Highly regioselective Lewis acid-catalyzed [3+2] cycloaddition of alkynes with donor-acceptor oxiranes by selective carbon-carbon bond cleavage of epoxides

Article abstract of DOI:10.1039/c1cc15669a

A novel, efficient, highly regioselective Sc(OTf)₃-catalyzed [3+2] cycloaddition of electron-rich alkynes with donor-acceptor oxiranes via highly chemoselective C-C bond cleavage under mild conditions was developed.

Full text of DOI:10.1039/c1cc15669a

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COMMUNICATION
Highly regioselective Lewis acid-catalyzed [3+2] cycloaddition of
alkynes with donor–acceptor oxiranes by selective carbon–carbon bond
cleavage of epoxidesw
Renrong Liu,a Mei Zhanga and Junliang Zhang*ab
Received 13th September 2011, Accepted 28th October 2011
DOI: 10.1039/c1cc15669a
A novel, efficient, highly regioselective Sc(OTf)3-catalyzed
[3+2] cycloaddition of electron-rich alkynes with donor–
acceptor oxiranes via highly chemoselective C–C bond cleavage
under mild conditions was developed.
generated from the decomposition of diazocompound and
carbonyl compounds, with the inter- or intramolecular alkynes
has been extensively studied.7 On the other hand, the selective
C–C bond cleavage of epoxides is believed to be the most
straightforward, economical and hazardous diazo-compound
free method to generate the reactive carbonyl ylide.5 However,
the required harsh reaction conditions undermine their wide
use in practical synthesis. For example, de March et al.5b have
reported a [3+2] cycloaddition reaction of oxiranyl diesters
with alkynes under harsh conditions (160 1C) and only
restricted to intramolecular reactions due to the generated
carbonyl ylide being not reactive enough. We8 very recently
developed a novel strategy to address this issue by introduc-
tion of electron-withdrawing group(s), which can be selectively
activated by binding to a Lewis acid. For example, a highly
diastereo- and chemo-selective [3+2] cycloaddition of aryl
oxiranyl diketones with aldehydes under mild conditions has
been demonstrated.8b During the course of these studies, we
envisaged that the generated metallo-carbonyl ylide will be
more reactive than the corresponding carbonyl ylide without
metal activation, and thus in turn will be easy to undergo the
intermolecular [3+2] cycloaddition with alkynes, leading to
the corresponding highly functionalized 2,5-dihydrofurans.
We wish to report herein a novel, efficient Sc(OTf)3-catalyzed
inter- and intramolecular cycloaddition of alkynes with oxiranes
via the selective C–C bond cleavage of epoxide under mild
conditions, which provides a general, rapid, diazo-compound
free access to functionalized 2,5-dihydrofurans.
2,5-Dihydrofurans are widely used as building blocks in organic
synthesis and frequently found as subunits in many bioactive
natural products.1 Examples include (+)-furanomycin,2a salvias-
peranol,2b diplobifuranylone B,2c cryptoresinol2d and griseolic acid
(Fig. 1).2e Thus, the development of efficient and versatile synthetic
methods for these compounds has been continuously highly desir-
able. Marshall, Krause, Ma, and other groups have done seminal
work on the synthesis of these compounds by metal-catalyzed
cyclization of 1,2-allenic alcohols.3 Ring-closing metathesis of
bisallyl ether provides another efficient way to 2,5-dihydrofurans.4
Pioneered by Huisgen,5a carbonyl ylide as an important and
reactive 1,3-dipole for assembling of five member heterocycles
has attracted much attention during the last few decades.5–7
The transition metal catalysed [3+2] cycloaddition of carbonyl ylide,
We tested our hypothesis by using 3-aryloxiranyl diketone 1a
and alkyne 2a as model substrates. Gratifyingly, after many
attempts (see ESIw), the desired cycloaddition product 3a was
obtained in 98% isolated yield as a single regioisomer after
running the reaction for 3 hours using 5 mol% of Sc(OTf)3 as
catalyst in DCE in the presence of 4 A MS. Other commonly
used Lewis acids such as Sn(OTf)2, In(OTf)3, Ni(ClO4)2ꢀ6H2O,
Y(OTf)3 and Yb(OTf)3 could also achieve the catalytic cycle, but
failed to improve the yield. The reactions running in other
solvents such as DCM and toluene resulted in slightly lower
but reasonable yields. It is noteworthy that only a trace of the
product (less than 10% yield) could be detected without Lewis
acid by enhancing the temperature to more than 100 1C.
Fig. 1 Some natural products containing a 2,5-dihydrofuran skeleton.
a Shanghai Key Laboratory of Green Chemistry and Chemical
Processes, Department of Chemistry, East China Normal University,
3663 N, Zhongshan Road, Shanghai 200062, P. R. China.
E-mail: jlzhang@chem.ecnu.edu.cn; Fax: +86 21-6223-5039
b State key Laboratory of Organometallic Chemistry, Shanghai Institute of
Organic Chemistry, Chinese Academy of Sciences, P. R. China
w Electronic supplementary information (ESI) available: Representative
experimental procedure and characterization of reaction products. See
DOI: 10.1039/c1cc15669a
With the optimal reaction conditions in hand, we investigated
the scope and limitation of this Lewis acid-catalyzed regioselective
c
12870 Chem. Commun., 2011, 47, 12870–12872
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Table 1 Variation of the alkyne components
Table 2 Variation of the oxirane components
Oxirane 1
R/R1/R2
Entry R1/R2 (1)
R3/R4 (2)
Yield 3c (%)
Entry
Time/h
Yield 3a (%)
1
2
3
4
Me/Me (1a) 2a
3a (98)
3b (88)
3c (92)
3d (90)
3e (68)
3f (96)
1
4-MeC6H4/Me/Me (1c)
4-BrC6H4/Me/Me (1d)
2-BrC6H4/Me/Me (1e)
3-BrC6H4/Me/Me (1f)
4-FC6H4/Me/Me (1g)
Ph/Ph/Ph (1b)
1-Naphthyl/Ph/Ph (1h)
4-MeOC6H4/Ph/Ph (1i)
4-BrC6H4/Ph/Ph (1j)
Ph/Me/OEt (1k)
3
3
12
3
3
2
2
2
2
4
4
2
3i (97)
3j (98)
3k (95)
3l (85)
3j (98)
3n (93)
3o (90)
3p (94)
3q (94)
3r (93)
3s (85)
3t (53)
1a
1a
1a
1a
1a
1a
4-MeOC6H4/n-C4H9 (2b)
4-MeOC6H4/cyclopropyl (2c)
2-thienyl/H (2d)
4-MeC6H4/H (2e)
4-MeOC6H4/(CH2)3Cl (2f)
2
3b
4
5
5
6
7
8
6
7a
8b
4-MeOC6H4/4-MeOC6H4 (2g) 3g (69)
4-MeOC6H4/Br (2h)
Ph/Ph (1b)
3h (82)
a
b
Including 9% 2,3-dihydrofuran isomer. The reaction was carried
9
10c
11d
12
c
out with 5 mol% of Ni(ClO4)2ꢀ6H2O instead of Sc(OTf)3. Isolated
Ph/Ph/OEt (1l)
Ph/OMe/OMe (1m)
yield, no other regioisomer is detected.
a
Unless otherwise specified, no other stereoisomer is detected.
c
10 mol% of catalyst was used. dr = 7 : 1, for major isomer: Ph is
b
[3+2] cycloaddition reaction. Firstly, we tested this transformation
by variation of alkynes 2 (Table 1). Several points are noteworthy
from these results: (1) alkynes 2a and 2d are more efficient than
alkyne 2e to give higher yields (Table 1, entries 1, 4 vs. 5), to our
surprise, the reaction of more electron rich 1,2-bis(4-methoxy-
phenyl) ethyne 2g gives a slightly lower yield (Table 1, entry 7); (2)
not only the terminal alkynes but also internal ones are compatible
to give the desired products in good to excellent yields with excellent
regioselectivity (the aryl group is always located at the 3-position of
2,5-dihydrofurans), for example, the internal alkynes with one alkyl
substituent such as 2b, 2c and 2f with a convertible C–Cl bond are all
applicable to this transformation, affording the desired 2,5-dihydro-
furans with a tetrasubstituted alkene motif in excellent yields; (3) the
reactive and synthetically useful cyclopropyl group is tolerant under
the reaction conditions, furnishing dihydrofuran 3b in 92% yield; (4)
to our delight, the alkynyl bromide is also compatible and 2,5-
dihydrofuran 3h can be isolated in 82% yield, which provides an
opportunity for further modification by transition metal catalyzed
cross-coupling reactions (Table 1, entry 8).
d
syn with COMe dr = 4 : 1, for major isomer: R(Ph) is syn with
COPh. PMP = 4-MeOPh.
cycloaddition reaction with electron-donating alkyne gives
higher yield (eqn (1) and (2)).
ð1Þ
ð2Þ
In order to gain insight into the mechanism, enantioenriched 1b
was prepared according to the procedure developed by Lattanzi and
Zhao et al.9 After running for 3 hours under the standard conditions,
the reaction afforded a racemic cycloadduct 3m (eqn (3)), which
indicated that in the presence of Lewis acid, the substrate first
undergoes C–C bond cleavage to give the zwitterionic intermediate,
which would react with an alkyne to give the product. Attempts to
asymmetric catalysis have also been undertaken; the preliminary
result indicates that this reaction is amendable to enantioselective
catalysis albeit the ee has not been acceptable so far (eqn (4)).
We next turned to examine the scope of this reaction by variation
of oxirane components under optimized conditions and the results
are summarized in Table 2. In general, various electron-donating
and withdrawing groups can be introduced to the aryl moiety R
and [3+2] cycloadducts were obtained in excellent yields (Table 2,
entries 1–5). Halogen Br can be well incorporated into the phenyl
group at 2, 3, or 4-position (entries 2–4). When the acceptor groups
(R1 and R2) were switched to phenyl, the desired products 3n–3q
were furnished in 90–94% yields regardless of the electronic density
of the aryl moiety (Table 2, entries 6–9). It is noteworthy that one of
two acceptor groups can be replaced by an ester (1k, 1l); the reactions
still proceed smoothly to give the desired products in good yields with
good diastereoselectivities (Table 2, entries 10 and 11), the structure
of the major isomer of 3s is confirmed by X-ray crystallography
analysis (see ESIw). When both ketone groups are changed to ester
groups (1m), there is a significant drop in the yield (Table 2, entry 12).
The scope of this Lewis acid promoted intermolecular [3+2]
cycloaddition can be well extended to the intramolecular case.
For example, tricyclic 2,3-fused 2,5-dihydrofurans 7 and 8
could be achieved from the corresponding substrates 5 and 6
in moderate yields under mild conditions. Again, the
ð3Þ
ð4Þ
c
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2001, 3, 2537; (d) N. Morita and N. Krause, Angew. Chem., Int.
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Scheme 1 Synthetic applications.
Synthetic applications of 2,5-dihydrofurans 3 have been show-
cased by the representative compound 3a (Scheme 1). Reduction
of 3a by Pd/C hydrogenation would afford the highly substituted
tetrahydrofuran 9 in 95% yield with a moderate diastero-
selectivity. Trisubstituted furan 10 could be obtained in high
yields by the treatment of 3a with DDQ (2,3-dichloro-5,6-
dicyanobenzoquinone) or air in the presence of Cs2CO3 in
refluxing CH3OH. Addition of 3a to a solution of 1.5 equivalents
of KOH in methanol afforded the 2,3-dihydrofuran 11 in 90%
yield. Finally, in the presence of m-CPBA, 3a could be oxidized
to 2,5-dihydrofuranone 12 in 38% yield.
6 For recent reviews, please see: (a) A. Padwa, Helv. Chim. Acta, 2005,
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In summary, we have established an efficient [3+2] cycloaddition
reaction of alkynes with an oxirane motif by Lewis acid
catalyzed selective C–C bond cleavage to build up functiona-
lized 2,5-dihydrofurans in high yields with excellent regio-
selectivities. Furthermore, the resulting 2,5-dihydrofuran can
be easily converted to synthetically useful furans, 2,3-dihydro-
furan, tetrahydrofuran, and 2,5-dihydrofuranone, in moderate
to excellent yield. Further studies including asymmetric cata-
lysis and expansion of the scope of dipolarophiles are ongoing
in our laboratory and will be reported in due course.
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12872 Chem. Commun., 2011, 47, 12870–12872
This journal is The Royal Society of Chemistry 2011