Regio- and stereoselective ring-opening reactions of epoxides with indoles and pyrroles in 2,2,2-trifluoroethanol

Article abstract of DOI:10.1002/chem.200701366

Aliphatic and aromatic epoxides react regio- and stereoselectively with indoles and pyrroles in 2,2,2-trifluoroethanol without the use of a catalyst or any other additive. While aromatic epoxides are selectively attacked at the benzylic position, aliphatic epoxides react at the less-substituted position. Chiral epoxides react with > 99% ee (ee = enantiomeric excess).

Full text of DOI:10.1002/chem.200701366

DOI: 10.1002/chem.200701366
Regio- and Stereoselective Ring-Opening Reactions ofEpoxides with Indoles
and Pyrroles in 2,2,2-Trifluoroethanol
Martin Westermaier and Herbert Mayr*[a]
Dedicated to Professor Emanuel Vogel on the occasion of his 80th birthday
Abstract: Aliphatic and aromatic epoxides react regio- and stereoselectively with
À
indoles and pyrroles in 2,2,2-trifluoroethanol without the use of a catalyst or any
other additive. While aromatic epoxides are selectively attacked at the benzylic
position, aliphatic epoxides react at the less-substituted position. Chiral epoxides
react with >99% ee (ee=enantiomeric excess).
Keywords: C C coupling · electro-
philic substitution · enantioselectivi-
ty · heterocycles · regioselectivity
Introduction
tically pure styrene oxide gave 2-(1H-indol-3-yl)-2-phenyl-
ethanols in good yields and 99% ee (ee=enantiomeric ex-
cess),[9b] and InCl3 has been successfully employed as a cata-
lyst for the reactions of indoles with racemic styrene oxide
in CH2Cl2. Under the same conditions, aliphatic epoxides
gave mixtures of regioisomeric products with favored attack
at the less-substituted oxirane position.[9c] High enantioselec-
tivities but lower yields (up to 64%) were obtained when
the reaction of 1-methylindole with enantiopure styrene
oxide was catalyzed by a polymer-supported indium Lewis
acid (Amberlyst-In).[9d]
To avoid undesired isomerizations, most investigations of
the reactions of indoles with epoxides employed mild Lewis
acids. Thus, LiClO4 has been reported to catalyze the reac-
tions of aliphatic and aromatic epoxides with indoles to give
high yields of 3-substituted indoles (Scheme 1); the stereo-
chemistry of these reactions was not investigated.[10a,b]
Somewhat lower yields of these substitution products
were obtained when the reactions of indoles with styrene
oxide were catalyzed by nanocrystalline titanium(IV)
oxide.[10c]
Indoles and pyrroles are key motifs in many pharmacologi-
cally and biologically active compounds, and the synthesis of
optically active indolyl and pyrrolyl derivatives has been the
topic of numerous investigations.[1] Many methods for the
stereoselective ring opening of epoxides with N-, O- and S-
nucleophiles have been developed[2] including enzymatic
processes,[3] but regio- and stereoselective reactions with
carbon nucleophiles are rare.[4–8] Apart from reactions with
trimethylsilyl cyanide[4] and strong nucleophiles, such as phe-
nyllithium,[5] dialkyl zinc compounds,[6] or enolates,[7] reac-
tions with electron-rich arenes, for example, indoles and pyr-
roles, have been reported.[8–14]
As the nucleophilicity of indoles and pyrroles is not suffi-
cient for a direct attack at ordinary epoxides, activation of
the C O bond is generally needed. The use of strong Lewis
acids is problematic, because they may trigger isomeriza-
tions of the epoxides with formation of carbonyl com-
pounds. Thus, Ranu and Jana reported a selective synthesis
of benzylic aldehydes and ketones by treatment of the cor-
À
responding epoxides with indium
A
Aliphatic and aromatic epoxides were reported to react
with indole, pyrrole, furan, and thiophene in the presence of
other hand, the InBr3-catalyzed reaction of indoles with op-
[a] Dipl.-Chem. M. Westermaier, Prof. Dr. H. Mayr
Department Chemie und Biochemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5–13 (Haus F)
81377 München (Germany)
Fax : (+49)89-2180-77717
E-mail: Herbert.Mayr@cup.uni-muenchen.de
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Scheme 1. Reactions of indole with aliphatic and aromatic epoxides cata-
lyzed by LiClO4 under solvent-free conditions (608C).[10a]
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Chem. Eur. J. 2008, 14, 1638 – 1647

FULL PAPER
10 mol% [ZrCl2Cp2] (Cp=cyclopentadienyl) to give good
yields of substitution products. The NMR spectra, which
were claimed to indicate the regioselective 3-attack at these
heteroarenes, have not been published, however. Because
enantiopure epoxides were not used in this study, the stereo-
chemical course of these reactions could not be derived.[10d]
Results and Discussion
Screening ofthe reaction conditions : Winsteinꢁs investiga-
tions on the rates of nucleophilic substitutions have shown
À
that the heterolyses of C X bonds are assisted by protic sol-
vents with a high ionizing power Y.[17] To examine whether
electrophilic assistance by protic solvents can also enable
the attack of electron-rich arenes at epoxides, we studied
the reactions of (R)-(+)-styrene oxide [(R)-1] with the
parent indole (2a) and 1,2-dimethylindole (2b) in various
solvents (Scheme 3).
Ytterbium(III) triflate was found to be the most efficient
A
Lewis acid to catalyze the regio- and stereoselective reaction
of indole with glycidyl phenyl ether at 10 kbar.[11]
At elevated pressure (10 kbar) indole reacts with aromatic
epoxides in acetonitrile even without a catalyst to give mod-
erate yields of 2-(1H-indol-3-yl)-2-phenylethanols.[12] Later
studies on the stereochemistry of the reaction of (R)-styrene
oxide with indole in acetonitrile at 10 kbar and 428C
showed that the substitution product was formed in 56%
yield and 92% ee (Scheme 2). Addition of silica gel in-
creased the yield but resulted in a slight decrease in stereo-
selectivity.[13a]
Scheme 3. Reactions of (R)-styrene oxide ((R)-1) with indole (2a) and
1,2-dimethylindole (2b) in different solvents.
Table 1 (entries 1–3) shows that indole (2a) did not react
with styrene oxide (1) in methanol, ethanol, or 90% aque-
ous acetonitrile at 70–908C. In the latter case, no conversion
of 1 took place, while in methanol and ethanol small
amounts of the corresponding 2-alkoxy-2-phenylethanols 4b
and 4c were obtained (<3% GCMS). Previously, we discov-
ered that indoles are allylated and benzylated in 80% aque-
ous acetone in good yields when allyl and benzyl halides
were stirred with the indoles in this solvent.[18] Under these
conditions, no conversion of indole (2a) was observed at
room temperature (entry 4), but at 608C, the reaction of 2a
with (R)-1 gave 9% of (R)-3a with high enantiomeric
excess (>99% ee, entry 5). Better yields of 3a have been
obtained in 40% aqueous ethanol (16% at room tempera-
ture and 45% at 808C, entries 6 and 7).
Best chemical yields (up to 79%, entries 8 and 9) with
high enantiomeric excesses (>99% ee) were observed when
the reactions were performed in 2,2,2-trifluoroethanol.
1,2-Dimethylindole (2b) reacted similarly, but gave some-
what better yields. Again, nucleophilic attack of 2b at rac-1
was not observable in methanol, ethanol, and acetonitrile/
water (90:10 v/v, entries 10–12). When using 80% aqueous
acetone as the solvent, 7% of (R)-3b was isolated after 72h
at room temperature (entry 13); at 608C the yield increased
to 17% after 14 h (>99% ee in both cases, entry 14). As
with 2a, higher yields of (R)-3b were obtained in ethanol/
water (40:60 v/v, entries 15 and 16) and even 90% of enan-
tiopure (R)-3b has been obtained when 2,2,2-trifluoroetha-
nol was used as the solvent (entries 17 and 18).
Scheme 2. High pressure and silica-gel assisted reaction of indole with
optically pure (R)-styrene oxide.[12, 13a]
Also the HBF4-silica-gel-supported reactions of styrene
oxide with indoles and pyrroles in CH2Cl2 were reported to
give substitution products in good yields, but the stereo-
chemistry was not investigated; aliphatic epoxides did not
react.[13b]
Enantioselective addition of 2-methylindole to aromatic
epoxides catalyzed by [Cr(salen)] complexes resulted in ki-
G
netic resolution and formation of 3-substituted indoles in
moderate yields but with high enantiomeric excesses.[14]
The well-known ionizing power of fluorinated alcohols[15]
was previously employed by BØguØ[16] to assist the ring
opening of epoxides in their reactions with aromatic amines.
We report now that 2,2,2-trifluoroethanol is also a suitable
solvent for the noncatalyzed reactions of epoxides with in-
doles and pyrroles.
Abstract in German: Aliphatische und aromatische Epoxide
reagieren regio- und stereoselektiv mit Indolen und Pyrrolen
in 2,2,2-Trifluorethanol ohne Zusatz eines Katalysators oder
eines anderen Additivs. Während aromatische Epoxide selek-
tiv an der benzylischen Position angegriffen werden, reagie-
ren aliphatische Epoxide an der sterisch weniger gehinderten
Position. Die Reaktion chiraler Epoxide liefert sehr hohe
Enantiomerenüberschüsse (>99% ee).
The yields correlate with Winsteinꢁs solvent ionizing
power Y.[15,17] No reactions took place in poorly ionizing sol-
vents, such as ethanol (Y=À2.40) or methanol (Y=À1.12)
Chem. Eur. J. 2008, 14, 1638 – 1647
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1639

H. Mayr and M. Westermaier
Table 1. Reactions of (R)-styrene oxide ((R)-1) with indole (2a) and 1,2-dimethylindole (2b) in different solvents (1m solutions) to yield compounds
(R)-3a or (R)-3b.
Entry
Solvent[a]
Y[b]
N[c]
t [h]
T [8C]
Yield 3 [%][d]
ee [%][e]
Reactions with indole (2a)
[f]
1
EtOH
À2.40
À1.127.54
–
À0.70
À0.70
2.62
2.62
2.53
2.53
7.44
72
80
–
–
[g]
[h]
[h]
2MeOH
72 70
–
–
3
4
5
6
7
8
9
MeCN/H2O 90:10
acetone/H2O 80:2 0
acetone/H2O 80:2 0
EtOH/H2O 40:60
EtOH/H2O 40:60
CF3CH2OH
4.56
5.77
5.77
5.81
5.81
1.23
1.23
7290
72RT
7260
72
72
48
–
–
9
–
–
>99
>99
>99
>99
>99
RT
80
RT
80
16
45
65[i]
79
CF3CH2OH
10
Reactions with 1,2-dimethylindole (2b)
[f]
10
11
EtOH
MeOH
À2.40
À1.127.54
–
À0.70
À0.70
2.62
2.62
2.53
2.53
7.44
72
80
–
–
–
–
>99
>99
>99
>99
>99
>99
[g]
[h]
72 70
–
12MeCN/H
2O 90:10
acetone/H2O 80:2 0
acetone/H2O 80:2 0
EtOH/H2O 40:60
EtOH/H2O 40:60
CF3CH2OH
4.56
5.77
5.77
5.81
5.81
1.23
1.23
7290
72RT
14
72
12
–
7
13
14
15
16
17
18
60
RT
80
RT
80
17
29
54
77
90
24
3
CF3CH2OH
[a] Solvent mixtures are given as v/v. [b] Ionizing powers Y taken are YBr from reference [15]. [c] Solvent nucleophilicities are taken from reference [19].
[d] Isolated yields of 3a (entries 1–9) or 3b (entries 10–18) after column chromatography. [e] Enantiomeric excess determined by chiral HPLC from the
reaction mixtures and isolated compounds by comparing their retention times to those reported in the literature (see also the Experimental Section).
[f] Trace amounts of 4c have been detected in GCMS. [g] Trace amounts of 4b have been detected in GCMS. [h] No conversion. [i] Trace amounts of 4d
have been detected in GCMS.
while slow ring opening was observed in 80% aqueous ace-
tone (Y=À0.70). The increased yields obtained in 40%
aqueous ethanol reflect the higher ionizing power Y of this
solvent (Y=2.62). The excellent yields obtained in 2,2,2-tri-
fluoroethanol are due to its high ionizing power (Y=2.53)
and low solvent nucleophilicity,[19] which explains the ab-
sence of side products which were observed in ethanol or
methanol.
groups were used, the yields of the substitution products 3
decreased. 5-Bromoindole (2 f) with N=4.38[20] gave only
45% of 3 f accompanied by 19% of the trifluoroethyl ether
4d, which is formed by nucleophilic attack of 2,2,2-trifluoro-
ethanol at the benzylic position of 1. The nucleophilicity of
5-cyanoindole (2g) is so low (N=2.83)[20] that it does not act
as a nucleophile at all and, again, the only reaction product
obtained after 72h at 80 8C was 17% of the ether 4d. In
line with these findings, the even weaker nucleophile anisole
(N=À1.18)[21] did not react with styrene oxide (1) under
these conditions. When CF3CH2OH acted as a nucleophile,
styrene oxide (1) was also regioselectively attacked at the
benzylic position to yield ether 4d.
Variation ofthe nucleophiles : The conditions of experiments
9 and 18 (Table 1), that is, heating of equimolar amounts of
heteroarenes and styrene oxide (1) in CF3CH2OH at 808C,
were then employed for screening the scope of nucleophiles
for this reaction (Scheme 4).
Evidence for the constitution of 4d comes from 13C NMR
and mass spectroscopy. A 2:1 mixture of 4d and 4e is
formed by heating styrene oxide (1) in CF3CH2OH/
CF3CH2ONa for 11 h at 808C. Both ethers show only very
Scheme 4. Reactions of indoles 2a–g with (R)-styrene oxide ((R)-1).
FG=functional group.
+
The reactions of the indoles 2a–e (N>5)[20] gave exclu-
sively the (R)-2-(1H-indol-3-yl)-2-phenylethanols 3a–e in
good yields with a high enantiomeric excess (Table 2). Ex-
clusive substitution at the 3-position of the indole skeleton
was observed. When indoles bearing electron-withdrawing
small M+ peaks, m/z: 220, but PhCHOCH2CF3 (m/z: 189)
appears only in the spectrum of 4d, whereas PhCHOH+
(m/z: 107) was found in the spectrum of 4e.
Both fragments are typical for each compound. Another
argument for the differentiation of 4d and 4e is given by
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Epoxides
FULL PAPER
Table 2. Reactions of (R)-styrene oxide ((R)-1) with indoles 2a–g in CF3CH2OH (808C).
was detectable by GC. The
ratio 6a/6b decreased to 5.5:1
after 30 min, to 2.7:1 after
45 min and, finally, to 2.0:1
after 1 h. Attempts to elucidate
the mechanism of the rear-
rangement of 6a into 6b have
not been made. The bisalkylat-
ed pyrrole, 2-[5-(2-hydroxy-1-
phenylethyl)-1H-pyrrol-2-yl]-2-
phenylethanol,[13a] was obtained
in 17% yield as a side product.
Bisalkylation was suppressed
when styrene oxide (1) was
combined with five equivalents
of pyrrole (5a).
Indole
N[a]
t [h]
Product 3
Yield [%][b]
ee [%][c]
>99
2a
2b
5.55
4
3a
3b
67
6.54
5.75
3
4
90
73
>99
>99
2c
3c
1-Methylpyrrole (5b) reacted
with (R)-1 within 1 h to give a
1:1 mixture of (R)-7a and (R)-
7b, which did not change
during the reaction (entry 2).
Pyrroles 5c and 5d, in which
the 2- and 5-positions of the
pyrrole ring are blocked by
methyl groups, gave the 3-sub-
stitution products rac-8 with
rac-1 and (R)-9 with (R)-1 in 30
and 74% yields, respectively.
2,4-Dimethylpyrrole (5e) and
3-ethyl-2,4-dimethylpyrrole
(5 f), the strongest nucleophiles
in the series of alkyl-substituted
pyrroles, reacted with rac-1
within 1 h to give rac-10 and
rac-11 in 55 and 56% yields, re-
spectively. The fact that in all
reactions with pyrroles only
2d
2e
6.91
6.22
3
3
3d
3e
72
>99
>99
72
2 f
2g
4.38
2.83
72
72
3 f
3g
45[d]
>99
[e]
–
–
–
[a] Nucleophilicities of the indoles taken from ref. [20]; [b] Isolated yields of 3 after column chromatography.
[c] Enantiomeric excess determined by chiral HPLC from the reaction mixtures and isolated compounds.
[d] 19% of ether 4d has been detected; conversion was not complete. [e] 17% of 4d has been detected along
with the starting materials.
the chemical shifts in the carbon NMR spectra. While the
benzylic carbon of 4d absorbs at d=84.6 ppm and the meth-
ylene group at d=67.1 ppm, 4e shows the corresponding
peaks at d=72.9 and 78.0 ppm. This is in line with the shifts
in 1-phenylethane-1,2-diol (4a) in which the benzylic proton
absorbs at d=74.7 ppm and the CH2 group at d=
Scheme 5. Reactions of pyrroles 5a–f with (R)-styrene oxide ((R)-1).
67.9 ppm.[22] The ratio of 2:1 (4d/4e) was derived from the
1
peak areas in GCMS and the H NMR spectroscopic inte-
grals.
moderate yields of substitution products are observed is
probably due to the high tendency of pyrroles to oligomer-
ize or polymerize leading to nonvolatile distillation residues.
The isolated products showed high enantiomeric excesses
(>99% ee in all examined cases).
Reactions ofpyrroles : As the pyrroles 5a–f are somewhat
more nucleophilic than the analogously substituted indoles,
their reactions with styrene oxide (1) in CF3CH2OH at 808C
were faster (Scheme 5, Table 3).
An equimolar mixture of the parent pyrrole (5a) and (R)-
1 gave a 2:1 mixture of the two regioisomers (R)-6a and
(R)-6b in 68% yield within 1 h (Table 3, entry 1). Monitor-
ing the reaction via GCMS revealed a change of the 6a/6b
ratio during the reaction. After 15 min only the 2-isomer 6a
All reactions described in Tables 2and 3, which were in-
vestigated stereochemically, were performed with racemic
and optically pure styrene oxide (1). Because the two enan-
tiomers obtained with racemic styrene oxide (rac-1) were
separable by chiral HPLC, we can conclude that the substi-
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1641

H. Mayr and M. Westermaier
Table 3. Reactions of (R)-styrene oxide ((R)-1) with pyrroles 5a–f in CF3CH2OH at 808C (1 h).
acted stereospecifically with 2b
and 2c, and the NMR spectra
of the resulting triarylethanols
showed that the diastereomers
obtained from trans-12 differed
from those obtained from cis-
12. In diastereomer 13ba, ob-
tained from trans-12 and 1,2-di-
methylindole (2b), the two ben-
zylic protons absorb as doublets
(J=9.9 Hz) at d=4.49 and
5.76 ppm, while the correspond-
ing resonances of the diastereo-
mer 13bb are at d=4.55 (d, J=
8.9 Hz) and d=5.76 ppm (dd,
J=8.9, 3.6 Hz). The additional
3.6 Hz splitting of the d=
5.76 ppm resonance in CD3CN
is due to coupling with the OH
proton (d=3.05 ppm, d, J=
3.6 Hz). Analogous spectra
were observed for the products
obtained from the reactions of
the stilbene oxides with 1-meth-
ylindole (2c).
Entry
Pyrrole
Product
Yield [%][a]
ee [%][b]
>99
1
5a
5b
5c
5d
6a/b
7a/b
8
68[c]
2
3
4
55
30
74
>99
n.d.[d]
>99
9
5
6
5e
5 f
10
11
55
56
n.d.[d]
Reactions with other aromatic
epoxides: rac-(p-Methoxyphe-
nyl)oxirane (14) reacted with
n.d.[d]
1,2-dimethylindole
(2b)
in
2,2,2-trifluoroethanol within 4 h
to give rac-15 in 69% yield
(Scheme 7).
[a] Isolated yields after column chromatography. [b] Enantiomeric excess determined by chiral HPLC from re-
action products and isolated compounds. [c] 17% of 2-[5-(2-hydroxy-1-phenylethyl)-1H-pyrrol-2-yl]-2-phenyl-
ethanol has been isolated as a side product. [d] Not determined; reaction was only studied with rac-1.
rac-3-Phenyloxirane-2-car-
boxylic acid ethyl ester (16),
tution products obtained with enantiopure styrene oxide
((R)-1) had an ee value of more than 99%.
which was used as a 8:1 mixture of trans and cis isomers,
turned out to be particularly reactive and gave better yields
with 5-bromoindole (2 f) than styrene oxide (Scheme 8).
NMR spectroscopic and GCMS analysis of the products re-
vealed that only one of the potential diastereomers of rac-17
and rac-18 was formed. With the assumption that, again,
back-side attack of the nucleophile at the epoxide takes
place, we conclude that an exclusive reaction with the major
isomer (trans-16) took place while the cis-isomer was not at-
tacked.
Reactions with stilbene oxides: Analogous reactions with
cis- and rac-trans-stilbene oxide (12) were studied with the
indoles 2a–c (Scheme 6).
Reactions with aliphatic epoxides: 1,2-Dimethylindole (2b)
was used as a probe to examine reactions with aliphatic ep-
oxides. Cyclohexene oxide (19) gave only 21% of rac-20
after 72 h, whereas 2-(2,2,2-trifluoroethoxy)cyclohexanol
(rac-21) was formed as the major product (Scheme 9). The
yield of 20 increased to 31% when the reaction mixture was
heated for one week and an additional 1.5 equivalents of 19
was added after 3 and 5 d. Again, back-side attack at the ep-
oxide is observed, and rac-20 is formed as the only diaste-
reomer. The trans configuration of 20 can be determined by
an analysis of the coupling constants of the axial proton of
Scheme 6. Reaction of indoles 2a–c with trans- and cis-stilbene oxide
(12) in CF3CH2OH at 808C.
In all cases, the reactions with trans-12 gave considerably
better yields than with cis-12; indole (2a) did not react with
cis-12, and the starting materials have been recovered
(Table 4, entry 2). Both diastereomers of stilbene oxide re-
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Epoxides
FULL PAPER
Table 4. Reactions of indoles 2a–c with trans- and cis-stilbene oxide (12) in CF3CH2OH at 808C.
the CHOH group. It shows two
axial–axial couplings of 10.4 Hz
and one axial-equatorial cou-
pling of 4.1 Hz, indicating that
the OH group and the indolyl
group occupy equatorial posi-
tions on the cyclohexane ring.
The monosubstituted aliphat-
ic epoxides rac-22 and rac-23
were selectively attacked at the
Entry
Indole
Stilbene oxide
t [h]
Product 13
Yield [%][a]
1
2
2a
2a
rac-trans-12
cis-12
42
rac-13aa
37
[b]
42–
–
–
3
4
5
6
2b
2b
2c
2c
rac-trans-12
9
24
29
29
rac-13ba
rac-13bb
rac-13ca
rac-13cb
66
17
69
19
less-substituted
(Scheme 10).
position
rac-1,2-Epoxyhexane (rac-22)
gave 32% of alcohol 24 after
10 h as well as 28% of 1-(2,2,2-
trifluoroethoxy)-hexan-2-ol (de-
termined by GCMS). The con-
stitution of compound 24 is de-
rived from its 1H NMR spec-
cis-12
trum with
a
multiplet for
rac-trans-12
CHOH at d=3.84 ppm and two
dd at d=2.74 and 2.94 ppm for
the diastereotopic protons at C-
1 and from the 13C NMR spec-
trum in which all CH2 groups
resonate at d <38 ppm. The re-
gioisomeric primary alcohol
arising from nucleophilic attack
at the higher substituted posi-
cis-12
[a] Isolated yields after column chromatography. [b] No conversion observed.
Scheme 9. Reaction of cyclohexene oxide (19) with 1,2-dimethylindole
(2b).
Scheme 7. Reaction of rac-(p-methoxyphenyl)oxirane (14) with 1,2-dime-
thylindole (2b).
Scheme 10. Reactions of rac-1,2-epoxyhexane (rac-22) and rac-glycidyl
methyl ether (rac-23) with 1,2-dimethylindole (2b) in CF3CH2OH at
808C.
1
tion of 22 should show the H and 13C NMR spectroscopic
resonances of the CH2OH group at lower field. Analogous
NMR arguments allowed us to identify 25 as a secondary al-
cohol, which was formed in 51% yield when glycidyl methyl
Scheme 8. Reactions of rac-3-phenyloxirane-2-carboxylic acid ethyl ester
(16) with 1,2-dimethylindole (2b) and 5-bromoindole (2 f).
Chem. Eur. J. 2008, 14, 1638 – 1647
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1643

H. Mayr and M. Westermaier
Workup C: When aqueous solvent mixtures were used, Et2O (10 mL) and
then H2O (10 mL) were added and the aqueous phase was extracted with
Et2O (3”10 mL). The combined organic phases were dried (MgSO4), and
after evaporation of the solvent in vacuo, the crude product was purified
by Kugelrohr distillation and/or column chromatography.
ether (rac-23) was heated with 1,2-dimethylindole (2b) for
48 h in CF3CH2OH.
(R)-2-(1H-Indol-3-yl)-2-phenylethanol (3a):[9c,10b,c,12,13] Indole (2a,
351 mg, 3.00 mmol) and (R)-styrene oxide [(R)-1, 342 mL, 3.00 mmol]
were stirred in CF3CH2OH (3 mL) at 808C (10 h) to yield after column
chromatography (silica gel, hexanes/ethyl acetate 2:1) 3a as a colorless
solid (477 mg, 67%). Rf =0.211; [a]2D0 =+12.8 (c=1.60 in CHCl3);
1H NMR (400 MHz, CDCl3): d=1.64 (brs, 1H; OH), 4.16 (dd, J=7.1,
11 Hz, 1H; 1-H), 4.23 (dd, J=6.7, 11 Hz, 1H; 1-H), 4.47 (t, J=6.9 Hz,
1H; 2-H), 7.04 (ddd, J=0.9, 7.1, 7.9 Hz, 1H; ArH), 7.07 (d, J=2.2 Hz,
1H; ArH), 7.15–7.24 (m, 2H; ArH), 7.28–7.34 (m, 5H; ArH), 7.44 (d,
J=7.9 Hz, 1H; ArH), 8.09 ppm (brs, 1H; NH); 13C NMR (100 MHz,
CDCl3): d=45.6 (d; 2-C), 66.4 (t; 1-C), 111.1 (d; 7’-C), 116.0 (s; 3’-C),
119.4 (d; 4’-C), 119.5 (d; 5’-C), 121.9 (d; 6’-C), 122.3 (d; Ph), 125.8 (d; 2’-
C), 128.3 (s; 3a’-C), 128.6 (d; Ph), 128.7 (d; Ph), 136.5 (s; 7a’-C),
141.6 ppm (s; Ph), signal assignments are based on gHMBC and gHSQC
experiments; GCMS (t=12.6 min): m/z (%): 237 (13) [M+], 207 (18), 206
(100), 204 (17), 178 (13); Chiral HPLC: OD-H (isocratic, heptane/isopro-
Conclusion
Aromatic and aliphatic epoxides can be attacked nucleophi-
lically by electron-rich arenes when the ring-opening reac-
tion is electrophilically assisted by 2,2,2-trifluoroethanol.
The high stereoselectivites of the reactions (>99% ee) indi-
cate the operation of SN2-type processes. This is also the
case for styrene oxides, in which nucleophilic attack occurs
regioselectively at the benzylic position, that is, at the posi-
tion which is usually favored in SN1-type reactions. The prin-
ciple of electrophilic solvent assistance of SN2-type reactions
demonstrated in this work should systematically be explored
also for other types of SN2reactions.
panol 85:15, 0.5 mLminÀ1
, UV at 215 nm, t(S)=28.7 min, t(R)=
37.8 min); IB (isocratic, heptane/isopropanol 95:5 containing 0.01% di-
ethylamine, 1.0 mLminÀ1, UV at 275 nm, t(S)=40.5 min, t(R)=47.9 min),
>99% ee.
Experimental Section
(R)-2-(1,2-Dimethyl-1H-indol-3-yl)-2-phenylethanol (3b):[9d] 1,2-Dime-
thylindole (2b, 726 mg, 5.00 mmol) and (R)-styrene oxide ((R)-1, 571 mL,
5.00 mmol) were stirred in CF3CH2OH (5 mL) at 808C (4 h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 1:1) 3b as
a yellow oil (1.19 g, 90%). Rf =0.565; [a]2D0 =À77.0 (c=1.45 in CHCl3);
1H NMR (300 MHz, CDCl3): d=1.53 (brs, 1H; OH), 2.29 (s, 3H; 2’-Me),
3.59 (s, 3H; NMe), 4.26 (d, J=7.6 Hz, 2H; 1-H), 4.43 (t, J=7.6 Hz, 1H;
2-H), 6.93 (ddd, J=1.1, 7.0, 8.0 Hz, 1H; ArH), 7.05–7.12(m, 2H; ArH),
7.15–7.27 (m; 5H), 7.39 ppm (d, J=8.0 Hz, 1H; ArH); 13C NMR
(75.5 MHz, CDCl3): d=10.7 (q), 29.6 (q), 45.4 (d), 65.1 (t), 108.9 (d),
109.3 (s), 119.1 (d), 119.2 (d), 120.7 (d), 126.2 (d), 127.9 (s), 128.4 (d),
135.2(s), 136.9 (s), 141.9 ppm (s); GCMS ( t=13.5 min): m/z (%): 265
(18) [M+], 235 (20), 234 (100), 218 (10); Chiral HPLC: OD-H (isocratic,
heptane/isopropanol 85:15, 0.5 mLminÀ1, UV at 215 nm, t(S)=24.3 min,
t(R)=29.0 min); IB (isocratic, heptane/isopropanol 95:5 containing
0.01% diethylamine, 1.0 mLminÀ1, UV at 275 nm, t(S)=11.7 min, t(R)=
26.3 min), >99% ee.
General: All solvents were distilled prior to use. Water was purified with
Millipore MilliQplus. All starting materials were commercially available
and used as received, 1-methylindole (2c), 2,5-dimethylpyrrole (5c), and
2,4-dimethylpyrrole (5e) were distilled. 1,2-Dimethylindole (2b) was re-
crystallized from methanol prior to use. 2-(4-Methoxyphenyl)oxirane (14)
was synthesized according to a literature procedure.[24] 1H NMR spectra
were recorded on a Bruker ARX 300 or Varian Inova 400. Chemical
shifts refer to TMS or the solvent resonance as the internal standards
(CDCl3: d=7.26 ppm, CD3CN: d=1.94 ppm). Multiplicities are given as
s=singlet, d=doublet, t=triplet, q=quartet, br=broad, and m=multip-
let. 13C NMR spectra were recorded on Bruker ARX 300 or Varian VXR
400 spectrometers with broad-band proton decoupling. Chemical shifts
refer to TMS or the solvent as internal standards (CDCl3: d=77.0 ppm,
CD3CN: d=1.32, 118.3 ppm). Spin multiplicities are derived from
DEPT135 spectra. GCMS spectra were recorded on an Agilent 5973
MSD spectrometer (HP-5MS capillar column with 30 m length, 0.25 mm
diameter, 1.0 mLminÀ1 flow rate, injector, split, He carrier gas, quadrupol
mass spectrometer). Chromatographic purification was carried out with
Merck silica gel 60 (mesh 40–63 mm) by common or flash-column chro-
matography. MPLC separation was done on a Büchi Sepacore System
(pump manager C-615, C-605 pumps, C-660 fraction collector and C-635
photometer). HPLC analysis was performed on a Waters HPLC system
(550 pumps, degasser, PDA, single injector). Chiralpak IB was used as a
stationary phase (0.46 cm ID”25 cm length) at 208C and calibrated with
flavanone prior to use. Eluents, flow rate, detection, and retention times
are listed. In some cases, Chiracel OD-H (0.46 cm ID”25 cm length) was
used as a chiral column. Kugelrohr distillations were performed by using
a Büchi GKR-50 Kugelrohr oven. The boiling points refer to the oven
temperature. Optical rotations were measured by using a Perkin–Elmer
polarimeter 343 over a path length of 10 cm with the sample temperature
maintained at 208C in the solvent indicated.
2-Methoxy-2-phenylethanol (4b):[25] GCMS: (t=7.1 min): m/z (%): 152
(5) [M+], 135 (7) [M+ÀH2O], 121 (100) [M+ÀCH2OH], 91 (8).
2-Ethoxy-2-phenylethanol (4c):[26] GCMS (t=7.9 min): m/z (%): 165 (5)
[M+], 135 (100) [M+ÀCH2OH], 91 (6).
2-Phenyl-2-(2,2,2-trifluoroethoxy)ethanol (4d) and 1-phenyl-2-(2,2,2-tri-
fluoroethoxy)ethanol (4e):
A solution of rac-styrene oxide (rac-1,
571 mL, 5.00 mmol) in CF3CH2OH (5 mL) was cooled to 08C and sodium
hydride (204 mg, 5.10 mmol) was added in portions. The reaction mixture
was then allowed to come to room temperature and was heated to 808C
for 10 h. The mixture was poured onto saturated NaCl solution (20 mL)
and the aqueous phase was extracted with Et2O (3”30 mL). The com-
bined organic layers were washed with H2O (30 mL) and dried (MgSO4).
After removal of the solvent in vacuo, the crude product was purified by
Kugelrohr distillation (5”10À2 mbar, 131–1408C) to yield a 2:1 mixture
of 4d and 4e as a colorless liquid (561 mg, 51%). 1H NMR (300 MHz,
CDCl3): d=2.55 (brs; 1H; OH of 4d and 4e), 3.59–3.99 (m, 4H; two
CH2 of 4d and 4e), 4.54 (dd, J=3.6, 8.3 Hz, 0.66H; CH of 4d), 4.89 (dd,
J=3.2, 8.6 Hz, 0.34H; CH of 4e), 7.27–7.40 ppm (m, 5H; ArH of 4d and
General reaction procedure: The epoxide (3.0 mmol) was added all at
once to a solution of the nucleophile (3.0 mmol) in the corresponding sol-
vent (3 mL), and the resulting mixture was stirred for the specified time
at room temperature or under reflux. Three different workup techniques
were used.
4e); 13C NMR (75.5 MHz, CDCl3): d=66.2(q,
JCF =34 Hz), 67.1 (t), 68.8
(q, JCF =34 Hz), 72.9 (d), 78.0 (t), 84.6 (d), 123.9 (q, JCF =288 Hz), 126.2
(d), 126.9 (d), 128.1 (d), 128.2 (d), 128.6 (d), 128.9 (d), 136.7 (s),
139.7 ppm (s); 19F NMR (282 MHz, CDCl3): d=À74.59 (t, J=8.8 Hz, 3F
of 4e), À74.46 ppm (t, J=8.8 Hz, 3F of 4d); GCMS: 4e (t=6.2min): m/z
(%): 189 (100); 4d (t=6.5 min): m/z (%): 107 (100), 79 (59), 77 (37).
(R)-2-(1-Methyl-1H-indol-3-yl)-2-phenylethanol (3c):[10c,12,13a] 1-Methylin-
dole (2c, 384 mL, 3.00 mmol) and (R)-styrene oxide ((R)-1, 342 mL,
Workup A: When the reaction was finished, the solvent was removed in
vacuo and the crude product was purified by Kugelrohr distillation and/
or column chromatography.
Workup B: When the product precipitated from the reaction mixture it
was filtered off, washed with cold EtOH (3”5 mL), and recrystallized
from EtOH.
1644
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1638 – 1647

Epoxides
FULL PAPER
3.00 mmol) were stirred in CF3CH2OH (3 mL) at 808C (4 h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 1:1) 3c as
a yellow oil (550 mg, 73%). Rf =0.659; [a]2D0 =+3.9 (c=1.66 in CHCl3);
1H NMR (300 MHz, CDCl3): d=1.82(brs, 1H; OH), 3.73 (s, 3H; NMe),
4.14 (dd, J=7.1, 11 Hz, 1H; 1-H), 4.21 (dd, J=6.7, 11 Hz, 1H; 1-H), 4.46
(t, J=6.9 Hz, 1H; 2-H), 6.93 (s, 1H; ArH), 7.03 (ddd, J=1.2, 6.9, 8.0 Hz,
1H; ArH), 7.17–7.35 (m, 7H; ArH), 7.45 ppm (td, J=0.9, 8.0 Hz, 1H;
ArH); 13C NMR (75.5 MHz, CDCl3): d=32.7 (q), 45.6 (d), 66.4 (t), 109.2
(d), 114.4 (s), 119.0 (d), 119.4 (d), 121.8 (d), 126.6 (d), 126.7 (d), 127.4
(d), 128.2 (s), 128.6 (d), 137.2 (s), 141.8 ppm (s); GCMS (t=12.0 min):
m/z (%): 251 (13) [M+], 221 (18), 220 (100), 204 (11); Chiral HPLC:
(100), 128 (17); Chiral HPLC: OD-H (isocratic, heptane/isopropanol
85:15, 0.5 mLminÀ1, UV at 215 nm, 6a: t(S)=38.7 min, t(R)=41.1 min):
>99% ee; 6b: t(S)=25.9 min, t(R)=31.0 min: >99% ee.
(R)-2-Phenyl-2-(1-methyl-1H-pyrrol-2-yl)ethanol (7a) and (R)-2-phenyl-
2-(1-methyl-1H-pyrrol-3-yl)ethanol (7b):[13] 1-Methylpyrrole (5b, 119 mL,
1.00 mmol) and (R)-styrene oxide ((R)-1, 114 mL, 1.00 mmol) were stirred
in CF3CH2OH (1 mL) at 808C (1 h) to yield after column chromatogra-
phy (silica gel, hexanes/ethyl acetate 1:1) a 1:1 mixture of 7a and 7b as a
yellow oil (111 mg, 55%) which was separated by column chromatogra-
1
phy. Rf =0.420 (7a), 0.391 (7b); H NMR (300 MHz, CDCl3): 7a: d=1.78
(brs, 1H; OH), 3.33 (s, 3H; NMe), 3.89–4.20 (m, 3H; 1-H, 2-H), 6.14–
6.18 (m, 2H; ArH), 6.59 (t, J=2.4 Hz, 1H; ArH), 7.14–7.32 ppm (m,
5H); 7b: d=1.78 (brs, 1H; OH), 3.60 (s, 3H; NMe), 3.94–4.10 (m, 3H;
1-H, 2-H), 6.03 (t, J=2.1 Hz, 1H; ArH), 6.43 (s, 1H; ArH), 6.56 (t, J=
2.1 Hz, 1H; ArH), 7.20–7.31 ppm (m, 5H; ArH); 13C NMR (75.5 MHz,
CDCl3): 7a: d=33.7 (q), 46.5 (d), 66.4 (t), 105.5 (d), 106.8 (d), 122.4 (d),
126.9 (d), 128.2 (d), 128.7 (d), 131.6 (s), 140.2 ppm (s); 7b: d=41.8 (q),
47.2 (d), 67.3 (t), 107.8 (d), 120.1 (s), 122.3 (d), 123.8 (d), 126.7 (d), 128.3
(d), 128.7 (d), 142.8 ppm (s); GCMS: 7a (t=10.7 min): m/z (%): 201 (9)
[M+], 170 (100); 7b (t=10.4 min): m/z (%): 201 (11) [M+], 170 (100);
Chiral HPLC: OD-H (isocratic, heptane/iso-propanol 85:15,
OD-H (isocratic, heptane/isopropanol 85:15, 0.5 mLminÀ1
, UV at
215 nm, t(S)=22.7 min, t(R)=45.3 min), IB (isocratic, heptane/isopropa-
nol 90:10 containing 0.01% diethylamine, 1.0 mLminÀ1, UV at 275 nm,
t(S)=13.6 min, t(R)=23.3 min): >99% ee.
(R)-2-(2-Methyl-1H-indol-3-yl)-2-phenylethanol (3d):[9c,10b,c,12,13] 2-Meth-
ylindole (2d, 394 mg, 3.00 mmol) and (R)-styrene oxide ((R)-1, 342 mL,
3.00 mmol) were stirred in CF3CH2OH (3 mL) at 808C (4 h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 1:1) 3d as
a yellow oil (536 mg, 72%). Rf =0.479; 1H NMR (300 MHz, CDCl3): d=
2.03 (s, 3H, Me), 2.56 (s, 1H; OH), 4.16 (d, J=7.6 Hz, 2H; 1-H), 4.31 (t,
J=7.6 Hz, 1H; 2-H), 6.90–7.14 (m, 7H; ArH), 7.20–7.22 (m, 2H; ArH),
7.37 (d, J=7.8 Hz, 1H; ArH), 7.99 ppm (s, 1H; NH); 13C NMR
(75.5 MHz, CDCl3): d=11.6 (q), 30.4 (d), 64.6 (t), 109.6 (d), 110.4 (d),
117.2 (d), 119.0 (d), 120.5 (d), 125.9 (d), 127.7 (d), 128.1 (d), 128.9 (s),
133.0 (s), 135.2(s), 141.6 ppm (s); GCMS ( t=13.3 min): m/z (%): 251
(15) [M+], 221 (19), 220 (100), 204 (8), 178 (7); Chiral HPLC: IB (iso-
cratic, heptane/isopropanol 90:10 containing 0.01% diethylamine,
1.0 mLminÀ1, UV at 275 nm, t(S)=18.4 min, t(R)=21.1 min): >99% ee.
0.5 mLminÀ1
, UV at 215 nm, 7a: t(S)=17.2min, t(R)=10.5 min:
>99% ee; 7b: t(S)=9.2min, t(R)=12.6 min): >99% ee.
rac-2-(2,5-Dimethyl-1H-pyrrol-3-yl)-2-phenylethanol (8):[13a] 2,5-Dime-
thylpyrrole (5c, 119 mL, 1.00 mmol) and rac-styrene oxide (rac-1, 114 mL,
1.00 mmol) were stirred in CF3CH2OH (1 mL) at 808C (1 h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 1:1) 8 as
an orange oil (65 mg, 30%). Rf =0.311; 1H NMR (400 MHz, CD3CN):
d=2.07 (s, 3H; 2’-Me), 2.12 (s, 3H; 5’-Me), 2.44 (brs, 1H; OH), 3.88–
3.97 (m, 3H; 1-H, 2-H), 5.64 (s, 1H; 4’-H), 7.12–7.27 (m, 5H; ArH),
8.43 ppm (brs, 1H; NH); 13C NMR (100 MHz, CD3CN): d=11.0 (q), 12.7
(q), 46.6 (d), 66.9 (t), 105.2 (d), 127.4 (d), 128.5 (d), 128.9 (d), 129.2 (s),
130.6 (s), 138.3 (s), 145.4 ppm (s); GCMS (t=9.0 min): m/z (%): 215 (12)
[M+], 185 (15), 184 (100).
(R)-2-(5-Methoxy-1H-indol-3-yl)-2-phenylethanol (3e):[10c,13] 5-Methoxy-
indole (2e, 442mg, 3.00 mmol) and ( R)-styrene oxide ((R)-1, 342 mL,
3.00 mmol) were stirred in CF3CH2OH (3 mL) at 808C (3 h) to yield
after column chromatography (hexanes/ethyl acetate 1:1) 3e as a beige
solid (577 mg, 72%). Rf =0.420; 1H NMR (300 MHz, CDCl3): d=2.51
(brs, 1H; OH), 3.61 (s, 3H; OMe), 4.00 (dd, J=7.2, 11 Hz, 1H; diaste-
reotopic 1-H), 4.07 (dd, J=6.8 Hz, 1H, 1H; diastereotopic 1-H), 4.30 (t,
J=6.9 Hz, 1H; 2-H), 6.73–6.82 (m, 3H; ArH), 7.00–7.24 (m, 6H; ArH),
8.37 ppm (brs, 1H; NH); 13C NMR (75.5 MHz, CDCl3): d=45.3 (d), 55.5
(q), 66.0 (t), 101.0 (d), 111.7 (d), 111.8 (d), 115.0 (s), 122.7 (d), 126.3 (d),
127.2 (s), 128.1 (d), 128.2 (d), 131.5 (s), 141.7 (s), 153.4 ppm (s); GCMS
(t=17.2min): m/z (%): 267 (16) [M+], 237 (18), 236 (100), 204 (13);
Chiral HPLC: IB (isocratic, heptane/isopropanol 90:10 containing 0.01%
(R)-2-Phenyl-2-(1,2,5-trimethyl-1H-pyrrol-3-yl)ethanol (9): 1,2,5-Trime-
thylpyrrole (5d,
2 3m8L, 2.00 mmol) and (R)-styrene oxide ((R)-1,
228 mL, 2.00 mmol) were stirred in CF3CH2OH (2mL) at 80 8C (1 h) to
yield after column chromatography (silica gel, hexanes/ethyl acetate 3:1)
9
as a
yellow oil (339 mg, 74%). Rf =0.313; 1H NMR (400 MHz,
CD3CN): d=2.09 (s, 3H), 2.14 (s, 3H), 2.49 (brs, 1H; OH), 3.31 (s, 3H;
NMe), 3.82–3.97 (m, 3H; 1-H, 2-H), 5.71 (s, 1H; 4’-H), 7.13–7.17 (m,
1H; ArH), 7.22–7.29 ppm (m, 4H; ArH); 13C NMR (100 MHz, CD3CN):
d=10.1 (q), 12.4 (q), 30.4 (q), 46.8 (d), 66.9 (t), 104.6 (d), 119.3 (s), 124.9
(s), 126.6 (d), 127.7 (s), 128.9 (d), 129.0 (d), 145.5 ppm (s); GCMS: (t=
9.4 min): m/z (%): 229 (14) [M+], 198 (100), 196 (7), 182(7), 181 (6);
Chiral HPLC: IB (isocratic, heptane/iso-propanol 90:10 containing
0.01% diethylamine, 1.0 mLminÀ1, UV at 275 nm, t(S)=31.5 min, t(R)=
36.6 min): >99% ee. HR-EIMS: calcd for C15H19NO: 229.1467; found:
229.1473.
diethylamine, 1.0 mLminÀ1
, UV at 275 nm, t(S)=31.5 min, t(R)=
33.4 min): >99% ee.
(R)-2-(5-Bromo-1H-indol-3-yl)-2-phenylethanol (3 f):[9b,d,13b] 5-Bromoin-
dole (2 f, 588 mg, 3.00 mmol) and (R)-styrene oxide ((R)-1, 342 mL,
3.00 mmol) were stirred in CF3CH2OH (3 mL) at 808C (72h) to yield 3 f
1
as colorless crystals (427 mg, 45%). H NMR (300 MHz, CDCl3): d=1.80
(brs, 1H; OH), 4.09 (dd, J=7.1, 11 Hz, 1H; diastereotopic 1-H), 4.16
(dd, J=6.6, 11 Hz, 1H; diastereotopic 1-H), 4.41 (t, J=6.7 Hz, 1H; 2-H),
7.11 (s, 1H; ArH), 7.20–7.43 (m, 7H; ArH), 7.58 (s, 1H; ArH), 8.28 ppm
(brs, 1H; NH); 13C NMR (75.5 MHz, CDCl3): d=45.4 (d), 66.4 (t), 112.6
(d), 112.8 (s), 115.8 (s), 121.8 (d), 123.1 (d), 125.1 (d), 126.9 (d), 128.2 (d),
128.7 (d), 128.8 (s), 135.0 (s), 141.2 ppm (s); GCMS (t=21.1 min): m/z
(%): 317 (12), 315 (12), 287 (15), 286 (99), 285 (17), 284 (100), 204 (39),
176 (10); Chiral HPLC: IB (isocratic, heptane/isopropanol 98:2contain-
ing 0.01% diethylamine, 1.0 mLminÀ1, UV at 275 nm, t(S)=45.3 min,
t(R)=53.8 min): >99% ee.
rac-2-(3,5-Dimethyl-1H-pyrrol-2-yl)-2-phenylethanol (10): 2,4-Dimethyl-
pyrrole (5e, 119 mL, 1.00 mmol) and rac-styrene oxide (rac-1, 114 mL,
1.00 mmol) were stirred in CF3CH2OH (1 mL) at 808C (1 h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 1:1) 10 as
1
a yellow oil (118 mg, 55%). Rf =0.298; H NMR (400 MHz, CD3CN): d=
1.90 (s, 3H; 3’-Me), 2.13 (s, 3H; 5’-Me), 2.80 (brs, 1H; OH), 3.93–4.01
(m, 2H; 1-H), 4.11–4.14 (m, 1H; 2-H), 5.52 (s, 1H; 4 ’-H), 7.16–7.31 (m,
5H; ArH), 8.59 ppm (brs, 1H; NH); 13C NMR (100 MHz, CD3CN): d=
11.2 (q), 12.8 (q), 45.9 (d), 65.7 (t), 108.5 (d), 115.2 (s), 126.4 (s), 127.0
(d), 127.1 (s), 128.9 (d), 129.3 (d), 143.6 ppm (s); GCMS (t=8.5 min):
m/z (%): 215 (12) [M+], 185 (15), 184 (100).
(R)-2-Phenyl-2-(1H-pyrrol-2-yl)ethanol (6a) and (R)-2-phenyl-2-(1H-
pyrrol-3-yl)ethanol (6b):[13] Pyrrole (5a, 119 mL, 1.00 mmol) and (R)-sty-
rene oxide ((R)-1, 114 mL, 1.00 mmol) were stirred in CF3CH2OH (1 mL)
at 808C (1 h) to yield after column chromatography (silica gel, hexanes/
ethyl acetate 1:2) a 2:1 mixture of 6a and 6b as a yellow oil (127 mg,
68%). 6a: Rf =0.313, 6b: Rf =0.373; 1H NMR (200 MHz, CDCl3): d=
2.73 (brs, 1H), 3.02 (brs, 2H), 3.87–4.17 (m, 9H), 5.90–5.93 (m, 2H),
6.02–6.09 (m, 3H), 6.57–6.61 (m, 1H), 6.62–6.71 (m, 3H), 7.18–7.40 (m,
15H), 9.08 (brs, 3H); GCMS: 6a (t=10.8 min): m/z (%): 187 (100) [M+
], 156 (100), 128 (12); 6b (t=10.4 min): m/z (%): 187 (8) [M+], 156
rac-2-(4-Ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-2-phenylethanol
(11):
3-
Ethyl-2,4-dimethylpyrrole (5 f, 246 mg, 2.00 mmol) and rac-styrene oxide
(rac-1, 2 2 m9L, 2.00 mmol) were stirred in CF3CH2OH (2mL) at 80 8C
(1 h) to yield after column chromatography (silica gel, hexanes/ethyl ace-
tate 2:1) 11 as
a
yellow oil (272 mg, 56%). Rf =0.331; 1H NMR
(400 MHz, CD3CN): d=0.98–1.03 (m, 3H; CH2CH3), 1.88 (s, 3H; 3’-Me),
2.09 (s, 3H; 5’-Me), 2.29–2.35 (m, 2H; CH2CH3), 3.79 (s, 1H; OH), 3.94
(dd, J=6.8, 11 Hz, 1H; 1-H), 3.99 (dd, J=6.6, 11 Hz, 1H; 1-H), 4.13 (dd,
Chem. Eur. J. 2008, 14, 1638 – 1647
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
1645

H. Mayr and M. Westermaier
J=6.7, 6.7 Hz, 1H; 2-H), 7.24–7.32 (m, 5H; ArH), 8.40 ppm (brs, 1H;
NH); 13C NMR (100 MHz, CD3CN): d=9.26 (q), 10.8 (q), 16.1 (q), 18.1
(t), 45.9 (d), 65.6 (t), 113.9 (s), 126.7 (s), 127.0 (d), 128.9 (d), 129.2 (s),
129.3 (d), 143.7 ppm (s); GCMS (t=9.2min): m/z (%): 243 (15) [M+],
213 (21), 212 (100), 196 (8), 181 (9).
rac-2-(1,2-Dimethyl-1H-indol-3-yl)-2-(4-methoxyphenyl)ethanol (15): 1,2-
Dimethyl-indole (2b, 436 mg, 3.00 mmol) and 2-(4-methoxyphenyl)oxir-
ane (14, 451 mg, 3.00 mmol) were stirred in CF3CH2OH (3 mL) at 808C
(4 h) to yield after column chromatography (silica gel, hexanes/ethyl ace-
tate 2:1) 15 as
a
yellow oil (611 mg, 69%). Rf =0.415; 1H NMR
rac-2-(1H-Indol-3-yl)-1,2-diphenylethanol (13aa):[9c,10c,12] Indole (2a,
234 mg, 2.00 mmol) and trans-stilbene oxide (rac-trans-12, 392mg,
2.00 mmol) were stirred in CF3CH2OH (2mL) at 80 8C (42h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 2:1) 13aa
(300 MHz, CDCl3): d=1.61 (brs, 1H; OH), 2.36 (s, 3H; 2’-Me), 3.66 (s,
3H; NMe), 3.75 (s, 3H; OMe), 4.29 (d, J=8.4 Hz, 2H; 1-H), 4.45 (t, J=
7.8 Hz, 1H; 2-H), 6.80 (d, J=6.3 Hz, 2H; ArH), 7.00 (dd, J=8.1, 8.1 Hz,
1H; ArH), 7.14 (dd, J=8.1, 8.1 Hz, 1H; ArH), 7.22–7.28 (m, 3H; ArH),
7.46 ppm (d, J=8.1 Hz, 1H; ArH); 13C NMR (75.5 MHz, CDCl3): d=
10.6 (q), 29.6 (q), 44.6 (d), 55.2 (q), 65.3 (t), 108.8 (d), 109.5 (s), 113.8 (d),
119.1 (d), 119.3 (d), 120.6 (d), 126.6 (s), 128.8 (d), 133.9 (s), 135.0 (s),
136.9 (s), 157.9 ppm (s); GCMS (t=19.7 min): m/z (%): 295 (11) [M+],
277 (11), 265 (21), 264 (100), 262 (8), 220 (9).
as
a
pale-yellow oil (231 mg, 37%). Rf =0.517; 1H NMR (400 MHz,
CD3CN): d=3.24 (d, J=4.3 Hz, 1H; OH), 4.63 (d, J=8.7 Hz, 1H; 2-H),
5.46 (dd, J=4.3, 8.7 Hz, 1H; 1-H), 6.94–7.50 (m, 15H; ArH), 9.06 ppm
(brs, 1H; NH); 13C NMR (100 MHz, CD3CN): d=50.9 (d), 76.6 (d),
110.9 (d), 116.8 (s), 119.2 (d), 119.3 (d), 122.0 (d), 122.5 (d), 126.6 (d),
126.8 (d), 127.0 (s), 127.4 (d), 128.0 (d), 128.3 (d), 129.4 (d), 135.9 (s),
140.2(s), 142.8 ppm (s); GCMS: ( t=26.0 min): m/z (%): 313 (1) [M+],
207 (28), 206 (100), 204 (13), 178 (10), 77 (4).
rac-Ethyl-3-(1,2-dimethyl-1H-indol-3-yl)-2-hydroxy-3-phenylpropanoate
(17): 1,2-Dimethylindole (2b, 290 mg, 2.00 mmol) and trans-ethyl-2-phe-
nylglycidate (16, 343 mL, 2.00 mmol) were stirred in CF3CH2OH (2mL)
at 808C (5 h) to yield after column chromatography (silica gel, hexanes/
ethyl acetate 2:1) 17 as colorless crystals (513 mg, 76%). Rf =0.349;
1H NMR (300 MHz, CDCl3): d=0.87 (t, J=7.1 Hz, 3H; OCH2CH3), 2.32
(s, 3H; 2’-Me), 2.78 (d, J=7.3 Hz, 1H; OH), 3.62(s, 3H; NMe), 3.93,
3.95 (2”q, J=7.1 Hz, 2H; diastereotopic OCH2CH3), 4.70 (d, J=6.6 Hz,
1H; 3-H), 5.01 (dd, J=6.6, 7.3 Hz, 1H; 2-H), 6.98–7.04 (m, 1H; ArH),
7.09–7.27 (m, 5H; ArH), 7.42 (d, J=7.7 Hz, 2H; ArH), 7.59 ppm (d, J=
7.7 Hz, 1H; ArH); 13C NMR (75.5 MHz, CDCl3): d=10.8 (q), 13.6 (q),
29.5 (q), 47.1 (d), 61.2 (t), 73.5 (d), 108.5 (d), 110.5 (s), 119.0 (d), 119.5
(d), 120.6 (d), 126.3 (d), 127.0 (s), 128.2 (d), 128.6 (d), 134.1 (s), 136.6 (s),
140.6 (s), 174.1 ppm (s); GCMS (t=17.4 min): m/z (%): 337 (3) [M+],
235 (19), 234 (100), 218 (7).
rac-2-(1,2-Dimethyl-1H-indol-3-yl)-1,2-diphenylethanol (13ba): 1,2-Di-
methylindole (2b, 291 mg, 2.00 mmol) and trans-stilbene oxide (rac-trans-
12, 392mg, 2.00 mmol) were stirred in CF 3CH2OH (2mL) at 80 8C (9 h)
to yield 13ba as colorless crystals (450 mg, 66%). 1H NMR (300 MHz,
CDCl3): d=2.02 (s, 3H; 2’-Me), 2.26 (s, 1H; OH), 3.42 (s, 3H; NMe),
4.49 (d, J=9.9 Hz, 1H; 2-H), 5.76 (d, J=9.9 Hz, 1H; 1-H), 6.99–7.33 (m,
11H; ArH), 7.58–7.60 (m, 2H; ArH), 7.69–7.71 ppm (m, 1H; ArH);
13C NMR (75.5 MHz, CDCl3): d=10.2 (q), 29.4 (q), 52.1 (d), 74.9 (d),
108.6 (d), 111.2 (s), 118.7 (d), 119.6 (d), 120.1 (d), 126.3 (d), 126.4 (d),
126.6 (s), 127.2 (d), 127.7 (d), 128.5 (d), 128.8 (d), 133.6 (s), 136.7 (s),
142.0 (s), 143.1 ppm (s); GCMS (t=25.2 min): m/z (%): 341 (1) [M+],
235 (20), 234 (100), 218 (8).
rac-Ethyl-3-(5-bromo-1H-indol-3-yl)-2-hydroxy-3-phenylpropanoate (18):
5-Bromoindole (2 f, 980 mg, 5.00 mmol) and trans-ethyl-2-phenylglycidate
(16, 858 mL, 5.00 mmol) were stirred in CF3CH2OH (5 mL) at 808C
(24 h) to yield after column chromatography (silica gel, hexanes/ethyl
acetate 1:1) 18 as a yellow oil (912mg, 47%). Rf =0.614; 1H NMR
(600 MHz, CDCl3): d=1.27 (t, J=7.2Hz, 3H; OCH 2CH3), 2.90 (d, J=
6.6 Hz, 1H; OH), 4.20 (q, J=7.2Hz, 2H; OC H2CH3), 4.69–4.71 (m, 1H;
3-H), 4.86–4.89 (m, 1H; 2-H), 7.17–7.29 (m, 7H; ArH), 7.47 (s, 1H;
ArH), 7.49 (s, 1H; ArH), 8.20 ppm (brs, 1H; NH); 13C NMR (150 MHz,
CDCl3): d=14.2 (q), 46.0 (d), 61.9 (t), 73.8 (d), 112.5 (d), 112.7 (s), 115.9
(s), 121.5 (d), 124.2 (d), 124.9 (d), 127.3 (d), 128.3 (d), 128.7 (s), 129.1 (d),
134.6 (s), 138.1 (s), 173.4 ppm (s); GCMS (t=7.8 min): m/z (%): 212
(34), 211 (12), 210 (100), 175 (51), 165 (49), 147 (80), 137 (31), 129 (29),
102(90), 77 (15), 75 (17), 51 (17); HR-EIMS: calcd for C 19H1835BrNO3:
388.0538; found: 388.0531.
rac-2-(1,2-Dimethyl-1H-indol-3-yl)-1,2-diphenylethanol (13bb): 1,2-Di-
methylindole (2b, 294 mg, 2.00 mmol) and cis-stilbene oxide (cis-12,
392mg, 2.00 mmol) were stirred in CF 3CH2OH (2mL) at 80 8C (2 4 h) to
yield after column chromatography (silica gel, hexanes/ethyl acetate 2:1)
1
13bb as colorless crystals (116 mg, 17%). Rf =0.484; H NMR (400 MHz,
CD3CN): d=2.34 (s, 3H; 2’-Me), 3.05 (d, J=3.6 Hz, 1H; OH), 3.63 (s,
3H; NMe), 4.55 (d, J=8.9 Hz, 1H; 2-H), 5.76 (dd, J=3.6, 8.9 Hz, 1H; 1-
H), 6.98–7.05 (m, 2H; ArH), 7.09–7.14 (m, 3H; ArH), 7.17–7.26 (m, 3H;
ArH), 7.30–7.36 (m, 5H; ArH), 7.81 ppm (d, J=8.0 Hz, 1H; ArH);
13C NMR (100 MHz, CD3CN): d=10.8 (q), 30.0 (q), 52.7 (d), 75.8 (d),
109.8 (d), 111.3 (s), 119.5 (d), 120.6 (d), 121.1 (d), 126.6 (d), 127.8 (s),
128.0 (d), 128.2 (d), 128.7 (d), 128.8 (d), 129.5 (d), 136.3 (s), 137.9 (s),
144.2(s), 145.2ppm (s); GCMS ( t=26.8 min): m/z (%): 341 (1) [M+],
235 (20), 234 (100), 218 (8).
rac-2-(1-Methyl-1H-indol-3-yl)-1,2-diphenylethanol (13ca): 1-Methylin-
rac-2-(1,2-Dimethyl-1H-indol-3-yl)cyclohexanol (20):[23] 1,2-Dimethylin-
dole (2b, 436 mg, 3.00 mmol) and cyclohexene oxide (19, 304 mL,
3.00 mmol) were stirred in CF3CH2OH (3 mL) at 808C (72h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 4:1) 20 as
white crystals (153 mg, 21%). When this reaction was repeated, and an-
other 3.00 mmol (304 mL) of 19 were added after 72h and 1.50 mmol
(152 mL) of 19 after 160 h, 20 was obtained in 31% yield. Rf =0.297;
1H NMR (300 MHz, CDCl3): d=1.15–2.21 (m, 9H), 2.40 (s, 3H; 2’-Me),
2.61–2.75 (m, 1H; 2-H), 3.66 (s, 3H; NMe), 4.06 (td, J=4.1, 10 Hz, 1H;
1-H), 7.00–7.28 (m, 3H; ArH), 7.68 ppm (d, J=8.0 Hz, 1H; ArH);
13C NMR (75.5 MHz, CDCl3): d=10.7 (q), 25.2 (t), 26.6 (t), 29.6 (q), 31.5
(t), 34.3 (d), 35.7 (t), 73.7 (d), 108.9 (d), 109.1 (s), 110.5 (d), 118.7 (d),
120.6 (d), 132.3 (s), 137.0 (s), 137.1 ppm (s); GCMS (t=10.9 min): m/z
(%): 243 (86) [M+], 184 (78), 171 (19), 158 (100), 144 (12), 115 (7).
dole (2c,
2 60mL, 2.00 mmol) and trans-stilbene oxide (rac-trans-12,
392mg, 2.00 mmol) were stirred in CF 3CH2OH (2mL) at 80 8C (2 9 h) to
yield after column chromatography (silica gel, hexanes/ethyl acetate 3:1)
13ca as an orange oil (452mg, 69%). Rf =0.435; 1H NMR (300 MHz,
CDCl3): d=2.33 (brs, 1H; OH), 3.36 (s, 3H; NMe), 4.52 (d, J=6.3 Hz,
1H; 2-H), 5.33 (d, J=6.3 Hz, 1H; 1-H), 6.87–6.92(m, 2H; ArH), 7.03–
7.15 (m, 10H; ArH), 7.18–7.22 (m, 2H; ArH), 7.27 ppm (ddd, J=0.7, 1.8,
7.8 Hz, 1H; ArH); 13C NMR (75.5 MHz, CDCl3): d=32.3 (q), 50.8 (d),
76.3 (d), 108.9 (d), 115.2 (s), 118.6 (d), 119.1 (d), 121.3 (d), 126.4 (d),
126.5 (d), 127.1 (d), 127.2 (d), 127.3 (s), 127.8 (d), 128.0 (d), 129.3 (d),
136.6 (s), 140.4 (s), 142.9 ppm (s); GCMS: (t=22.6 min): m/z (%): 327
(1) [M+], 221 (20), 220 (100), 204 (8), 178 (5).
rac-2-(1-Methyl-1H-indol-3-yl)-1,2-diphenylethanol (13cb):[14] 1-Methyl-
indole (2c, 2 60mL, 2.00 mmol) and cis-stilbene oxide (cis-12, 397 mg,
2.00 mmol) were stirred in CF3CH2OH (2mL) at 80 8C (29 h) to yield
after column chromatography (silica gel, hexanes/ethyl acetate 2:1) 13cb
as white crystals (124 mg, 19%). Rf =0.543; 1H NMR (300 MHz,
CD3CN): d=2.53 (brs, 1H; OH), 3.77 (s, 3H; NMe), 4.56 (d, J=8.1 Hz,
1H; 2-H), 5.31 (d, J=8.1 Hz, 1H; 1-H), 7.00–7.28 (m, 14H; ArH),
7.44 ppm (brd, J=7.8 Hz, 1H; ArH); 13C NMR (75.5 MHz, CD3CN): d=
32.8 (q), 52.2 (d), 77.7 (d), 109.2 (d), 113.7 (s), 119.1 (d), 119.5 (d), 121.9
(d), 126.2 (d), 126.8 (d), 127.2 (d), 127.3 (d), 127.9 (d), 128.0 (s), 128.1
(d), 128.6 (d), 137.1 (s), 141.9 (s), 142.5 ppm (s); GCMS (t=22.6 min):
m/z (%): 327 (1) [M+], 221 (20), 220 (100), 204 (8), 178 (5).
rac-2-(2,2,2-Trifluoroethoxy)cyclohexanol (21): GCMS (t=7.9 min): m/z
(%): 198 (5) [M+], 180 (17), 152(32), 139 (10), 98 (68), 81 (100), 70 (17),
55 (12), 41 (20).
rac-1-(1,2-Dimethyl-1H-indol-3-yl)hexan-2-ol (24): 1,2-Dimethylindole
(2b, 436 mg, 3.00 mmol) and 1,2-epoxyhexane (22, 362 mL, 3.00 mmol)
were stirred in CF3CH2OH (3 mL) at 808C (48 h) to yield after column
chromatography (silica gel, hexanes/ethyl acetate=3:1) 24 as a pale-
yellow oil (236 mg, 32%). Rf =0.610; 1H NMR (300 MHz, CDCl3): d=
0.92(t, J=6.9 Hz, 3H; 6-H), 1.32–1.62 (m, 6H; 3-H, 4-H, 5-H), 2.37 (s,
3H; 2’-Me), 2.74 (dd, J=8.7, 14 Hz, 1H; 1-H), 2.94 (dd, J=4.2, 14 Hz,
1646
www.chemeurj.org
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2008, 14, 1638 – 1647

Epoxides
FULL PAPER
1H; 1-H), 3.65 (s, 3H; NMe), 3.79–3.89 (m, 1H; 2-H), 7.04–7.26 (m, 3H;
ArH), 7.51 ppm (d, J=7.8 Hz, 1H; ArH); 13C NMR (75.5 MHz, CDCl3):
d=10.5 (q), 14.1 (q), 22.8 (t), 28.2 (t), 29.5 (q), 32.9 (t), 36.6 (t), 71.1 (d),
107.1 (s), 108.5 (d), 118.1 (d), 118.9 (d), 120.7 (d), 127.9 (s), 134.4 (s),
136.7 ppm (s); GCMS (t=10.2min): m/z (%): 245 (15) [M+], 159 (13),
158 (100), 143 (5).
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803; b) J. S. Yadav, B. V. S. Reddy, G. Parimala, J. Chem. Res. Synop.
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rac-1-(1,2-Dimethyl-1H-indol-3-yl)-3-methoxypropan-2-ol (25): 1,2-Dime-
thylindole (2b, 436 mg, 3.00 mmol) and glycidyl methyl ether (23,
265 mg, 3.00 mmol) were stirred in CF3CH2OH (3 mL) at 808C (48 h) to
yield after column chromatography (silica gel, hexanes/ethyl acetate 1:1)
25 as a colorless oil (357 mg, 51%). Rf =0.404; 1H NMR (300 MHz,
CDCl3): d=2.29 (s, 3H; 2’-Me), 2.62 (brs, 1H; OH), 2.88 (d, J=6.9 Hz,
2H; 1-H), 3.23–3.36 (m, 5H; 3-H, NMe), 3.52 (s, 3H; OMe), 3.95–4.03
(m, 1H; 2-H), 7.01–7.18 ppm (m, 3H; ArH), 7.49 ppm (d, J=7.8 Hz, 1H;
ArH); 13C NMR (75.5 MHz, CDCl3): d=10.2 (q), 28.6 (t), 29.4 (q), 58.9
(q), 70.8 (d), 75.9 (t), 106.4 (s), 108.5 (d), 117.9 (d), 118.8 (d), 120.6 (d),
127.9 (s), 134.2 (s), 136.5 ppm (s); GCMS (t=9.6 min): m/z (%): 233 (21)
[M+], 159 (11), 158 (100).
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Received: August 30, 2007
Published online: December 6, 2007
Chem. Eur. J. 2008, 14, 1638 – 1647
ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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