Highly enantioselective iron(ii)-catalyzed opening reaction of aromatic meso-epoxides with indoles

Article abstract of DOI:10.1039/c3ob41782d

A highly enantioselective method for the catalytic cis-stilbene oxide opening reaction with indole derivatives was developed. The scope of the reaction was studied with a selection of aromatic meso-epoxides and various indoles, and the desired 2-(indol-3-yl)ethanol derivatives were obtained in good to excellent yields with excellent enantioselectivities (from 96 to >99% ee).

Full text of DOI:10.1039/c3ob41782d

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Highly enantioselective iron(II)-catalyzed opening
reaction of aromatic meso-epoxides with indoles†
Cite this: DOI: 10.1039/c3ob41782d
Received 1st September 2013,
Accepted 26th September 2013
Baptiste Plancq, Mathieu Lafantaisie, Simon Companys, Cendrella Maroun and
Thierry Ollevier*
DOI: 10.1039/c3ob41782d
www.rsc.org/obc
A highly enantioselective method for the catalytic cis-stilbene
From an environmental point of view, the development of
oxide opening reaction with indole derivatives was developed. new efficient benign chemical processes is in high demand. In
The scope of the reaction was studied with a selection of aromatic connection with our ongoing studies involving C–C bond
1
2
meso-epoxides and various indoles, and the desired 2-(indol-3-yl)- forming reactions using green Lewis acids, we disclose
ethanol derivatives were obtained in good to excellent yields herein our results using iron(II) perchlorate conjointly with
1
3
with excellent enantioselectivities (from 96 to >99% ee).
Bolm’s ligand 1. To the best of our knowledge, iron has
never been used as a catalyst for a highly enantioselective
epoxide opening reaction with indoles. Iron is one of the most
abundant metals on earth; it is inexpensive, environmentally
benign, and relatively nontoxic in comparison with other
The meso-epoxide opening reaction is well-recognized as one
of the most powerful, atom-economical bond-forming reac-
1
tions. In this reaction, a clean S 2 addition of achiral nucleo-
N
philes allows the formation of two neighboring stereogenic
centers in one straightforward operation. This transformation
has been successfully realized using various nucleophiles,
14
metals.
First, we screened various conditions for the meso-stilbene
oxide opening reaction with indole catalyzed by chiral iron
complexes (Table 1).
2
3
4
5
6
7
such as azides, cyanides, amines, alcohols, water, thiols,
8
9
10
selenols, halides, and indoles. The meso-epoxide opening
reaction with indoles is certainly an essential achievement in
the field. This route provides a rapid access to 2-(indol-3-yl)-
ethanol derivatives, which have induced many synthetic efforts
due to their motifs, often seen in natural products and bio-
active molecules. Nitrogen-containing heterocycles are essen-
tial cores in natural products and drugs. The synthesis of
enantio-enriched N-heteroaromatic derivatives is therefore a
major challenge.
It was found that a iron(II) Lewis acid, such as Fe(ClO ) ,
4
2
was an effective catalyst for the reaction and afforded the
corresponding alcohol 4a in moderate yield but high
1
1
a
Table 1 Optimization of reaction conditions
The enantioselective ring-opening reaction of meso-epox-
ides with indole derivatives has been reported to occur
1
0a
efficiently in the presence of [Cr(salen)] complexes.
The
reaction has also been disclosed in water in the presence of
III
II
Sc and Cu surfactant-type catalysts affording the corres-
b
ponding products in moderate to high yields with good to
Conc. Yield 4a ee 4a
1
0b,c
Entry Conditions
(M)
(%)
(%)
excellent enantioselectivities.
However, moderate yields
and decreased enantioselectivities with some substrates and
conversion problems when the reaction is performed in
organic solvents, sometimes restrict their utilization.
1
2
3
4
5
6
7
8
5 mol% Fe(ClO
4
)
4
2
·6H
2
O
0.5
0.5
50
50
91
90
88
76
53
27
98
99
>99
>99
>99
92
10 mol% Fe(ClO
10 mol% Fe(ClO
10 mol% Fe(ClO
10 mol% Fe(ClO
10 mol% Fe(OTf)
10 mol% Fe(ClO
10 mol% Fe(ClO
)
)
)
)
2
2
2
2
·6H
·6H
·6H
·6H
2
2
2
2
O
4
4
4
O, 4 Å MS 0.5
O, 4 Å MS 1.0
O, 4 Å MS 1.0
1.0
c
2
·H
2
O
4
)
)
3
·6H
2
O, 4 Å MS 1.0
O, 4 Å MS 1.0
97
99
Département de chimie, Université Laval, 1045 avenue de la Médecine,
Québec (Québec) G1V 0A6, Canada. E-mail: thierry.ollevier@chm.ulaval.ca
d
4
2
·6H
2
a
b
†
Electronic supplementary information (ESI) available. CCDC 864123. For
ESI and crystallographic data in CIF or other electronic format see DOI:
0.1039/c3ob41782d
Epoxide (1.0 equiv.), indole (1.2 equiv.), 1/[Fe] 1.2 : 1. Determined
c
d
by chiral HPLC analysis. Reaction run at 0 °C, 48 h. Reaction
performed in tert-butyl methyl ether.
1
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enantioselectivity (Table 1, entry 1). By using 10 mol% catalyst, Table 2 Catalytic asymmetric meso-epoxide opening reaction with differently
a
substituted indoles – substrate scope
an excellent enantioselectivity was achieved, but still in moder-
ate yield (Table 1, entry 2). The use of molecular sieves in our
reaction conditions allowed us to obtain an excellent yield and
a near-complete enantioselectivity (Table 1, entry 3). Next, we
demonstrated that the reaction could be run in more concen-
trated conditions (1.0 M vs. 0.5 M) without significant changes
in the results (Table 1, entry 4). In terms of selectivity and
yield, the reaction was as efficient at 0 °C as it was at room
temperature, albeit with an extended reaction time (Table 1,
b
Entry
Indole
R
Yield 4 [%]
ee 4 (%)
entry 5). When Fe(OTf)2 was used instead of Fe(ClO ) , the
4 2
III
enantioselectivity decreased (Table 1, entry 6). A Fe salt, such
1
2
3
4
5
6
7
8
9
H
90
63
99
80
87
64
86
89
82
>99
97
>99
>99
>99
99
98
98
96
as Fe(ClO
4
)
3
, was not as effective as a Lewis acid when used in
4-Cl
5-Me
5-MeO
5-Br
5-NO
6-F
the same conditions since the product could only be isolated
1
5
in lower yield and enantioselectivity (Table 1, entry 7). In our
attempt to use greener solvents, the reaction was performed in
tert-butyl methyl ether (Table 1, entry 8). Although the selecti-
vity obtained in such solvent was very high, the yield remained
low and dichloromethane was kept as the solvent of choice. In
our optimized conditions, the chiral catalyst is prepared by
2
7-MeO
1
1
0
1
79
76
>99
>99
4 2
stirring a mixture of Fe(ClO ) with ligand 1 in a 1 : 1.2 ratio
with powdered 4 Å molecular sieves at room temperature in
dichloromethane for 0.5 h.
To the best of our knowledge, the enantioselectivity
observed is the highest found with a chiral Lewis acid for this
ring-opening model reaction. Moreover, this reaction has the
advantage of using a cheap and environmentally benign Lewis
a
b
Epoxide (1.0 equiv.), indole (1.2 equiv.). Determined by chiral HPLC
acid. In comparison, Umani-Ronchi reported a good enantio- analysis.
selectivity for the reaction of epoxide 2a with indole 3a (93%
ee), but using chiral salen complexes containing toxic chro-
1
0a
mium salts.
Kobayashi also reported the same reaction
III
II
10b,c
using Sc and Cu -based catalysts.
Enantioselectivities
obtained were very good (92% and 96% ee respectively), but
the scarcity and the increasing price of rare earth metals (Sc)
restricts their use. Copper remains a good green alternative
but a slight decrease in enantioselectivities and lower yields
were observed when using substituted indoles.
Other examples of the ring-opening reaction are summar-
ized in Table 2.
To further probe the generality and scope of the reaction,
differently substituted indoles were examined (Table 2, entries
1
–8). In all cases, good to excellent yields (63–99%) and very
high enantioselectivities (97 to >99% ee) were obtained. Elec-
tron-donating (Me, OMe) and -withdrawing (Br, Cl, F, NO2)
substituents, irrespective of their positions on the indole ring
(
4, 5, 6 or 7), had negligible influence on the enantioselectivity.
Scheme 1 Catalytic asymmetric aromatic meso-epoxide opening reaction with
N-Methylated indole also proved to be an excellent substrate
a a
b
indole.
Epoxide (1.0 equiv.), indole (1.2 equiv.). Determined by chiral HPLC
for this reaction since the corresponding N-methylated analysis.
product was obtained in good yield and excellent enantio-
selectivity (Table 2, entry 9). Di-substituted indoles were also
used and the corresponding 2-(indol-3-yl)ethanol derivatives 2-(indol-3-yl)ethanol derivatives were obtained in good yield
were isolated with >99% ee (Table 2, entries 10–11). The reac- and high enantioselectivity (ee ≥ 96%). In preliminary experi-
tion with 5-bromo-7-iodoindole is of prime interest since the ments, decreased enantioselectivities were obtained using
product could be further regioselectively functionalized.
non aromatic meso epoxides (e.g. cyclohexene oxide, ee < 10%).
Two other aromatic meso-epoxides were tested in the
Finally, we also tested our reaction conditions in the kinetic
opening-reaction with indole (Scheme 1). The corresponding resolution of trans-stilbene oxide (Scheme 2). Under our
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indoles. High enantioselectivities (ee up to >99%) and very
good yields have been obtained. Structural evidence of the pre-
catalyst revealed a very rare heptacoordination around the
metal center. Our method has the advantage of using a cheap
and environmentally benign Lewis acid. In addition, the chiral
ligand can be easily recycled at the end of the reaction. Further
studies to clarify the precise mechanism are now in progress.
This work was financially supported by the Natural Sciences
and Engineering Research Council of Canada (NSERC), the
Centre in Green Chemistry and Catalysis (CGCC), the Canada
Foundation for Innovation (CFI), and Université Laval. We thank
F. Bélanger-Gariépy (Université de Montréal) for X-ray analysis.
M.L. thanks NSERC and the Fonds Québécois de la Recherche –
Nature et technologies (FQRNT) for M.Sc. scholarships.
II
Scheme 2 Kinetic resolution of trans-stilbene oxide using Fe -derived chiral
a
catalyst. Determined by chiral HPLC analysis.
standard conditions at −20 °C, indole 3a reacted smoothly.
The unreacted trans-stilbene oxide and the 2-(indol-3-yl)-
ethanol derivative were isolated with moderate enantio-
selectivities (48% ee and 54% ee, respectively). The only pre-
cedents reported for the kinetic resolution of trans-stilbene
Notes and references
1
0a,16
oxide used [Cr(salen)] complexes.
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1
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(
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Bolm’s ligand 1 (Fig. 1).
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contains
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discrete
monomeric
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Fig. 1 ORTEP (50% ellipsoid) of [1·Fe·2THF·H
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