Intermolecular Electrophilic Addition of Epoxides to Alkenes: [3+2] Cycloadditions Catalyzed by Lewis Acids

Article abstract of DOI:10.1002/ejoc.201600651

Described are the first examples of intermolecular electrophilic additions of epoxides to alkenes, which proceed through a classic cationic mechanism initiated by epoxide C–O bond cleavage. Treatment of styrene oxides and either styrenes or dienes with a variety of Lewis-acidic triflate salts generates tetrahydrofurans as products of [3+2] cycloaddition in moderate to good yields (up to 71 %). Careful choice of catalyst and reaction conditions favors the desired intermolecular reaction over epoxide degradation without requiring additional reagents or additives. The reaction proceeds diastereoselectively and provides only one regioisomer of the product. Additional highlights include inexpensive precursors, mild conditions, short reaction times, low catalyst loading, and scalability.

Full text of DOI:10.1002/ejoc.201600651

DOI: 10.1002/ejoc.201600651
Communication
Epoxide Cycloadditions
Intermolecular Electrophilic Addition of Epoxides to Alkenes:
[3+2] Cycloadditions Catalyzed by Lewis Acids
William G. Shuler,[a][‡] Logan A. Combee,[a][‡] Isaac D. Falk,[a] and Michael K. Hilinski*[a]
Abstract: Described are the first examples of intermolecular reaction conditions favors the desired intermolecular reaction
electrophilic additions of epoxides to alkenes, which proceed
through a classic cationic mechanism initiated by epoxide C–O
bond cleavage. Treatment of styrene oxides and either styrenes
or dienes with a variety of Lewis-acidic triflate salts generates
tetrahydrofurans as products of [3+2] cycloaddition in moder-
ate to good yields (up to 71 %). Careful choice of catalyst and
over epoxide degradation without requiring additional reagents
or additives. The reaction proceeds diastereoselectively and
provides only one regioisomer of the product. Additional high-
lights include inexpensive precursors, mild conditions, short re-
action times, low catalyst loading, and scalability.
Introduction
controlled assembly of complex multicyclic frameworks en
route to the total synthesis of natural products.[2d] Despite this
long history, to the best of our knowledge no intermolecular
examples of reactions between alkenes and epoxides proceed-
ing through this well-studied mechanistic pathway have ap-
peared in the literature. Herein we disclose our discovery of
conditions that enable this reactivity, resulting in Lewis acid
catalyzed intermolecular [3+2] cycloadditions between epox-
ides and either styrenes or dienes.
Acid-promoted electrophilic additions to alkenes and acid-pro-
moted nucleophilic additions to epoxides are both fundamental
organic transformations with wide-ranging applications in syn-
thesis. Methods that combine the two modes of reactivity, in
which the epoxide acts as an electrophile in a classic addition
reaction to an alkene that proceeds with epoxide C–O bond
cleavage, have been described for intramolecular cases going
as far back as 1962 (Figure 1).[1] The use of a Lewis acid catalyst
to activate the epoxide can result in either a [3+2] cycloaddition
to form a tetrahydrofuran ring or, when the substrate contains
multiple C–C π-bonds, an epoxide-initiated cationic polyene cy-
clization.[2] In particular the latter class of transformations has
been employed with considerable success for the rapid stereo-
Results and Discussion
There are considerable challenges to achieving an intermolec-
ular cycloaddition, and chief among them is the instability of
the formal 1,3-dipole that results from heterolytic C–O bond
cleavage of the epoxide. Among the possible unwanted side
reactions are a 1,2-hydride shift (also known as Meinwald rear-
rangement),[3] dimerization, polymerization, or elimination. No-
tably, the Meinwald rearrangement has been employed as a
strategy to convert epoxides to aldehydes in situ prior to Lewis
acid catalyzed electrophilic addition,[4] and is a substantial con-
founding factor even for the previously reported intramolecular
cycloadditions.[2] In light of this, it was clear that careful manip-
ulation of reaction conditions to control the relative rates of
desired vs. undesired processes would be crucial to the success
of an intermolecular method.
Accordingly, we envisioned that high-concentration condi-
tions combined with slow addition of the epoxide might favor
the desired bimolecular event (Table 1). This quickly led to the
discovery that Lewis-acidic triflate salts proved particularly suit-
able for catalyzing the cycloaddition of styrene oxide and α-
methylstyrene at room temperature in only 10 min, generally
providing good yields of the tetrahydrofuran 6a at 2 % loading
while demonstrating selectivity over the two most commonly
observed epoxide degradation products 4 and 5. Consistent
with a cationic pathway, only one regiosomer was observed,
Figure 1. Cycloadditions of alkenes and epoxides proceeding with C–O bond
cleavage.
[a] Department of Chemistry, The University of Virginia
McCormick Road, Charlottesville, VA 22904, USA
E-mail: hilinski@virginia.edu
http://www.hilinskilab.com
[‡] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201600651.
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resulting presumably from nucleophilic attack of the alkene on
the more substituted carbon atom of the epoxide. Additionally,
the syn diastereomer was modestly favored. In a control experi-
ment, the use of triflic acid as a catalyst resulted in a complex
mixture containing only trace amounts of the desired prod-
uct.[5] Ultimately, we elected to conduct further experiments
using Sc(OTf)3, which consistently provided the highest yields
of the tetrahydrofuran. The use of 2 equiv. of styrene was opti-
mal, and addition of the epoxide over periods of time longer
than 10 min offered no benefit. Remarkably, on this scale the
catalyst loading could be decreased to 0.25 mol-% with minimal
effect on the reaction yield.
Table 2. Scope with regard to the epoxide component.
Table 1. Screening of Lewis acid catalysts.[a]
Entry
Cat. (mol-%)
4 [%][b]
5 [%][b]
6a [%][b]
[a] Isolated yield. Diastereomeric ratios are based on 1H NMR spectroscopy of
the crude reaction mixture. [b] Reaction performed using 1.0 mol-% Sc(OTf)3.
1
2
3
4
5
6
AgBF4 (2)
AgPF6 (2)
AgOTf (2)
Cu(OTf)2 (2)
In(OTf)3 (2)
Yb(OTf)3 (2)
20
26
23
19
13
26
trace
trace
3
14
19
2[c]
trace[c]
16[c]
62
60
57
(e.g. 2-methylstyrene) are tolerated and provide a small increase
in diastereoselecivity (3.2:1 dr for example 7h). To demonstrate
the potential utility of this method in synthesis, cycloaddition
13
7
9
Sc(OTf)3 (2)
8
16
69
8
HOTf (2)
13
28
trace[d]
Sc(OTf)3 (0.25)
19
18
60
Table 3. Scope with regard to the alkene component.
[a] Reaction conditions: styrene 2a (4 mmol) and catalyst were dissolved in
anhydrous CH2Cl2 (0.5 mL) under N2. Epoxide 1a (2 mmol) was added drop-
wise at room temperature over 10 min. [b] Corrected GC yield using dodec-
ane as an internal standard unless otherwise noted. Yields for 5 are based
on 2 equiv. of 1a. [c] Incomplete consumption of epoxide. [d] Full consump-
tion of styrene and epoxide.
With optimized conditions in hand, we initially explored the
scope of the method with respect to the epoxide (Table 2). In
general, both electron-withdrawing and -donating substituents
were tolerated. In the case of the bromo-substituted series, the
decreasing trend in yield seen for para-, meta-, and ortho-sub-
stituted epoxides reflected the presumed influence of both ster-
ics and inductive destabilization of a partial or full positive
charge at the benzylic carbon atom on product distribution.
Nevertheless, halogen substitution at the para position was pre-
ferred in certain cases, with the F- and Cl-substituted styrene
oxides giving the highest yields of the tetrahydrofuran product
(60 % and 67 % yield, respectively).
A variety of substituted styrenes were evaluated to ascertain
the effect of aryl substitution of the alkene on the reaction
yield (Table 3). A para-cyclohexyl-substituted styrene gave the
highest yield observed for any epoxide/alkene combination,
providing 71 % of tetrahydrofuran 7a. Halogen substitution led
to reduced reaction yields, consistent with inductive withdraw-
ing effects reducing the nucleophilicity of the styrene. In each
case the syn diastereomer was favored, but the magnitude of
diastereoselectivity was modest. Sterically hindered alkenes
[a] Isolated yield. Diastereomeric ratios are based on 1H NMR spectroscopy
of the crude reaction mixture. [b] Average of two experiments. [c] Reaction
performed using 1.0 mol-% Sc(OTf)3. [d] Reaction performed using 0.5 mol-
% Sc(OTf)3. [e] Reaction performed using 0.35 mol-% Sc(OTf)3.
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between styrene and styrene oxide provided a mixture of the prior to epoxide ring opening, enantiopure (R)-styrene oxide
diastereomeric natural products Calyxolanes A (7g, anti dia- was employed in a cycloaddition reaction with 3-bromo-α-
stereomer) and B (7g, syn diastereomer) in a single step.[6] As methylstyrene. In this case, only racemic product was observed,
evidence of the mild reaction conditions, a ferrocene-substi- suggesting that nucleophilic attack by the alkene on a fully
tuted alkene survived the reaction unscathed and provided the carbocationic center is the dominant mechanistic pathway and
corresponding tetrahydrofuran 7e. In all cases the only major that diastereoselectivity is set during the subsequent ring clo-
side products observed were epoxide degradation products 4 sure.[10] Previously, successful competition of intermolecular nu-
and 5. Unreacted alkene can be readily recovered from the reac- cleophilic attack with Meinwald rearrangement under similar
tion mixture.
circumstances has only been observed with heteroatomic nu-
cleophiles.[11]
In order to further probe the scope with regards to alkenes,
we attempted a cycloaddition between styrene oxide and 2,3-
dimethylbuta-1,3-diene (8; Scheme 1). Notably, this diene sub-
strate provided only tetrahydrofuran 9 and none of the double
cycloaddition product 10, suggesting a high degree of selectiv-
ity for conjugated over non-conjugated alkenes.[7] Additionally,
no [4+3] product was observed.
Scheme 1. Diene–epoxide [3+2] cycloaddition.
Scheme 3. Investigation of the reaction mechanism.
The reported [3+2] cycloaddition has potential advantages
over other cycloaddition methods that form tetrahydrofuran
rings[8] in that it utilizes abundant and inexpensive or easily
prepared precursors and a single reagent in catalytic amounts.
The prospect of an efficient, catalyzed preparation of tetra-
hydrofurans from simple building blocks such as alkenes and
styrene oxides led us to explore the potential advantages of
the method on a gram-scale (Scheme 2). Starting with 12.08 g
of styrene oxide ($0.09/g) and 23.63 g of α-methylstyrene
($0.04/g), catalyst loading could be reduced 2.5-fold to 0.1 mol-
% without affecting the yield, providing 12.88 g of tetrahydro-
furan 6a. In comparison, other Lewis acid catalyzed cycloaddi-
tions that form tetrahydrofurans, for example those occurring
between donor–acceptor cyclopropanes and aldehydes, typi-
cally employ 5–10 mol-% catalyst.[8h,8m,8n] Given that tetra-
hydrofurans are common motifs in pharmaceutical drugs and
bioactive natural products,[9] this general approach that em-
ploys readily available substrates and only a single catalytic
reagent could ultimately prove advantageous for the practical
synthesis of drug leads.
Conclusions
We have developed conditions that enable for the first time
intermolecular electrophilic additions of epoxides to alkenes
that proceed with epoxide C–O bond cleavage. The Lewis acid
catalyzed [3+2] cycloaddition results in the scalable and highly
regioselective synthesis of substituted tetrahydrofurans from
readily available and inexpensive starting materials using ex-
ceptionally low catalyst loadings. Ultimately, careful choice of
catalyst and reaction conditions allowed for the desired inter-
molecular reaction to successfully compete with epoxide degra-
dation, enabling reactivity that was previously only observed
for intramolecular examples. Current efforts seek to expand the
scope and stereoselectivity of the reaction and to explore re-
lated intermolecular cycloadditions with other previously unre-
active π-nucleophiles.
Experimental Section
Representative Procedure for Cycloaddition: A 5 mL round-bot-
tomed flask was charged with a magnetic stir bar, Sc(OTf)3 (2.5 mg,
0.05 mmol), 1-methyl-1-phenylethene (2a; 0.52 mL, 4 mmol), and
anhydrous dichloromethane (0.5 mL). To the resulting mixture un-
der N2 and at room temperature was added 1-phenyloxirane (1a;
0.23 mL, 2 mmol) dropwise by syringe pump over 10 min. After
the addition was complete, the crude reaction mixture was loaded
directly onto a silica gel column and purified by chromatography
(100 % hexanes to ethyl acetate/hexanes, 5:95) to provide product
Scheme 2. Multigram-scale reaction.
Mechanistically, the observation of aldehyde 4 arising from
Meinwald rearrangement implicates the formation of fully ring-
opened dipolar intermediate 11 (Scheme 3). To evaluate
whether nucleophilic attack by the alkene occurs to any extent 6a (259 mg, 54 %, 1.5:1 dr) as a colorless oil.
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[7] When unactivated alkenes are used as substrates under these conditions,
tetrahydrofuran formation is typically observed, but in substantially re-
duced yields (≤ 10 %).
Acknowledgments
We thank the University of Virginia for financial support. We
also thank Abigail Cole for assistance preparing substrates and
Prof. Lin Pu for use of chiral HPLC columns.
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Keywords: Alkenes · Cycloaddition · Epoxides ·
Heterocycles · Ring expansion
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Received: May 26, 2016
Published Online: ■
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Communication
Epoxide Cycloadditions
W. G. Shuler, L. A. Combee,
I. D. Falk, M. K. Hilinski* ................... 1–5
Intermolecular Electrophilic Addi-
tion of Epoxides to Alkenes: [3+2]
Cycloadditions Catalyzed by Lewis
Acids
An intermolecular cycloaddition be- The cycloaddition proceeds diastereo-
tween epoxides and styrenes to form selectively and with complete control
tetrahydrofurans has been developed. of regioselectivity. Advantages of scal-
The reaction is catalyzed by Lewis ac- ability and minimal catalyst loading
ids and proceeds through a mecha- are demonstrated.
nism involving cationic intermediates.
DOI: 10.1002/ejoc.201600651
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