Novel deoxygenation reaction of epoxides by indium

Article abstract of DOI:10.1021/jo047904d

A novel, mild, ecofriendly protocol for the deoxygenation of epoxides to alkenes using indium metal and indium(I) chloride or ammonium chloride in alcohol has been developed. It was necessary for the presence of good radical-stabilizing groups adjacent to the oxirane ring for the deoxygenation reaction to occur. It is proposed that this reaction occurs through an SET process with indium as an electron donor.

Full text of DOI:10.1021/jo047904d

Novel Deoxygenation Reaction of Epoxides by Indium
Mohan Mahesh,† John A. Murphy,*,† and Hans Peter Wessel‡
Department of Pure and Applied Chemistry, University of Strathclyde, 295, Cathedral Street,
Glasgow G1 1XL, UK, and Pharma Research, Discovery Chemistry, F. Hoffmann-La Roche, Ltd.,
Basel, CH-4070, Switzerland
john.murphy@strath.ac.uk
Received November 25, 2004
A novel, mild, ecofriendly protocol for the deoxygenation of epoxides to alkenes using indium metal
and indium(I) chloride or ammonium chloride in alcohol has been developed. It was necessary for
the presence of good radical-stabilizing groups adjacent to the oxirane ring for the deoxygenation
reaction to occur. It is proposed that this reaction occurs through an SET process with indium as
an electron donor.
Introduction
precise intermediates have not been established in most
cases. The first electron would certainly be transferred
with much greater ease than subsequent electrons, as
Electron-transfer reactions mediated by indium have
attracted the attention of synthetic chemists due to its
low first ionization potential1 of 5.79 eV, which is lower
than many reducing metals such as aluminum2 (5.98 eV),
tin2 (7.34 eV), magnesium2 (7.65 eV), and zinc2 (9.39 eV)
and close to that of alkali metals2,3a such as sodium (5.12
eV) and lithium (5.39 eV). Having such a low ionization
potential makes indium attractive for conducting reduc-
tions. This is particularly so because it is so much easier
to handle than alkali metals; for example, the metal
remains unaffected by air or oxygen at ordinary temper-
atures and is practically unaffected by water even at high
temperatures1,3a and very resistant to alkaline conditions.3a
Thus, there is a practical convenience of performing
indium-mediated reactions in water or moisture-contain-
ing solvents.1,3a,b It is noteworthy that indium metal
apparently has no significant toxicity1,3a and has found
considerable utility in dental alloys.1
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Indium metal has been effectively used in modern
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† University of Strathclyde.
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10.1021/jo047904d CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/21/2005
4118
J. Org. Chem. 2005, 70, 4118-4123

Novel Deoxygenation Reaction of Epoxides by Indium
SCHEME 1a
the second ionization potential for indium is much higher
(18.86 eV). Indium metal has been successfully studied
as a single-electron transfer (SET) radical initiator in
tandem radical addition/cyclization/trapping reactions in
aqueous media or in alcohol solvents,36 and recently,
indium-iodine-mediated reductive radical cyclization of
iodoalkenes and iodoalkynes has been reported.37 Whereas
indium metal has been used for so many reduction
reactions, it has not been exploited in the reduction of
epoxides. Herein we report a novel deoxygenation reac-
tion of epoxides to alkenes mediated by electron transfer
from indium.
a Reagents and conditions: (a) indium (2 equiv), THF-H2O (1:
1), rt, 48 h, 22%.
SCHEME 2a
Alkenes are very important in organic synthesis (me-
tathesis, pericyclic reactions, Heck reaction, dihydroxyl-
ation, etc.). With a plethora of protective groups available
for various types of functional groups, it is rather
surprising that no practical protecting groups have been
developed for double bonds. Epoxidation can be used as
a means of protecting double bonds; however, the suc-
cessful implementation of this strategy would largely
depend on the effective deoxygenation of epoxides back
to alkenes. In efforts to explore a more facile and
environment-friendly protocol for the deoxygenation of
epoxides, we developed a mild methodology of deoxygen-
ation of epoxides with good radical-stabilizing groups
adjacent to the oxirane ring, using indium metal and
indium(I) chloride or ammonium chloride in alcohol as a
solvent. This reaction is a good complement to known
methods of deoxygenation of epoxides,38-54 showing ex-
a Reagents and conditions: (a) indium (2.7 equiv), NH4Cl (2
equiv), EtOH, 78 °C, 24 h, 22% (2), 19% (4).
quisite levels of chemoselectivity for epoxides bearing
radical-stabilizing groups on the epoxide carbons.
Results and Discussion
The deoxygenation of epoxides by indium metal was
discovered in our hands when radical ring-opening reac-
tions were attempted on 2-bromomethyl-3-phenyloxirane
1 with indium metal to yield cinnamyl alcohol in 22%
yield (Scheme 1).
When the reaction was repeated using indium and
ammonium chloride using ethanol as the solvent, cin-
namyl alcohol 2 was obtained in 22% yield along with
the 1-[(E)-3-ethoxyprop-1-enyl]benzene 4 in 19% yield
(Scheme 2).
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Mahesh et al.
TABLE 1. Deoxygenation of trans-Stilbene Oxide Using Indium/NH4Cl
isolated yield (%)
entry
equiv of indium
salt used/equiv
solvent
time
temp (°C)
6a
5 (recovered)
i
7.0
-
7.0
7.0
7.0
NH4Cl (2 equiv)
NH4Cl (2 equiv)
-
NH4Cl (2 equiv)
NH4Cl (2 equiv)
ethanol (98%)
ethanol (98%)
THF-H2O (1:1)
acetone
96 h
96 h
96 h
96 h
96 h
80
80
25
56
65
92
-
5
-
99
92
70
87
iia
iii
iv
v
0
THF
5
a Control reaction performed in the absence of indium metal.
TABLE 2. Deoxygenation of trans-Stilbene Oxide Using Indium/InCl
entry
equiv of indium
salt used/equiv
solvent
time
temp (°C)
isolated yield of 6a (%)
i
2.5
0
InCl (2 equiv)
InCl (2 equiv)
InCl (2 equiv)
InCl (2 equiv)
InCl (2 equiv)
InCl (2 equiv)
InCl (2 equiv)
InCl (2 equiv)
InCl (2 equiv)
ethanol (98%)
ethanol (98%)
DMF
THF (anhydrous)
1,2-dimethoxyethane
t-BuOH (anhydrous)
CF3CH2OH
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
6 h
80
80
80
0
iia
iii
iv
v
2.5
2.5
2.5
2.5
2.5
2.5
2.5
120
65
7
0
85
0
vi
vii
viii
ix
83
0
80
0
(CF3)2CHOH
acetonitrile
59
0
82
0
a Control reaction performed in the absence of indium metal.
SCHEME 3a
a Reagents and conditions: (a) indium (3.5 equiv), InCl (1.5 equiv), EtOH, 80 °C, 7 h, 11% (8), 87% (9); (b) indium (3.5 equiv), InCl (1.5
equiv), EtOH, 80 °C, 8 h, 30% (6a), 63% (11).
We proposed that the cinnamyl alcohol 2 and unsatur-
ated ether 4 were derived from cinnamyl bromide, which
was formed as a result of deoxygenation of the epoxide 1
by indium. These preliminary results invited more
investigation of the deoxygenation of epoxides.
The experimental conditions for this deoxygenation
reaction were studied in detail using trans-stilbene oxide
5 as the standard epoxide. The preliminary results of
deoxygenation of trans-stilbene oxide 5 to trans-stilbene
6a using indium/NH4Cl are summarized in Table 1.
At this stage, the role of the ammonium chloride in
our reactions was questioned. One role would involve
activation of the epoxide (lowering of the energies of the
C-O σ* orbitals) through hydrogen bonding to the
epoxide. An alternative means of activating the epoxide
would be by Lewis acid activation using an indium(I)
species formed by the oxidation of indium metal through
a single electron-transfer mechanism. To probe this
possibility, the reaction was repeated using indium/
indium(I) chloride, and encouraging results were ob-
tained. Utilization of indium(I) chloride, instead of NH4-
Cl, considerably decreased not only the total time of the
reaction from 96 to 6 h but also the number of equivalents
of indium metal required from 7 to 2.5 equiv [compare
entry i of Tables 1 and 2]. The deoxygenation reaction of
trans-stilbene oxide was studied using indium/indium-
(I) chloride in different solvents, and the results are
summarized in Table 2.
Ethanol was the most effective solvent in the above
reaction; however, it was not effective for the deoxygen-
4120 J. Org. Chem., Vol. 70, No. 10, 2005

Novel Deoxygenation Reaction of Epoxides by Indium
TABLE 3. Deoxygenation Reaction of Epoxides by Indium
a Reactions performed in anhydrous tert-butyl alcohol. b All E:Z ratios were determined from the peak area ratio of the 1H NMR spectral
analysis. c The stereochemistry of the alkene 21 were determined by one-dimensional 1H NOE, two-dimensional 1H NOESY, and DQFCOSY
NMR experiments
J. Org. Chem, Vol. 70, No. 10, 2005 4121

Mahesh et al.
SCHEME 4a
to the alkene following any of the proposed mechanisms
A, B, or C (Scheme 6).
Conclusion and Scope. We have developed a mild
and effective methodology to deoxygenate epoxides using
indium metal under mild conditions. The presence of a
radical-stabilizing group adjacent to the oxirane ring was
necessary for the deoxygenation. The reaction requires
protic solvents such as ethanol or methanol or t-butanol
and a salt like ammonium chloride or indium(I) chloride
for the deoxygenation. The presence of minute quantities
of water in the solvent is necessary for the deoxygenation.
For sensitive aryl epoxides that are susceptible to a
nucleophilic attack of alcohols, tert-butyl alcohol-H2O is
a better solvent system.
a Reagents and conditions: (a) indium (4 equiv), InCl (2 equiv),
t-BuOH-H2O (24:1), 84 °C, 30 h, 81% (E:Z ) 1:0.7); (b) indium (4
equiv), InCl (2 equiv), t-BuOH-H2O (24:1), 84 °C, 30 h, 84% (E:Z
) 1:0.8).
Investigation of deoxygenation of epoxides with differ-
ent activating groups adjacent to the oxirane ring and
mechanistic aspects of the reaction is currently in
progress.
SCHEME 5a
Experimental Section
Deoxygenation of Epoxides: General Procedure A
[Deoxygenation of trans-Stilbene Oxide (5) Using In-
dium/NH4Cl in Ethanol as Solvent]. trans-Stilbene oxide
5 (0.3925 g, 2.0 mmol, 1.00 equiv) was dissolved in 98% ethanol
(20 mL), and indium metal powder (0.459 g, 4.0 mmol, 2.00
equiv), followed by ammonium chloride (0.214 g, 4.0 mmol,
2.0 equiv), was added to the solution. The reaction mixture
was heated to reflux at 80 °C under a nitrogen atmosphere
for 24 h. After 24 h, an additional quantity of indium metal
powder (1.148 g, 10.0 mmol, 5.00 equiv) was added to the
reaction mixture, and reflux was continued for a further 72 h
(96 h in total) at 80 °C. The reaction mixture was diluted with
diethyl ether (100 mL), and the white-grey precipitate was
filtered through Celite. The filtrate was washed with saturated
brine solution (3 × 100 mL), and the organic layer was
separated. The organic phase was dried over anhydrous
magnesium sulfate, filtered, and concentrated to dryness under
reduced pressure to obtain trans-stilbene 6a (0.331 g, 92%)
as a white solid: mp 123-124 °C (lit.55 123-124 °C) [found
(EI) M+• 180.0931, C14H12 requires M 180.0934]; IR (KBr) 3078,
3060, 3020, 1598, 1577, 1495, 1451, 1332, 1300, 1220, 1184,
1155, 1072, 1029, 983, 961, 909, 761 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.11 (s, 2H), 7.22-7.29 (m, 2H), 7.36-7.39 (m, 4H),
7.49-7.53 (m, 4H); 13C NMR (75.5 MHz, CDCl3) δ 127.0 (CH),
128.1 (CH), 129.1 (CH), 129.2 (CH), 137.8 (C); m/z (EI) 180
(M+•, 97%), 179 (100), 178 (70), 176 (14), 165 (52), 152 (16),
151 (7), 139 (5), 126 (4), 115 (6), 102 (10), 89 (18), 77 (10), 76
(14), 63 (9), 51 (11). The spectroscopic data of trans-stilbene
6a were identical with those of an authentic commercial
sample and consistent with those reported in the literature.56
General Procedure B [Deoxygenation of trans-Stil-
bene Oxide Using Indium/InCl in Ethanol as Solvent].
Indium metal powder (0.287 g, 2.5 mmol, 2.50 equiv) and
indium(I) chloride (0.301 g, 2.0 mmol, 2.00 equiv) were added
to a stirred solution of trans-stilbene oxide 5 (0.196 g, 1.0
mmol, 1.00 equiv) in 98% ethanol (20 mL) at rt. The reaction
mixture was heated to reflux at 80 °C and stirred vigorously
under an argon atmosphere for 6 h. A white turbidity appeared
in the reaction mixture initially that later turned to a white-
grey precipitate. When the reaction was complete, the reaction
mixture was cooled to rt and diluted with diethyl ether (100
a Reagents and conditions: (a) indium (3 equiv), InCl (1.5 equiv),
t-BuOH-H2O (24:1), 84 °C, 4 h, 24%.
ation reactions of some epoxides that were sensitive to
nucleophilic attack due to the competing ring-opening
reaction by ethanol on the oxirane ring (Scheme 3).
However, this problem was overcome by using less
nucleophilic tert-butyl alcohol-H2O (24:1) as the solvent
system (Table 3). It is noteworthy that none of the
deoxygenation reactions worked in anhydrous tert-butyl
alcohol, thereby indicating the importance of minute
quantities of water for the deoxygenation in that solvent
(Table 3).
Oxirane 20 underwent smooth deoxygenation to afford
the alkene 21 in excellent 81% yield (Table 3). The
formation of the alkene 21 can be explained via the
reduction of the expected dienone intermediate 26 by
indium metal (Scheme 4). In an independent experiment,
when â-ionone 26 was treated with identical conditions
of indium/indium(I) chloride in tert-butyl alcohol-H2O,
it resulted in the formation of the same alkene 21 in a
comparable yield of 84% with similar E:Z ratio (Scheme
4).
The deoxygenation of the terminal epoxide 2-methyl-
2-phenyloxirane 22 was not successful due to the compet-
ing indium(I) chloride-promoted ring-opening reaction of
epoxide via the stable tertiary carbocation intermediate
30. Eventually the alcohol 31 was isolated as the major
product from the reaction in 24% yield (Scheme 5).
Table 3 shows that the presence of an activating group
(phenyl or vinyl) adjacent to the oxirane ring was
necessary for the deoxygenation reaction. Epoxides with-
out the activating group adjacent to the oxirane ring did
not undergo deoxygenation.
Although the exact mechanism for the deoxygenation
is not known at this stage, it may be proposed that the
first step involves a single electron-transfer from the
indium metal to the low-lying σ* orbital of the C-O bond,
giving rise to a radical 34, which can eventually break
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4122 J. Org. Chem., Vol. 70, No. 10, 2005

Novel Deoxygenation Reaction of Epoxides by Indium
SCHEME 6
mL), and the precipitate was filtered through Celite using a
sintered funnel. The filtrate was evaporated to dryness under
reduced pressure to obtain a white semisolid that was redis-
solved in diethyl ether (100 mL) and washed with saturated
brine solution (3 × 100 mL). The organic phase was separated
using a separating funnel, dried over anhydrous sodium
sulfate, filtered, and concentrated to dryness to obtain a white
semisolid. This was purified by flash chromatography on silica
gel [ethyl acetate/n-heptane ) 1:49] to afford trans-stilbene
6a (0.144 g, 80%) as white crystals, mp 123-124 °C (lit.55 mp
123-124 °C). The spectroscopic data of the trans-stilbene 6a
were identical with those of the same compound reported
earlier and those reported in the literature.56
General Procedure C [Deoxygenation of Ethyl-(()-3-
phenylglycidate (7) by Indium/InCl Using tert-Butyl
Alcohol-Water as the Solvent]. Indium metal powder
(0.172 g, 1.5 mol, 3.00 equiv), indium(I) chloride (0.113 g, 0.75
mmol, 1.50 equiv), and deionized water (0.2 mL) were added
to a solution of ethyl-(()-3-phenylglycidate 7 (0.1045 g of a
92% mixture of cis and trans, 0.5 mmol, 1.00 equiv) in tert-
butyl alcohol (4.8 mL) at 30 °C. The reaction mixture was
heated to reflux at 84 °C while stirring vigorously under an
argon atmosphere for 4 h. A white turbidity appeared in the
reaction mixture initially, which later turned to a deep white-
grey precipitate. When the reaction was complete, the reaction
mixture was cooled to rt and filtered through Celite with ethyl
acetate (3 × 25 mL). The filtrate was concentrated under
reduced pressure to yield a colorless oil that was redissolved
in ethyl acetate (75 mL) and washed with saturated brine
solution (3 × 75 mL). The organic phase was separated using
a separating funnel, dried over anhydrous sodium sulfate,
filtered, and concentrated in vacuo to obtain a colorless oil.
The crude material was purified by flash chromatography on
silica gel [ethyl acetate/petroleum ether ) 1:9] to afford trans-
ethyl cinnamate 8 (0.086 g, 98%) as a colorless oil: IR (neat)
3062, 3029, 2982, 1714, 1639, 1579, 1496, 1450, 1393, 1367,
1311, 1270, 1203, 1176, 1096, 1072, 1039, 980, 865, 839, 768,
1
712 cm-1; H NMR (400 MHz, CDCl3) δ 1.35 (t, J ) 7.1 Hz,
3H), 4.28 (q, J ) 7.1 Hz, 2H), 6.45 (d, J ) 16.0 Hz, 1H), 7.33-
7.43 (m, 3H), 7.49-7.56 (m, 2H), 7.70 (d, J ) 16.0 Hz, 1H);
13C NMR (100.61 MHz, CDCl3) δ 14.8 (CH3), 61.0 (CH2), 118.8
(CH), 128.6 (CH), 129.4 (CH), 130.7 (CH), 135.0 (C), 145.1
(CH), 167.5 (C); GC-MS retention time 13.20 min, m/z (EI) 176
(M+•, 37%), 148 (24), 147 (23), 131 (100), 103 (44), 91 (4), 77
(16), 51 (8). The spectroscopic data of the trans-ethyl cinnamate
8 were consistent with those in the literature.57
Acknowledgment. We thank Universities UK
(CVCP) for the award of Overseas Research Scholarship
(ORS), University of Strathclyde for an International
Research Scholarship, and F. Hoffmann-La Roche, Ltd.,
Basel, for a CASE award to M.M., EPSRC for funding,
and the National Mass Spectrometry Service, Swansea,
for mass spectral analysis and Dr. John A. Parkinson
for NOE experiments.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds not included in
the Experimental Section, as well as 1H and 13C NMR spectra
for compounds 1, 2, 4, 6a, 8, 9, 11-13, 15-17, 19-22, 25, and
31. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO047904D
(57) (a) Aggarwal, V. K.; Fulton, J. R.; Sheldon, C. G.; de Vicente,
J. J. Am. Chem. Soc. 2003, 125, 6034. (b) Chen, Y.; Huang, L.; Ranade,
M. A.; Zhang, X. P. J. Org. Chem. 2003, 68, 3714.
J. Org. Chem, Vol. 70, No. 10, 2005 4123