Supporting Information
© Wiley-VCH 2005
69451 Weinheim, Germany
HIGHLY ENANTIOSELECTIVE ORGANOCATALYTIC
HYDROXYALKYLATION OF INDOLES WITH ETHYL
TRIFLUOROPYRUVATE**
Béla Török,* Mohammed Abid, Gábor London, Joseph Esquibel, Marianna Török,
Shilpa C. Mhadgut, Ping Yan, and G. K. Surya Prakash*
MATERIALS The cinchona alkaloids (cinchonidine (denoted as CD), cinchonine (denoted as CN),
quinine (denoted as QN) and quinidine (denoted as QD), dihydroquinidine (denoted as DHQD), Nbenzyl-cinchonidine (denoted as NBzCD), N-benzyl-cinchonine (denoted as NBzCN) were purchased
from Fluka and used without further purification. The 9-O-acetyl cinchona derivatives have been
synthesized according to a literature procedure (I. Kun, B. Török, K. Felföldi, M. Bartók, Appl. Catal.
2000, 203, 71). Indole derivatives and ethyl 3,3,3-trifluoropyruvate were Aldrich products. CDCl3 used
as a solvent (99.8%) for the NMR studies was a Cambridge Isotope Laboratories product.
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F NMR
reference compound CFCl3 was purchased from Aldrich. Other solvents used in synthesis with
minimum purity of 99.5% were Fisher products. K-10, a solid acid used in the purification protocol
was obtained from Fluka.
GC-MS ANALYSIS : The mass spectrometric identification of the products have been carried out by a
Shimadzu QP5050 gas chromatograph-mass spectrometer system (70 eV electron impact ionization)
using a 30m long DB-5 type column (J&W Scientific).
HPLC ANALYSIS: The determination of the enantiomeric excesses have been carried out by chiral
HPLC analysis using a Jasco PU-2080 HPLC coupled with an PU-2075 UV-VIS detector. The samples
have been analyzed in a hexane/isopropyl alcohol=20/80 mobile phase using a Chiralcel OJ-H (Daicel)
analytical column at 260 nm wavelength.
NMR ANALYSIS. The 1 H, 13 C and
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F NMR spectra were obtained on a 400 MHz superconducting
Varian Innova 400 NMR spectrometer, in CDCl3 solvent with tetramethylsilane and CCl3F as internal
standards. The temperature was 25 °C (accuracy ±1 °C) and controlled by the Varian control unit.
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The enantiomeric excess of some products have been determined by
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F NMR using Quinine and
Quinidine as chiral solvating agents. A product/cinchona mixture was dissolved in CDCl3 and the CF 3
substituent of the products have been used as reporting group. The ee values determined were
reproducible within 0.5%. The concentration of the CF3 compounds was usually 8 mg/ml, and the
alkaloid was added in 3 fold molar excess. A comparison with HPLC analyses showed good agreement
in the case of 3a and 3b.
PREPARATION OF COMPOUNDS The assignment of the enantiomeric peaks both in NMR and HPLC
studies was based on a comparison with samples synthesized by Cu(II)-bisoxazoline catalysis
following the procedure published by Zhuang et al. This process provided the (S)-enantiomers in
excess.
(a) A typical experimental procedures for cinchona alkaloid catalyzed hydroxyalkylation of indoles
with ethyl 3,3,3-trifluropyruvate
(S)-3,3,3-trifluoro-2-hydroxy-2-(3-indolyl)-propionic acid ethyl ester (3a)
Indole (0.5 mmol) and cinchonidine (0.0375 mmol) were placed into a glass reaction vessel and 3 mL
Et2 O was added. The mixture was stirred at –8 ºC (salt-ice cooling bath) for 30 min. 0.75 mmol of
ethyl 3,3,3 trifluoropyruvate was then added and the mixture was stirred at –8 ºC (salt-ice cooling bath)
for 3 hrs and the progress was monitored by TLC. After the reaction was completed, the solvent and
excess ethyl trifluoropyruvate were removed by evaporation. The mixture then was dissolved in ether
and the catalyst was removed by a treatment with 500 mg of K-10 montmorillonite (a solid acid). After
the treatment cinchonidine-K-10 complex was removed by filtration and the solvent was evaporated. A
colorless solid was obtained in 98% yield. The enantiomeric excess of the product has been determined
by HPLC (see below). The product purity was 95% ee.
(R)-3,3,3-trifluoro-2-hydroxy-2-(3-indolyl)-propionic acid ethyl ester (4a)
Indole (0.5 mmol) and cinchonine (0.0375 mmol) were placed into a glass reaction vessel and 3 mL
Et2 O was added. The mixture was stirred at –8 ºC (salt-ice cooling bath) for 30 min. 0.75 mmol of
ethyl 3,3,3 trifluoropyruvate was then added and the mixture was stirred at –8 ºC (salt-ice cooling bath)
for 4 hrs and the progress was followed by TLC. After the reaction was completed, the solvent and
excess ethyl trifluoropyruvate were removed by evaporation. The mixture then was dissolved in ether
and the catalyst was removed by a treatment with 500 mg of K-10 (a solid acid). After the treatment,
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cinchonidine-K-10 complex was removed by filtration and the solvent was evaporated. A colorless
solid was obtained in 98% yield. The enantiomeric excess of the product has been determined by
HPLC (see below). The product purity was 90% ee.
(b) Assignment of chirality
The assignment of individual enantiomers was based on a comparison with an authentic sample. The
sample has been prepared according to the method described in W. Zhuang, N. Gathergood, R.G.
Hazell, K.A. Jørgensen, J. Org. Chem. 2001, 66, 1009 (ref.8 in the manuscript). The authors used
single crystal X-ray crystallography to assign the chirality of the products. The reaction have been
carried out by using 2,2’-isopropylidenebis[(4S)-4-tert-butyl-2-oxazoline] modified copper triflate
catalyst to yield the (S)-enantiomer in excess and analyzed by chiral HPLC (for details see above).
Here, we show the chirality assignment for both 3, 3, 3-trifluoro -2-hydroxy-2-(indole-3-yl)-propionic
acid ethyl ester enantiomers obtained with cinchonidine and cinchonine catalysis, respectively (Fig.1).
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Figure 1.
Assignment of 3, 3, 3-trifluoro -2-hydroxy-2-(indol-3-yl)-propionic acid ethyl ester enantiomers based
on a comparison with an authentic sample: starting material (indole) and reaction products obtained in
the reaction of indole and ethyl 3,3,3-trifluoropyruvate catalyzed by (a) Cu(OTf) 2-bisoxazoline
(authentic sample), (b) cinchonidine and (c) cinchonine
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Determination of the enantiomeric composition of the products:
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6
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8
9
10
11
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Characterization of the products:
3, 3, 3-Trifluoro-2-hydroxy-2-(indol-3-yl)-propionic acid ethyl ester
F3C
COOEt
OH
N
H
colorless crystals. (m.p. 70.5-71.8 o C)
1
H NMR (399.81 MHz, CDCl3), d (ppm) 8.25 (bs, 1H, NH), 7.89 (d,J=8.3 Hz, 1H, Ar), 7.45 (d,
J=2.3Hz, 1H, Ar), 7.35 (dd, J=7.99, 1.19 Hz,1H, Ar), 7.21 (dd, J= 7.19, 1.19 Hz, 1H, Ar), d 7.14 (ddd,
J=7.19, 1.19 Hz, 1H, Ar), 4.44 (dq, J=7.2, 3.6 Hz, 1H, CH2), 4.39 (s, 1H, OH), 4.34 (dq, J=7.2, 3.6 Hz,
1H, CH2 ), 1.35 (td, J=7.19 Hz, 3H, CH3)
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C NMR (100.53 MHz, CDCl3 ), d (ppm) 169.6, 136.5, 125.3, 125.1, 124.5, 122.9, 122.3, 121.4,
120.7, 111.5, 108.9, 64.4, 14.1,
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F NMR (376.19 MHz, CDCl3, CFCl3 -Ref), d (ppm) -77.15 (s, 3F)
MS-C 13 H12F 3 NO3 (287), m/z (%): 287 (M+, 33), 214 (100), 144 (65), 117 (70), 89 (30).
3, 3, 3-Trifluoro-2-hydroxy-2-(5-methyl-indol-3-yl)-propionic acid ethyl ester.
F3C
H3C
COOEt
OH
N
H
Light brown crystals. (m.p. 75.2-76.5 o C)
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1
H NMR (399.81 MHz, CDCl3 ), d (ppm) 8.16 (bs, 1H, NH), 7.66 (s, 1H, Ar), 7.40 (d, J=2.3 Hz, 1H,
Ar), 7.24 (d, J=8.3 Hz, 1H, Ar), 7.03 (dd, J=8.3, 1.5 Hz, 1H, Ar), 4.43 (dq, J=7.19, 3.6 Hz, 1H, CH2 ),
4.39 (s, 1H, OH), 4.34 (dq, J=7.19, 3.5 Hz, 1H, CH2 ), 2.43 (s, 3H, CH3 ), 1.35 (td, J=7.19 Hz, 3H,
CH3 ).
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C NMR (100.53 MHz, CDCl3 ), d (ppm) 169.6, 151.7, 134.8, 130.0, 125.6, 124.5, 123.4, 122.3,
120.9, 111.1, 108.4, 64.3, 21.8, 14.0
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F NMR (376.19 MHz, CDCl3, CFCl3 -Ref), d (ppm) -77.12 (s, 3F)
MS-C 14 H14F 3 NO3 (301), m/z (%): 301 (M+, 11), 130 (100).
3, 3, 3-Trifluoro-2-hydroxy-2-(5-chloro -indol-3-yl)-propionic acid ethyl ester.
F3C
COOEt
OH
Cl
N
H
Red crystals. (m.p. 51-52.3 o C)
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H NMR (399.81 MHz, CDCl3 ), d (ppm) 8.30 (bs, 1H, NH), 7.91 (t, J=0.8 Hz, 1H, Ar), 7.50 (d, J=2.8
Hz, 1H, Ar), 7.28 (dd, J=8.8, 0.8 Hz, 1H, Ar), 7.17 (dd, J=6.8, 2.0Hz, 1H, Ar), 4.45 (dq, J=7.2, 3.6 Hz,
1H, CH2 ), 4.41 (s, 1H, OH), 4.36 (dq, J=7.2, 3.6 Hz, 1H, CH2), 1.36 (td, J=7.2 Hz, 3H, CH3 )
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C NMR (100.54 MHz, CDCl3 ), d (ppm) 169.3, 134.9, 126.5, 126.3, 125.9, 125, 123.2, 122.1, 121.1,
112.5, 108.3, 64.6, 14.0.
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F NMR (376.15 MHz, CDCl3, CFCl3-Ref), d (ppm) -77.53 (s, 3F)
MS-C 13 H11F 3ClNO3 (321), m/z (%): 321 (M+, 20), 248 (100), 178 (60), 151 (85).
3, 3, 3-Trifluoro-2-hydroxy-2-(5-bromo -indol-3-yl)-propionic acid ethyl ester
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F3C
COOEt
OH
Br
N
H
Reddish-brown crystals. (m.p. 51-52.5 oC)
1
H NMR (399.81 MHz, CDCl3 ), d (ppm) 8.32 (bs, 1H, NH), 8.07 (t, J=0.7 Hz, 1H, Ar), 7.47 (d, J=
2.7 Hz, 1H, Ar), 7.29 (dd, J= 8.8, 2.0 Hz, 1H, Ar), 7.22 (dd, J=8.8, 0.3Hz, 1H, Ar), 4.45 (dq, J=7.2, 3.6
Hz, 1H, CH2 ), 4.39 (s, 1H, OH), 4.36 (dq, J=7.2, 3.9 Hz, 1H, CH2 ), 1.36 (td, J=7.2 Hz, 3H, CH3 ).
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C NMR (100.54MHz, CDCl3 ), d (ppm) 169.3, 135.2, 127.0, 125.9, 125.8, 125, 124.26, 122.1, 114.2,
112.9, 108.7, 64.7, 14.1.
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F NMR (376.15 MHz, CDCl3, CFCl3 -Ref), d (ppm) -77.5 (s, 3F)
MS-C 13 H11F 3 BrNO3 (367), m/z (%): 367 (M+, 10), 295 (45), 225 (20), 144 (100).
3, 3, 3-Trifluoro-2-hydroxy-2-(5-iodo-indol-3-yl)-propionic acid ethyl ester
F3C
COOEt
OH
I
N
H
Dark brown crystals. (m.p. 74.3-76 o C)
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H NMR (399.81 MHz, CDCl3 ), d (ppm) 8.35 (bs, 1H, NH), 8.27 (s, 1H, Ar), 7.45 (dd, J=8.8, 2.0 Hz,
1H, Ar), 7.40 (d, J=2.4 Hz, 1H, Ar), 7.11 (dd, J=8.8, 0.4 Hz, 1H, Ar), 4.44 (dq, J=7.2, 3.6 Hz, 1H,
CH2 ), 4.38 (s, 1H, OH), 4.35 (dq, J=7.2, 3.6Hz, 1H, CH2 ), 1.36 (td, J=7.2 Hz, 3H, CH3 ).
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C NMR (100.54MHz, CDCl3 ), d (ppm)169.3, 135.6, 131.3, 130.4, 127.4, 125.5, 124.9, 122.1, 113.4,
108.3, 84.5, 64.7, 14.1.
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F NMR (376.15 MHz, CDCl3, CFCl3-Ref), d (ppm) -77.46 (s, 3F)
MS-C 13 H11F 3 INO 3 (413), m/z (%): 413 (M+ , 33), 340 (60), 270 (20), 144 (100).
3, 3, 3-Trifluoro-2-hydroxy-2-(5-methoxy-indol-3-yl)-propionic acid ethyl ester.
F3C
COOEt
OH
MeO
N
H
Colorless crystals. (m.p. 74.5-75.8 o C)
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H NMR (399.81 MHz, CDCl3 ), d (ppm) 8.25 (bs, 1H, NH), 7.40 (d, J=2.8Hz, 1H, Ar), 7.35 (d, J=2.4
Hz, 1H, Ar), 7.22 (d, J=8.8 Hz, 1H, Ar), 6.87 (dd, J=8.8, 2.4 Hz, 1H, Ar), 4.45 (dq, J=7.2, 3.6 Hz, 1H,
CH2 ), 4.40 (s, 1H, OH), 4.34 (dq, J=7.2, 3.6 Hz, 1H, CH2 ), 3.83 (s, 3H, CH3), 1.34 (td, J=7.2 Hz, 3H,
CH3 ).
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C NMR (100.53 MHz, CDCl3 ), d (ppm) 169.6, 154.7, 131.6, 125.9, 125.2, 125, 122.3, 113.4, 112.2,
108.5, 103, 64.4, 56.0, 14.2
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F NMR (376.15 MHz, CDCl3, CFCl3 -Ref), d (ppm) -77.15 (s, 3F)
MS-C 14 H14F 3 NO4 (317), m/z (%): 317 (M+, 25), 244 (95), 270 (65), 147 (100).
3, 3, 3-Trifluoro-2-hydroxy-2-(2-methyl-indol-3-yl)-propionic acid ethyl ester
F3C
COOEt
OH
N
H
CH3
Red crystals. (m.p. 67-68.5 o C)
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1
H NMR (399.81 MHz, CDCl3 ), d (ppm) 7.99 (bs, 1H, NH), 7.79 (d, J=7.9 Hz, 1H, Ar), 7.24 (dq,
J=6.7, 0.7 Hz, 1H, Ar), 7.12 (ddd, J=7.1, 1.1, Hz, 1H, Ar), 7.08 (ddd, J=6.7, 1.1 Hz, 1H.Ar), 4.43 (dq,
J=7.2, 3.6 Hz, 1H, CH2 ), 4.34 (dq, J=7.2, 3.6 Hz, 1H, CH2), 3.95 (s, 1H, OH), 2.51 (s, 3H, CH3 ), 1.33
(t, J=7.19 Hz, 3H, CH3 ).
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C NMR (100.54MHz, CDCl3 ), d (ppm) 169.5, 135.4, 134.8, 127, 125.5, 122.7, 121.8, 120.7, 120.4,
110.4, 104.1, 63.77, 14.4, 14.0.
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F NMR (376.15 MHz, CDCl3, CFCl3 -Ref), d (ppm) -77.91 (s, 3F)
MS-C 14 H14F 3 NO3 (301), m/z (%): 301 (M+, 30), 228 (100), 158 (66), 131 (90).
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