrate
P
ee (%)10,12
2a
2b
2c
2d
2e
2f
acetate
50
38
60
24
62
78
pivalate
benzoate
4-bromobenzoate
4-methoxybenzoate
3,4-dimethoxybenzoate
mizes the interactions between catalyst and substrate, es-
pecially in a non-polar solvent. Temperature also played a
role, as the % ee was eroded at temperatures above –40 °C
(Entries 9, 10). Additionally, the % ee was slightly lower
when less than one equivalent of CF3TMS was used.
However, the reaction concentration, order of reagent ad-
dition, and rate of CF3TMS addition did not significantly
impact the enantioselectivity.
Figure 1 X-ray single crystal of 6d
The preparation of these catalysts was straightforward
(Scheme 4). These derivatives of Cinchona alkaloids
have been used as catalysts in a number of important
transformations.13 We found that the best method for the
formation of the ammonium salt was by treating cincho-
nine with 1.2 equiv of the benzyl halide in the presence of
a catalytic amount of Bu4NI (3 mol%) in refluxing THF.
The advantage of using THF over the commonly-used tol-
uene is that any unreacted cinchonine remains in solution.
The ammonium salt is filtered followed by ion exchange
using Dowex-F– in MeOH.14 The catalysts were isolated
by filtration from methyl tert-butyl ether and proved to be
air stable. In the case of catalysts 5c and 5d, the ether for-
mation was performed prior to the ion exchange.15
Table 2 Solvent and Temperature Effects of CF3TMS Addition (2
equiv) to Ketone 2f Using 20 mol% of Catalyst 5b
HO
+
N
5b, Ar = 3,5-MeOPh
-
F
Ar
N
Entry
Solvent
Temp.
(ºC)
Conversion
(%)
ee
(%)
1
2
DMAC
MeCN
toluene
THF
–15
–40
–78
–78
–78
–40
–78
–40
–20
0
0
0
NA
NA
NA
NA
NA
<1
3
0
1) ArCH2X (1.2 equiv.)
Bu4NI (3 mol%)
4
0
HO
HO
THF, reflux
+
N
N
-
5
2-MeTHF
DMF
0
F
2) Dowex-F-
Ar
N
MeOH
N
6
81
70
66
28
<5
Cinchonine
7
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
80
93% overall when Ar = 1-naphthyl (5i)
8
80
Scheme 4
9
52
Finally, we looked at different substrates using either cat-
alysts 5b and 5i (Table 4). The enantioselectivity ob-
served in these cases is not as high as for the substrate for
which we optimized our catalyst. However, it is conceiv-
able that for each substrate the catalyst could be optimized
to provide an acceptable level of enantioselectivity in the
CF3 addition.
10
42
We next studied the catalyst structure and loading
amounts (Table 3). Protection of the secondary alcohol as
a methyl or allyl ether resulted in no reaction (Entries 1,
2). Evaluation of the catalyst loading revealed that the use
of a lower mol% of catalyst 5b led to higher conversion
and enantioselectivity (Entries 3–6). Higher catalyst load-
ing may increase the potential for competitive enolization
of the ketone by the basic fluoride anion. Finally, several
catalysts were prepared and surveyed under the optimal
A cinchonine-derived catalyst 5i was developed for the
enantioselective addition of a trifluoromethyl anion to ke-
tone 2f to generate a quaternary center in 92% ee using
only 4 mol% of catalyst. This reaction represents the high-
Synthesis 2003, No. 11, 1693–1698 © Thieme Stuttgart · New York

PAPER
Enantioselective Addition of a Trifluoromethyl Anion to Aryl Ketones and Aldehydes
1695
Table 3 Optimization of the Catalyst and Catalyst Loading
RO
+
N
-
F
Ar
N
5
2f
4f
CF3TMS (1.5 equiv)
CH2Cl2, -78 °C
Ar
R
Catalyst
5c
Quantity (mol%)
Conversion (%)
ee (%)12
NA
NA
69
1
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
3,5-(MeO)2C6H3
4-MeOC6H4
3-MeOC6H4
3,5-(CF3)2C6H3
4-CF3C6H4
Me
Allyl
H
20
20
50
20
10
4
0
0
2
3
5d
5b
5b
5b
5b
5e
27
71
96
98
88
86
21
77
95
97
86
4
H
77
5
H
82
6
H
83
7
H
4
58
8
H
5f
4
74
9
H
5g
4
70
10
11
12
13
H
5a
4
69
9-anthracyl
H
5h
5i
4
85
1-naphthyl
H
4
92
4-biphenyl
H
5j
4
68
Yield 16.96g (94%) as a 10:1 mixture of regioisomers; oil.
IR: 1737, 1674, 1604, 1567, 1358, 1290, 1037 cm–1.
1H NMR: = 2.05 (s, 3 H), 2.59 (s, 3 H), 3.29 (t, 2 H, J = 6.8), 3.89
(s, 3 H), 4.33 (t, 2, J = 6.8), 6.81 (d, 1 H, J = 2.5), 6.85 (dd, 1 H,
J = 8.6, 2.6), 7.82 (d, 1 H, J = 8.6).
est enantioselectivity in the addition of a trifluoromethyl
anion to a carbonyl using organocatalysis. While this cat-
alyst did not prove to be generally applicable to a variety
of ketones it demonstrated that highly enantioselective
CF3 anion additions to ketones are feasible with the prop-
erly designed catalyst.
13C NMR: = 22.28, 30.37, 3536, 56.63, 66.11, 101.21, 112.63,
119.17, 131.00, 134.24, 142.90, 163.24, 172.32.
All starting materials were obtained from commercial suppliers and
used without further purification. Solvents were purchased from Al-
drich in Sure/Seal™ bottles. Reactions were performed under an an-
hyd N2 atmosphere. Silica gel chromatography was carried out with
J.T.Baker 40 m silica gel according to Still's procedure.17 Mps
were measured in open capillary tubes. 1H (400 MHz) and 13C NMR
(100 MHz) were measured in CDCl3 unless otherwise indicated. J
values are given in Hz. IR spectra were recorded as thin films using
a Nicolet Avatex 300 FTIR.
Anal. Calcd for C13H22O4: C, 65.71; H, 7.21. Found: C, 66.09; H,
6.83.
Acetic Acid 2-[5-Methoxy-2-(2,2,2-trifluoro-1-methyl-1-trime-
thylsilanyloxyethyl)phenyl]ethyl Ester [(R)-4]
To ketone 2a (7.21g, 30.5 mmol) in DMF (40.0 mL) was added CsF
(0.550g, 3.62 mmol). The solution was cooled to 0 ºC and CF3TMS
(5.90mL, 39.9 mmol) was added dropwise. After 40 min, no starting
material was detected by GC–MS. For characterization purposes,
the reaction mixture was poured into H2O and extracted with methyl
tert-butyl ether (MTBE) (100 mL). The organic layer was washed
with H2O (2 × 75 mL) and brine (50 mL), dried (MgSO4), filtered
and concentrated to provide acetic acid 2-[5-methoxy-2-(2,2,2-trif-
luoro-1-methyl-1-trimethylsilanyloxyethyl)phenyl]ethyl ester as a
crude oil.
Acetic Acid 2-(2-Acetyl-5-methoxyphenyl)ethyl Ester (2a)
To AlBr3 (51.15g, 191.8 mmol) in CH2Cl2 (80 mL) at 0 ºC was
slowly added acetyl bromide (17.0 mL, 230 mmol). The solution
was allowed to warm to 15 ºC and alcohol 3 (11.68g, 76.75 mmol)
was added in CH2Cl2 (20 mL + 10 mL rinse) over 35 min. The or-
ange solution was allowed to stir for 1 h and was poured over ice
(100mL) and aq HCl (1 M; 100 mL). The product was extracted
with CH2Cl2 (2 × 50 mL) and the organic extracts were washed with
aq NaOH (1 M; 50 mL). The organic layer was filtered through
Celite and concentrated.
IR: 2961, 1741, 1610, 1383, 1286, 1255, 1165, 1140, 1039, 864,
846 cm–1.
1H NMR: = 0.19 (s, 9 H), 1.93 (s, 3 H), 2.10 (s, 3 H), 3.23–3.33
(m, 1 H), 3.42–3.52 (m, 1 H), 3.83 (s, 3 H), 4.26–4.32 (m, 2 H), 6.77
(dd, 1 H, J = 8.9, 2.8), 6.86 (d, 1 H, J = 2.9), 7.32 (d, 1 H, J = 8.9).
Synthesis 2003, No. 11, 1693–1698 © Thieme Stuttgart · New York

1696
S. Caron et al.
PAPER
4-Bromobenzoic Acid 2-(3-Methoxyphenyl)ethyl Ester
Table 4 Alternative Substrates Using 4 mol% of Catalyst, CF3TMS
(1.5 equiv), in CH2Cl2 at –50 °C
1H NMR: = 3.10 (t, 2 H, J = 7.0), 3.85 (s, 3 H), 4.58 (t, 2 H,
J = 7.0), 6.82–6.93 (m, 3 H), 7.26–7.32 (m, 1 H), 7.62 (d, 2 H,
J = 8.9), 7.92 (d, 2 H, J = 8.9).
Entry Substrate
Catalyst Conversion ee
(%)
(%)16
4-Methoxybenzoic Acid 2-(3-Methoxyphenyl)ethyl Ester
1H NMR: = 3.10 (t, 2 H, J = 7.0), 3.84 (s, 3 H), 3.91 (s, 3 H), 4.55
(t, 2 H, J = 7.0), 6.82–6.98 (m, 3 H), 6.96 (d, 2 H, J = 8.9), 7.26–
7.32 (m, 1 H), 8.03 (d, 2 H, J = 9.0).
O
O
1
5b
5i
63
88
64
25
MeO
2
5b
5i
78
65
30
39
3,4-Dimethoxybenzoic Acid 2-(3-Methoxyphenyl)ethyl Ester
1H NMR: = 3.08 (t, 2 H, J = 7.0), 3.82 (s, 3 H), 3.95 (s, 3 H), 3.97
(s, 3 H), 4.54 (t, 2 H, J = 7.0), 6.80 (dd, 1 H, J = 2.6, 0.8), 6.83 (dd,
1 H, J = 2.6, 0.8), 6.87 (t, 1 H, J = 1.9), 6.90 (d, 1 H, J = 8.6), 7.24
(d, 1 H, J = 7.8), 7.54 (d, 1 H, J = 1.9), 7.69 (dd, 1 H, J = 8.4, 2.0).
MeO
3
5b
5i
100
100
28
1
O
O2N
Friedel–Crafts Acylation of Esters; General Procedure
To a solution of the ester in CH2Cl2 (10 volumes) at 0 °C was added
TiCl4 (1.5 equiv) and AcCl (2.0 equiv). The reaction was followed
by either TLC or HPLC. Upon disappearance of the starting mate-
rial, the reaction was poured into ice and aq HCl (1 M; 10 volumes)
was added. The layers were separated and the organic layer was
washed with H2O, dried (Na2SO4), filtered and concentrated. The
product was purified by crystallization or chromatography.
4
5b
5i
88
100
58
9
CHO
MeO
5
6
5b
5i
100
100
14
6
MeO
CHO
5b
5i
100
100
11
9
CHO
OMe
2,2-Dimethylpropionic Acid 2-(2-Acetyl-5-methoxyphenyl)eth-
yl Ester (2b)
Yield: 70%; filtered through a SiO2 pad, EtOAc–hexanes, 80:20.
IR: 2972, 1723, 1674, 1603, 1656, 1249, 1239, 1155 cm–1.
1H NMR: = 1.16 (s, 9 H), 2.58 (s, 3 H), 3.28 (t, 2 H, J = 6.5), 3.86
(s, 3 H), 4.32 (t, 2 H, J = 6.5), 6.80–6.84 (m, 2 H), 7.81 (d, 1 H,
J = 8.4).
13C NMR: = 27.40, 29.27, 34.45, 38.88, 55.55, 64.86, 111.64,
118.25, 139.80, 133.24, 142.13, 162.13, 178.67, 199.51.
7
8
9
5b
5i
100
96
28
27
O
Me
MeO
MeO
5b
5i
96
96
32
43
O
Me
5b
5i
100
100
6
5
O
Anal. Calcd for C16H22O4: C, 69.04; H, 7.97. Found: C, 68.84; H,
8.34.
Me
Me
Benzoic Acid 2-(2-Acetyl-5-methoxyphenyl)ethyl Ester (2c)
Yield: 90%; chromatography EtOAc–hexane, 30:70.
IR: 1717, 1673, 1603, 1567, 1275, 1251, 1115, 713 cm–1.
1H NMR: = 2.56 (s 3 H), 3.39 (t, 2 H, J = 6.6), 3.78 (s, 3 H), 4.56
(t, 2 H, J = 6.4), 6.79–6.83 (m, 2 H), 7.39 (d, 1 H, J = 7.3), 7.41 (d,
1 H, J = 7.9), 7.41–7.48 (m, 2 H), 7.79 (d, 1 H, J = 8.5), 7.99 (dd, 2
H, J = 8.3, 1.2).
13C NMR: = 29.34, 34.56, 55.58, 65.61, 112.04, 118.08, 128.54,
129.81, 130.40, 130.74, 133.04, 133.28, 142.12, 162.29, 166.77,
199.60.
13C NMR: = 2.03, 21.03, 24.64, 32.86, 55.11, 65.54, 78.90 (q,
J = 30.3), 111.26, 117.44, 125.70 (q, J = 287), 129.56, 129.79,
139.77, 159.17, 171.09.
Anal. Calcd for C17H25F3O4Si: C, 53.95; H, 6.66. Found: C,53.72;
H, 6.53.
Acylation of Alcohol 3; General Procedure
To a solution of an alcohol 3 in CH2Cl2 (10 volumes) at 0 °C was
added Et3N (1.1 equiv), the acid chloride (1.1 equiv) and DMAP
(0.2 equiv). The reactions were followed by TLC and quenched
with H2O (10 volumes) upon disappearance of the starting material.
The layers were separated and the organic layer was dried
(Na2SO4), filtered and concentrated. The esters were used directly
in the next step without further purification.
Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.38; H,
6.34.
4-Bromobenzoic Acid 2-(2-Acetyl-5-methoxyphenyl)ethyl Ester
(2d)
Yield: 95%; silica pad, EtOAc–hexanes, 30:70.
IR: 1715, 1670, 1591, 1565, 1267, 1235, 1102, 1068, 1011, 756
cm–1.
1H NMR: = 2.56 (s 3 H), 3.38 (t, 2 H, J = 6.6), 3.80 (s, 3 H), 4.55
(t, 2 H, J = 6.6), 6.80 (s, 1 H), 6.81 (dd, 1 H, J = 7.5, 2.9), 7.54 (d,
2 H, J = 8.7), 7.79–7.82 (m, 1 H), 7.85 (d, 2 H, J = 8.7).
2,2-Dimethylpropionic Acid 2-(3-Methoxyphenyl)ethyl Ester
1H NMR: = 1.20 (s, 9 H), 2.94 (t, 2 H, J = 7.0), 3.83 (s, 3 H), 4.30
(t, 2 H, J = 7.0), 6.79–6.86 (m, 3 H), 7.24 (dd, 1, J = 8.7, 7.5).
Benzoic Acid 2-(3-Methoxyphenyl)ethyl Ester
13C NMR: = 29.31, 64.54, 55.60, 65.85, 111.88, 118.23, 128.13,
129.64, 129.94, 131.33, 131.89, 133.37, 141.90, 162.31, 165.98,
199.50.
1H NMR: = 3.09 (t, 2 H, J = 7.0), 3.83 (s, 3 H), 4.57 (t, 2 H,
J = 7.0), 6.81–6.93 (m, 3 H), 7.29 (t, 1 H, J = 3.5), 7.44–7.50 (m, 2
H), 7.56–7.59 (m, 1 H), 8.07 (dd, 2 H, J = 8.4, 1.4).
Anal. Calcd for C18H17BrO4: C, 57.31; H, 4.54. Found: C, 57.09; H,
4.39.
Synthesis 2003, No. 11, 1693–1698 © Thieme Stuttgart · New York

PAPER
Enantioselective Addition of a Trifluoromethyl Anion to Aryl Ketones and Aldehydes
1697
4-Methoxybenzoic Acid 2-(2-Acetyl-5-methoxyphenyl)ethyl Es-
ter (2e)
Yield: 95%; silica pad, EtOAc–hexanes, 30:70; mp 99–100 °C.
IR: 1706, 1671, 1602, 1248, 1166, 1101, 1027, 770 cm–1.
1H NMR: = 2.55 (s 3 H), 3.38 (t, 2 H, J = 6.6), 3.78 (s, 3 H), 3.83
(s, 3 H), 4.52 (t, 2 H, J = 6.6), 6.78–6.82 (m, 2 H), 6.88 (d, 2 H,
J = 9.1), 7.78 (d, 1 H, J = 8.3), 7.94 (d, 2 H, J = 9.1).
1H NMR: (DMSO-d6): = 0.82–0.95 (m, 1 H), 1.59–1.81 (m, 3 H),
2.19–2.25 (m, 1 H), 2.57 (q, 1 H, J = 8.3), 2.95 (q, 1 H, J = 9.5),
3.45 (t, 1 H, J = 11.2), 3.74 (s, 6 H), 3.81–3.87 (m, 1 H), 4.28 (t, 1
H, J = 9.5), 4.86 (d, 1 H, J = 12.0), 5.11 (d, 1 H, J = 12.0), 5.17 (d,
1 H, J = 18.7), 5.18 (d, 1 H, J = 9.5), 5.98 (ddd, 1 H, J = 17.4, 10.4,
7.1), 6.34 (br s, 1 H), 6.55 (t, 1 H, J = 2.1), 6.81–6.84 (m, 2 H), 7.63
(t, 1 H, J = 7.9), 7.75 (d, 1 H, J = 4.1), 7.73–7.78 (m, 1 H), 8.03 (d,
1 H, J = 7.9), 8.15 (d, 1 H, J = 8.3), 8.87 (d, 1 H, J = 4.1).
13C NMR: = 29.35, 34.55, 55.55, 55.62, 65.27, 111.95, 113.74,
117.98, 123.10, 129.93, 131.77, 133.21, 142.17, 162.20, 163.47,
166.49, 199.58.
13C NMR: (DMSO-d6): = 21.32, 23.79, 26.97, 37.47, 54.34, 56.05,
56.88, 62.77, 65.21, 68.29, 101.98, 112.42, 117.57, 120.81, 124.22,
125.11, 127.66, 129.78, 130.40, 130.59, 137.89, 146.41,
146.24,150.71, 161.09.
Anal. Calcd for C19H20O5: C, 69.50; H, 6.14. Found: C, 69.13; H,
6.14.
(1-Naphthalen-1-ylmethyl-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl)-
quinolin-4-ylmethanol Chloride
3,4-Dimethoxybenzoic Acid2-(2-Acetyl-5-methoxyphenyl)ethyl
Ester (2f)
IR: 3067, 2953, 1591, 1510, 1267, 781, 739 cm–1.
1H NMR: (DMSO-d6): = 0.95–1.07 (m, 1 H), 1.67–1.79 (m, 3 H),
2.25–2.31 (m, 1 H), 3.00 (q, 1 H, J = 10.0), 3.22 (t, 1 H, J = 10.8),
4.03–4.17 (m, 2 H), 4.31–4.36 (m, 1 H), 5.09 (d, 1 H, J = 17.0), 5.15
(d, 1 H, J = 10.4), 5.45 (d, 1 H, J = 12.9), 5.77 (d, 1 H, J = 13.3),
5.95 (ddd, 1 H, J = 17.4, 10.4, 7.0), 6.69 (br s, 1), 7.45 (d, 1 H,
J = 4.1), 7.61–7.65 (m, 1 H), 7.68–7.77 (m, 4 H), 7.81–7.89 (m, 2
H), 8.03 (d, 1 H, J = 7.1), 8.09 (t, 2 H, J = 8.3), 8.17 (d, 1 H,
J = 8.3), 8.45–8.48 (m, 2 H), 8.99 (d, 1 H, J = 4.1).
13C NMR: (DMSO-d6): = 21.62, 23.85, 37.52, 55.13, 56.97, 59.15,
65.58, 67.70, 117.70, 120.89, 124.60, 124.69, 125.14, 126.10,
126.98, 127.88, 128.15, 129.89, 130.11, 130.47, 132.00, 133.85,
134.47, 135.17, 137.80, 145.94, 148.33, 150.91.
Yield: 89%; mp 110–111 °C; i-PrOH–hexanes, 6:1.
IR: 1709, 1672, 1602, 1270, 1223, 1031, 533 cm–1.
1H NMR: = 2.57 (s, 3 H), 3.39 (t, 2 H, J = 6.6), 3.79 (s, 3 H), 3.90
(s, 3 H), 3.92 (s, 3 H), 4.54 (t, 2 H, J = 6.6), 6.81 (dd, 1 H, J = 8.3,
2.5), 6.84 (d, 1 H, J = 2.5), 6.86 (d, 1 H, J = 8.3), 7.49 (d, 1 H,
J = 2.1), 7.64 (dd, 1 H, J = 8.7, 2.1), 7.80 (d, 1 H, J = 8.7).
13C NMR: = 29.33, 34.56, 55.52, 56.13, 56.20, 65.37, 110.37,
111.62, 112.10, 118.37, 123.17, 123.72, 129.90, 133.30, 142.13,
148.71, 153.04, 162.16, 166.47, 199.53.
Anal. Calcd for C20H22O6: C, 67.03; H, 6.19. Found: C, 67.27; H,
6.27.
Preparation of the Catalysts; General Procedure
Catalyst 5i
To cinchonine (1.0 equiv) in THF (15 volumes) was added the ben-
zyl halide (1.2 equiv) and Bu4NI (0.03 equiv). The mixture was
heated at reflux for 18 h (until disappearance of the cinchonine by
HPLC analysis). The reaction was cooled to r.t., filtered and the sol-
id washed with THF to provide a white solid. To the solid in MeOH
(5 volumes) was added Dowex F– (equal weight as the alkaloid,
Dowex F– was prepared by neutralizing Dowex 66 HO– with aque-
ous HF followed by wash with MeOH and MTBE). The suspension
was stirred for 10 h, filtered, and washed with MeOH and MTBE.
The filtrate was concentrated to a low volume and MTBE was add-
ed to provide a white solid, which was filtered.
Yield: 93% from cinchonine.
IR: 3414, 2947, 2834, 1663, 1032, 746 cm–1.
1H NMR: = 0.50–0.59 (m, 1 H), 1.50–1.66 (m, 3 H), 1.95–2.05 (m,
2 H), 2.59–2.66 (m, 1 H), 2.88 (t, 1 H, J = 11.2), 3.95–4.06 (m, 2
H), 4.61 (t, 1 H, J = 10.4), 4.96 (d, 1 H, J = 17.4), 5.05 (d, 1 H,
J = 10.4), 5.76 (ddd, 1 H, J = 17.4, 10.4, 7.5), 5.86 (d, 1 H,
J = 12.5), 6.16–6.20 (m, 1 H), 6.35 (br s, 1 H), 6.75 (t, 1 H, J = 7.5),
7.12–7.29 (m, 5 H), 7.37–7.43 (m, 2 H), 7.55 (d, 1 H, J = 4.2), 7.60–
7.65 (m, 2 H), 8.14–8.16 (m, 1 H), 8.40 (d, 1 H, J = 8.7), 8.56 (d, 1
H, J = 4.6).
13C NMR: = 21.70, 24.30, 38.60, 54.86, 56.68, 58.44, 65.94,
68.04, 117.92, 119.77, 123.09, 123.54, 124.02, 124.43, 124.51,
125.80, 127.29, 127.74, 128.60, 128.67, 129.30, 130.96, 133.14,
133.27, 134.76, 135.94, 145.58, 147.20, 149.69.
{1-(3,5-Dimethoxybenzyl)-5-vinyl-1-azabicyclo[2.2.2]oct-2-yl}-
quinolin-4-ylmethanol Chloride
IR: 3029, 1601, 1462, 1206, 1156, 859 cm–1.
1H NMR: (DMSO-d6): = 0.99–1.05 (m, 1 H), 1.67–1.83 (m, 3 H),
2.22–2.28 (m, 1 H), 2.61–2.65 (m, 1 H), 2.98 (q, 1 H, J = 10.0),
3.49–3.55 (m, 1 H), 3.75–3.84 (m, 1 H), 3.81 (s, 6 H), 3.89–3.94 (m,
1 H), 4.03–4.24 (m, 1 H), 4.92–5.01 (m, 2 H), 5.19–5.23 (m, 2 H),
5.98 (ddd, 1 H, J = 17.8, 10.0, 6.6), 6.45 (br s, 1 H), 6.67 (t, 1 H,
J = 2.1), 6.90–6.92 (m, 2 H), 7.10 (d 1 H, J = 4.1), 7.69–7.73 (m, 1
H), 7.79 (d, 1 H, J = 4.1), 7.79–7.83 (m, 1 H), 8.08 (d, 1 H, J = 7.9),
8.27 (d, 1 H, J = 8.3), 8.95 (d, 1 H, J = 4.1).
13C NMR: (DMSO-d6) 21.35, 23.73, 26.91, 37.43, 54.54, 56.19,
56.98, 62.85, 65.00, 68.03, 102.16, 112.57, 117.64, 120.81, 124.45,
125.05, 127.86, 130.00, 130.47, 130.62, 137.90, 145.88,
148.29,150.84, 161.18.
(1R)-3,4-Dimethoxybenzoic Acid 2-[5-Methoxy-2-(2,2,2-trifluo-
ro-1-methyl-1-trimethylsilanyloxyethyl)phenyl]ethyl Ester (4f)
To a solution of ketone 2f (200 mg, 0.558 mmol) and catalyst 5i
(10.1 mg, 4 mol%) in CH2Cl2 (2.0 mL) at –50 °C was added
CF3TMS (0.12 mL, 8.1 mmol). The solution was stirred at –50 °C
for 3 h and allowed to warm to r.t. overnight. HPLC analysis
showed a 97% conversion and 92% ee. The mixture was poured into
H2O and extracted with CH2Cl2. The organic extract was concen-
trated to provide an oil. For analytical purposes, the material was
purified by chromatography (SiO2; EtOAc–hexanes, 20:80).
IR: 1711, 1604, 1515, 1270, 1223, 1174, 1134, 1027, 861, 846, 763
cm–1.
Anal. Calcd for C28H33ClN2O6: C, 69.91; H, 6.91, N, 5.82. Found:
C, 69.59; H, 6.90, N, 5.84.
1H NMR: = 0.22 (s, 9 H), 1.96 (s, 3 H), 3.42 (ddd, 1 H, J = 13.4,
8.4, 6.5), 3.56–3.65 (m, 1 H), 3.81 (s, 3 H), 3.97 (s, 3 H), 3.98 (s, 3
H), 4.44–4.59 (m, 2 H), 6.78 (dd, 1 H, J = 9.0, 2.8), 6.94 (d, 1 H,
J = 8.4), 6.96 (d, 1 H, J = 2.8), 7.34 (d, 1 H, J = 9.0), 7.60 (d, 1 H,
J = 1.9), 7.74 (dd, 1 H, J = 8.4, 1.9).
Catalyst 5b
Yield: 86% from cinchonine.
IR: 2950, 1598, 1462, 1206, 1156, 738 cm–1.
13C NMR: = 2.31, 24.84, 33.40, 55.29, 56.13, 56.20, 66.09, 79.24
(q, J = 30.1), 110.45, 111.53, 112.13, 117.92, 123.10, 123.79,
Synthesis 2003, No. 11, 1693–1698 © Thieme Stuttgart · New York

1698
S. Caron et al.
PAPER
124.18 (q, J = 286), 129.76, 130.05, 140.09, 148.80, 153.15,
159.43, 166.56.
(3) Takeshi, N.; Ait-Mohand, S.; Médebielle, M.; Dolbier, W.
R. Jr. Tetrahedron Lett. 2002, 43, 4317.
(4) Prakash, G. K. S.; Krishnamurti, R.; Olah, G. A. J. Am.
Chem. Soc. 1989, 111, 393.
(5) Singh, R. P.; Shreeve, J. M. Tetrahedron 2000, 56, 7613.
(6) Prakash, G. K. S.; Mandal, M.; Olah, G. A. Org. Lett. 2001,
3, 2847.
(7) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994,
35, 3137.
(8) Kuroki, Y.; Iseki, K. Tetrahedron Lett. 1999, 40, 8231.
(9) Sternberg, E. D.; Vollhardt, K. P. C. J. Org. Chem. 1984, 49,
1574.
(10) The enantiomeric excess was determined by evaluation of
the corresponding diol (obtained by treating the silyl ether
with TBAF followed by NaOH) by HPLC (Chiracel OD, 4.6
× 250 mm; 40 °C; 1.5 mL/min; 230 nm; hexanes–i-PrOH–
TFA, 90:10:0.1). The absolute configuration was
determined single crystal X-ray analysis of 4-
bromobenzoate(6d).
(11) The starting material was obtained by esterificaton of
alcohol 3 with 3,4-dimethoxybenzoyl chloride (CH2Cl2,
Et3N, DMAP, 100%) and Friedel–Crafts acylation (AcCl,
TiCl4, CH2Cl2, 89%).
Anal. Calcd for C24H31F3O6Si: C, 57.58; H, 6.24. Found: C, 57.16;
H, 6.30.
(1R)-4-Bromobenzoic Acid 2-[5-Methoxy-2-(2,2,2-trifluoro-1-
hydroxy-1-methylethyl)phenyl]ethyl Ester (6d)
IR: 3461, 1702, 1271, 1247, 1158, 1105, 1070, 1012, 757 cm–1.
1H NMR: = 1.84 (s, 3 H), 2.79–2.91 (m, 1 H), 3.13 (dt, 1 H,
J = 13.3, 7.5), 3.69 (dq, 1 H, J = 7.5, 6.2), 3.76 (s, 3 H), 4.48–4.63
(m, 2 H), 6.75 (dd,1 H, J = 8.7, 2.9), 6.84 (d, 1 H, J = 2.9), 7.28 (d,
1 H, J = 9.1), 7.55 (d, 2 H, J = 8.7), 7.85 (d, 2 H, J = 8.7).
13C NMR: = 26.05, 34.78, 55.38, 67.28, 111.91, 118.70, 128.29,
128.39, 129.42, 129.87, 126.16 (q, J = 286), 131.30, 131.92, 139.79
159.50, 166.23.
Supporting Information Available
The author has deposited atomic coordinates for structure 6d with
the Cambridge Crystallographic Data Centre. The coordinates can
be obtained, on request, from the Director, Cambridge Crystallo-
graphic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK.
(12) The enantiomeric excess was determined by evaluation of
the corresponding tertiary alcohol (obtained by treating the
silyl ether with TBAF) by HPLC (Chiracel OD, 4.6 × 250
mm; 40 °C; 1.5 mL/min; 230 nm; hexanes–i-PrOH–TFA,
80:20:0.2).
(13) Kacprzak, K.; Gawronski, J. Synthesis 2001, 961.
(14) Ando, A.; Miura, T.; Tatematsu, T.; Shiori, T. Tetrahedron
Lett. 1993, 34, 1507.
(15) Lygo, B.; Wainwright, P. G. Tetrahedron 1999, 55, 6289.
(16) The absolute stereochemistry was not determined.
(17) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43,
2923.
Acknowledgement:
We would like to thank Ernie B. Pollard for his analytical support
on this project and Jon Bordner for solving the X-ray crystal struc-
ture of compound 6d.
References
(1) McClinton, M. A.; McClinton, D. A. Tetrahedron 1992, 48,
6555.
(2) Langlois, B. R.; Billard, T. Synthesis 2003, 185; and
references cited therein.
Synthesis 2003, No. 11, 1693–1698 © Thieme Stuttgart · New York