Enantioselective Friedel-Crafts reaction of indoles with trifluoroacetaldehyde catalyzed by Cinchona alkaloids

Article abstract of DOI:10.1002/chir.20982

The first direct asymmetric synthetic preparation of trifluoro-1-(indol-3- yl)ethanols (TFIEs) is described by an enantioselective organocatalytic method from indoles and inexpensive trifluoroacetaldehyde methyl hemiacetal. The reaction is catalyzed by hydroquinine to produce TFIEs in an almost quantitative yield and with enantioselectivities up to 75% at room temperature. The enantioselectivity is strongly dependent on the concentration of substrates and catalyst due to the competitive noncatalyzed reaction. Copyright

Full text of DOI:10.1002/chir.20982

CHIRALITY 23:612–616 (2011)
Enantioselective Friedel–Crafts Reaction of Indoles with
Trifluoroacetaldehyde Catalyzed by Cinchona Alkaloids
´
¨
¨
*
DMITRY A. BORKIN, SHAINAZ M. LANDGE, AND BELA TOROK
Department of Chemistry, University of Massachusetts Boston, Boston, Massachusetts
ABSTRACT
The first direct asymmetric synthetic preparation of trifluoro-1-(indol-3-yl)ethanols
(TFIEs) is described by an enantioselective organocatalytic method from indoles and inexpensive
trifluoroacetaldehyde methyl hemiacetal. The reaction is catalyzed by hydroquinine to produce
TFIEs in an almost quantitative yield and with enantioselectivities up to 75% at room temperature.
The enantioselectivity is strongly dependent on the concentration of substrates and catalyst due to
C
VV
the competitive noncatalyzed reaction. Chirality 23:612–616, 2011.
2011 Wiley-Liss, Inc.
KEY WORDS: enantioselective; organocatalysis; Cinchona; indole; fluoral; chiral trifluoro-
methylated alcohols
INTRODUCTION
One particularly versatile group of compounds is the family
of Cinchona alkaloids, which are known to be the catalyst of
choice for many applications such as additions, substitutions,
acylations, rearrangements, decarboxylations etc. providing
excellent yields and stereoselectivity.29,30
Herein, extending our efforts in the development of sus-
tainable synthetic methods we describe the first effective
asymmetric organocatalytic synthesis of TFIEs via enantiose-
lective Friedel–Crafts hydroxyalkylation of indoles with tri-
fluoroacetaldehyde methyl hemiacetal.
Organofluorine compounds, particularly trifluoromethy-
lated derivatives, are highly important substances in organic
and medicinal chemistry. As compared to their nonfluori-
nated analogues, the presence of the powerful electron-with-
drawing substituent, its small size and lipophilic character
generate significant changes in the chemistry and the biologi-
cal effects of these compounds.1,2 The increased lipophilicity
of such molecules results in active agrochemical and pharma-
ceutical compounds with improved adsorption-distribution-
metabolism-excretion characteristics in vivo, enabling lower
dose rates.3–5 Commonly available trifluoromethylated com-
pounds are nonchiral aryl CF3 and OCF3 containing com-
pounds, however, there has been recent interest in the appli-
cation of products carrying the CF3 group at a stereogenic
center.6–8 The number of available starting materials for such
transformations is few hindering the development of methods
for preparation of compounds with the CF3 at a stereogenic
center.9–12 Trifluoroacetaldehyde (fluoral) is among the most
useful CF3 synthons that fueled the asymmetric synthetic
developments,13–15 including its chiral Friedel–Crafts reac-
tions.16,17 Enantiomerically pure trifluoro-1-(indol-3-yl)etha-
nols (TFIEs) are of particular interest as they are analogous
to trifluoromethyl-indolyl-hydroxypropionic acid esters, which
were found to be potent inhibitors of fibrillogenesis of Alzhei-
mer’s amyloid b (Ab) peptide,18–20 and fructose 1,6-biphos-
phatase enzyme, that is a frequent target of drug develop-
ment for the type II diabetes.21,22 The only method that
describes preparation of enantiomerically enriched TFIEs
applies an enzyme-catalyzed kinetic resolution.23
EXPERIMENTAL
General Information
All reactions were carried out in closed vials without inert atmosphere.
Solvents were purchased from Fisher and/or Aldrich and kept on MS 4
˚
A molecular sieves for at least 2 days before use. All reagents and cata-
lysts were purchased from Aldrich except trifluoroacetaldehyde methyl
hemiacetal, 7-ethylindole, 5-benzyloxyindole (Alfa Aesar) and two cata-
lysts which were synthesized according to literature procedures: cata-
lysts 531 and 9.32 NMR spectra (1H, 13C, 19F) were recorded on Varian-
300 NMR spectrometer with tetramethylsilane, residual solvent signal
and CFCl3 as references. Reactions were monitored by gas chromatogra-
phy/mass spectrometry with an Agilent 6850-5973N GC-MS system
(30m DB-5 type column, 70 eV impact ionization). Chromatographic puri-
fications were carried out using self-prepared preparative TLC plates (1.5
mm thickness, Aldrich silica gel with gypsum binder as stationary
phase). The enantiomeric excess was determined using chiral high-per-
formance liquid chromatography (HPLC) with Daicel Chiralcel OD-H,
AS-H or OJ-H on columns a Jasco PU-2080/2070 HPLC system with UV
detection at 260 nm.
Assignment of Absolute Configuration
Enantioselective Friedel–Crafts reaction of indoles is a
powerful tool to access a diverse pool of enantiopure indole
derivatives. The most commonly applied catalysts for such
transformations are metal-based chiral Lewis acids.24 While
these catalysts are usually effective and selective, metal-free
catalytic systems appear preferable due to environmental
concerns. In addition, the metal complex-based Lewis acid
catalysts often include expensive synthetic ligands, are mois-
ture and air sensitive and the reactions require inert atmos-
phere. Recent developments in enantioselective organocatal-
ysis appear to provide solution for some of these prob-
lems.25,26 Organocatalysts are usually based on natural
products, that are commercially available and economic.27,28
The absolute configuration of the products was assigned on the basis
of literature data.23 The optical rotation of (S)-2,2,2-trifluoro-1-(indol-3-
yl)ethanol in 97% enantiomeric excess is [a]20 5 114.58 (c 5 0.5,
D
Shainaz M. Landge is currently at Department of Chemistry,
Georgia Southern University, Statesboro, Georgia 30485
Contract grant sponsor: National Institute of Health; Contract grant number:
R-15 AG025777-03A1
Contract grant sponsor: University of Massachusetts Boston
*Correspondence to: Be´la To¨ro¨k, Department of Chemistry, University of
Massachusetts Boston, 100 Morrissey Blvd, Boston, MA 02125.
E-mail: bela.torok@umb.edu
Received for publication 27 January 2011; Accepted 17 May 2011
DOI: 10.1002/chir.20982
Published online 11 July 2011 in Wiley Online Library
(wileyonlinelibrary.com).
C
VV
2011 Wiley-Liss, Inc.

ADDITION OF TRIFLUOROACETALDEHYDE TO INDOLES
613
Fig. 1. Structures of chiral organocatalysts, used for asymmetric Friedel–Crafts hydroxyalkylation of indoles with trifluoroacetaldehyde methyl hemiacetal.
EtOH).23 The measured optical rotation of 3a in 58% enantiomeric
67.18 (q, J 5 33.5 Hz). 19F NMR (300 MHz, CDCl3): 277.84 (d, J 5 6.9
Hz).
excess is [a]20 5 18.28 (c 5 1.04, CHCl3). Based on the data, the con-
D
figuration was assigned to be (S) for all indole derivatives.
(S)-2,2,2-trifluoro-1-(5-bromoindol-3-yl)ethanol (3d). Colorless
solid, mp.: 170–1718C. MS (EI, 70 eV); m/z: 225 (100%), 226 (92%),
117 (67%), 293 (64%, M1), 295 (63%, M1), 277 (51%). 1H NMR (300
MHz, CDCl3): d (ppm) 8.41 (br s, 1H), 7.78 (s, 1H), 7.11–7.27 (m,
3H), 5.16 (q, J 5 6.6 Hz, 1H), 3.35 (br, 1H). 13C NMR (75 MHz,
CDCl3): d (ppm) 134.57, 127.19, 126.47, 125.60, 125.14, 121.79, 113.63,
112.96, 108.72, 66.19 (q, J 5 33.3 Hz). 19F NMR (300 MHz, CDCl3):
277.80 (d, J 5 6.6 Hz).
General Experimental Procedure for the Enantioselective
Hydroxyalkylation of Indoles with Trifluoroacetaldehyde
Methyl Hemiacetal
To solution of indole (58.5 mg, 0.5 mmol) and hydroquinine
(48.9 mg, 0.15 mmol) in dry dichloromethane (0.5 ml), trifluoroace-
taldehyde methyl hemiacetal (70 ll, 0.625 mmol) was added. The
reaction mixture was kept in a tightly closed vial and stirred for
the indicated period of time, and then analyzed by GC-MS to deter-
mine conversion. After completion, the product was purified using
preparative TLC affording pure TFIE. Finally, all products were
characterized by MS and NMR and the optical purity was deter-
mined by HPLC.
(S)-2,2,2-trifluoro-1-(5-iodoindol-3-yl)ethanol (3e). Colorless
solid, mp.: 143–1448C. MS (EI, 70 eV); m/z: 341 (100%, M1), 272
(58%), 145 (55%), 144 (52%), 323 (28%). 1H NMR (300 MHz, CDCl3):
d (ppm) 8.34 (br s, 1H), 8.08 (s, 1H), 7.15-7.51 (m, 3H), 5.28 (q, J 5
6.9 Hz, 1H), 2.59 (br, 1H). 13C NMR (75 MHz, CDCl3): d (ppm)
135.08, 131.30, 128.31, 128.14, 126.47, 124.50, 122.74, 113.35, 84.19,
67.83 (q, J 5 33.6 Hz). 19F NMR (300 MHz, CDCl3): 277.97 (d, J 5
6.9 Hz).
General Experimental Procedure for the Enantioselective
Hydroxyalkylation of Indoles with Neat Fluoral
Fluoral was produced using a procedure described earlier.33 The gas
(approximately twofold excess) was condensed at 2788C in nitrogen
atmosphere and solution of indole (58.5 mg, 0.5 mmol) and catalyst
hydroquinine (32.6 mg, 0.1 mmol) in DCM (0.5 ml) was slowly added.
After stirring for 5 minutes, the reaction mixture was allowed to warm to
room temperature. The reaction mixture was kept in a tightly closed vial
for the indicated period of time; the progress was determined by GC-
MS. The crude product was purified by preparative TLC and the pure
product was characterized by NMR. The optical purity was determined
by HPLC.
(S)-2,2,2-trifluoro-1-(5-methoxyindol-3-yl)ethanol (3f). Viscous
oil. MS (EI, 70 eV); m/z: 245 (100%, M1), 176 (82%), 227 (43%), 148
(37%), 133 (33%). 1H NMR (300 MHz, (CD3)2CO): d (ppm) 10.36 (br s,
TABLE 1. Effect of catalysts on the enantioselective
Friedel-Crafts hydroxyalkylation of indole with
trifluoroacetaldehyde methyl hemiacetal
(S)-2,2,2-trifluoro-1-(indol-3-yl)ethanol (3a). Colorless solid,
mp.: 134–1368C. MS (EI, 70 eV); m/z: 197 (100%), 146 (86%), 215 (74%,
M1), 118 (71%). 1H NMR (300 MHz, CDCl3): d (ppm) 8.25 (br s, 1H),
7.71 (d, J 5 7.5 Hz, 1H), 7.16–7.41 (m, 4H), 5.31 (q, J 5 6.9 Hz, 1H), 2.48
(br, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 135.97, 126.67, 125.62,
123.81, 123.52, 122.89, 120.57, 119.24, 111.48, 67.47 (q, J 5 33.5 Hz). 19F
NMR (300 MHz, CDCl3): 277.82 (d, J 5 6.9 Hz).
Entry
Catalyst
CIndole (M) Time (h) Yield (%)a ee (%)b
1
2
3
4
5
6
7
8
No catalyst
1
0.5
1
96
48
48
48
48
96
48
48
96
96
96
96
96
45
95
98
0
0
0
0
4
5
6
7
8
(S)-2,2,2-trifluoro-1-(5-fluoroindol-3-yl)ethanol (3b). Viscous
oil. MS (EI, 70 eV); m/z: 164 (100%), 233 (71%, M1), 136 (71%), 215
(45%), 109 (36%). 1H NMR (300 MHz, CDCl3): d (ppm) 8.42 (br s, 1H),
7.32 (d, J 5 9.9 Hz, 1H), 6.92–7.25 (m, 3H), 5.20 (q, J 5 6.9 Hz, 1H), 3.26
(br, 1H). 13C NMR (75 MHz, CDCl3): d (ppm) 159.64, 132.51, 125.62,
112.29, 112.16, 111.45, 111.10, 104.54, 104.22, 67.36 (q, J 5 33.5 Hz). 19F
NMR (300 MHz, CDCl3): 277.87 (d, J 5 6.9 Hz).
0.5
0.5
0.5
0.5
1
20
97
80
95
0
9
0
0
9
10
11
12
13
14
14
97
9
0.5
0.5
1
1
2
80
96
97
98
19(R)
37(S)
39(R)
46(S)
52(S)
10
11
12
13
(S)-2,2,2-trifluoro-1-(5-chloroindol-3-yl)ethanol (3c). Colorless
solid, mp.: 167–1698C. MS (EI, 70 eV); m/z: 180 (100%), 249 (70%, M1),
117 (55%), 182 (35%), 231 (27%), 251 (23%, M1). 1H NMR (300 MHz,
CDCl3): d (ppm) 8.51 (br s, 1H), 7.63 (s, 1H), 7.12–7.25 (m, 3H), 5.19 (q,
J 5 6.9 Hz, 1H), 3.83 (br, 1H). 13C NMR (75 MHz, CDCl3): d (ppm)
134.33, 125.30, 123.68, 123.08, 122.76, 119.42, 118.74, 112.55, 111.44,
>99
aGC yield.
bDetermined by HPLC.
Chirality DOI 10.1002/chir

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614
BORKIN, LANDGE, AND TOROK
TABLE 2. Effect of hydroquinine loading on the
enantioselective Friedel-Crafts hydroxyalkylation of indole
with trifluoroacetaldehyde methyl hemiacetala
RESULTS AND DISCUSSION
Recently, it was observed in our laboratory that indole
readily reacted with trifluoroacetaldehyde methyl hemiacetal
under microwave conditions producing TFIE in good yield.
Due to our interest in enantioselective organocatalytic Frie-
del–Crafts reactions with organofluorine electrophiles, the
above observation initiated further exploration of this reac-
tion, to develop an asymmetric catalytic reaction to synthe-
size enantiomerically pure products. To the best of our
knowledge, the chiral target compounds have never been
directly synthesized. In the only report describing these chi-
ral compounds, enzymatic kinetic resolution was used to
obtain the products.18 First, the performance of several orga-
nocatalysts in the reaction was investigated. The group of
catalysts studied included a chiral benzyl alcohol, several
proline and Cinchona derivatives (Fig. 1). Such compounds
are well-known organocatalysts.29,34 The screening of differ-
ent organocatalysts (Table 1) showed promising results in
the reaction at room temperature. A comparative reaction
without a catalyst resulted in 45% conversion after 96 h (entry
1). While the racemic reaction occurs without catalysis, all
organocatalysts bearing the 1,2-aminoalcohol moiety
increased the reaction rate. The inactivity in the only excep-
tion, prolinol (entry 4), can be explained by formation of a
stable adduct with trifluoroacetaldehyde.35 Catalysts 4, 5, 7,
and 9 showed the highest activity and short reaction times,
however, produced racemic product. Overall, hydroquinine
was found to be the best catalyst, providing the product with
almost quantitative yield and ee of 52 % (entry 13).
Entry
Ccatalyst (mol%)
Time (h)
Yield (%)b
ee (%)c,d
1
2
3
4
5
10
20
30
40
50
96
96
72
96
96
87
>99
>99
88
46
52
58
55
53
81
a2M of Indole in DCM, RT.
bGC yield.
cDetermined by HPLC.
dIn all products (S) enantiomer were formed in excess.
1H), 7.44 (s, 1H), 7.32 (d, J 5 8.7 Hz , 1H), 7.25 (s, 1H), 6.80 (dd, 1J 5
8.7 Hz, 2J 5 2.4 Hz, 1H) 5.44 (q, J 5 6.9 Hz, 1H), 3.80 (s, 3H), 3.25 (br,
1H). 13C NMR (75 MHz, CDCl3): d (ppm) 154.30, 127.91, 125.23, 125.06,
124.18, 112.34, 112.28, 112.25, 101.29, 55.14, 66.89 (q, J 5 25.1 Hz). 19F
NMR (300 MHz, CDCl3): 277.19 (d, J 5 6.9 Hz).
(S)-2,2,2-trifluoro-1-(7-ethylindol-3-yl)ethanol (3i). Colorless
solid, mp.: 137–1398C. MS (EI, 70 eV); m/z: 174 (100%), 243 (84%, M1),
118 (42%), 225 (34%), 224 (31%), 146 (29%). 1H NMR (300 MHz,
CDCl3): d (ppm) 8.23 (br s, 1H), 7.52 (d, J 5 8.2 Hz, 1H), 7.05–7.20 (m,
3H), 5.24 (q, J 5 6.9 Hz, 1H), 2.98 (br, 1H), 2.78 (q, J 5 7.8 Hz, 2H),
1.30 (t, J 5 7.8 Hz, 3H). 13C NMR (75 MHz, CDCl3): d (ppm) 134.84,
126.96, 126.71, 125.41, 123.48, 121.22, 120.77, 116.81, 109.87, 67.37 (q,
J 5 25.1 Hz), 23.75, 13.64. 19F NMR (300 MHz, CDCl3): 277.78 (d, J 5
6.9 Hz).
(S)-2,2,2-trifluoro-1-(5-benziloxyindol-3-yl)ethanol (3k). Viscous
oil. MS (EI, 70 eV); m/z: 91 (100%), 321 (20%, M1), 230 (18%), 305 (17%).
1H NMR (300 MHz, CDCl3): d (ppm) 8.20 (br s, 1H), 6.87–7.43 (m, 9H),
5.16 (q, J 5 6.9 Hz, 1H), 5.02 (s, 2H), 3.00 (br, 1H). 13C NMR (75 MHz,
CDCl3): d (ppm) 153.47, 137.08, 131.30, 128.58, 128.53, 128.08, 127.96,
127.75, 124.61, 113.75, 112.26. 103.52, 102.71, 71.01, 67.10 (q, J 5 24.4
Hz). 19F NMR (300 MHz, CDCl3): 277.67 (d, J 5 6.9 Hz).
Based on the data in Table 1, hydroquinine was selected
as a catalyst for further studies, investigating the effect of
hydroquinine concentration (Table 2). A decrease in con-
centration of the catalyst to 10 mol% led to lower yield and
ee of product as compared to Table 1 entry 13. The
increase in catalyst amount to 30 mol%, however, resulted
in the products in quantitative yield and 58% ee (entry 3),
after 72 h. Further increase in catalyst loading up to 50
mol% slowed down the reaction with no further increase in
enantiomeric excess.
(S)-2,2,2-trifluoro-1-(5-methylindol-3-yl)ethanol (3l). Viscous
oil. MS (EI, 70 eV); m/z: 211 (100%), 160 (65%), 229 (52%, M1), 132
(47%), 210 (37%). 1H NMR (300 MHz, CDCl3): d (ppm) 8.11 (br s,
1H), 7.45 (s, 1H), 7.04–7.22 (m, 3H), 5.19 (q, J 5 6.9 Hz, 1H), 2.93
(br, 1H), 2.43 (s, 3H). 13C NMR (75 MHz, CDCl3): d (ppm) 134.23,
129.96, 125.80, 124.98, 124.47, 123.97, 122.94, 118.65, 111.16, 67.34
(q, J 5 33.3 Hz), 21.40. 19F NMR (300 MHz, CDCl3): 277.73 (d,
J 5 6.9 Hz).
To further optimize reaction conditions, the different sour-
ces of fluoral as electrophile were evaluated. In addition to
neat fluoral, different hemiacetals of trifluoroacetaldehyde
can be used in this reaction (Table 3). Methyl, ethyl and
TABLE 3. Effect of different sources of trifluoroacetaldehyde on the enantioselective Friedel-Crafts hydroxyalkylation of indolea
Entry
Trifluoroacetaldehyde source
Time (h)
Temp.
Yield (%)b
ee (%)c
1
2
3
4
5
CF3CH(OH)OMe, 2a
96
96
96
96
96
RT
2788C-RT
RT
97
67
96
97
96
46
45
43
45
45
CF3CHOd, 2b
CF3CH(OH)OEt (90% water solution), 2c
CF3CH(OH)OEt (90% ethanol solution), 2c
CF3CH(OH)OBn, 2d
RT
RT
a1M of indole in DCM.
bIsolated yield.
cDetermined by HPLC.
dSee text for details.
Chirality DOI 10.1002/chir

ADDITION OF TRIFLUOROACETALDEHYDE TO INDOLES
615
TABLE 4. Enantioselective hydroquinine-catalyzed
Friedel-Crafts hydroxyalkylation of indoles
with trifluoroacetaldehyde methyl hemiacetala
ducted using hydroquinine as a catalyst, trifluoroacetalde-
hyde methyl hemiacetal as a source of CF3CHO and
dichloromethane as a solvent, at room temperature.
The above mentioned optimum conditions were used in a
reaction of substituted indoles to determine the scope of the
reaction (Table 4). In most cases, the presence of moderate
electron-withdrawing or electron-donating groups in the 5-
position of indole resulted in higher enantioselectivity with
ee up to 75% for 5-chloroindole (entries 2-4, 6). The enantiose-
lectivity strongly depends on the size of the substituent and
in the presence of large iodo- and benzyloxy-groups (entries
5, 10), the ee decreases compared to that of a nonsubstituted
indole. N-methyl indole produced a racemic product, illustrat-
ing the crucial importance of the hydrogen connected to
nitrogen in substrate-catalyst interactions (entry 7). Position
7, which is sterically close to the nitrogen as well, also nega-
tively affects the enantioselectivity providing further support
to the importance of hydrogen at position 1 (entry 9). The
strong electron-withdrawing nitro group completely deacti-
vates the indole resulting in no product formation (entry 8).
The absolute configuration of 3a, which was prepared by
hydroquinine catalysis, was determined by comparison of its
optical rotation to literature data23 and was assigned to be
(S) for all indole derivatives. The catalyst can be recovered
from the reaction mixture by acid-base extraction and used
again without significant loss of activity.36
Entry
R
Product
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
9
5-H (1a)
5-F (1b)
5-Cl (1c)
5-Br (1d)
5-I (1e)
5-MeO (1f)
1-Me (1g)
5-NO2 (1h)
7-Et (1i)
5-BnO (1k)
5-Me (1l)
3a
3b
3c
3d
3e
3f
3g
3h
3i
98
96
96
95
95
94
67
58
68
75
59
47
65
0
No reaction
92
96
95
46
48
30
10
11
3k
3l
aReaction time for all runs 72 h.
bIsolated yield.
cDetermined by HPLC.
Some characteristic limitations of the procedure provide
an idea of a possible mechanism of the reaction. These limi-
tations are: (i) The N-position of the indole should be under-
ivatized, having a hydrogen to observe enantioselectivity af-
ter the reaction; (ii) Cinchona alkaloids with substituents on
their free OH or quinuclidine N, produce racemic products;
(iii) 2-substituted indoles do not react with fluoral. Interest-
ingly, the reaction of indole with trifluoroacetaldehyde
methyl hemiacetal described here has the same limitations
and features as the asymmetric organocatalytic reaction of
indole and trifluoropyruvate published earlier.37 Based on
the similar experimental facts, it is suggested that both reac-
tions have similar mechanisms. It is proposed that the
weakly acidic indole N-H forms a complex with hydroquinine
through a hydrogen bond. Then, the OH of hydroquinine
activates the carbonyl of fluoral. During this step, the hydro-
quinine provides a chiral environment for enantiodifferentia-
tion of prochiral sites of fluoral making the formation of (S)-
isomer favored. The suggested intermediate (Fig. 2) involves
a cyclic arrangement to form the product. The presence of
substituents in the C-2 position of indole would disrupt this
cycle and thus result in racemic or no product.
benzyl hemiacetals were applied to observe the steric effect
of alkyl groups on the reaction. The reaction, including both
yield and optical purity appeared to be nonsensitive to the
steric demand of the alkyl group of acetal part of the
reagents. Water and ethanol solution of trifluoroacetaldehyde
ethyl hemiacetal gave the identical results as well. This
indicates that the O-alkyl part does not participate in enantio-
differentiation step. This hypothesis was supported by data
obtained by using neat fluoral 2b, that was produced via a
literature procedure.33 The product was obtained with the
same enantioselectivity, but in a lower yield (entry 1) possi-
bly due to low yield of recovered fluoral.
The reaction, however, is very sensitive to different sol-
vents. Nonpolar solvents such as hexane and toluene
resulted in significantly lower enantioselectivity in the reac-
tion, while ethanol, diethyl ether and other polar solvents
inhibited the reaction completely. Only chlorinated solvents
(dichloromethane and dichloroethane) provided good enan-
tioselectivity and high product yield.
Based on the above studies optimized conditions for the
reaction were determined and further studies were con-
CONCLUSION
The first direct asymmetric synthetic preparation of TFIEs
from indoles and inexpensive trifluoroacetaldehyde methyl
hemiacetal is described. The reaction was catalyzed by a
well-known organocatalyst, hydroquinine and produced
TFIEs in almost quantitative yield and ee up to 75% at room
temperature. Based on the experimental data a mechanistic
explanation is also provided.
ACKNOWLEDGMENTS
The authors thank Omar De Paolis for optical rotation
measurements.
Fig. 2. Proposed enantioselection model for the enantioselective hydrox-
yalkylation of indoles with CF3ꢀꢀ(R)C¼O electrophiles.
Chirality DOI 10.1002/chir

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BORKIN, LANDGE, AND TOROK
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Chirality DOI 10.1002/chir