Stereospecific Deoxygenation of Aliphatic Epoxides to Alkenes under Rhenium Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b01583

The combination of a catalytic amount of Re₂O₇ and triphenyl phosphite as a reductant is effective for the deoxygenation of unactivated aliphatic epoxides to alkenes. The reaction proceeds stereospecifically with variously substituted epoxides under neutral conditions and is compatible with various functional groups. Protection and deprotection of a double bond functionality using an epoxide are shown as an example of the current rhenium-catalyzed deoxygenation protocol. The effect of reductants for the stereoselectivity has also been studied, indicating that the use of electron-deficient phosphines or phosphites is the key for the stereospecific deoxygenation. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.orglett.5b01583

Letter
pubs.acs.org/OrgLett
Stereospecific Deoxygenation of Aliphatic Epoxides to Alkenes
under Rhenium Catalysis
Takuya Nakagiri,† Masahito Murai,*,† and Kazuhiko Takai*,†,‡
†Division of Applied Chemistry, Graduate School of Natural Science and Technology, Okayama University, 3-1-1 Tsushimanaka,
Kita-ku, Okayama 700-8530, Japan
‡Research Center of New Functional Materials for Energy Production, Storage and Transport, Okayama University, 3-1-1
Tsushimanaka, Kita-ku, Okayama 700-8530, Japan
S
* Supporting Information
ABSTRACT: The combination of a catalytic amount of
Re2O7 and triphenyl phosphite as a reductant is effective for
the deoxygenation of unactivated aliphatic epoxides to alkenes.
The reaction proceeds stereospecifically with variously
substituted epoxides under neutral conditions and is
compatible with various functional groups. Protection and
deprotection of a double bond functionality using an epoxide are shown as an example of the current rhenium-catalyzed
deoxygenation protocol. The effect of reductants for the stereoselectivity has also been studied, indicating that the use of
electron-deficient phosphines or phosphites is the key for the stereospecific deoxygenation.
eoxygenation of epoxides into alkenes is a fundamental
but important transformation in both organic1 and
studying the chemo- and stereoselective deoxygenation of
epoxides with readily available catalysts and practical reductants
under mild reaction conditions. We now report the rhenium-
catalyzed deoxygenation of epoxides to alkenes under relatively
mild conditions using triphenyl phosphite as a reductant.8 In
addition, we disclose here that the structure of the reductants
affects the regioselectivity of the deoxygenation.
D
biological chemistry.2 Although the corresponding reverse
oxygenation reactions, epoxidation of alkenes, have been well-
investigated and widely applied in organic synthesis,3 catalytic
deoxygenation of epoxides leading to alkenes has been much
less developed. Stemming from the seminal work by Sharpless
et al. in 1972 using a stoichiometric amount of WCl6 and nBuLi,
a variety of promoters have been developed for the effective
deoxygenation of epoxides.4,5 In recent years, catalytic
deoxygenation has been realized with high valent oxorhenium
complexes including MeReO3 and ReIO2(PPh3)2, and an
oxoruthenium complex together with PPh3, H2, or Na2SO3 as
reductants.6 While synthetically attractive, most of these
protocols still suffer from relatively high catalyst loadings,
harsh conditions, and limited scope of substrates (e.g., only
effective for activated epoxides such as styrene oxides (aryl
epoxides) or conformationally locked cyclohexene oxides
(cyclic epoxides)). Far less attention has been focused on
stereospecific deoxygenation of unactivated aliphatic epoxides. This
is because the reported catalytic system generally requires high
temperatures (usually 150 °C or higher) and longer reaction
times (12−100 h), which tend to form side products from
isomerization of intermediates. The reaction also occurs
without control of product stereochemistry, leading to the
formation of the thermodynamically favored (E)-alkene as the
major product.6 Thus, the operationally simple and stereo-
specific deoxygenation of the more abundant unactivated
epoxides with a combination of an inexpensive catalyst and
reductant under mild conditions would be of significant
interest.
Deoxygenation of cis-1,6-diphenyl-3-hexene oxide 1a was
carried out as a model reaction in toluene at 100 °C in the
presence of various rhenium catalysts (10 mol %−Re) with
PPh3 as a reductant. Although the reaction took place in the
presence of MeReO3, ReOCl3(PPh3)2, and ReIO2(PPh3)2,
which showed high catalytic performance against styrene oxides
and cyclohexene oxide under the previously reported reaction
conditions,6 moderate to low stereoselectivities were observed
(Table 1, entries 1−3). Low-valent rhenium complexes
including Re2(CO)10 and [ReBr(CO)3(thf)]2 were ineffective,
and 1a was recovered intact. Among the catalysts screened,
Re2O7, which is less expensive and easy to handle, showed the
highest catalytic efficiency to yield 2a in >99% yield (Z/E = 60/
40) and thus was chosen as the catalyst for further optimization
(entry 4).9,10 Excellent stereoselectivity (Z/E = 92/8) was
observed using P(OPh)3 as a reductant in place of PPh3 (entry
5). It should be noted that P(OPh)3 is a valuable reductant due
to its low cost, low toxicity, and good stability in the air.11
Finally, 1a was isolated in 94% yield (>99% GLC yield) with
excellent stereocontrol even with a reduced catalyst loading
(2.5 mol %) (entry 6). Control experiments demonstrated that
no deoxygenation by P(OPh)3 occurred in the absence of
Based on our recent studies on the use of rhenium complexes
Received: May 30, 2015
as valuable catalysts for organic reactions,7 we initiated a project
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01583
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Letter
a
Table 1. Rhenium-Catalyzed Deoxygenation of Epoxide 1a
Table 2. Rhenium-Catalyzed Deoxygenation of Epoxides 1
b
a
entry epoxide
catalyst
MeReO3
reductant
yield /%
Z/E
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a′
1a
PPh3
97
88/12
24/76
65/35
60/40
92/8
ReOCI3(PPh3)2
RelO2(PPh3)2
Re2O7
PPh3
59
PPh3
87
PPh3
>99
Re2O7
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
P(OPh)3
>99
c
Re2O7
>99 (94)
>99
97/3
d
e
c
Re2O7
98/2
Re2O7
>99
99/1
Re2O7
>99 (96)
>99 (92)
1/99
ef
,
10
Re2O7
98/2
a
b
Determined by GLC. Determined by 1H NMR. Values in
c
parentheses are isolated yields. 2.5 mol % of Re2O7 and 1.2 equiv
of P(OPh)3 for 6 h. 2.5 mol % of Re2O7 and 1.2 equiv of P(OPh)3 at
80 °C for 36 h. 0.25 mol % of Re2O7 and 1.2 equiv of P(OPh)3 for 48
h. 5 mmol scale.
d
e
f
Re2O7 even at 150 °C for 24 h. Importantly, almost complete
retention of stereochemistry (Z/E = 98/2) was observed when
the reaction was examined at 80 °C, although a prolonged
reaction time (36 h) was required for achieving complete
conversion of 1a (entry 7). Moreover, deoxygenation occurred
with complete retention of stereochemistry to furnish 2a
quantitatively, when the amount of catalyst loading was
decreased to 0.25 mol % (entry 8). Under the same reaction
conditions described in entry 6, trans-1,6-diphenyl-3-hexene
oxide 1a′ furnished exclusively the E-olefin in 96% yield with
complete retention of configuration (Z/E = 1/99) (entry 9). A
similar reaction time was required for complete conversion of
these cis- and trans-epoxides. The results in entries 6 and 9
clearly showed that the current deoxygenation proceeded
stereospecifically. The reaction proceeded even on a gram scale.
Treatment of a mixture of 1.26 g (5.0 mmol, cis/trans = >99/
<1) of 1a with a Re2O7 catalyst (1.0 mol %) in toluene in a 50
mL Schlenk flask at 100 °C for 18 h gave 1.09 g of 2a with
retention of stereochemistry (entry 10).
With the optimized reaction conditions in hand, a variety of
epoxides were subjected to the deoxygenation reaction in the
presence of Re2O7. The series of epoxides having linear,
branched, and cyclic alkyl chains shown in Table 2 were
deoxygenated to the corresponding alkenes with complete
retention of stereochemistry in all cases (all the reactions were
examined on 0.50 mmol scale). For example, isopropyl group
substituted epoxide 1b and cyclic cis-cyclododecene oxide 1c
were deoxygenated efficiently to give the corresponding olefins
2b and 2c with complete retention of stereochemistry (entries
1 and 2). The deoxygenation of arylene oxide 1d proceeded
with high selectivity (entry 3). To determine the influence of
the number of substituents on the epoxide rings, deoxygena-
tions of mono- and trisubstituted aliphatic epoxides 1e and 1f
were carried out next. The epoxides gave the corresponding
mono- and trisubstituted olefins 2e and 2f in excellent yields
even with a reduced amount of catalyst (entries 4 and 5). The
current protocol was also extended to catalytic deoxygenation
of α,β-epoxyesters. Both (E)- and (Z)-α,β-unsaturated esters 2g
and 2h were obtained selectively in 93% and 90% yields from
a
0.50 mmol scale. Ratio of stereoisomers was determined by GLC.
1.0 mol % of Re2O7 was used.
b
trans- and cis-α,β-epoxyesters 1g and 1h with excellent
stereocontrol (entries 6 and 7).
Since the reaction proceeded under neutral and relatively
mild conditions, chemoselective deoxygenation was achieved in
the presence of other chemicals including ketone, ester, ether,
halide, and nitrile (Table S1 in Supporting Information).12 The
reaction proceeded without affecting these functional groups to
furnish the corresponding olefin 2a in >93% yields with almost
complete retention of stereochemistry, and additives were
recovered quantitatively. When aldehyde, 3-phenylpropanal,
was added to the reaction mixture, the recovery yields of the
additive was decreased to 48%.
The excellent tolerance of functional groups demonstrated
above makes the current reaction quite useful especially for the
total synthesis of natural products. This is further demonstrated
by the stereospecific deoxygenation of the monoterpene oxide,
geraniol oxide (Table 2, entry 8). Deoxygenation of the
hydroxy group protected geraniol oxide 3 proceeded without
isomerization of the double bond to afford 4 in 81% yield. This
result illustrates good chemoselectivity against the silyl group as
B
DOI: 10.1021/acs.orglett.5b01583
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
well as the wide substrate scope of the current stereospecific
deoxygenation even with the sterically crowded trisubstituted
epoxide. Furthermore, it is possible to protect the double bond
functionality by applying the current rhenium-catalyzed
deoxygenation.1 For example, olefin cross-metathesis13 follow-
ing the deoxygenation (deprotection) of 3, which was prepared
by the epoxidation (protection) of geraniol, resulted in the
selective functionalization of one of the double bonds with the
allylic double bonds intact (Scheme 1). In contrast, the direct
olefin metathesis of 4 or geraniol without the current
protection/deprotection protocol gave a complex mixture of
products.
Scheme 2. Reactivity Switch of Re2O7 in the Presence of
P(OPh)3
a
Determined by GLC.
sharp contrast, the yield of olefin 2a decreased less than 1% and
the formation of 1,2-diol 7 was observed in 69% yield, when the
same reaction was examined in the absence of P(OPh)3.15 We
further confirmed that treatment of 0.50 equiv of P(OPh)3 with
2.5 mol % of Re2O7 and 1a for 6 h furnished a 50% yield of 2a
with high stereoselectivity (Z/E = 96/4). These results imply
that phosphite plays a role in (1) the reduction of the high
valent Re2O7 to form the rhenium active species suitable for the
achievement of stereospecific deoxygenation of epoxides and
(2) the regeneration of the rhenium species by deoxygenation
after one catalytic cycle.
Scheme 1. Chemoselective Transformation of Double Bond
t
by Epoxidation/Deoxygenation Protocol (Si = SiMe2 Bu)
Based on the above observations, a plausible reaction
mechanism is shown in Figure 1.16 The reaction initiates with
As shown in Table 1, the choice of reductants is crucial for
the current stereospecific deoxygenation of epoxides. Prelimi-
nary studies to elucidate the origin of the selectivity and the
reaction mechanism were carried out. First, the deoxygenation
of 1a in the presence of several phosphines and phosphites was
carried out.14 Among the results obtained, we focused on the
following two observations. (1) The deoxygenation occurred
efficiently when triarylphosphines or phosphites were used as
reductants. Alkylphosphines including tributylphosphine,
tricyclohexylphosphine, and 1,2-bis(diphenylphosphino)ethane
did not promote the reaction. (2) Good to excellent
stereoselectivities were observed with the sterically hindered
or electron-deficient phosphines and phosphites. Control
experiments, in which (Z)-2a was subjected independently to
the reaction conditions, demonstrated that none of the
stereoisomer (E)-2a was produced in the presence of Re2O7
and phosphines and phosphites. This result clearly indicates
that the isomerization from the (Z)- to (E)-isomer occurred
during the deoxygenation process.
To obtain insight into the effect of phosphite, the reaction of
Re2O7 with an equimolar amount of P(OPh)3 in C6D6 was
monitored by 31P NMR spectroscopy. The formation of
OP(OPh)3 was observed even at 25 °C for 5 min, indicating
that the current catalytic reaction is initiated by the rapid
deoxygenation of Re2O7 by P(OPh)3 to generate the active
catalytic species. Furthermore, P(OPh)3 was found to
dramatically change the reactivity of Re2O7 by the reduction
of a rhenium center. In the presence of 1.2 equiv of P(OPh)3,
the expected 2a was obtained in 91% yield with high
stereoselectivity (Z/E = 96/4) even in the presence of water
(Scheme 2). This result also proved the robustness of the
present stereoselective deoxygenation reaction against water. In
Figure 1. Proposed reaction mechanism.
the rapid reduction of Re2O7 by P(OPh)3.17 Subsequent
coordination of the epoxide to the resulting oxorhenium species
followed by the ring-opening of the epoxide gives five-
membered-ring rhena-2,5-dioxolane intermediate A with
retention of configuration. Finally, olefin extrusion via the
cleavage of A and regeneration of the oxorhenium species by
reduction with P(OPh)3 complete the catalytic cycle.18
In summary, the present study describes the operationally
simple deoxygenation of unactivated aliphatic epoxides to the
corresponding alkenes using the reductant, P(OPh)3, with
Re2O7 catalyst. The reductant and catalyst are both inexpensive.
The reaction proceeded with complete regioselectivity with
broad functional group tolerance. This catalytic system
promises to be useful, especially in natural products and
pharmaceutical syntheses, which require mild conditions,
selectivity, and functional group tolerance.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, spectroscopic data for all new
1
compounds, and copies of H and 13C NMR spectra. The
C
DOI: 10.1021/acs.orglett.5b01583
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem., Int. Ed. 2013, 52, 12905. (f) Davis, J.; Srivastava, R. S.
Tetrahedron Lett. 2014, 55, 4178. (g) McClain, J. M.; Nicholas, K. M.
ACS Catal. 2014, 4, 2109.
Supporting Information is available free of charge on the ACS
Publications website at DOI: 10.1021/acs.orglett.5b01583.
(9) Investigation of other catalysts with 2 equiv of PPh3:
ReCl3(PPh3)2 (MeCN) 57% (Z/E = 72/28), ReOCl3(PPh3)2 81%
(86/14), MoO2Cl2 43% (94/6), MoO2Cl2(dmf) 80% (96/4),
Mo(CO)6 10% (85/15), MoO2 (acac)2 59% (47/53). Deoxygenation
of 1a was not observed with the following transition metal catalysts:
Re2(CO)10, [ReBr(CO)3(thf)]2, MoO3, W(CO)6, and MnO2.
(10) Investigation of solvents with 2.5 mol% of Re2O7 and 1.2 equiv
of P(OPh)3 for 6 h: ClC6H5 >99% (Z/E = 97/3), decane >99% (97/
3), ClCH2CH2Cl >99% (97/3), dioxane >99% (97/3), MeCN 22%
(95/5), DMF 18% (82/18).
(11) The price per 500 g of P(OPh)3 is $26, and that for PPh3 is $82
(TCI America Fine Chemicals).
(12) For intermolecular additive screens, see: (a) Collins, K. D.;
Glorius, F. Nat. Chem. 2013, 5, 597. (b) Collins, K. D.; Glorius, F. Acc.
Chem. Res. 2015, 48, 619.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: masahito.murai@okayama-u.ac.jp.
*E-mail: ktakai@cc.okayama-u.ac.jp.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by a Grant-in-Aid (No.
26248030) from JSPS, Japan, and the MEXT program for
promoting the enhancement of research universities.
(13) For recent reviews, see: (a) Handbook of Metathesis; Grubbs, R.
H., Ed.; Wiley-VCH: Weinheim, Germany, 2003. (b) Metathesis in
Natural Product Synthesis: Strategies, Substrates, and Catalysts, 1st ed.;
Cossy, J., Arseniyadis, S., Meyer, C., Eds.; Wiley-VCH: Weinheim,
Germany, 2010. (c) Nickel, A.; Pedersen, R. L. In Olefin Metathesis:
Theory and Practice; Grela, K., Ed.; Wiley-VCH: Weinheim, Germany,
2014.
(14) Effect of phosphines and phosphites (1.2 equiv) on the
regioselectivity in the deoxygenation of 1a with 2.5 mol% of Re2O7 for
6 h: PPh3 >99% (Z/E = 60/40), P(furyl)3 76% (68/32), P(o-tol) 7%
(98/2), P(C6F5)3 55% (95/5), P(O(4-FC6H4))3 >99% (97/3), PnBu3
2%, PCy3 0%, dppe 7%.
(15) Diol 7 was not converted to olefin 2a in the presence of a Re2O7
catalyst with P(OPh)3. Therefore, the active catalytic species generated
from the reduction of Re2O7 with P(OPh)3 should directly convert 1a
to 2a without producing 7, thus having different reactivity compared
with the original high valent Re2O7 species.
(16) For a mechanism study of rhenium-catalyzed deoxygenation of
epoxides, see: Bi, S.; Wang, J.; Liu, L.; Li, P.; Lin, Z. Organometallics
2012, 31, 6139.
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