Asymmetric Friedel-Crafts reaction of indoles with ethyl trifluoropyruvate using a copper(I)-bisoxazolidine catalyst

Article abstract of DOI:10.1002/adsc.201000918

Bisoxazolidine 1 is an effective ligand in the copper(I)-catalyzed Friedel-Crafts reaction of alkyl trifluoropyruvates and indoles. A range of ethyl 2-(3'-indolyl)-3,3,3-trifluoro-2-hydroxypropanoates was produced in up to 99% yield and 94% ee within 30-m

Full text of DOI:10.1002/adsc.201000918

FULL PAPERS
DOI: 10.1002/adsc.201000918
Asymmetric Friedel–Crafts Reaction of Indoles with Ethyl
Trifluoropyruvate Using a Copper(I)-Bisoxazolidine Catalyst
Christian Wolfa,* and Peng Zhanga
a
Department of Chemistry, Georgetown University, Washington, DC 20057, USA
Fax : (+1)-202-687-6209; phone: (+1)-202-687-3468; e-mail: cw27@georgetown.edu
Received: December 3, 2010; Revised: January 20, 2011; Published online: March 15, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000918.
Abstract: Bisoxazolidine 1 is an effective ligand in substituents in various positions in the indole ring.
the copper(I)-catalyzed Friedel–Crafts reaction of Yields ranging from 90–97% and ee values between
alkyl trifluoropyruvates and indoles. A range of ethyl 90 and 94% were obtained at optimized tempera-
2-(3’-indolyl)-3,3,3-trifluoro-2-hydroxypropanoates
tures with substrates carrying substituents in position
was produced in up to 99% yield and 94% ee within 1 or 7.
30 min to 4 h. The effect of temperature on conver-
sion and enantioselectivity proved to be substrate
specific and was optimized individually. Of particular Keywords: asymmetric catalysis; bisoxazolidines;
interest is that this method tolerates the presence of Friedel–Crafts reaction; indoles; trifluoropyruvates
Introduction
Brønsted acids to this reaction has provided efficient
alternatives.[10] The organocatalytic Friedel–Crafts var-
The increasing demand for chiral fluorinated com- iant generally tolerates substituents at position 5 but
pounds by the pharmaceutical and agrochemical in- essentially racemic mixtures are obtained with N-
dustries has nourished the development of catalytic methylindole and only moderate enantioselectivity is
Friedel–Crafts reactions with trifluoromethyl ke-
tones.[1] This reaction provides access to secondary
and tertiary alcohols bearing a neighboring trifluoro-
methyl group as well as ether and ester derivatives
thereof. This structural motif has become an impor-
tant component in several drugs. Selected examples
include anticonvulsants,[2] peptidomimetic matrix met-
alloproteinase (MMP) inhibitors,[3] CJ-17,493, a neu-
rokinin 1 receptor antagonist,[4] and the anti-HIV
agent Efavirenz[5] (Figure 1).
To date, indoles have been used extensively in
asymmetric Friedel–Crafts reactions with a wide
range of carbonyl electrophiles[6] but few examples of
this reaction with methyl or ethyl trifluoropyruvate
have been reported, Scheme 1.[7] Excellent results for
the metal-catalyzed Friedel–Crafts reaction of indoles
and trifluoropyruvates towards 2-(3’-indolyl)-3,3,3-tri-
fluoro-2-hydroxypropanoates have been achieved
with chiral copper(II) and titanium(IV) complexes
but remaining drawbacks are either long reaction
times[8] or a limited substrate scope, e.g., several pro-
cedures provide low ee values when N-alkylindoles
Figure 1. Structures of selected drugs containing a trifluoro-
are used as substrate.[9] The introduction of chiral methyl-derived alcohol, ether or ester group.
760
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Adv. Synth. Catal. 2011, 353, 760 – 766

Asymmetric Friedel–Crafts Reaction of Indoles with Ethyl Trifluoropyruvate
Results and Discussion
We initiated this study by screening the effect of
metal salt, catalyst loading, solvent, temperature etc.
on the conversion, reaction time, and enantioselectivi-
ty of the Friedel–Crafts reaction between methyl tri-
fluoropyruvate and indole. Using 10 mol% of bisoxa-
zolidine (+)-1 and either CuACHTUNTRGNEUNG(OTf)2 or (CuOTf)2-tolu-
ene complex in dichloromethane, chloroform, toluene,
tetrahydrofuran, diethyl ether, tert-butyl methyl ether,
ethanol, and combinations thereof with hexane at
À428C, we found that methyl 2-(3’-indolyl)-3,3,3-tri-
fluoro-2-hydroxypropanoate, 2, is formed in up to
Scheme 1. Formation of 2-(3’-indolyl)-3,3,3-trifluoro-2-hy-
droxypropanoates by asymmetric Friedel–Crafts reaction
with indoles and ethyl trifluoropyruvate.
observed when a methyl group is present at position 92% yield and 79% ee, Table 1. In particular, results
7. Accordingly, the development of a method that obtained with dichloromethane and diethyl ether
provides high yields and ee values with indoles carry- were encouraging, see entries 1, 5 and 8. The perfor-
ing a substituent at the nitrogen atom or at carbon 7 mance of several copper, silver, zinc, and magnesium
is still desirable. Herein, we wish to report a cop- salts in dichloromethane was then evaluated, en-
per(I)-catalyzed asymmetric Friedel–Crafts reaction tries 13–17. Since 2 was obtained in only moderate ee
using a bisoxazolidine ligand that overcomes the limi- values under these conditions, Cu
ACHTUNGTRENN(NUG OTf)2 or (CuOTf)2-
tations mentioned above. toluene complex were tested in dichloromethane at
Asymmetric catalysis with chiral oxazolidine li- À788C (entries 18 and 19). The latter gave superior
gands has received increasing attention during the last results and furnished 2 in 97% yield and 88% ee
decade. Current applications of this relatively unex- when diethyl ether was used as solvent (entry 20).
plored class of ligands include asymmetric alkylations,
A decrease in the catalyst loading to 5 mol% of
alkynylations, allylic alkylations, cycloadditions, and (CuOTf)2-toluene complex and 6 mol% of ligand 1
aldol reactions.[11] We have demonstrated the general did not affect the results and we were pleased to find
usefulness of the aminoindanol-derived bisoxazolidine that the copper(I)-catalyzed asymmetric Friedel–
1 in several asymmetric carbon-carbon bond forming Crafts reaction proceeds with 95% yield and 89% ee
reactions, Figure 2.[12] This ligand catalyzes the enan- in diethyl ether at À788C. Importantly, the reaction
tioselective alkynylation of aromatic and aliphatic al- was complete after 1 hour. We realized that compara-
dehydes, generating chiral propargylic alcohols in ble results are obtained with ethyl trifluoropyruvate
high yield and ee.[13] Excellent results have also been and therefore decided to screen several indoles with
obtained for the alkylation of aldehydes with Me2Zn this ketone.
and Et2Zn.[14] Bisoxazolidine 1 proved to be a versa-
The Friedel–Crafts reaction between indole and
tile ligand in the asymmetric nitroaldol reaction. We ethyl trifluoropyruvate gave ethyl 2-(3’-indolyl)-3,3,3-
found that it catalyzes the reaction between aromatic trifluoro-2-hydroxypropanoate, 3, in 98% yield and
and aliphatic aldehydes with nitroalkanes in the pres- 91% ee within 30 min, see entry 1 in Table 2. Intro-
ence of dimethylzinc, which generates the reactive duction of electron-donating and electron-withdraw-
zinc nitronate in situ.[15] A wide range of Henry prod- ing groups to position 5 in the indole ring revealed
ucts was obtained with yields and ee values of up to that yields and ee values slightly decrease with 5-
99% yield and 95% ee, respectively. Alternatively, the fluoro- and 5-bromoindole even when the reaction
Cu(I)OAc-catalyzed variant proceeds with similar ef- was conducted at À988C (entries 2–5). However, ex-
ficiency but shows the opposite sense of asymmetric cellent results were obtained with unprotected 5-hy-
induction.[16] Most recently, we have extended the use droxyindole at À608C and the corresponding Friedel–
of 1 to the nitroaldol reaction with trifluoromethyl ke- Crafts reaction product 8 was isolated in 96% yield
tones and a-keto esters.[17]
and 85% ee (entry 6). With this substrate, the ee
values decreased at lower temperatures to 79% at
À788C and 58% at À988C. This observation prompt-
ed us to look more closely at temperature effects, and
we found a similar trend for the Friedel–Crafts reac-
tion with N-methylindole, see below. Our reaction
protocol also tolerates indole substrates carrying a
methyl group in position 6 and, more importantly, in
position 7 (entries 7 and 8). The synthesis of 10 from
7-methylindole and ethyl trifluoropyruvate was ac-
complished with 97% yield and 94% ee at À988C
Figure 2. Structure of bisoxazolidine (+)-1.
Adv. Synth. Catal. 2011, 353, 760 – 766
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Christian Wolf and Peng Zhang
FULL PAPERS
Table 1. Optimization of the enantioselective Friedel–Crafts reaction with indole.
Entry
Metal Complex
Cu(OTf)2
Solvent
Yield [%][a]
ee [%]
1
2
3
4
5
6
7
8
G
CH2Cl2
CHCl3
EtOH
CH2Cl2:hexanes (1:1)
CH2Cl2
CHCl3
toluene
Et2O
THF
97
99
<5%
95
92
99
91
92
96
88
99
99
86
82
73
61
91
98
96
97
59
53
n.d.
49
70
65
45
79
39
68
63
73
34
14
9
Cu
Cu
U
Cu
A
ACHTUNGTRENNUNG
N
R
R
N
T
E
AHCTUNGTRENNUNG
9
10
11
12
13
14
15
16
17
18[b]
19[b]
20[b]
TBME
CH2Cl2:Et2O (1:1)
Et2O:hexanes (4:1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
AHCTUNGTRENNUNG
R
25
10
60
74
88
G
G
N
G
Et2O
[a]
Isolated yields.
À788C.
[b]
Table 2. Scope of the enantioselective Friedel–Crafts reaction with indoles.[a]
Entry
1
Substrate
Product
T [oC]
t [h]
Yield[b] [%]
ee[c,d] [%]
À60
À78
À98
0.5
0.5
3.0
95
98
52
82 (R)
91
65
À60
À78
À98
0.5
1.0
1.0
96
93
99
85 (R)
90
90
2
3
À60
À78
À98
0.5
1.0
1.5
96
95
99
84 (R)
86
86
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Asymmetric Friedel–Crafts Reaction of Indoles with Ethyl Trifluoropyruvate
Table 2. (Continued)
Entry
Substrate
Product
T [oC]
t [h]
Yield[b] [%]
ee[c,d] [%]
À60
À78
À98
0.5
2.0
3.0
92
94
90
72 (R)
77
86
4
À60
À78
À98
1.0
1.0
4.0
99
90
86
59 (R)
70
81
5
6
7
À60
À78
À98
3.0
3.0
4.0
96
92
87
85 (R)
79
58
À60
À78
À98
0.5
1.0
4.0
99
95
75
90 (R)
91
92
À60
À78
À98
0.5
0.5
2.0
98
96
97
84 (R)
90
94
8
À60
À78
À98
0.5
1.0
3.0
95
93
87
89 (R)
90
77
9
À60
À78
À98
0.5
0.5
0.5
99
92
90
86 (R)
90
91
10
À60
À78
À98
0.5
2.0
2.0
96
93
90
84 (R)
88
92
11
[a]
All reactions were performed on a 0.5 mmol scale using 6 mol% of ligand 1, 5 mol% of (CuOTf)2-toluene complex, and
1.1 equiv. of ethyl 3,3,3-trifluoropyruvate in 6 mL of Et2O.
Isolated yields.
[b]
[c]
[d]
The ee values were determined by chiral HPLC on Chiralcel OD, Chiralcel OJ, Chiralpak AS, Chiralpak AD.
The absolute configuration was determined by comparison of the elution order as described in ref.[9] or by analogy.
within 2 h. The same reaction is complete after to À988C, and 11 was obtained in 87% yield and 77%
30 min when it is performed at À788C and 10 was ee. The opposite trend was found with N-benzylin-
prepared in 96% yield and 90% ee under these condi- dole: while 13 was produced in 93% yield and 88% ee
tions. The general substrate scope of the Cu(I)-bisoxa- at À788C, the results improved to 90% and 92% ee at
zolidine-catalyzed reaction is further highlighted by À988C.
the results obtained with N-substituted indoles. Prod-
ucts 11–13 were generated in unprecedented yields
and ee values and in very short reaction times (en- Conclusions
tries 9–11). A significant decrease in the enantioselec-
tivity of the Friedel–Crafts reaction of N-methylin- In conclusion, we have shown that bisoxazolidine 1 is
dole was observed when the temperature was reduced an effective ligand in the Cu(I)-catalyzed asymmetric
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Christian Wolf and Peng Zhang
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(R)-Ethyl 3,3,3-trifluoro-2-hydroxy-2-(5’-methylindol-3’-
Friedel–Crafts reaction of indoles with 3,3,3-trifluoro-
pyruvates. High yields and ee values were achieved
with a wide range of substrates in relatively short re-
action times. In particular, the reaction between in-
doles carrying a substituent in position 1 or 7 and
ethyl 3,3,3-trifluoropyruvate gave yields and ee values
that compare favorably with previously reported
methods. The use of bisoxazolidine 1 in other asym-
metric reactions is currently explored in our laborato-
ries.
yl)propanoate:[9c]
Chromatographic
purification
(Et2O:hexanes=2:3) gave a white solid; yield: 145 mg
1
(0.47 mmol, 93%, 90% ee). H NMR (400 MHz, CDCl3): d=
1.31 (t, J=7.1 Hz, 3H), 2.43 (s, 3H), 4.32 (dq, J=3.5 Hz,
7.1 Hz, 1H), 4.41 (s, 1H), 4.43 (dq, J=3.5 Hz, 7.1 Hz, 1H),
7.03 (dd, J=1.2 Hz, 8.3 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H),
7.30 (d, J=2.6 Hz, 1H). 7.66 (s, 1H), 8.12 (bs, 1H);
13C NMR (100 MHz, CDCl3): d=13.8, 21.5, 64.1, 76.7 (q,
J
C,F =31.5 Hz), 107.8, 110.9, 120.4, 123.5 (q, JC,F =286.2 Hz),
124.2, 124.3, 125.2, 129.7, 134.5, 169.4. The ee was deter-
mined by HPLC on Chiralcel OJ using IPA:hexanes (15:85)
as mobile phase: t1 (major)=27.7 min, t2 (minor)=37.7 min,
a=1.40.
Experimental Section
(R)-Ethyl 3,3,3-trifluoro-2-hydroxy-2-(5’-methoxyindol-3’-
yl)propanoate:[9c]
Chromatographic
purification
All commercially available reagents and solvents were used
without further purification. Anhydrous diethyl ether was
used as purchased and not dried any further. NMR spectra
were obtained at 400 MHz (1H NMR) and 100 MHz
(13C NMR). Chemical shifts are reported in ppm relative to
TMS. Reaction products were purified by column chroma-
tography on silica gel (particle size 32–63 mm).
(Et2O:hexanes=2:3) gave a colorless oil; yield: 151 mg
1
(0.48 mmol, 95%, 86% ee). H NMR (400 MHz, CDCl3): d=
1.31 (t, J=7.1 Hz, 3H), 3.82 (s, 3H), 4.32 (dq, J=3.6 Hz,
7.1 Hz, 1H), 4.43 (dq, J=3.6 Hz, 7.2 Hz, 1H), 4.45 (s, 1H),
6.85 (dd, J=2.5 Hz, 8.9 Hz, 1H), 7.15 (d, J=8.9 Hz, 1H),
7.31 (d, J=2.7 Hz, 1H), 7.35 (d, J=2.2 Hz, 1H), 8.27 (bs,
1H); 13C NMR (100 MHz, CDCl3) d=13.9, 55.7, 64.1, 76.8
(q, JC,F =31.5 Hz), 102.7, 108.0, 112.1, 113.1, 123.5 (q, JC,F
=
286.4 Hz), 125.0, 125.6, 131.4, 154.4, 169.3. The ee was deter-
mined by HPLC on Chiralcel OD using IPA:hexanes
(10:90) as mobile phase: t1 (major)=30.4 min, t2 (minor)=
43.0 min, a=1.46.
General Friedel–Crafts Reaction Procedure
The bisoxazolidine ligand (11.2 mg, 0.03 mmol) and
(CuOTf)2-toluene complex (12.9 mg, 0.025 mmol) were dis-
solved in 4 mL of anhydrous Et2O under nitrogen at room
temperature. After 30 min, ethyl 3,3,3-trifluoropyruvate
(96.4 mg, 0.55 mmol) dissolved in 1 mL of Et2O was added,
and the solution was stirred for an additional 10 min. It was
then cooled to the optimized reaction temperature shown in
Table 2 and kept for another 10 min. Finally, the indole
(0.5 mmol) dissolved in 1 mL of Et2O was added. After
completion of the reaction, the crude residue was loaded di-
rectly onto a silica gel column and purified by flash chroma-
tography as described below.
(R)-Ethyl
3,3,3-trifluoro-2-hydroxy-2-(5’-fluoroindol-3’-
Chromatographic purification
yl)propanoate:[9c]
(Et2O:hexanes=2:3) gave a colorless oil; yield: 135 mg
1
(0.45 mmol, 90%, 86% ee). H NMR (400 MHz, CDCl3): d=
1.35 (t, J=7.2 Hz, 3H), 4.35 (dq, J=3.5 Hz, 7.2 Hz, 1H),
4.44 (dq, J=3.5 Hz, 7.2 Hz, 1H), 4.46 (s, 1H), 6.94 (ddd, J=
2.5 Hz, 9.0 Hz, 9.0 Hz, 1H), 7.20 (dd, J=4.3 Hz, 4.5 Hz,
1H), 7.42 (d, J=2.8 Hz, 1H), 7.57 (dd, J=2.2 Hz, 10.4 Hz,
1H), 8.34 (bs, 1H): 13C NMR (100 MHz, CDCl3): d=13.8,
64.4, 76.7 (q, JC,F =31.7 Hz), 106.3 (d, JC,F =25.2 Hz), 108.6
(d, JC,F =4.6 Hz), 111.2 (d, JC,F =26.5 Hz), 112.0 (d, JC,F
=
(R)-Methyl 3,3,3-trifluoro-2-hydroxy-2-(indol-3’-yl)propa-
noate:[9a] Chromatographic purification (Et2O:hexanes=
2:3) gave a colorless oil; yield: 133 mg (0.49 mmol, 97%,
9.8 Hz), 123.5 (q, JC,F =286.2 Hz), 125.5 (d, JC,F =10.8 Hz),
126.0, 132.8, 158.0 (d, JC,F =234.8 Hz), 169.1. The ee was de-
termined by HPLC on Chiralcel OD using IPA:hexanes
(5:95) as mobile phase: t1 (major)=23.4 min, t2 (minor)=
27.1 min, a=1.19.
1
88% ee). H NMR (400 MHz, CDCl3): d=3.86 (s, 3H), 4.41
(bs, 1H), 7.11–7.25 (m, 4H), 7.82 (d, J=7.9 Hz, 1H), 8.15
(bs, 1H); 13C NMR (100 MHz, CDCl3): d=54.4, 76.8 (q,
(R)-Ethyl
3,3,3-trifluoro-2-hydroxy-2-(5’-bromoindol-3’-
Chromatographic purification
J
J
C,F =31.6 Hz), 108.2, 111.5, 120.6, 120.7, 122.7, 123.6 (q,
C,F =286.3 Hz), 124.4, 125.0, 136.2, 169.9. The ee was deter-
yl)propanoate:[9c]
(Et2O:hexanes=2:3) gave a colorless oil; yield: 156 mg
mined by HPLC on Chiralpak AD using IPA:hexanes
(10:90) as mobile phase: t1 (major)=16.5 min, t2 (minor)=
20.4 min, a=1.29.
1
(0.43 mmol, 86%, 81% ee). H NMR (400 MHz, CDCl3): d=
1.33 (t, J=7.1 Hz, 3H), 4.34 (dq, J=3.5 Hz, 7.2 Hz, 1H),
4.43 (dq, J=3.5 Hz, 7.2 Hz, 1H), 4.51 (bs, 1H), 7.25 (d, J=
8.7 Hz, 1H), 7.31 (dd, J=1.8 Hz, 8.7 Hz, 1H), 7.48 (d, J=
2.7 Hz, 1H), 8.05 (s, 1H), 8.40 (bs, 1H); 13C NMR
(100 MHz, CDCl3): d=13.8, 64.5, 76.7 (q, JC,F =31.8 Hz),
108.0, 112.8, 113.7, 123.5 (q, JC,F =286.4 Hz), 123.7, 125.5,
125.7, 126.7, 135.0, 169.0. The ee was determined by HPLC
on Chiralpak AS using IPA:hexanes (10:90) as mobile
phase: t1 (minor)=11.2 min, t2 (major)=13.3 min, a=1.27.
(R)-Ethyl 3,3,3-trifluoro-2-hydroxy-2-(5’-hydroxyindol-3’-
(R)-Ethyl 3,3,3-trifluoro-2-hydroxy-2-(indol-3’-yl) propa-
noate:[9c] Chromatographic purification (Et2O:hexanes=
2:3) gave a colorless oil; yield: 141 mg (0.49 mmol, 98%,
1
91% ee). H NMR (400 MHz, CDCl3): d=1.28 (t, J=7.1 Hz,
3H), 4.30 (dq, J=3.5 Hz, 7.1 Hz, 1H), 4.41 (dq, J=3.5 Hz,
7.1 Hz, 1H), 4.45 (s, 1H), 7.12–7.24 (m, 3H), 7.28 (d, J=
2.4 Hz, 1H), 7.87 (d, J=8.0 Hz, 1H), 8.23 (bs, 1H);
13C NMR (100 MHz, CDCl3): d=13.9, 64.2, 76.8 (q, JC,F
31.5 Hz), 108.4, 110.4, 120.5, 121.0, 122.6, 123.5 (q, JC,F
=
=
yl)propanoate:
Chromatographic
purification
286.3 Hz), 124.5, 125.1, 136.3, 169.4. The ee was determined
by HPLC on Chiralcel OD using IPA:hexanes (10:90) as
mobile phase: t1 (major)=19.8 min, t2 (minor)=23.3 min,
a=1.21.
(Et2O:hexanes=2:3, gradually changed to 4:1) gave a white
solid; yield: 145 mg (0.48 mmol, 96%, 85% ee). 1H NMR
(400 MHz, CDCl3): d=1.34 (t, J=7.2 Hz, 3H), 4.35 (bs,
764
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Asymmetric Friedel–Crafts Reaction of Indoles with Ethyl Trifluoropyruvate
1H), 4.36 (dq, J=3.6 Hz, 7.1 Hz, 1H), 4.46 (dq, J=3.6 Hz,
7.1 Hz, 1H), 4.64 (bs, 1H), 6.82 (dd, J=2.4 Hz, 8.7 Hz, 1H),
7.22 (d, J=8.7 Hz, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.43 (d, J=
2.7 Hz, 1H), 8.18 (bs, 1H); 13C NMR (100 MHz, CDCl3):
d=13.9, 64.2, 76.7 (q, JC,F =31.6 Hz), 105.5, 108.0, 112.0,
112.6, 123.5 (q, JC,F =286.3 Hz), 125.2, 126.0, 131.5, 150.0,
169.2. The ee was determined by HPLC on Chiralpak AD
using IPA:hexanes (15:85) as mobile phase: t1 (major)=
34.2 min, t2 (minor)=40.8 min, a=1.21. Anal. calcd. for
C13H12F3NO4: C 51.49, H 3.99, N 4.62, found: C 51.31, H
4.13, N 4.47.
31.6 Hz), 106.7, 109.8, 120.0, 121.4, 122.4, 123.8 (q, JC,F
=
286.2 Hz), 125.9, 128.0, 136.6, 169.5. The ee was determined
by HPLC on Chiralcel OD using IPA:hexanes (10:90) as
mobile phase: t1 (major)=7.8 min, t2 (minor)=15.6 min, a=
2.63. Anal. calcd. for C17H20F3NO3: C 59.47, H 5.87, N 4.08;
found: C 59.04, H 5.86, N 4.12.
(R)-Ethyl
yl)propanoate:
3,3,3-trifluoro-2-hydroxy-2-(1’-benzylindol-3’-
Chromatographic purification
(Et2O:hexanes=1:5) gave a colorless oil; yield: 170 mg
1
(0.45 mmol, 90%, 92% ee). H NMR (400 MHz, CDCl3): d=
1.30 (t, J=7.2 Hz, 3H), 4.33 (dq, J=3.6 Hz, 7.2 Hz, 1H),
4.39 (s, 1H), 4.44 (dq, J=3.6 Hz, 7.2 Hz, 1H), 5.28 (s, 2H),
7.08–7.31 (m, 8H), 7.39 (s, 1H), 7.93 (d, 7.9 Hz, 1H);
13C NMR (100 MHz, CDCl3): d=13.9, 50.3, 64.2, 76.8 (q,
(R)-Ethyl 3,3,3-trifluoro-2-hydroxy-2-(6’-methylindol-3’-
yl)propanoate:[10a]
Chromatographic
purification
(Et2O:hexanes=2:3) gave
a
slightly yellow oil; yield:
142 mg (0.48 mmol, 95%, 91% ee). 1H NMR (400 MHz,
CDCl3): d=1.29 (t, J=7.2 Hz, 3H), 2.42 (s, 3H), 4.32 (dq,
J=3.6 Hz, 7.2 Hz, 1H), 4.38 (bs, 1H), 4.44 (dq, J=3.6 Hz,
7.2 Hz, 1H), 6.95-6.99 (m, 2H), 7.20 (d, J=2.5 Hz, 1H), 7.73
(d, J=8.6 Hz, 1H), 8.02 (bs, 1H); 13C NMR (100 MHz,
CDCl3): d=13.9, 21.5, 64.2, 76.7 (q, JC,F =31.6 Hz), 108.2,
111.4, 120.5, 122.3, 122.8, 123.7 (q, JC,F =286.2 Hz), 123.8,
132.5, 136.8, 169.4. The ee was determined by HPLC on
Chiralcel OD using IPA:hexanes (4:96) as mobile phase: t1
(minor)=21.8 min, t2 (major)=24.9 min, a=1.16.
J
J
C,F =31.6 Hz), 107.5, 110.0, 120.3, 121.5, 122.4, 123.6 (q,
C,F =287.2 Hz), 126.0, 126.8, 127.8, 128.4, 128.8, 136.6, 136.9,
169.4. The ee was determined by HPLC on Chiralpak AD
using IPA:hexanes (10:90) as mobile phase: t1 (major)=
13.8 min, t2 (minor)=20.1 min, a=1.58. Anal. calcd. for
C20H18F3NO3: C 63.66, H 4.81, N 3.71; found: C 63.41, H
4.59, N 3.61.
(R)-Ethyl 3,3,3-trifluoro-2-hydroxy-2-(7’-methylindol-3’-
Acknowledgements
yl)propanoate:[10b]
Chromatographic
purification
(Et2O:hexanes=2:3) gave a white solid; yield: 144 mg
(0.49 mmol, 97%, 94% ee). H NMR (400 MHz, CDCl3): d=
Funding from the National Science Foundation (CHE-
0848301) is gratefully acknowledged.
1
1.30 (t, J=7.1 Hz, 3H), 2.40 (s, 3H), 4.30 (dq, J=3.6 Hz,
7.1 Hz, 1H), 4.42 (bs, 1H), 4.43 (dq, J=3.6 Hz, 7.1 Hz, 1H),
6.95 (d, J=7.1 Hz, 1H), 7.06 (dd, J=7.2 Hz, 7.9 Hz, 1H),
7.38 (d, J=2.5 Hz, 1H), 7.72 (d, J=8.0 Hz, 1H), 8.19 (bs,
1H); 13C NMR (100 MHz, CDCl3): d=13.9, 16.4, 64.2, 76.7
(q, JC,F =31.5 Hz), 109.0, 118.7, 120.5, 120.6, 123.1, 123.5 (q,
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1
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=
Adv. Synth. Catal. 2011, 353, 760 – 766
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
765

Christian Wolf and Peng Zhang
FULL PAPERS
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766
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ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2011, 353, 760 – 766